星希亞的抗癌日誌

【肺癌患者日常照顧　10大原則】： 1.戒菸及禁二手菸。 2.改善居家及工作環境之空氣品質。 3.避免到公共場所，以減少上呼吸道感染的機會。 4.避免暴露於對呼吸道有刺激性的環境。 5.舫注意是否有感染或出血的徵象或症狀。 6.避免接觸有機溶劑，特別是石棉、柏油、電鍍等。 7.改進烹調習慣、避免高溫烹調、烤炸。 8.避免攝食過多高脂肪食物。 9.須有適當的運動，特別是能增加肺活量的運動，如氣功、瑜珈、太極拳等。 10.肺癌的飲食應攝取天然新鮮的蔬果為主。 11、如有發燒、寒顫、呼吸速度加快、臉潮紅、牙齦出血、血尿、脈搏速度加快，應立即回院就醫。

Cincia(星希亞)

感謝Peter分享！！:)

2014-10-19 21:14

1.自從來星希亞部落格發現肺癌的可怕,今年2月底去做底劑量ct發現2顆0.29及0.37結節,雖然後續2次ct追蹤都沒變化,但這裡太多例子如kim部落格,所以不能太放心 2.目前早上常吃地爪,水煮2個蛋白,生洋蔥,大蒜,少吃糖,每天一杯500cc紅蘿蔔馬鈴薯加水果綜合果汁,避免攝食過多高脂肪,烤炸食物 3.2天跑1次5-6公里及練太極氣功,爬山,希望明年2月底再去做底劑量ct只是虛驚一埸,但也快50歲了,告訴自己上述吃東西及運動要認真,持之以恆大家共勉之

Cincia(星希亞)

Dear Peter, 照第二回戰友會顏博士的建議，馬鈴薯不是好物耶！！我們一起調整吧～ 你這麼認真保養身體，明年的檢查一定沒問題，我對你有信心！！:)

2014-10-19 21:16

我在去年七月確診為肺腺癌第四期，移轉脊椎, 經過化療4次加放療，穩定控制了半年多，後來追蹤發現肺部有新的不明點出現，醫生建議開刀拿掉，拿出來後來發現只是發炎，今年七月又發現腦轉移，做了全腦放療，10月追蹤發現腦部長出了約3~4公分的囊腫，主治醫生建議追蹤、放射醫生建議開刀、腦神經外科也建議開刀，請問各位朋友或有認識的人有相關的經驗可以給予分享或建議，謝謝!

To Fred: 我母親是今年9月確診肺癌轉移腦部，因為已出現手腳不協調症狀，故先於林口長庚處理腦部腫瘤，放療10次後，情況改善很多，腦部腫瘤若長得太大影響生活或出現癲癇都是非常危險的，給您參考。

Cincia(星希亞)

感謝分享，也希望另堂的狀況可以穩定控制喔！一起與癌細胞和平共處，加油～

2014-10-19 07:57

謝謝您的分享，我現雖有腦轉移，現在又出現了一個大囊腫，但幸運的是位置的關系，目前是沒有明顯的症狀，我也做過全腦放療了10次，現在如果要處理只能開腦，所以很難決定

Cincia(星希亞)

如果沒有明顯症狀的話，我會傾向先不處理，但密切觀察。 以上個人建議供參考，還是要和醫師多討論再說。^^

2014-10-19 21:05

to Fred, 可以再跟醫師確認是否有立即危險性, 如果可以追蹤, 多久複檢. 另外關於處理方式, 腦部腫瘤還可以用"加馬刀"和"電腦刀"處理, 不過腫瘤不能太大, 但不知囊腫適不適合這種方式.

請問一下您的意見和建議,肺腺癌的病患有適合喝滴雞精嗎?因有人說可以喝補身體,但是又有人說太補對癌細胞不好,不知您的觀點如何?謝謝~

Cincia(星希亞)

之前化療期間身體虛弱時，我媽也有自製雞精給我喝，對於蛋白質補充應該很好。 雖然也有人主張吃植物性蛋白就好，但我想雞肉算是白肉，總比喝牛肉湯來的好，這是我的一點想法，給你參考囉！

2014-10-20 09:54

謝謝Andrew Chen、Penny 的回覆，現在我和老婆考慮也是傾向先密切追蹤，畢竟開腦的風險沒法預測(雖然我的位置相對安全些)

Cincia(星希亞)

Hi Fred, 要相信自己會沒事，信念真的很重要，一起加油！！

2014-10-23 14:02

謝謝Cincial 的鼓勵, 一起加油; 對了，我已加入fb且得到您的批準，謝謝，另外我還有加您的fb 哦，我fb 用的是中文拼音 chienhao

Cincia(星希亞)

加囉～

2014-10-24 17:49

*****

Cincia 有沒有聽過Adaptive T cell transfer? 這是我所知最有效的治療方法 把病人的T細胞在體外培養 擴充到幾百億個再打回病人體內 在治療黑色素瘤有很好的效果(45%) 有能擊殺癌細胞種T細胞在淋巴腺和血液裡 不但能縮小腫瘤 也可以阻止腫瘤擴散 因為T細胞 天性喜歡聚集在肺部和淋巴腺治療肺癌效果 應該更好 人體免疫系統有記憶 療效是長期的不像標靶藥物有突變抗藥性的問題 以下這段影片 美國安德森治癌中心 Dr. Patrick Hwu 對Adaptive T cell transfer 用在治療黑色素瘤 有很詳細的說明 雖然講的是黑色素瘤 但是對肺癌一樣有效 請仔細觀看 看後一定能讓妳了解 為什麼這是最有效的治療方法 https://www.youtube.com/watch?v=yGzJzzGj5Jw 我提出來給Cincia參考Cincia可以找這方面的資訊 美國安德森治癌中心 MD Anderson cancer center在這方面研究有多年經驗 是全美排名第二的癌症醫院 他們有許多 clinical trials 網址如下 http://www.mdanderson.org/patient-and-cancer-information/cancer-information/clinical-trials/clinical-trials-at-md-anderson/index.html 此外我在卡斯柏的網站 知道日本東京大學也有肺腺癌T細胞療法 建議Cincia考慮試試

Cincia 有沒有聽過Adaptive T cell transfer? 這是很有效的治療方法 把病人的T細胞在體外培養 擴充到幾百億個 訓練T細胞辨識擊殺癌細胞 再打回病人體內 在治療黑色素瘤有很好的效果(45%) 能擊殺癌細胞種T細胞在淋巴腺和血液裡 不但能縮小腫瘤 也可以阻止腫瘤擴散 目前研究都在致力於提高治療效果 癌細胞很狡猾 有些癌細胞在其外膜有anti-PD1的突出體 能夠躲避T細胞擊殺 這方面已有幾種藥品上市 Keytruda (from Merk) Opdivo (from BMS) 可以克服 另一個問題是T細胞 天性喜歡聚集在肺部和淋巴腺 對一些癌症效果不好 如果癌細胞在腦部T細胞都聚集在肺部 那麼治療腦癌 皮膚癌效果當然不如治療肺癌的好 針對這方面 研究人員對T細胞基因加上 一些修改(基改) 讓T細胞能被癌細胞吸引 類似螞蟻被糖吸引 基改聽起來很可怕 過去也發生T細胞攻擊病人腦的事件 那是因為以前只有加上 一個探頭 現在都加上兩個不相干的探頭T細胞攻擊自體細胞的機會大大降低 我個人非常厭惡基改食物 但不得不稱讚基改對癌症治療的貢獻 人體免疫系統有記憶 療效是長期的不像標靶藥物有突變抗藥性的問題

Cincia(星希亞)

Hi David, 感謝你提供這麼豐富的資訊給我們參考，e-mail我也有收到，不過還需要一些時間來消化一下內容，太感謝你了。 ps.感覺你應該是醫學研究相關人員是嘛？不然怎麼會研究這麼透徹。^^

2015-02-07 14:31

以下這段影片 美國安德森治癌中心 Dr. Patrick Hwu 對Adaptive T cell transfer 用在治療黑色素瘤 有很詳細的說明 雖然講的是黑色素瘤 但是對肺癌一樣有效 請仔細觀看 看後一定能讓妳了解 T細胞療法治療方式 https://www.youtube.com/watch?v=yGzJzzGj5Jw 我提出來給Cincia參考Cincia可以找這方面的資訊 我在卡斯柏的網站 知道日本東京大學也有肺腺癌T細胞療法 Cincia可以找這方面的資訊

以下這段影片對Adaptive T cell transfer有很詳細的說明 提供給大家參考 https://www.youtube.com/watch?v=yGzJzzGj5Jw

我知道一段影片對Adaptive T cell transfer有很詳細的說明 有興趣的朋友可以到youtube 網站尋找 T-cell Adoptive Therapy for Melanoma - Melanoma Education Symposium, Patrick Hwu MD

美國MD Anderson Cancer Center有許多人體實驗 可到醫院網站首頁找Browse Clinical Trials

再接再厲 美國National Cancer Institute 有12000個正在進行的人體實驗 網址 w w w . c a n c e r. g o v / c l I n I c a l t r I a l s

美國 MD Anderson Cancer Center正在進行的人體實驗 網址 w w w . m d a n d e r s o n . o r g 首頁可以找到clinical trials 連結

繼續為癌友盡一份心力 翻譯一段從美國NCI介紹T細胞治療的文章 更多內容在 w w w . c a n c e r . g o v / c a n c e r t o p i c s / r e s e a r c h - u p d a t e s / 2 0 1 3 / C A R - T - C e l l s T細胞療法像是有生命的藥物 從病人取出T細胞 把這些T細胞基因改造 在T細胞表面生成特殊的感受體 這些感受體讓T細胞能夠辨識癌細胞表面的抗原 然後在把這些基因改造的T細胞培養到上百億 再把這些上百億的T細胞輸入病人體內 這些基因改造T細胞會在病人體內繼續繁殖 經由植入的感受體辨識和殺死癌細胞 Adoptive cell transfer is like “giving patients a living drug,” continued Dr. Brentjens. That’s because ACT’s building blocks are T cells, a type of immune cell collected from the patient’s own blood. After collection, the T cells are genetically engineered to produce special receptors on their surface called chimeric antigen receptors (CARs). CARs are proteins that allow the T cells to recognize a specific protein (antigen) on tumor cells. These engineered CAR T cells are then grown in the laboratory until they number in the billions. (See the box below.) The expanded population of CAR T cells is then infused into the patient. After the infusion, if all goes as planned, the T cells multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill cancer cells that harbor the antigen on their surfaces.

繼續為癌友盡一份心力 美國肺癌有關人體實驗 http://www.cancerresearch.org/cancer-immunotherapy/impacting-all-cancers/lung-cancer

Cincia(星希亞)

感謝Daivd的熱心，查那多資料，想必花費了你不少時間，Many thanks~

2015-02-13 09:55

回Cincia 我不是醫療工作人員 我在矽谷從事軟體工作 我爸去年10月檢查出得到黑色素瘤 我擔心我爸的病 開始研究有關黑色素瘤治療方法 也因此對T細胞療法有些初步認識 T細胞和B細胞是人體免疫反應主力 腫瘤擴張期 一部份癌細胞也會死亡 在一部份的人身上死亡的癌細胞會激起身體的免疫反應 然而癌細胞有幾種機制逃避Ｔ細胞的攻擊 最近上市幾種免疫治療藥品就是阻斷癌細胞逃避Ｔ細胞的攻擊的機制 然而只有兩成的人對腫瘤有免疫反應　因此效果不如標靶藥物來的好 T細胞療法採取完全不一樣的方法 從病人取出對能摧毀癌細胞的T細胞(tumor infiltrating lymphocytes or TILs) 把這些T細胞基因改造 讓T細胞表面生成特殊的感受體 這些感受體讓T細胞能夠辨識癌細胞表面的抗原 然後在把這些基因改造的T細胞培養到上百億 再把這些上百億的T細胞輸入病人體內 這些基因改造T細胞會在病人體內繼續繁殖 經由植入的感受體辨識和殺死癌細胞 經過治療許多病人腫瘤縮小或病情穩定 而且這免疫反應是相當持久的　不是幾個月　是幾年甚至10年以上 T細胞療法最大的問題是有此技術的醫院不多 不像吃藥打針　醫院一個月只能處理幾個病人 在美國主要是 National Cancer Institute (Maryland), MD Anderson Cancer Center (Taxas), Moffitt Cancer Center (Florida). NCI在T細胞療法有10多年經驗　NCI對於非小細胞肺癌人體實驗已經開始　

需要說明以上關於免疫藥品只有2成療效的敘述 就像前文說的　癌細胞有幾種機制逃避Ｔ細胞的攻擊 目前已經有藥的機制(pathway) 1) CTLA-4: Yervoy 2) PD-1: KeyTruda, Opdivo 一種藥Yervoy可能只對兩成人有效 另種藥KeyTruda可能只對兩成人有效 兩種藥都用對四成人會有效 不同阻斷機制藥效是可以相加的 免疫治療藥品藥效是長效的 因為免疫系統是有記憶的 CTLA-4和 PL-1機制在許多癌症都有 所以對不能用標靶藥的人是好消息 唯一就是太昂貴

Immunotherapy: unleashing immune system to attack cancer https://www.youtube.com/watch?v=2kEc2aa63NQ

Keytruda將提前被核准用於非小細胞肺癌治療 Merck poised for early Keytruda launch in lung cancer http://www.fiercepharma.com/story/merck-poised-early-keytruda-launch-lung-cancer-analyst-says/2015-01-05

Cincia(星希亞)

感謝David, 希望台灣也可以早點看到這個藥物，下次回診問廖醫師看看有沒有消息～

2015-02-13 09:43

Merk正進行Keytruda用於30種癌症臨床實驗 其中用於非小細胞肺癌治療已得到FDA重大突破地位 將可提前上市 Merck Receives FDA Breakthrough Therapy Designation for KEYTRUDA® (pembrolizumab) in Advanced Non-Small Cell Lung Cancer http://www.mercknewsroom.com/news-release/oncology-newsroom/merck-receives-fda-breakthrough-therapy-designation-keytruda-pembroli

這篇報導說非小細胞癌患者有10-30% 是EGFR possitive 只有3%是ALK possitive. 對於大部份患者　這幾年都沒新藥　對於這些患者 Keytruda是個好消息 http://www.pharmaphorum.com/news/mercks-keytruda-gains-breakthrough-status-in-lung-cancer

Cincia(星希亞)

非小細胞癌患者有10-30% 是EGFR possitive 只有3%是ALK possitive，這數字在東方好像比較高，我看過的數字EGFR應該約50-60％，而ALK是5%左右～

2015-02-13 09:53

日本的研究發現沒做過化療的癌症病人體內的T細胞B細胞和自然殺手細胞的數量都遠低於健康的人 除了環境污染 身體免疫力低下 是人們罹癌的原因 Recent progress has been made in understanding the mechanisms of antitumor immune responses, which may further clarify the immune status of cancer patients. In this study, we performed a detailed evaluation of the immunological status of 47 patients with advanced solid cancer, who had received no immunosuppressive treatment, and compared the results with 32 healthy subjects. Flow-cytometry data for peripheral blood were obtained using 19 monoclonal antibodies against various cell surface and intracellular molecules. Absolute numbers of T cells, several T cell subsets, B cells, and NK cells were significantly decreased in patients compared with healthy subjects. The percentage of CD27(+)CD45RA(+) T cells was lower and that of CD27(-)CD45RA(-) T cells was higher in patients compared with controls. Regulatory and type 2 helper T cells were elevated in patients relative to healthy subjects. The percentage of perforin(+) NK cells was significantly lower in patients than in controls. These results suggest a dysfunctional anti-tumor immune response in cancer patients. Furthermore, peripheral blood from 26 of 47 cancer patients was analyzed after adoptive T cell immunotherapy (ATI). ATI increased the number of T cell subsets, but not B and NK cells. The number and percentage of regulatory T cells decreased significantly. These results suggest that ATI can restore impaired and imbalanced T cell immune status. http://www.ncbi.nlm.nih.gov/pubmed/24269583

Cincia, 下面這個網頁是很重要的網頁 請加入妳的書籤 http://www.cancerresearch.org/cancer-immunotherapy/impacting-all-cancers/lung-cancer 這個網頁有美國正在進行中的針對非小細胞免疫治療的臨床實驗 我會繼續在這裡解釋每一種治療的原理 Cincia有50個願望 要有健康的身體才能全部達成 免疫治療可以還給Cincia 健康 達成所有願望和未來的新願望 希望Cincia 持續注意免疫治療這方面的訊息 因為免疫系統是人類最終能擊敗癌症的利器

許多人認為免疫系統根本不會攻擊腫瘤 如果免疫系統會攻擊腫瘤 腫瘤沒有機會作大擴散 而應該會逐漸縮小 甚至消失 的確 要引起免疫反應 腫瘤表面必須具有能被免疫系統識別為外來物的抗原 多數腫瘤並不會引起免疫反應 因為免疫系統無法辨識它 Source: http://www.microbiologybook.org/mobile/m.immuno-18.htm

那麼肺腺癌會引起免疫反應嗎? 觀察最近Keytruda和 Opdivo 針對非小細胞肺癌治療臨床實驗結果 答案是肯定的 但是有沒有免疫反應 是因人而異 必竟80歲老人不比30歲年輕人吧 Keytruda和 Opdivo可以幫助有免疫反應的人縮小甚至清除腫瘤 下面我會解釋Keytruda和 Opdivo如何運作

科學家在癌症免疫研究經過許多挫折 因為科學家對免疫機制如何運作有許多盲點 針對各類癌症發展出的許多癌症疫苗 証實沒有效果 直到幾年前 科學家 才瞭解 在T細胞 表面有幾個接受器是免疫系統用來調節T細胞 的攻擊性的 請Cincia 參考下面網頁的圖 http://www.onclive.com/publications/contemporary-oncology/2014/February-2014/Immune-Checkpoint-Blockade-in-Cancer-Inhibiting-CTLA-4-and-PD-1PD-L1-With-Monoclonal-Antibodies 圖上有 T cell, Tumor cell, Dendritic cell (樹突細胞) 先稍微解釋一下樹突細胞 樹突細胞是免疫系統的記憶體 樹突細胞的表面有妳身體曾經見過的疫苗細菌病毒或是腫瘤的抗原 T細胞經由樹突細胞表面的抗原 瞭解敵人的長像 T細胞 表面有兩個接受器CD28 和CTLA4 樹突細胞一旦接上 CD28 (on switch) 可以起動T細胞 進入戰鬥狀態 樹突細胞一旦接上CTLA4 (off switch) 可以撤銷T細胞的戰鬥狀態 我之前提到免疫藥Yervoy就是堵住CTLA4 讓T細胞持續戰鬥狀態 讓腫瘤無法經由樹突細胞來停止對其攻擊 腫瘤還有另一個方法來 瓦解T細胞的攻擊 在T細胞 表面還有另一個接受器 PD1 這也是個off switch 有些腫瘤表面會有PDL1的接受器 一旦T細胞 靠近腫瘤 馬上會被腫瘤的PDL1黏上 瓦解攻擊 Keytruda和 Opdivo的運作就是堵住PD1讓腫瘤無法瓦解T細胞攻擊

相信Cincia現在知道什麼是CTLA4, PD1, PDL1了 上面請Cincia加入書籤的網頁有許多這類的藥正在做非小細胞肺癌的臨床實驗 要強調的是有些臨床實驗是可以跟ALK或EGFR標靶藥一起吃的 目的在測試免疫藥的輔助功效 像是這個 https://clinicaltrials.gov/ct2/show/NCT01998126 下次可以問妳的醫師有沒有適合妳的

下次介紹Adoptive T cell Transfer的非小細胞肺癌的臨床實驗

禮來達成兩項合作，以研究其癌癥治療藥物與百時時美施貴寶及默沙東抗pd-1治療藥物的合并用藥方案，三家公司于1月13日如此報道稱。“合并治療將會成為解決腫瘤異質性與不可避免耐藥性的關鍵，此次合作可能會開發出最有前景的新型個體化治療藥物方案，”禮來腫瘤部門產品開發及醫療事務高級副總裁gaynor評論稱。 在一項1/2期試驗中，禮來將研究其試驗性轉化生長因子（tgf）βr1激酶抑制劑與百時美施貴寶opdivo (nivolumab)合并用于晚期膠質母細胞瘤、肝細胞癌及非小細胞肺癌(nsclc)。兩家公司指出，該合作將檢驗一種假說，即pd-1與tgfβ陰性信號共同抑制與抑制其中一條通路相比是否會導致增強的抗腫瘤免疫響應。 禮來還將進行一項1/2期試驗，用來評價該試驗性重組人igg1單克隆抗體necitumumab與默沙東keytruda (pembrolizumab)合并用于nsclc。此外，禮來將進行一項1/2期研究檢測cyramza (ramucirumab)與keytruda合并用于多種腫瘤。兩項研究均有望于今年開始。 此外，默沙東將進行一項2期研究以測試keytruda與禮來培美曲塞合并一線用于非鱗狀nsclc，目前該研究正在招募患者。合作的其它條款未披露。 keytruda成為首款fda批準的pd-1抑制劑，其于去年獲批用于晚期或不可切除的黑色素瘤，默沙東最近披露計劃擬尋求擴大批準這款治療藥物用于egfr突變陰性及alk重排陰性nsclc患者治療。 與此同時，opdivo被fda加速批準用于不可切除或轉移性黑色素瘤患者治療，適用于不再對其它藥物響應的患者。百時美施貴寶于1月12日表示，在先前有過治療的晚期、鱗狀細胞nsclc患者中進行的一項該藥物與多西他賽對比的3期試驗因達到試驗終點而提前停止。 Source: http://big.sunyet.com/med/a/n864424.html

SMB 公佈了Opdivo (Nivolumab) 治療非小細胞肺癌第一階段臨床實驗結果 一年存活率42％ 兩年存活率24％ 對藥物有反應的病人比率（ORR）為17％ http://news.bms.com/press-release/rd-news/additional-survival-data-nivolumab-investigational-pd-1-immune-checkpoint-inhi 這些免疫藥品藥效大多長期的 因為免疫系統有記憶 對有藥物反應的病人 能減少擴散 減少復發 或 延長復發時間 Anti-PD1, Anti-PDL1, Anti-CTLA4 是目前免疫藥品主流 有沒有效還是看個人的免疫系統 一日7蔬果 規律生活 充足睡眠 適當運動 老生常談 還是有效的防癌抗癌處方

Anti-PD1藥品有沒有效 要看腫瘤細胞表面有沒有PDL1表像 越多腫瘤細胞有PDL1表像 藥品效果越好 PDL1表像 多於50%的一組和PDL1表像最少的一組反應差三倍 Findings from the proof-of-principle (POP) clinical study, presented at the 2014 AACR meeting, showed that advanced NSCLC tumours with strong PD-L1 expression responded better to MK-3475 (Pembrolizumab®) than did tumours with weak or no expression of PD-L1. PD-L1 tumour tissue expression of more than 50 per cent by immunohistochemistry is the most informative cut-off for response to therapy. Strong PD-L1 expression in NSCLC was associated with an MK-3475 (Pembrolizumab®) response rate three times higher than that associated with weakly positive PD-L1 tumours. Source: http://lsconnect.thomsonreuters.com/targeted-therapy-nsclc-part-vi-immune-therapy/#sthash.8sTLGIZ2.dpuf 那麼為什麼腫瘤會有PDL1表像呢? 其實腫瘤只有在受到免疫系統攻擊時才會有PDL1表像 PDL1是腫瘤躲避免疫系統攻擊的方法 之一 如果腫瘤只受到少數零星T細胞的攻擊 PDL1表像自然會少

Opdivo 治療非小細胞肺癌第三階段臨床實驗傳來好消息 該實驗證實效果比化療藥品Docetaxel 好的多 而且負作用小 而提前結束實驗 我預計應該今年能得到美日相關單位准許用於治療非小細胞肺癌 希望未來免疫藥品能取代化療 Source: http://www.ono.co.jp/eng/news/pdf/sm_cn150115_02.pdf

在MK-3475(Keytruda) I期臨床試驗，非小細胞肺癌（NSCLC）患者中PD-L1陽性的患者和沒有PD-L1表象的患者相比有顯著更好的結果。在治療6個月後，PD-1陽性的患者的41％的人 沒有疾病進展。患者的腫瘤具有低PD-L1的表達的患者只有17％沒有疾病進展。 In a phase I trial, non–small-cell lung cancer (NSCLC) patients with tumors that expressed PD-L1 had significantly better outcomes with MK-3475 therapy compared with patients with PD-L1–negative tumors. At 6 months after initiation of treatment, 41% of PD-L1–positive patients had no disease progression compared with 17% of patients whose tumors had low PD-L1 expression. Source: http://www.cancernetwork.com/aacr-2014/pd-l1-expression-mk-3475-treated-lung-cancer-correlates-better-outcomes#sthash.S6Cyogb0.dpuf

修正第29號留言: > 多數腫瘤並不會引起免疫反應 因為免疫系統無法辨識它 最近才學到 正常人體細胞會把細胞內的蛋白質碎片經由MHC1呈現在細胞膜表面 細胞內的許多蛋白質碎片 也都會呈現在細胞膜表面 供免疫系統辨識 癌細胞是正常細胞突變 也會把突變的蛋白質碎片呈現在細胞膜表面 供免疫系統辨識 免疫系統就是透過這些細胞膜表面的蛋白質碎片辨識這細胞是否正常 一旦T細胞 發現不正常的蛋白質 會開起一連串的免疫反應 複製繁衍增生自己 到成千上萬 一部份後代會成為 記憶型T細胞 一部份後代會成為 毒殺型T細胞 不論是記憶型T細胞 或是毒殺型T細胞 都有專一性 毒殺型T細胞 只會攻擊 那些表面有不正常的蛋白質的細胞 免疫系統是你我身體裡的主力軍隊 這是場免疫系統與癌症腫瘤的戰爭 請愛惜你的免疫系統 不到必要不用化療 一些臨床實驗已經證實 在NSCLC免疫藥比化療藥有效 免疫系統如果有效壓制癌症 可以防堵癌症擴散 效果是長期的 免疫藥修復你的免疫系統 讓免疫系統能與腫瘤作戰 在未來免疫藥應該是第一線用藥品 而不是在被化療藥殘害後才用

我把免疫系統講的那麼神 到底真的假的? 如果免疫系統可以辨識 腫瘤癌細胞 也能鏟除癌細胞 那麼人為什麼還會得癌? 很明顯的 癌細胞躲過免疫系統的監視 才會作大 科學家已經知道癌細胞有幾種方法躲過免疫系統的監視 PD1 PDL1是其中之一 癌細胞所長的位置 在 較少白血球巡邏的地方也有關 病人自己本身因為生活習慣 (睡眠不足 不吃蔬果 常外食 煙酒 工作壓力大) 造成免疫力低下 年紀越大 免疫力也會差 除了生活要健康外 要盡量避開生活裡所有已知的致癌物 例如 香煙 汽機車廢氣 PAH (燒烤的煙 ) 燒香紙錢產生的煙 廚房油煙 空氣污染(PM2.5 微粒) 蔬菜水果裡的農藥 丙烯酰胺(薯條雞排) 雜環銨(烤焦的肉) 亞硝酸鹽(香腸) 甲醛 肉類水產裡的重金屬如汞鉻鉛 三聚氰胺 等等 我常在想如果自己出身在兩百年前的台灣 那時代沒有那麼多污染 出門看不到車子 空氣是乾淨的 土地沒有被工廠廢水污染 海裡河裡的魚沒有重金屬污染 我大概很少聽到癌症 也不用擔心得到癌症

找到這篇2015 2月Opdivo 肺癌臨床實驗的報導 這篇不再是一些統計數字 而是一位老太太的故事 看到這篇報導　我是蠻開心的 因為我對這些Anti-PD1 藥有很高的期盼 Barbara Marder 73歲 三年前右肺發現肺癌 醫師切除一部份右肺並給予化療 一年後癌症復發 這次是在她的左肺有許多腫瘤 她的醫師Dr. Julie Brahmer 建議她參加Opdivo 肺癌臨床實驗 在用Opdivo幾週後Barbara 的腫瘤開始完全消失 Marder 開始Opdivo治療後一年 還是沒有腫瘤的蹤影 免疫系統有記憶力(via Memory T cell) 沒有人知道這記憶力能持續多久 （我知道最早用Yervoy治癒黑色素瘤的一個女子　已經10年沒有復發 我希望Anti-PD1藥效果也能同樣持久） Source: http://www.npr.org/blogs/health/2015/02/09/373292216/harnessing-the-immune-system-to-fight-cancer

最新消息 3/4/2015: FDA 允許Opdivo 用於非小細胞肺癌鱗狀細胞癌治療 Opdivo’s efficacy to treat squamous NSCLC was established in a randomized trial of 272 participants, of whom 135 received Opdivo and 137 received docetaxel. The trial was designed to measure the amount of time participants lived after starting treatment (overall survival). On average, participants who received Opdivo lived 3.2 months longer than those participants who received docetaxel. The safety and efficacy of Opdivo to treat squamous NSCLC was supported by a single-arm trial of 117 participants who had progressed after receiving a platinum-based therapy and at least one additional systemic regimen. The study was designed to measure objective response rate (ORR), or the percentage of participants who experienced partial shrinkage or complete disappearance of the tumor. Results showed 15 percent of participants experienced ORR, of whom 59 percent had response durations of six months or longer. Source: FDA http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436534.htm

這則新聞說明Opdivo能取代化療 效果比化療藥品Docetaxel 好 而且負作用小 化療摧殘病人的免疫系統 只能延長病人生命幾個月 免疫系統是人存活的必要條件 千萬不要讓你的醫生傷害你的免疫系統 參與實驗的117位病人 都被化療摧殘過 還有15%的反應 前面有提過 如果腫瘤有PD-L1表象 對Opdivo的反應是3倍42%

免疫系統淺介 我過去兩個月研讀了許多關於免疫系統的書 有了些基本概念 漸漸的一些醫學論文也開始能看的懂了 免疫系統真是個亞馬遜叢林 什麼奇怪的細胞都有 這些細胞聯合起來日夜不停的守護著你 你應該感謝他們 也許你該花點時間瞭解他們的功能 免疫細胞 分為兩大類 先天性免疫系統(innate immunity) 先天性免疫系統主要由白血球裡的 巨噬細胞 樹突細胞 和自然殺手細胞所構成 這些細胞的作用在於識別和消滅可能導致感染的病原體(細菌 病毒 癌細胞) 這些細胞在吞噬消化病原體後 會將病原體的氨基酸片段經由MHC 2受體表現在細胞膜上 這就是所謂的抗原 這是激起後序免疫反應的重要步驟 先天性免疫沒有專一性 只要是外來物質 一律先吞再說 第二類叫適應性免疫系統 (adaptive immunity) 適應性免疫系統主要由B細胞 T細胞構成 當前面那些巨噬細胞 和樹突細胞回到淋巴結時 他們帶回病原體的氨基酸片(抗原) 如果某一個T細胞 表面的氨基酸片段能接合帶回的抗原 再加上B細胞也帶回同樣的抗原 顯示病原體入侵 這個T細胞 開始被激活 開始大量繁衍自己 繁衍兩類T細胞 一種是記憶型T細胞 一種是殺手型T細胞 記憶型T細胞 的功用在於記得抗原 日後再碰到 同類的病原體會馬上反應 記憶型T細胞 是免疫療法長效性的原因 即使記憶型T細胞自然凋亡 它的後代也記得敵人的長像 記憶型T細胞也是使用免疫療法癌症不容易復發的原因(除非癌細胞突變) 殺手型T細胞 能分泌酵素溶解病原體(腫瘤)的細胞膜 殺手型T細胞有專一性 只會攻擊有抗原的目標 (細菌 被病毒入侵的細胞 腫瘤) 因為它有專一性 近年來成為科學家對抗腫瘤的首選 待續

Cincia(星希亞)

感謝David兄提供的資訊，Cincia最近有認真在研究免疫療法的資訊，到時候也可以整理整理跟大家分享～

2015-03-31 12:53

這是篇參與Opdivo黑色素瘤臨床實驗的病患的經歷 My Nivo (Opdivo) trial - first dose - 4 years ago 12/29/2010 - thoughts... 回頭看過去4年是多麼奇怪的！。好像是昨天。這似乎是很久以前的事。抗PD1的藥物是一個未知數。只有極少數的患者在幾個研究用了Anti-PD1藥品。ipilimumab（Yervoy）或是BRAF抑製劑都未獲得FDA的批准。默克的產品Keytruda並不存在。驚訝的是我還活著。我簡直不能相信我在那6個月辦到了隔週工作看病的行程：週一，週二，週三工作12小時工作 週四開車到Atlanta飛往Tempa。租車和晚餐。在La Quinta旅館休息。週五黎明跳上車趕往Moffitt醫院實驗室，見醫生，打針，輸藥。像瘋了一樣開回機場。飛往亞特蘭大。再開兩小時車回Chattanooga。週一繼續上班。我後來發現，許多在像我在臨床實驗的人在治療過程中沒有工作。不過許多人在用Keytruda Yervoy仍然繁忙的生活。剩下的兩年中，只需要每12週去Tempa和輸藥。這似乎像一個休假！在這2年半我錯過了3個工作日內。還有那些誰說我是瘋了 我該休更多假的.....但是這不是我的個性。我是如此幸運。幸運的是能參加臨床實驗。幸運的是能夠有足夠錢參加臨床實驗。幸運地得到大家的支持。 這是很難說什麼我以為會發生什麼事。我真的沒有想到太多。當然，不像今天這麼多的各種板面，聊天室和論壇所談論的 我不認為Opdivo能治癒我的病。不要誤會我的意思。我很感激有這個選項。腦腫瘤，肺腫瘤，扁桃體腫瘤，另一個大腦快速連續地冒出腫瘤讓我清楚地知道，我迫切需要打破這種循環。我唯一的選擇是IL2或干擾素，我不知道我的未來是什麼。但是同樣沒有任何人知道我的未來是什麼。我只是擔心那些似乎很肯定的是抗PD1的藥物將是他們個人的解脫時，30-40％的有效率告訴我們，有一大部份的人會感到失望。 花了一輩子的閱讀研究報告，案例分析...這是超現實的經驗 閱讀一個你知道指的是你自己的經驗。 “33名患者參加10例復發患者中，有5名死於轉移性黑色素瘤。三名接受手術後呈現無病狀態54星期 一名病人自然消退......並一直無病3年以上。另一個的復發病人還活著，並在用dabrafenib加trametinib積極治療。“ 我對報告和結果的想法： 副作用： “Nivolumab用疫苗的耐受性良好” 耐受性好？嗯....根什麼相比呢？沿著山間小徑徒步旅行的輕鬆的一天，洗熱水澡，一本好書，一個舒適的壁爐和美味的晚餐？毫無疑問，許多人經歷困難得多治療。儘管如此Nivolumab注射部位反應，疲勞，皮疹，瘙癢，噁心，腹瀉和關節痛是常見的。低鉀血症（低血鉀...的東西，可危及生命），腸炎，結腸炎，垂體和甲狀腺炎人肯定是一些參與實驗的人的症狀。有1例1級pneumonititis。不知道那是誰？也許我的，也許不是。這是很奇怪有那些誰沒有黑色素瘤，也從來沒有得到可憐的那些疫苗或採取反PD1甚至有一次，確定彼此的體驗質量。 腦轉移： “10名患者切除了腦轉移腫瘤。”嗯......這是不完全準確。我的不是“切除”，它是通過電腦刀“切除”的。不能確定其他人是怎樣切除的。這10名病人只有2例有復發。一個轉移到肺。另一個顯然有顯著的中央神經疾病，雖然研究人員那時候沒有意識到，儘管這樣的損失，這是一個非常顯著的成果 因為黑色素瘤腦轉移，沒有治療我們的生命只有6個月左右。 放射治療： “放射治療被給予18例前或手術包括九名與切除腦轉移後。”這項研究並沒有推測，所有我能做的是...但隨著越來越多的研究著眼於回顧性數據和新的研究專門研究輻射結合IPI，抗PD1和BRAF抑製劑......我不得不相信這一組合對我們有正面的幫助。 PD-L1的 研究人員希望找到檢測腫瘤的生物標誌，可以告訴我們哪些患者會對哪種藥物有反應。 PD-L1的是其中的一個。我們有28我們的腫瘤進行測試。我仍然不知道我的有沒有PD-L1表象。但是，在我們的研究中，“有這個患者人群 PD-L1和無復發生存期之間沒有顯著的關聯，雖然目前還朝著那些腫瘤是PD-L1陽性更好的RFS無統計學顯著的趨勢......”對於什麼是值得。我懷疑測試PD-L1表象是不是很好的生物標誌，還有更多的關於這方面的研究。 無復發生存期： “回顧性研究顯示 在IV期黑色素瘤患者的12個月的中位 總生存期的中位數是12個月。”然而，我們這些參與實驗的人已經表現出了“令人印象深刻的無復發生存... 47.1個月 ”對於我來說，我現在： 診斷出黑色素瘤136個月 黑色素瘤第四階段黑色素瘤56個月 開始Opdivo 48個月 我的最後一次輸入Opdivo 18個月 這是一個奇妙的旅程。 以下是對其他參與實驗的人 說的 讓我們用愛迎接2015年！ Source: http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/12/my-nivo-opdivo-trial-first-dose-4-years.html

Cincia(星希亞)

看完了，感謝David持續分享，

2015-04-01 14:24

這是篇參與Opdivo黑色素瘤臨床實驗的病患的經歷 回頭看過去4年是多麼奇怪的！。好像是昨天。這似乎是很久以前的事。抗PD1的藥物是一個未知數。只有極少數的患者在幾個研究用了Anti-PD1藥品。ipilimumab（Yervoy）或是BRAF抑製劑都未獲得FDA的批准。默克的產品Keytruda並不存在。令人驚訝的是我還活著。我簡直不能相信我在那6個月辦到了隔週工作看病的行程：週一，週二，週三工作12小時工作 週四開車到Atlanta飛往Tempa。租車和晚餐。在La Quinta旅館休息。週五黎明跳上車趕往Moffitt醫院實驗室，見醫生，打針，輸藥。像瘋了一樣開回機場。飛往亞特蘭大。再開兩小時車回Chattanooga。週一繼續上班。我後來發現，許多在像我在臨床實驗的人在治療過程中沒有工作。不過許多人在用Keytruda Yervoy仍然繁忙的生活。剩下的兩年中，只需要每12週去Tempa和輸藥。這似乎像一個休假！在這2年半我錯過了3個工作日內。還有那些誰說我是瘋了 我該休更多假的.....但是這不是我的個性。我是如此幸運。幸運的是能參加臨床實驗。幸運的是能夠有足夠錢參加臨床實驗。幸運地得到大家的支持。 這是很難說什麼我以為會發生什麼事。我真的沒有想到太多。當然，不像今天這麼多的各種板面，聊天室和論壇所談論的 我不認為Opdivo能治癒我的病。不要誤會我的意思。我很感激有這個選項。腦轉移，肺轉移，扁桃體轉移，另一個大腦快速連續地冒出腫瘤讓我清楚地知道，我迫切需要打破這種循環。我唯一的選擇是IL2或干擾素，我不知道我的未來是什麼。但是同樣沒有任何人知道我的未來是什麼。我只是擔心那些似乎很肯定抗PD1的藥物將是他們個人的解脫時，30-40％的有效率告訴我們，有一大部份的人會感到失望。 花了一輩子的閱讀研究報告，案例分析...這是超現實的經驗 閱讀一個你知道指的是你自己的經驗。 “33名患者參加10例復發患者中，有5名死於轉移性黑色素瘤。三名接受手術後呈現無病狀態54星期 一名病人自然消退......並一直無病3年以上。另一個的復發病人還活著，並在用dabrafenib加trametinib積極治療。“

我對報告和結果的想法： 副作用： “Nivolumab用疫苗的耐受性良好” 耐受性好？嗯....根什麼相比呢？沿著山間小徑徒步旅行的輕鬆的一天，洗熱水澡，一本好書，一個舒適的壁爐和美味的晚餐？毫無疑問，許多人經歷困難得多治療。儘管如此Nivolumab注射部位反應，疲勞，皮疹，瘙癢，噁心，腹瀉和關節痛是常見的。低鉀血症（低血鉀...的東西，可危及生命），腸炎，結腸炎，垂體和甲狀腺炎人肯定是一些參與實驗的人的症狀。有1例1級pneumonititis。不知道那是誰？也許我的，也許不是。這是很奇怪有那些誰沒有黑色素瘤，也從來沒有得到可憐的那些疫苗或採取反PD1甚至有一次，確定彼此的體驗質量。 腦轉移： “10名患者切除了腦轉移腫瘤。”嗯......這是不完全準確。我的不是“切除”，它是通過電腦刀“切除”的。不能確定其他人是怎樣切除的。這10名病人只有2例有復發。一個轉移到肺。另一個顯然有顯著的中央神經疾病，雖然研究人員那時候沒有意識到，儘管這樣的損失，這是一個非常顯著的成果 因為黑色素瘤腦轉移，沒有治療我們的生命只有6個月左右。 放射治療： “放射治療被給予18例前或手術包括九名與切除腦轉移後。”這項研究並沒有推測，所有我能做的是...但隨著越來越多的研究著眼於回顧性數據和新的研究專門研究輻射結合IPI，抗PD1和BRAF抑製劑......我不得不相信這一組合對我們有正面的幫助。 PD-L1的 研究人員希望找到檢測腫瘤的生物標誌，可以告訴我們哪些患者會對哪種藥物有反應。 PD-L1的是其中的一個。我們有28我們的腫瘤進行測試。我仍然不知道我的有沒有PD-L1表象。但是，在我們的研究中，“有這個患者人群 PD-L1和無復發生存期之間沒有顯著的關聯，雖然目前還朝著那些腫瘤是PD-L1陽性更好的RFS無統計學顯著的趨勢......”對於什麼是值得。我懷疑測試PD-L1表象是不是很好的生物標誌，還有更多的關於這方面的研究。 無復發生存期： “回顧性研究顯示 在IV期黑色素瘤患者的12個月的中位 總生存期的中位數是12個月。”然而，我們這些參與實驗的人已經表現出了“令人印象深刻的無復發生存... 47.1個月 ”對於我來說，我現在： 診斷出黑色素瘤136個月 黑色素瘤第四階段黑色素瘤56個月 開始Opdivo 48個月 我的最後一次輸入Opdivo 18個月 這是一個奇妙的旅程。 以下是對其他參與實驗的人 說的 讓我們用愛迎接2015年！ http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/12/my-nivo-opdivo-trial-first-dose-4-years.html

上課了 這位老師介紹免疫系統 生動活潑 畫圖又漂亮 一共8堂課 通通上完保證對免疫系統有清楚瞭解 下面這堂是講T細胞 以及T細胞如何辨識癌細胞 https://www.khanacademy.org/science/biology/human-biology/immunology/v/review-of-b-cells-cd4-t-cells-and-cd8-t-cells

免疫監視(1) 免疫功能與腫瘤的發生、發展有密切關係。 Ehrlich免疫監視的理論最早在1909年提出 近 幾十年來的許多實驗證實免疫監視的存在 舉個例子 一項老鼠實驗給10隻 有先天缺乏免疫功能的老鼠注射癌細胞 10隻全部長出腫瘤 同樣的10隻 在健康的老鼠注射癌細胞 只有2隻長出腫瘤 另一個例子 早年器官移植的人 需長期吃降低免疫力的藥來避免排斥 許多人後來得到癌症 雖然免疫監視的確存在 但腫瘤仍能在人體生長、轉移、復發，這顯示腫瘤具有逃避免疫攻擊的能力。 下面我會免疫監視的3個階段: 1)癌細胞免疫系統被消滅 2)免疫與腫瘤平衡 3)腫瘤逃脫免疫監視 Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2265921/

免疫系統淺介 (2) 很特別的是每個T細胞表面的受體 都不一樣 T細胞表面的受體 可以有千億種變化 受體的功能是什麼呢? 受體讓來自 循環 神經 內分泌 免疫系統 或是臨近的細胞發出的訊息能傳到細胞內 起動細胞一連串後續反應 前面提到的和樹突細胞表面的抗原 和一個T細胞 表面的受體結合 會激活這個T細胞 起動免疫反應 也就是說T細胞 表面的受體讓T細胞可以辨認抗原(包括腫瘤表面的抗原) T細胞表面的受體 有千億種 也就是讓免疫系統能辨認千億種抗原 這是免疫系統有適應性的原因 能對從未見過的病毒 細菌 癌細胞產生免疫反應 T細胞 是由骨隨產生 新生的T細胞進入胸腺受訓和繼續演化 T細胞 在胸腺演化成T Helper cell (CD4 T cell) 和 Cytotoxic毒殺型 T cell (CD8 T cell) 胸腺功能在訓練T細胞認識自體細胞 避免T細胞離開胸腺後攻擊自體器官 造成自體免疫疾病如紅斑性狼瘡 類風濕性關節炎 大約90%的T細胞 會在這個階段被胸腺鏟除 只有少數T細胞能完成訓練 離開胸腺執行任務 T Helper cell (CD4 T cell)是免疫系統 的警報器 一旦被激活 會分泌介白素促進被激活 B細胞 不斷分裂 生產抗體 AIDS 就是HIV病毒攻擊T Helper cell削弱免疫系統 許多AIDS病患最後死於病毒細菌感染 免疫系統對人的重要性可想而知 待續

免疫監視是個重要話題 特別是腫瘤如何逃避免疫系統的監視 只有當人類了解腫瘤如何逃避免疫系統的監視 才能設計藥品協助免疫系統辨識消滅腫瘤 像PD1 CTL4 抑制劑的發明 開啟癌症治療的新時代 即使是末期全身轉移 也有例子用PD1 CTL4 抑制劑後腫瘤完全消失 我最近在讀這方面的醫學資訊 希望能提供正資訊

大概沒人在看這版吧 非常安靜

Cincia(星希亞)

很多人都有看David提供的資訊，真的很謝謝你的熱心呢！我想大家需要一點時間消化吸收啦！^^

2015-05-12 20:19

不會沒人看阿!像我一有空一定都會上來看看(雖然只是個過客) 很感謝David搜集一些有關免疫的資料給大家分享,也可時常提醒大家免疫的重要性及未來治愈癌症的方針,這些訊息也可帶給一些戰友正面思考及希望,不是嗎?

Cincia(星希亞)

感謝版友的回應，這樣David兄應該可以知道他收集的資訊幫助了不少人，真的很感謝～

2015-05-20 10:34

很感謝 David 搜集一些有關免疫的資料給大家分享 +1 To David, 這就是網路的特性，潛水的人居多啦! 其實你po的文章，大家還是有在看的。 你何時回台灣啊?? 大家可以找星希亞一起出來吃個飯，認識一下喔! ^_^

感謝Cincia j14552ms62 和Gary 的回應 也謝謝你們的關注 我覺得我還是把關於免疫療法的資訊PO在這版 方便病友版友查詢 Gary 我有機會回台 一定會跟你們聯繫

Cincia(星希亞)

真的很感謝David, 可惜免疫療法對肺腺癌的有效率只有30%，遠低於標靶的60-70%，不過當沒有標靶可吃的時候，免疫30%看起來也很高了，好矛盾的心理啊！

2015-05-15 18:26

固體腫瘤會形成微環境不利於免疫系統攻擊 Mayo Clinic研究人員試驗用探針伸進腫瘤 把腫瘤瞬間冷凍 造成大量的癌細胞死亡 在自然回溫的過程中 死亡的癌細胞 會釋放出細胞內不正常的蛋白質 (生魚片壽司也是用負20度冷凍和自然回溫來殺寄生蟲卵) 我在免疫系統淺有說明過 樹突細胞和巨噬細胞會吞下這些不正常的蛋白質 並把這些蛋白質的片段呈現在它的細胞膜 讓T細胞 B細胞辨認 激起後序免疫反應 醫界已經知道 CTLA4抑制劑 要有效 病人本身對腫瘤已經有免疫反應 CTLA4抑制劑主要功用在延續病人本身已經有免疫反應 Mayo Clinic 用冰凍法激發免疫反應 然後給病人CTLA4抑制劑 讓免疫反應持續 效果值得期待 Source: https://www.mskcc.org/blog/new-immunotherapy-approach-breast-shows-promise

淺談腫瘤逃避免疫監視的機制 Source: http://annonc.oxfordjournals.org/content/23/suppl_8/viii6.full Studies of cancer–immune system interactions have revealed that every known innate and adaptive immune effector mechanism participates in tumour recognition and control [5]. The first few transformed cells are detected by NK cells through their encounter with specific ligands on tumour cells. This leads to the destruction of some transformed cells and the uptake and processing of their fragments by macrophages and dendritic cells. In turn, these macrophages and dendritic cells are activated to secrete many inflammatory cytokines and present tumour cell-derived molecules to T- and B cells. Activation of T- and B cells leads to the production of additional cytokines that further promote activation of innate immunity and support the expansion and production of tumour-specific T cells and antibodies, respectively. The full power of the adaptive immune system leads to the elimination of remaining tumour cells and, importantly, to the generation of immune memory to specific tumour components that will serve to prevent tumour recurrence. 長期的研究發現所有參與先天性免疫和適應性免疫的免疫細胞都參與腫瘤辨識和管理 自然殺手細胞可能最先遇上突變的細胞 根據突變的細胞膜上的不正常的受體 判定這細胞不正常 進而消滅它 樹突細胞和巨噬細胞遇上突變細胞的遺骸 會把它吃掉 並把突變的細胞內的蛋白質的碎片表現在細胞膜上 這時樹突細胞和巨噬細胞會分泌介白素 吸引T細胞 和B細胞 引發適應性免疫反應T細胞和B細胞 開始大量繁衍 生產抗體和毒殺型T細胞 繁衍的T細胞 和B細胞會分泌更多不同的介白素 進一步激起免疫反應 最終導致癌細胞被鏟除 更重要的是記憶型T細胞 會記得癌細胞的樣子 可以預防癌症復發 Instead of defining immunosurveillance as the process by which cancer is recognised and eliminated and a diagnosis of cancer to represent the failure of this process, it is now recognised that in different individuals and with different cancers, the process can have at least three different but related outcomes: elimination, equilibrium, and escape 與其說免疫監視是免疫系統辨識和鏟除癌細胞的過程 而癌症的發生是免疫監視的失敗 現代醫界認為不同的癌症發生在不同的人身上 有3種不同的結果: 1) 腫瘤被免疫系統殲滅 2) 腫瘤與免疫系統保持平衡狀態 3) 腫瘤逃出免疫系統監視 A highly immunogenic tumour in a highly immunocompetent individual will result in optimal stimulation of the innate immune system leading to the production of highly immunostimulatory cytokines, acute inflammation, activation of a large number of T- and B cells, and prompt elimination of the arising tumour. 辨識度高的癌細胞在一個免疫力強的人身上會激起自體免疫反應導致癌細胞被免疫系統鏟除 With a less immunocompetent individual and/or less immunogenic tumour, however, there might not be a complete elimination leading to the survival of some cancer cells that nevertheless remain under immunosurveillance. Over a prolonged period of time, the slow growth of the tumour would be accompanied by repeated activation of the immune system and elimination of some tumour cells, followed by further cycles of tumour regrowth and immune-mediated destruction. This period, when the tumour is present but not yet a clinical disease, is known as equilibrium. 辨識度低的腫瘤或是一個免疫力低的人身上新生成的癌細胞一部份被免疫系統鏟除 但免疫系統無法鏟除所有癌細胞 這時腫瘤已經成型 但還不是癌症 腫瘤還是在免疫系統的控制中 這是所謂的平衡狀態 The equilibrium phase could be life-long, thus mimicking elimination, or be disturbed by changes in the tumour that allow it to avoid immunosurveillance or changes in the immune system that weaken its capacity for tumour surveillance. Either change ultimately leads to tumour escape 這平衡狀態可能維持相當久的時間 最後可能因為人的免疫力下降下 (熬夜 飲食不當 工作壓力 離婚 喪偶 吃類固醇藥物等等)或是腫瘤發生突變 而使腫瘤逃出免疫系統監視 產生癌症

淺談腫瘤逃避免疫監視的機制 (2) Source: http://annonc.oxfordjournals.org/content/23/suppl_8/viii6.full In many cancers, however, malignant progression is accompanied by profound immune suppression that interferes with an effective antitumour response and tumour elimination. Initially, most of the escape from immunosurveillance was ascribed to changes in the tumour cells themselves (loss of tumour antigens, loss of human leukocyte antigen molecules, loss of sensitivity to complement, or T cell or natural killer (NK) cell lysis), making them a poor target of an immune attack. 在許多癌症進展過程中伴隨著令人難以理解的免疫系統被壓制的現象 起初的想法是腫瘤產生突變 失去了可以辨識的抗原 失去了承現抗原的MHC 或者對T細胞或自然殺手細胞 分泌的溶解細胞膜的酵素不再有反應 (即T細胞或自然殺手細胞沒辦法溶解它的細胞膜進而消滅它) However, it has become clear that the suppression comes from the ability of tumours to subvert normal immune regulation to their advantage. The tumour microenvironment can prevent the expansion of tumour antigen-specific helper and cytotoxic T cells and instead promote the production of proinflammatory cytokines and other factors, leading to the accumulation of suppressive cell populations that inhibit instead of promote immunity. The best described are regulatory T cells and myeloid-derived suppressor cells. 後來的研究人員漸漸清楚 腫瘤是利用正常的免疫機制來壓抑免疫系統 腫瘤微環境能分泌介白素引起慢性發炎吸引　抑制型T細胞和MDSC細胞的聚集 抑制毒殺型T細胞 和T helper細胞繁衍 Source: http://www.nature.com/cmi/journal/v10/n3/full/cmi201310a.html Some tumors protect themselves by establishing an immune-privileged environment. For example, they can produce immunosuppressive cytokines IL-10 and transforming growth factor-β (TGF-β) to suppress the adaptive antitumor immune response, or skew the immune response toward a Th2 response with significantly less antitumor capacity.2,3,4 一些腫瘤會分泌抑制免疫系統的介白素像IL-10或TGF-β讓免疫反應趨向於抑制的方向 Some tumors alter their expressions of IL-6, IL-10, vascular epithelial growth factor or granulocyte monocyte-colony stimulating factor (GM-CSF), impairing DC functions via inactivation or suppressing maturation.5 In some cases, induced regulatory T cells suppress tumor-specific CD4+ and CD8+ T-cell responses.6 一些腫瘤會改變介白素像IL-6, IL-10,GM-CSF　阻礙樹突細胞的功能 抑制型T細胞 (regulatory T cells) 會壓抑毒殺型T細胞 (CD8+) 輔助型T細胞 (CD4+) 的功能 Tumor cells also minimally express or shed tumor-associated antigens, shed the ligands of NK cell-activating receptor such as the NKG2D ligands UL16-binding protein 2, major histocompatibility complex (MHC) class I chain-related molecules A and B molecules (MICA/MICB) or alter MHC-I and costimulatory molecule expression to evade the immune responses.7,8,9 一些腫瘤會突變失去原有的抗原 失去可辨識的配體 (ligand) 或MHC來蒙蔽免疫系統 Malignant cells may also actively eliminate immune cells by activation-induced cell death or Fas ligand (FasL) expression.10,11 In addition, primary cancer treatments like chemotherapy and ionizing radiation can compromise antitumor immune responses by their immunosuppressive side effects 一些腫瘤甚至會引發免疫細胞的凋亡機制 殺死免疫細胞 另外化療和放療都會傷害免疫系統

新光醫院季匡華醫師的腫瘤治療部落格的這篇 -控制腫瘤微環境 值得大家細讀 http://doctorchi.pixnet.net/blog/post/379494095

Cincia(星希亞)

感謝David兄分享～

2015-05-16 21:21

新光醫院腫瘤治療科的熱治療是去年8月向衛福部申請，以實驗名義從日本引進，之前我在該院做螺旋刀治療時，有遇到幾位癌友(大多是頭頸癌及肺癌，放化療搭配熱治療)，其表示使用熱治療的癌友還不多。

What have we learned from cancer immunotherapy in the last 3 years? (1) Given the numerous immune checkpoints that exist, combining immuno-oncology agents that target different checkpoint pathways is also an attractive therapeutic approach. Tumours exploit these pathways to turn off the immune response in different ways, either by decreasing T-cell proliferation or inactivating T cells at the tumour site [77]. For example, by inhibiting CTLA-4, ipilimumab promotes T-cell proliferation, increasing the number of activated T cells that can migrate to attack the tumour; conversely, anti-PD1 agents such as nivolumab counteract tumour defences specifically within the tumour microenvironment, reactivating T-cell activity and inducing tumour cell death [9,11]. The complementary roles of these two pathways in regulating adaptive immunity are supported by preclinical models in which simultaneous administration of anti-CTLA-4 and anti-PD1 antibodies resulted in enhanced antitumour activity compared with single agent treatments [78,79]. In a phase 1 combination study of ipilimumab and nivolumab in patients with advanced melanoma, 40% of patients treated with the concurrent combination regimen had objective responses and the 1-year OS rate was 82%; notably, responses with the combination were both rapid and deep [80,81]. This combination is being further evaluated versus ipilimumab or nivolumab monotherapy in a phase 3, randomised trial. Accumulating preclinical and clinical data also support the use of other investigational immunotherapy combinations such as nivolumab plus anti-LAG3 and ipilimumab plus GM-CSF [82,83]. http://www.translational-medicine.com/content/12/1/141

Phase III Study Finds Initial Nivolumab-Based Treatment Halts Melanoma Progression ASCO Perspective ASCO Expert Steven O’Day, MD “Immunotherapy drugs have already revolutionized melanoma treatment, and now we’re seeing how they might be even more powerful when they’re combined. But the results also warrant caution – the nivolumab and ipilimumab combination used in this study came with greater side effects, which might offset its benefits for some patients. Physicians and patients will need to weigh these considerations carefully.” A randomized phase III trial indicates that initial therapy with nivolumab alone or in combination with ipilimumab is significantly more effective than ipilimumab alone. Nivolumab alone more than doubled the average time to disease progression, compared to ipilimumab (6.9 months vs. 2.9 months), and the benefit was even greater when ipilimumab and nivolumab were combined (11.5 months). The response rates were also substantially higher in patients receiving the combination therapy (57.6%) and nivolumab (43.7%) alone, as compared to ipilimumab (19%). “We’re very encouraged that the initial observations about the efficacy of this combination held up in this large phase III trial,” said lead study author Jedd Wolchok, MD, PhD, Chief of Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center in New York, NY. “Our study also suggests that patients with a specific tumor marker appear to benefit the most from the combination treatment, whereas other patients may do just as well with nivolumab alone. This will help doctors provide important insight for patients on which treatment is right for them.” Nivolumab and ipilimumab are monoclonal antibodies that block two different immune checkpoints ─ PD-1 and CTLA-4, respectively. Both treatments, commonly referred to as checkpoint inhibitors, essentially boost the immune system’s ability to fight cancer. Prior research has shown that immune checkpoint inhibitors can improve survival for patients with melanoma and lung cancer. Both ipilimumab and nivolumab are FDA-approved for use as single agents in patients with unresectable (cannot be removed by surgery) or metastatic (advanced) melanoma that no longer responds to other drugs. This study randomly assigned 945 patients with previously untreated, advanced melanoma to receive ipilimumab, nivolumab, or the combination of the two. After a follow-up period of at least nine months, the median progression-free survival was 2.9 months for ipilimumab, 6.9 months for nivolumab, and 11.5 months for the combination. The differences between the combination and ipilimumab groups, and nivolumab and ipilimumab groups were statistically significant. The response rates for the combination, nivolumab, and ipilimumab groups were 57.6%, 43.7%, and 19%, respectively. The average reductions in tumor burden (depth of response) were 52% with the combination and 34% with nivolumab alone. In contrast, patients who received ipilimumab alone experienced a 5% increase in tumor burden. As expected, the rate of serious drug-related side effects was the highest in the combination group (55%), and 36% of patients in this group had to stop the therapy due to side effects. Dr. Wolchok remarked that prior studies have shown that many patients who stop immunotherapy early still continue to do well. This prolonged benefit is explained by the fact that immunotherapy works by activating the immune system rather than targeting the tumor directly. It is not yet clear how long patients need to be treated to fully activate the immune system, and the minimal duration of therapy probably varies from patient to patient. Quality of life data were collected on the study, and the analysis of those results will be reported at a later time. PD-L1 Status May Help Define Optimal Treatment The PD-1 protein on immune cells attaches to another protein called PD-L1, which is sometimes found on the surface of some tumor cells. Prior research suggested that patients who had detectable PD-L1 levels in their tumor (PD-L1-positive tumors) typically had better responses to PD-1 therapy. In this study, nivolumab alone seemed to be as effective against PD-L1-positive tumors as the combination of nivolumab and ipilimumab. For patients with PD-L1-negative tumors, however, the combination treatment was significantly more beneficial than nivolumab alone. This study received funding from Bristol-Myers Squibb.

什麼是CTLA4 ? 什麼是PD1? 分享一下最新的心得 人體對腫瘤產生免疫反應要經過一連串過程 這過程我在”免疫系統淺介”有說明過 腫瘤在免疫反應發生過程中每一步驟都可能干預 讓身體對腫瘤無法產生免疫反應 免疫系統裡負責辨識和擊殺癌細胞的主要成員是T細胞 T細胞 的表面 有兩個受體 是T細胞的死穴 一個受體叫做CTLA4 在正常狀態 抗原呈現細胞(樹突細胞)是起動T細胞 活化的重要推手 但腫瘤可以經由抗原呈現細胞來結合T細胞表面的CTLA4受體 讓T細胞 無法活化無法繁衍 T細胞 無法活化無法繁衍 自然無法對腫瘤產生免疫反應 T細胞 的表面另一個受體叫做 PD1 腫瘤可以經由癌細胞表面的PDL1的配體 來讓已經活化的毒殺型T細胞 失去攻擊力 平時癌細胞表面是沒有PDL1的配體的 但是當遭到獨殺型T細胞的攻擊 癌細胞就會產生PDL1來抵抗T細胞的攻擊 一旦T細胞PD1被癌細胞的PDL1黏上 可以讓T細胞失去攻擊力甚至自然凋亡 CTLA4 抑制劑與PD1抑制劑實際上是人造的蛋白質 一旦黏上T細胞的CTLA4和PD1 後 腫瘤將無法再經由這兩個受體阻蒙蔽免疫系統 這就是為什麼去年唐獎生技獎是搬給發現CTLA4和PD1機制的兩位教授

Cincia 和各位病友 今天我在研究化療放療對免疫系統的影響 化療放療對免疫系統的確傷害很大 而且看來傷害是長期的 我會提出數據和說明 妳們的心臟要夠強喔 先貼原文出處 Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777669/

#65 化療放療會傷害骨髓 傷害免疫系統 相信大家都知道 對免疫系統那些功能有傷害? 多久能復原? 這篇研究有數據 針對化療 放療 和化療+放療 對病人的免疫功能的影響 這篇研究在下列4個時間點測量病人的免疫功能的各項指數 治療前˙ 治療後2個月˙ 治療後6個月 ˙治療後12個月 結果如下 請看這頁 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777669/table/T3/ 每項數字是病人免疫功能回復到治療前的百分比 例如化療CD4 (T helper cell) 在治療後2個月有41%的病人恢復到治療前水準 但在治療後12個月這數字卻跌到18% 我特別在提一下 IL2 這介白素是促進T cell繁殖的 IL2不足會影響活化T cell的數量 只有6%的病人的IL2有回到正常值 整體來看 化療 放療 會嚴重影響病人的免疫系統 傷害是深切而且是長期的 因為我們還在放療化療當道的世界 肺癌免疫療法還在臨床實驗階段 因此我呼籲各位病友 化療 放療後 把握時間盡快做免疫療法修復你的免疫系統

各位病友 這段時間對免疫系統與癌症的探討 我的感想是正常的免疫系統是無法對抗癌症的 免疫系統內建許多讓免疫反應結束的方式 被腫瘤利用 因此免疫系統會對癌細胞視而不見 讓癌細胞恣意擴散 要用免疫系統控制癌症 還是需要藥品或醫療手段介入 我到 Keytruda 官網首頁看到這個公式 (稍作修改免得為Keytruda做廣告) 我的免疫系統 + 免疫治療 = 擊敗腫瘤的力量 免疫治療是防止癌症擴散的必要療法

Cincia(星希亞)

David兄真的很可愛，Keytruda不需要你幫忙做廣告好嗎？應該已經賺翻了，哈哈～ 我也相信免疫療法是可以期待的，需要進步快一點啊～please~

2015-06-12 09:42

#20 除了PD1 CTLA4抑制劑 我很少提到其他的免疫療法 原因是美國一年有上千個免疫療法臨床實驗 真正得到FDA Break through status 快速合准上市的也只有 那3種抑制劑 因為對4期癌症病友 做任何一項免疫治療都是拿生命做賭注 免疫療法要幾個月才知道有沒有效 選錯了可能錯過治療時機讓病情惡化 我真的不希望病友選錯 所以我很努力的把我知道的寫出來 Immunotherapy of Cancer: Statement of the problem Immunotherapy of cancer must do more than simply present antigen to the immune system It must disrupt a pre-existing state of functional tolerance toward tumor antigens 免疫療法必需要解決的問題 (也是你評估免疫療法的方法) 免疫療法不能只是把腫瘤的抗原承現給免疫系統 (疫苗 或樹突細胞療法) 免疫療法一定要破壞病人免疫系統對腫瘤的耐受性 (缺乏免疫反應) 1) because tolerance cannot be overcome simply by a good antigen and a strong adjuvant (i.e. response are actively suppressed) 2) because even vaccination or adoptive transfer of pre-activated T cells is still subject to suppression 原因是 1) 只是承現抗原 無法克服免疫系統對腫瘤的耐受性 (因為腫瘤會積極的壓抑免疫反應) 2) 疫苗 或體外培養未經活化的T cells仍然會受到腫瘤壓抑 以這樣評估免疫療法 目前也只有PD1 CTLA4抑制劑能破壞腫瘤壓制免疫系統的方式 讓免疫反應持續下去

Cincia(星希亞)

之前聽榮總蔡主任的演講，他的意見是主動免疫和被動免疫(PD1 CTLA4抑制劑)能雙管齊下的話效果更可以期待。 不過這多傷荷包阿～可以的話Cincia真的也很想兩者併用啊！ 之前詢問的結果，台大也有免疫療法試驗計畫，不過得重新切片，Cincia目前切片有難度，so....

2015-06-12 09:37

卡斯柏在久留米的實驗疫苗傳出令人振奮的好消息 他的免疫系統對抗原(胜肽)產生很大的反應 請看 "久留米醫院免疫治療的初步檢查結果"

Cincia(星希亞)

David兄, 我都有在follow Caspar的消息，看到的確令人很振奮，我該認真考慮來做免疫了。

2015-06-29 10:09

understanding the function and dysfunction of the immune system in cancer 1. O. J. Finn* + Author Affiliations 1. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, USA 1. ↵*Correspondence to: O. J. Finn, Department of Immunology, University of Pittsburgh School of Medicine, E1040 Biomedical Science Tower, Pittsburgh, PA 15261, USA. Tel: +1-412-648-9816; Fax: +1-412-648-7042; E-mail: ojfinn@pitt.edu Abstract The immune system has the greatest potential for the specific destruction of tumours with no toxicity to normal tissue and for long-term memory that can prevent cancer recurrence. The last 30 years of immuno-oncology research have provided solid evidence that tumours are recognised by the immune system and their development can be stopped or controlled long term through a process known as immunosurveillance. Tumour specificity of the immune response resides in the recognition of tumour antigens. Viral proteins in tumours caused by viruses and mutated proteins from oncogenes or other genes, as well as nonmutated but abnormally expressed self proteins found on all tumours, have been shown to be good antigens and good targets for immunosurveillance. In many cancers, however, malignant progression is accompanied by profound immune suppression that interferes with an effective antitumour response and tumour elimination. Initially, most of the escape from immunosurveillance was ascribed to changes in the tumour cells themselves (loss of tumour antigens, loss of human leukocyte antigen molecules, loss of sensitivity to complement, or T cell or natural killer (NK) cell lysis), making them a poor target of an immune attack. However, it has become clear that the suppression comes from the ability of tumours to subvert normal immune regulation to their advantage. The tumour microenvironment can prevent the expansion of tumour antigen-specific helper and cytotoxic T cells and instead promote the production of proinflammatory cytokines and other factors, leading to the accumulation of suppressive cell populations that inhibit instead of promote immunity. The best described are regulatory T cells and myeloid-derived suppressor cells. Great conceptual and technical advances in the field of immuno-oncology over the past 30 years have provided us with the knowledge and techniques to develop novel immunotherapeutic approaches for the treatment of cancer. These include methods that enhance tumour immunity by blocking inhibitory pathways and inhibitory cells in the tumour microenvironment (e.g. antibodies against cytotoxic T-lymphocyte-associated antigen-4, programmed death 1 or its ligand programmed death ligand 1, or low-dose chemotherapy). Of equal importance, they include methods that can enhance the specificity of antitumour immunity by inducing the expansion of T cells and antibodies directed to well-defined tumour antigens (e.g. cancer vaccines, potent adjuvants, immunostimulatory cytokines). Even as monotherapies, these approaches are having a substantial impact on the treatment of some patients with advanced, previously untreatable, malignancies. Most exciting of all, these successes provide a rationale to expect that used in various combinations or earlier in disease, current and future immunotherapies may transform cancer treatment, improving a prognosis for many patients. introduction Most people, and scientists are no exception, measure the passing of time by acknowledging substantial events from the past and looking towards future accomplishments. Using this ‘Janus’ principle, anniversaries that celebrate substantial events or are reminders of what remains to be done can be used to monitor the progress of scientific research. One reminder of the need for progress was recently marked by the 40th anniversary of the US National Cancer Act, a Senate Bill enacted on 23 December 1971 that strengthened the authority of the National Cancer Institute and provided it with new resources to create the National Cancer Program. The US National Cancer Act was prepared and passed in recognition of the serious problem that this lethal disease was posing with its ever-increasing frequency and apparent incurability. The expectation was that an increased understanding of the basic scientific nature of the cancer would be the best road to finding a cure. The bill also recognised the timeliness of this effort, coinciding both with rapid developments in many scientific disciplines and technological advances that appeared close to allowing the biological complexity of the cancer cell to be resolved. Forty years later, despite many brilliant discoveries around the world in fields as diverse as genetics and molecular biology, virology, chemistry, pharmacology and others, cancer continues to elude cures. However, the pace of scientific discovery and technological developments continues to increase and, as a result, the picture of cancer is being redrawn. Immunology, long considered not to be a critical discipline for understanding cancer, has provided important new clues to cancer biology and for the first time, immune-based therapy is a focus for pharmaceutical companies developing anticancer drugs. Until recently, investigations into the nature of cancer focused strictly on the cancer cell and on cancer as a genetic disease. This is perfectly illustrated in the widely cited and highly popular paper by Hanahan and Weinberg [1] published in 2000 that, after reviewing a large body of cancer research, proposed six consensus characteristics (hallmarks) that could be used to define a cell as cancerous. The hallmarks comprised the capacity to sustain proliferative signaling, to resist cell death, to induce angiogenesis, to enable replicative immortality, to activate invasion and metastasis, and to avoid growth suppressors. A decade later, and with increased emphasis on studying cancer as a systemic disease, there is a new understanding that cancer is not one disease, but many different diseases. Therefore, to understand cancer fully, studies must move their focus from the cancer cell to the host and the microenvironment in which the cancer grows; a very important component of which is the immune system. As a result, a new picture of cancer is emerging and, in 2011, four additional hallmarks were proposed. Two of these highlight the newly recognised dual interaction between cancer and the immune system: first, the ability to avoid immune destruction which results in acute inflammation and cancer elimination, and secondly, the potential for chronic inflammation that promotes tumour growth rather than elimination [2, 3]. interactions between the immune system and cancer Evidence has been accumulating since the middle of the last century, first from animal models and later from studies in cancer patients, that the immune system can recognise and reject tumours. The goal of tumour immunology has been to understand the components of the immune system that are important for tumour immunosurveillance and tumour rejection to understand how, when, and why they fail in cases of clinical disease. Immunotherapy, which involves strengthening the cancer patient's immune system by improving its ability to recognise the tumour or providing a missing immune effector function, is one treatment approach that holds promise of a life-long cure [4]. Studies of cancer–immune system interactions have revealed that every known innate and adaptive immune effector mechanism participates in tumour recognition and control [5]. The first few transformed cells are detected by NK cells through their encounter with specific ligands on tumour cells. This leads to the destruction of some transformed cells and the uptake and processing of their fragments by macrophages and dendritic cells. In turn, these macrophages and dendritic cells are activated to secrete many inflammatory cytokines and present tumour cell-derived molecules to T- and B cells. Activation of T- and B cells leads to the production of additional cytokines that further promote activation of innate immunity and support the expansion and production of tumour-specific T cells and antibodies, respectively. The full power of the adaptive immune system leads to the elimination of remaining tumour cells and, importantly, to the generation of immune memory to specific tumour components that will serve to prevent tumour recurrence. Effectors of adaptive immunity, such as CD4+ helper T cells, CD8+ cytotoxic T cells, and antibodies, specifically target tumour antigens; i.e. molecules expressed in tumour cells, but not in normal cells. Tumour antigens are normal cellular proteins that are abnormally expressed as a result of genetic mutations, quantitative differences in expression, or differences in posttranslational modifications [5]. In tumour types that have a well-documented viral origin, such as cervical cancer, caused by the human papillomavirus [5], or hepatocellular carcinoma caused by the hepatitis B virus [6], viral proteins can also serve as tumour antigens and targets for antitumour immune response [7]. The first indication that tumours carried molecules distinct from those on the normal cell of origin was derived from immunising mice with human tumours and selecting antibodies that recognised human tumour cells but not their normal counterparts. The major question was whether some, or all, of these molecules would also be recognised by the human immune system. 2011 was an important anniversary for human tumour immunology, marking 20 years since the publication by van der Bruggen et al. [8] that described the cloning of MAGE-1, a gene that encodes a human melanoma antigen recognised by patient's antitumour T cells. This was not a mutant protein; its recognition by the immune system was due to the fact that it was only expressed by transformed, malignant cells and, with the exception of testicular germ cells, was not expressed in normal adult tissue. Many similar discoveries followed, with each new molecule providing a better understanding of what might be good targets for different forms of cancer immunotherapy. Tumour antigens have been tested as vaccines, as targets for monoclonal antibodies, and as targets for adoptively transferred cytotoxic T cells. There is a wealth of publications from preclinical studies targeting these antigens and results from phase I/II clinical trials. Recently, these studies were critically reviewed and a list of tumour antigens with the largest body of available data compiled [9]. The goal was to encourage faster progress in the design, testing, and approval of immunotherapeutic reagents that incorporate or target the most promising antigens. Antitumour immune responses in animal models and cancer patients have contributed to the resurgence of the immunosurveillance theory; albeit one that has been modified to encompass different observed outcomes. Instead of defining immunosurveillance as the process by which cancer is recognised and eliminated and a diagnosis of cancer to represent the failure of this process, it is now recognised that in different individuals and with different cancers, the process can have at least three different but related outcomes: elimination, equilibrium, and escape [10]. A highly immunogenic tumour in a highly immunocompetent individual will result in optimal stimulation of the innate immune system leading to the production of highly immunostimulatory cytokines, acute inflammation, activation of a large number of T- and B cells, and prompt elimination of the arising tumour. With a less immunocompetent individual and/or less immunogenic tumour, however, there might not be a complete elimination leading to the survival of some cancer cells that nevertheless remain under immunosurveillance. Over a prolonged period of time, the slow growth of the tumour would be accompanied by repeated activation of the immune system and elimination of some tumour cells, followed by further cycles of tumour regrowth and immune-mediated destruction. This period, when the tumour is present but not yet a clinical disease, is known as equilibrium. The equilibrium phase could be life-long, thus mimicking elimination, or be disturbed by changes in the tumour that allow it to avoid immunosurveillance or changes in the immune system that weaken its capacity for tumour surveillance. Either change ultimately leads to tumour escape (Figure 1). To date, most studies of tumour/immune system interactions have been performed after cancer has been diagnosed, i.e. in the escape phase of immunosurveillance. This particular phase is characterised by an increase in previously unknown immunosuppressive cells, such as regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC), immunosuppressive cytokines derived from Treg, MDSC, and tumour cells and poorly functional effector T cells expressing molecules capable of preventing T-cell activation [11–13]. immunotherapy: old and new In the past, immunotherapy was referred to as ‘passive’ (e.g. the infusion of preformed immune effectors, such as antibodies, cytokines, or activated T cells, NK cells, or lymphokine-activated killer cells), presumably acting directly on the tumour and independent of the immune system or ‘active’ (e.g. vaccines), designed to activate and therefore be dependent on the patient's immune system. However, with increased understanding of the importance of multiple immune effector mechanisms for tumour elimination and of the immunosuppressive forces that influence these mechanisms in the tumour microenvironment, it has since become clear that both passive and active immunotherapies depend on the patient's immune system for long-term tumour control or complete tumour elimination. By directly targeting specific antigens expressed by cancer cells, anticancer monoclonal antibodies are a well-established class of immunotherapeutic agent; more than a dozen of which have been approved by the Food and Drug Administration as standard treatment of several different cancers, including trastuzumab for breast cancer and retuximab for B-cell lymphoma [4]. Although the mechanism of their direct antitumour action has been well studied and is clearly responsible for transient remissions in patients receiving this therapy, cure rates are still very low. The potential of these antibodies is drastically undermined by their administration relatively late in the disease course, when the patient's immune system is largely compromised. Under more optimal conditions, antibody treatment might result not only in the direct cytostatic or cytotoxic effect on the tumour cell, but also in the loading of antibody-bound tumour antigens onto antigen presenting cells (APC) in the tumour microenvironment. The resultant cross-presentation to antitumour T- and B cells could result in additional antibodies to these antigens being produced, and propagation of the immune response at the tumour site would maintain tumour elimination long after the infused monoclonal antibody is gone. Not only would the response change from a monoclonal antibody against a single epitope to a polyclonal response to multiple epitopes, thus avoiding antigen-negative tumour escape, but the effector T-cell response would also generate memory. The same scenario could be predicted for adoptively transferred T cells. Unlike antibodies, transferred T cells persist longer and may provide a memory response [14]; however, as long as the memory response is restricted to one clone, or a limited number of clones, then antigen-negative tumours will be able to escape. In addition, cancer vaccines encounter large numbers of immunosuppressive Treg and MDSC in circulation, as well as immunosuppressive cell-derived soluble products that flood the lymph nodes, preventing maturation of APCs and activation of T cells. Even when vaccines are delivered in the context of ex vivo matured and activated dendritic cells, their ability to activate T cells is compromised by the high-level expression of various molecules on T cells that block this process. The scenarios proposed above present a rather bleak picture of the potential of immunotherapy to achieve the cure for cancer that has eluded standard therapy [15]. Interestingly, failures of some standard therapies are beginning to be ascribed to their inability to activate the patient's immune system [16]. However, rather than seeing the picture as a deterrent, it should be considered as a road map, providing at least two major directions for new developments in immunotherapy. The first direction is to continue using the old classes of immunotherapy that target the cancer directly, but to use them in combination with therapies that target the immune system in the tumour microenvironment, such as cytokines, suppressors of Treg or MDSC activity, or antibodies that modulate T-cell activity. The recently approved antibody, ipilimumab, which acts to sustain cytotoxic T-cell activity by augmenting T-cell activation and proliferation, is one example of such an immunomodulatory agent [17]. The other direction is to use immunotherapies, both old and new, for preventing cancer in individuals at high risk [18]. Studies of the tumour microenvironment are providing information about immunosurveillance of tumours from early premalignant lesions to more advanced dysplastic lesions to cancer. At each step, tumour-derived and immune system-derived components have a unique composition that will have distinct effects on immunotherapy. Because these premalignant microenvironments are less developed and immunosuppression is less entrenched, it should be easier to modulate towards the elimination of abnormal cells. The lessons learnt from past accomplishments suggest that in the future, well-designed immunotherapies, administered at the right stage of tumour progression, have the potential to significantly change the ongoing immune response in the tumour microenvironment from tumour-promoting to tumour-rejecting (Figure 1). http://annonc.oxfordjournals.org/content/23/suppl_8/viii6.full

Cincia #70 這篇值得細讀

本來以為樹突細胞(DC)是促進免疫反應的推手 這週末才驚訝的發現 原來在腫瘤得以擴散前 腫瘤附近的樹突細胞和巨噬細胞都已被腫瘤收買 非但不促進免疫反應 反而抑制免疫反應 一部份的T細胞也被收買成為調節型T細胞(Treg) 抑制免疫反應 一旦腫瘤收買免疫機制 從此身體裡再也沒有可以阻止它擴散的力量 所幸Anti PD1 Anti CTLA4藥物已經問市 即使DC被收買也不能抑制T細胞活化 我深深感覺一種免疫治療是不夠的 多種免疫治療Anti CTLA4 Anti PD1 DC 療法 IL-2 才能喚醒免疫系統 或者免疫治療搭配標靶 或電腦刀 或放療 Dendritic cell switch DCs from mice in the early stages of ovarian tumorigenesis were immunocompetent (as measured by their ability to induce expansion of tumour-reactive T cells). Immunocompetence was lost by DCs in advanced tumours, and these DCs could also suppress the T cell expansion that was induced by immunocompetent DCs from early stage tumours. How do DCs change to become immunosuppressive? DCs from advanced mouse tumours expressed higher levels of programmed death ligand 1 (PDL1) and had strong arginase activity, both of which are immunosuppressive. High arginase activity was also observed in DCs taken from advanced human ovarian Source: http://www.nature.com/nrc/journal/v12/n4/full/nrc3253.html

Cincia(星希亞)

是阿~上次蔡主任就有提到他認為應該主動免疫搭配被動免疫兩者一起治療效果會最佳，只是單一就已經很貴了，加在一起負擔的起的病患真很少。

2015-07-14 09:59

David: Thanks for the sharing. Most of people belong to "quiet majority" category. I read most of your post and benefit from there.

#73 catwalk01 Thank you . I will continue post my latest study on these important topics.

腫瘤是怎樣抑制免疫系統 跟癌症擴散息息相關 一旦腫瘤能抑制免疫系統 從此身體裡再也沒有可以阻止它擴散的力量 所有罹癌的朋友的免疫系統都無法對體內的癌症產生有效免疫反應(進行攻擊清除) 即使你現在的吃的健康 有充足睡眠 也有運動 不常感冒 有感冒也很快能痊癒 你的免疫系統的確是運作正常的 能有效清除外來的細菌病毒 但是你的免疫系統卻任由腫瘤擴散 問題出在哪裡? 有些醫生說基因突變的癌細胞是屬於自己的基因 免疫系統認不得它是外來物 所以不會攻擊癌細胞 我只能說這醫生大概很久沒讀書沒看醫學報告了 根據Nature突變的癌細胞有上千種能被免疫系統認識的抗原 也就是說癌細胞有上千種方式激起可以攻擊腫瘤的免疫反應 但是為什麼免疫系統對腫瘤視而不見呢? 到這裡我們得先瞭解一下在正常情況下免疫系統是如何運作的 當癌細胞死亡時 細胞膜裡面的突變不正常的蛋白質外洩 會被身體的清道夫巨噬細胞 或是免疫系統的哨兵樹突細胞吞噬 巨噬細胞或樹突細胞消化後會把這些蛋白質片段(抗原)承現在它的細胞膜上 然後會經由血液淋巴液回到最近的淋巴結把抗原承現給T 細胞和B細胞 如果某一個T細胞 或B細胞表面的氨基酸能接合樹突細胞或巨噬細胞帶回的抗原 這個T細胞B細胞 開始被激活 開始大量繁衍自己 繁衍出兩 類T細胞 一種是 毒殺型T細胞 能夠辨識擊殺有同樣抗原的癌細胞 另一類T細胞 是輔助型T細胞 它的功能是分泌介質促進B細胞 和T細胞 繁衍 好啦 如果照著正常運作 免疫系統沒有理由對腫瘤視而不見 的確 如果是外來的細菌病毒 免疫系統就是照著上述正常運作方式 激起免疫反應B細胞繁殖大量抗體清除血液裡的外來物 毒殺型T細胞攻擊被病毒入侵的細胞 但是癌細胞是身體反叛的細胞 知道如何抑制免疫系統 實際上腫瘤是利用正常的免疫機制來壓抑免疫系統 腫瘤微環境能分泌介白素引起慢性發炎吸引　調節型T細胞和MDSC細胞 的聚集 抑制毒殺型T細胞 和T helper細胞繁衍 在腫瘤聚集的巨噬細胞或樹突細胞也受到腫瘤微環境的影響 改變成抑制型的 抑制型的巨噬細胞或樹突細胞如何抑制免疫反應呢? 當這些抑制型的巨噬細胞或樹突細胞的表面有PDL1 (大家應該都知道PDL1是讓T細胞失去攻擊性) 回到淋巴結把抗原承現給B細胞 和T細胞 辨識時 一邊承現癌細胞的抗原 一邊用解除已活化的毒殺型T細胞 和輔助型T細胞 這好像哨兵回報將軍時 一手拿著敵人的畫像 另一手拿刀刺死將軍 在老鼠實驗 研究人員發現 抑制型巨噬細胞或樹突細胞出現 伴隨著腫瘤快速擴展 巨噬細胞或樹突細胞被腫瘤收買後會積極為腫瘤消滅殘存的免疫反應 從此身體裡再也沒有可以阻止它擴散的力量 唯有經由多種免疫療法 AntiPD1, AntiCTLA4, DC therapy, T cell therapy, IL2 配合標靶 電腦刀 破壞腫瘤微環境 才能扭轉局勢

Patients clamor to get into trials for immunotherapy, the new frontier in cancer treatment http://www.houstonchronicle.com/news/houston-texas/houston/article/Patients-clamor-to-get-into-trials-for-6404567.php

Today, seven pharmaceutical companies are testing PD-1 drugs on more than two dozen cancers, from bladder to ovarian to bone. Two received FDA approval in the past year. M.D. Anderson specialists in lung cancer are now dropping everything else to focus on immunotherapy, says Heymach, chairman of the hospital's thoracic/head and neck medical oncology department. He's never seen anything like it. "More than anything else in lung cancer's history, it's changing the course of what we're doing," he says.

Deciphering and Reversing Tumor Immune Suppression Immunity Volume 39, Issue 1, 25 July 2013, Pages 61–73 Generating an anti-tumor immune response is a multi-step process that is executed by effector T cells that can recognize and kill tumor targets. However, tumors employ multiple strategies to attenuate the effectiveness of T-cell-mediated attack. They achieve this by interfering with nearly every step required for effective immunity, from deregulation of antigen-presenting cells to establishment of a physical barrier at the vasculature that prevents homing of effector tumor-rejecting cells and the suppression of effector lymphocytes through the recruitment and activation of immunosuppressive cells such as myeloid-derived suppressor cells, tolerogenic monocytes, and T regulatory cells. Here, we review the ways in which tumors exert immune suppression and highlight the new therapies that seek to reverse this phenomenon and promote anti-tumor immunity. Understanding anti-tumor immunity, and how it becomes disabled by tumors, will ultimately lead to improved immune therapies and prolonged survival of patients. Click here for full text http://www.sciencedirect.com/science/article/pii/S1074761313002896

標準治癌免疫療法簡介, 尤其日本衛生部專利認證之新法制作的自體樹狀細胞疫苗，皮內皮下注射, 配合專利新法制作之自體活性NK細胞點滴療法介紹, 優點是 1. 對任何癌, 對任何程度, 初期到末期, 即使第4期皆有效 2. 可與各式癌療法, 包括手術, 化療, 放射療, 漢方等療法配合使用 3. 沒有任何副作用 4. 可一再施打 請參閱本網文章及 http://www.abecancer.com/ あべ腫瘍内科クリニック is great because 為製作成熟的病患自體樹狀細胞疫苗，目前一般是採用類似血液淨化（apheresis）方式，兩側手臂血管與類似洗腎機的大型機器連結，將全身血液抽到機器內，單次採取足夠的單核球，冷凍保存，此過程需2-3小時，有危險性，尤對癌末病人是一大負擔。阿部醫師以其已獲得日本衛生部專利認證書的名為「多價樹狀細胞疫苗製作法」，是最高效能的癌症免疫療法。只需抽取25cc周邊靜脈血液，以培養後的疫苗，注射投與，經連續6次，每兩週1次的採血及注射，每次皆能不斷提昇樹狀細胞數量及免疫力，不但安全，而且培養的疫苗新鮮，質量皆佳。他以先進專利細胞培養技術，將單核球附加長鏈癌細胞胜肽（peptide），胜肽是人工的癌抗原，製作成為樹狀細胞，再將此培養後的成熟樹狀細胞接種注射到此病人癌附近的皮下淋巴節內，則此樹狀細胞擔任司令官角色，教導病人體內的T淋巴球，認識癌抗原，成為細胞傷害性淋巴球（CTL），對標的細胞，也就是癌細胞集中攻擊。多價的意思是以其專利技術製作的樹狀細胞，可附加5種以上癌症抗原胜肽。以阿部醫師的方法，於第一次注射時，疫苗中的樹狀細胞數每cc即可高達1千萬個以上，有效細胞率97％以上。並以此抽取的血液, 使用獲專利之新法, 制作新活性NK 細胞點滴療法; 阿部醫師由2002年起以其附設研究室，設置與國家級研究機關同水準的細胞培養技術單位（cell processing center，CPC），防止免疫細胞遭受細菌及病毒污染，已獲數項ISO認證。 病人有從韓國、美國及台灣來看診。他也接受國內外合作醫院委託製作疫苗。有任何問題可寫英日或中文, fax:002-81-3-6380-8032去給他本人, 阿部博幸教授會專答, 也可用中文接受診療, 他懂中文

あべ腫瘍内科クリニック 、對於已有復發或轉移者，建議疫苗療法為首選療法。配合 Opdivo(Nivolumab)是抗PD-1抗體, 目的是強化疫苗的効能、譲疫苗発揮１００％効能 於あべ腫瘍内科クリニック常規使用於任何癌, 作法是以其研究室製作的新樹狀細胞疫苗皮下淋巴內注射及新NK細胞點滴後, 續點滴Opdivo, Opdivo 1 支40mg, 4cc, 分成 5次點滴, 每次隔 3 週 , 每次抽0.8cc, 8 mg, 混入 100 cc 生理食鹽水 , 點滴30分鐘, 唯需配合他的新樹狀細胞疫苗皮下淋巴內注射及新NK細胞點滴、也可増成每次 ２０ mg

到２０１５現在為止、治癌免疫療法已有標準化、多價樹狀細胞疫苗療法皮下注射、配合自體活性NK細胞點滴及抗PD-1抗體Opdivo(Nivolumab)點滴。一点都不複雑。科学進歩只有這様子。

多價樹狀細胞疫苗療法皮下注射、配合自體活性NK細胞點滴及抗PD-1抗體Opdivo(Nivolumab)點滴,　台湾都無、最近的是日本

再次向病友說明令人擔心之點, #79 訪客説的阿部教授是執行醫療, 他掛心的是病人能不能被他治好,所以當然選對各該病人最有利的治療方式 , 讓病人能早日康復, 而日本的大學附設醫院在做試驗, 極可能病人被分配到無效組或未知效果組, 那就慘了, 兩者就差在此 、我這様説実話、引起恐慌、只好説対不起。

Cincia(星希亞)

請問一下有認識的人過去找阿部教授治療的嗎？成效如何呢？ Cincia想多收集資料看看，不過關於阿部博幸教授資料好少阿！日文網站居多，但有看沒有懂阿！-_-!

2015-08-13 17:59

我是在某大學醫學中心服務的腫瘤科主任, 剛好今天台風天, 下午病人少一點, 本來都上百的, 我閒著, 瀏覽一下網頁, 突然發現有這個網頁, 很多癌友, 遠赴久留米與千葉, 覺得很好奇, 又發現有一位自稱訪客的,推崇在台灣頂頂大名的日本免疫治癌專家阿部博幸教授, 這位訪客書寫有關癌症免疫及阿部醫師的治療方式簡潔扼要切題, 我想他極可能也是位資深腫瘤醫師, 我再看這位訪客寫的, 我深深的必須呼應強調的是, 就像他說的, 病人當然有自由選擇看病的地方的權利, 但在世界上哪裡都一樣, 醫學中心做的事就是臨床試驗, 久留米與千葉也不會例外, 試驗一定需分組, 有一半當然是被選為無效組, 這是一定的, 那位訪客說明有關阿部醫師治療的方式一點都沒錯, 阿部醫師不是做臨床試驗, 每位病人接受他的治療當然會很有效, 但我所知, 要接受阿部醫師治療, 可能還是得親自去日本找他, 因為這位訪客講的韓國模式在台灣可能還行不通

既然有位新訪客, 那弊人就用自謙用原訪客吧, 韓國模式需有在台灣的代理商 , 及在台灣的醫師, 代理商拿著醫師抽的病人25cc血, 親送日本到阿部教授處, 以其獲日本厚生省專利認證的新法製作疫苗, 於兩週後, 把製作好的新鮮疫苗, 於24小時內送回台灣讓原抽血醫師為病人施打, 到２０１５現在為止, 治癌免疫療法已有標準化, 多價樹狀細胞疫苗療法皮下注射、配合自體活性NK細胞點滴及抗PD-1抗體Opdivo(Nivolumab)點滴。一点都不複雑。科学進歩只有這様子。

原訪客有反應了, 那我就用新訪客; 治癌免疫標準療法就是, 以樹狀細胞疫苗療法皮下注射, 最好是皮內注射, 配合自體活性NK細胞點滴及抗PD-1抗體Opdivo 點滴, 對於任何癌症之任何stage都一樣, 治癌免疫醫學之目前進歩就只有這様子。阿部博士就是採此標準療法, 而以專利認證的新法製作, 半年前來台灣的醫學會做專題演講時已說過

請問原訪客, 您是不是也是腫瘤科醫師, 您說台灣近期不太可能開放癌症免疫療法, 原因我所瞭解的當然是不可能健保給付, 至於不太可能開放我同意就您所說的, 因在台灣社會不太能接受有錢人才能接受這種治療, 另一個原因是怕有非合格醫師亂來, 政治多事之秋, 主管機關多一事不如少一事的心態, 阿部來多做幾次演講或許可以催生吧

回答新訪客, 弊人不能透露名字, 其實我們應本來就認識, 阿部好像很忙, 今年年底前不太可能再來

您與阿部很熟嗎, 我想帶幾位年輕醫師去他CPC參訪學習

回答新訪客, 您可與他直接聯繫

請問新訪客, 您覺得在台灣要有代理商那麼困難嗎

我不敢回答, 會不會被追蹤, 反正我也不當代理商

在學會大家見面公開談吧

請問新訪客, 上次阿部演講時說免疫療法對復發及轉移最有效, 您認為呢

我個人覺得應是手術, 放療, 化療過後, 腫瘤有縮小, 為防復發及轉移時最有效, 阿部說的應是他的經驗, 為凸顯以其新法治療時, 甚至有復發及轉移皆會有效, 不過演講時, 他的數據就顯出他說的沒錯, 也許是他用他最近研發成功的日本衛生部專利認證過的新法, 才那麼有效吧

下次他來時應可再看到他的新數據吧

Cincia(星希亞)

期待有新數據可以分享廣大的癌症戰友參考，謝謝主任。^__^

2015-08-10 16:23

美女，有高手決戰光明頂了，趕快搬椅子來看。

不好意思借星星的版提問， 請教兩位醫師，如果想找阿部醫師治療，是不是直接透過上面提到的傳真，要傳那些資料，完整病歷嗎，還是可以直接寄去日本，不好意思我沒這方面經驗，還請不吝指教，謝謝您們。

To cecilia188, 　傳真　is OK， 不要完整病歷、手写、要傳：　病名、簡単治療経過、有無接受過免疫治療、最近診察時医師説目前状態　（復発、転移有無）

有任何問題可寫英日或中文, fax:002-81-3-6380-8032去給他本人, 阿部博幸教授會專答, 也可用中文接受診療, 他懂中文 、不要客気、附上e-mail可能他比較方便

醫生很感謝您哦！ 星不好意思。

Cincia(星希亞)

不會啦！姊決定要嘗試看看嗎？

2015-08-10 16:21

Dear星， 我想想先做完目前的，因為才邁出第一步而已， 把這當作沒路可走的最後一搏， 在臺灣治療還是比較方便的，對現在的我來說。 妳加油喔！ 妳本人比照片漂亮很多欸，不像我，老很多~>_<~

Cincia(星希亞)

Dear cecilia, 謝謝你不棄嫌我的頭巾造型， 我私心覺得還是有頭髮比較美一點，哈哈～ 那天碰面沒聊到什麼就各自去忙了， 改天見面多聊聊，一起加油喔～^___^

2015-08-11 15:35

請問訪客 我傳真給阿布醫師了 他有回mail給我 但我又email給他請教幾個問題 可是他都沒回 是沒收到嗎? 1 請問你確定他那裏有anti PD1 嗎?用洗腎機取單核細胞很特別 有大風險嗎? 2我知道antiPD1這些藥是在史丹佛大學做研究 他曾是那裏客座教授 所以有那個藥並不難 如果他真的曾在史丹佛大學那裏當客座教授 等於史丹佛大學幫你過濾了這個人的專業 不是嗎? 3日本的免疫療法收費已有一定行情 在行情價內就不貴 4我跑日本是為活下去 不是為了當白老鼠 當人家免費幫你做 另一個意思就是搞査了我不負責 5阿部醫師好不好 我還要去瞭解 但至少他會說中文 你可以去溝通 6 我實在看不下去拼命叫台灣人 翻山越嶺去當白老鼠 所以要主治醫師同意 還去那麼鄉下的地方 還叫癌患把標靶藥停一下 ---- 7請問cincia你在台大做人體實驗 但你會去類似屏東大學做人體實驗嗎? 8真的要去的話 要問清楚

訪客 以下是我寫給阿部醫師的信 對我的問題 請問你有沒有什麼看法?(要用中文回答喔!!謝謝) Dear Tsukada, This is XXX, thanks for the reply, I have a few questions for you: 1. How is the effect of the immunotherapy to 肺腺癌 3B 期 ALK 陽性? 2. I am now continue taking the 抗癌藥 (XALKORI), the tumor in my lung is under control, do you think I can prevent the further cancer cell metastasis to the brain again by receiving the immunotherapy? 3. There are six injections for the immunotherapy, what if I do not feel well and did not finish all six treatment, are there any risk to it? 4. Is there any side effect after the treatment everytime? Will I be able to go back to Taiwan the next day after the treatment or I will have to stay in Japan to recover for a couple days? 5. What should I bring to Japan if I meet with you in Japan at your clinic? 6. How do I pay the treatment? Do I pay everything at once or I can pay each treatment individually when I receive it everytime? Thank you so much! Sincerely,

Lisa and Cincia, This one is for you. CNS = Central Nerve System = brain metastasis CTLA-4 Blockade With Ipilimumab Induces Significant Clinical Benefit in a Female With Melanoma Metastases to the CNS Pathological review of this case revealed a predominantly cytotoxic antitumor immune response in the CNS following CTLA-4 blockade. The tumor destruction associated with this immune response correlated with the radiographic findings. The paucity of regulatory T cells in the infiltrate, as assayed by FoxP3 immunohistochemistry, also supports the mechanism for effective immune recognition of tumor. This is consistent with experimental findings that suggest that anti-CTLA-4 blockade causes a relative decrease in the frequency of regulatory T cells through preferential expansion of cytotoxic CD8+ T cells2 or by abrogating the function of regulatory T cells.[7] In this case, the pathological changes in the resected melanoma specimen following treatment suggest that such processes might also be applicable to CNS malignancies despite the inability of most drugs to penetrate the blood–brain barrier. This case provides rare evidence that immunotherapy with ipilimumab to affect CTLA-4 blockade can result in the effective treatment of tumors involving the CNS. Clinical features that should alert the clinician to the possibility of ipilimumab-mediated antitumor immune activity in the CNS are listed in Box 1 . The surgical pathology demonstrates the ability of immune effector cells to home to sites of CNS disease and contribute to tumor necrosis and edema; processes that, importantly, were associated with an improved outcome and extended survival in this patient. http://www.medscape.org/viewarticle/579416

上面網站需要註冊 我把原文貼在此 這篇文章提出在腦轉移病人打anti CTLA4 藥品後 免疫細胞在腦部和癌細胞作戰的醫學證據 所有證據都顯示免疫細胞可以進入腦部 CTLA-4 Blockade With Ipilimumab Induces Significant Clinical Benefit in a Female With Melanoma Metastases to the CNS Summary Background: A 63-year-old female presented to her primary physician with numbness and weakness in her left leg, which progressed over several days to involve her entire lower extremities. MRI of the spine and brain revealed multiple metastases. The patient received ipilimumab and after 3 months experienced intermittent confusion and focal seizures. Investigations: Electroencephalogram and MRI scans of the spine and brain, followed by surgical removal of a left frontal cortical brain metastasis and subsequent histological and pathological analyses. Diagnosis Metastatic melanoma from an unknown primary tumor. Management: The patient was treated with ipilimumab on a compassionate-use program and dexamethasone, celecoxib, and levetiracetam to treat the symptoms and seizures. Postoperative stereotactic radiosurgery was initiated. The Case A 63-year-old female presented to her primary physician with numbness and weakness in her left leg, which progressed over several days to involve her entire lower extremities. The patient’s medical history included removal of a benign bone tumor as a child and the removal of a squamous cell skin cancer within the few weeks before presentation. There was no patient history of primary melanoma, but her mother and daughter had both had melanoma, which in both cases had been successfully treated by local excision. A spinal MRI scan revealed metastatic disease involving the spinal cord at C5 and T3, and an 8 mm focal-enhancing T1 metastasis. A brain MRI scan revealed four metastases, including a dominant 3.5 cm × 2.2 cm × 2.7 cm lesion in the right posterior parietal cortex. Since the patient had a symptomatic metastasis in a surgically accessible location, a neurosurgical evaluation was conducted and this determined that function of her legs could be restored by removal of the tumor. In addition, resection of the tumor would allow the associated edema to resolve. The parietal cortex lesion was surgically removed revealing metastatic melanoma. As the patient presented with three brain metastases and no evidence of leptomeningeal disease, she was offered either whole-brain radiation therapy (WBRT), or WBRT plus stereotactic radiosurgery (SRS), or SRS alone. Given the relatively low efficacy of WBRT in melanoma and her reluctance to undergo initial WBRT, SRS alone[1] was used to treat the gross lesions and tumor bed. The patient received radiation to her spine and SRS to the brain lesions. Following radiation, she received temozolomide orally at 200 mg/m2 daily on days 1-5 of a 28-day cycle for 3 months. Restaging by chest, abdomen, pelvis, and head and spine MRIs revealed moderate disease progression in the lungs and central nervous system (CNS). The patient then received compassionate-use ipilimumab (MDX-010, Bristol-Myers Squibb, New York, NY and Medarex Inc. Princeton, NJ), a fully human monoclonal antibody directed against CTLA-4, a key negative regulator of T-cell-mediated immune responses.[2] (See Supplementary Figure 1 online). Ipilimumab was administered intravenously at 3 mg/kg once every 3 weeks for four doses with maintenance dosing anticipated every 12 weeks. A month after starting ipilimumab treatment, the patient complained of decreased sensation in her left thigh. A repeat spinal MRI revealed slight edema surrounding the previously identified cord metastases. These symptoms subsided over the following 2 weeks without additional intervention while the patient remained under observation. At 3 months after treatment initiation, she began to experience complex partial seizures characterized by confusion, aphasia, gait apraxia, and automatisms (lip smacking and fidgeting). An electroencephalography (EEG) was consistent with interictal activity arising from the left frontal lobe and a brain MRI confirmed moderate edema surrounding the known metastases, with evidence of central tumor necrosis. The patient was treated with celecoxib (200 mg by mouth twice a day) and levetiracetam (1,500 mg by mouth twice a day), which resulted in an immediate and marked improvement in symptoms. Over the following 3 months, the patient experienced intermittent confusion. Edema surrounding pre-existing CNS tumors was noted (Figure 1) and EEG revealed focal epileptic activity. Dexamethasone was added to the regimen and titrated (≤4 mg twice daily) to complete the resolution of symptoms. The patient returned to baseline function within 2 weeks of dexamethasone initiation. Several MRI scans of her spine over the following 6 months showed waxing and waning of the edema surrounding known spinal metastases with involution and complete disappearance of tumors in some areas (Figure 2). Her performance status continued to improve, such that she was able to play two rounds of golf each week while previously she had been home bound. At 7 months after the initiation of treatment with ipilimumab, the patient experienced recurrent confusion with evidence of edema and focal seizure activity associated with a left frontal cortical brain metastasis. Surgical removal of this lesion revealed focal areas of necrosis with marked infiltration of the tumor by lymphocytes and an abundance of melanophages throughout (Figures 3 and 4). This concerted immune- mediated response was dominated by CD8+ lymphocytes, with a paucity of FoxP3+ regulatory cells in the infiltrate of the brain lesion. Figure 3. Enlarge Pathological examination of resected brain metastasis following ipilimumab treatment. All specimens are stained with hematoxylin and eosin. (A) A heavily pigmented tumor with extensive infiltrating... Figure 4. Enlarge Pathological assessment of immune effector cells associated with melanoma brain metastases following ipilimumab treatment. Most of the resected brain metastasis following treatment is disrupted by abundant CD8+ tumorinfiltrating lymphocytes. Given the heavy pigmentation of the tumor, staining development was performed by use of a blue chromagen (Alkaline Phosphatase Substrate Kit III SK-5300 Vector) (A) CD3+ infiltrating lymphocytes (polyclonal DAKO A0452; 20×) (B) CD3+ lymphocytes at a greater magnification (40×) (C) Occasional CD4+ lymphocytes (clone 1F6 Biocare CM1538;circled; 40×) (D) Abundant CD8+-staining cells infiltrating the tumor mass (clone SP16 Biocare CM1548; 40×) (E) Occasional CD20+ cells (clone L26 DAKO M755; circled; 40×) (F) Rare FoxP3+-stained regulatory T cells (polyclonal Abcam 10563; circled; 40×). This patient did not have an objective response as defined by standard Response Evaluation Criteria in Solid Tumors (RECIST), although she experienced stable disease for 7 months after starting ipilimumab and lived for 2 years following her initial presentation. Discussion of Diagnosis CNS metastases occur in more than 50% of patients diagnosed with advanced melanoma.[3] The prognosis for these patients is poor, with a median survival of 4.[4] months and a 5-year survival rate of approximately 3%.[4] In a retrospective analysis of 702 patients with melanoma who presented with brain metastases, 94.5% had a CNS-related cause of death.[5] Even when systemic therapy produces responses to visceral metastases, the CNS is a frequent site of tumor recurrence. For example, approximately 50% of patients with metastatic melanoma who initially responded to biochemotherapy regimens developed recurrence or progression in the CNS.[6] Furthermore, single and multiple brain lesions can be treated with a combination of surgery and radiation, but tumor progression in the CNS is frequent even in heavily pretreated individuals, indicating the presence or recurrence of micrometastases that go undetected and are unaffected by the current standard therapies. Pathological review of this case revealed a predominantly cytotoxic antitumor immune response in the CNS following CTLA-4 blockade. The tumor destruction associated with this immune response correlated with the radiographic findings. The paucity of regulatory T cells in the infiltrate, as assayed by FoxP3 immunohistochemistry, also supports the mechanism for effective immune recognition of tumor. This is consistent with experimental findings that suggest that anti-CTLA-4 blockade causes a relative decrease in the frequency of regulatory T cells through preferential expansion of cytotoxic CD8+ T cells2 or by abrogating the function of regulatory T cells.[7] In this case, the pathological changes in the resected melanoma specimen following treatment suggest that such processes might also be applicable to CNS malignancies despite the inability of most drugs to penetrate the blood–brain barrier. This case provides rare evidence that immunotherapy with ipilimumab to affect CTLA-4 blockade can result in the effective treatment of tumors involving the CNS. Clinical features that should alert the clinician to the possibility of ipilimumab-mediated antitumor immune activity in the CNS are listed in Box 1 . The surgical pathology demonstrates the ability of immune effector cells to home to sites of CNS disease and contribute to tumor necrosis and edema; processes that, importantly, were associated with an improved outcome and extended survival in this patient. Treatment and Management MRI staging of both the brain and spinal cord provides a useful radiographic correlate to the pathology and clinical course. The disease stabilization and performance status resulting from ipilimumab treatment far exceeded the expectations for patients presenting with multiple CNS metastases from advanced melanoma. It is worth noting that although this patient received ipilimumab through a single-patient compassionate protocol at a dosage that had previously demonstrated clinical activity (3 mg/kg), subsequent multicenter phase II and III trials examined ipilimumab at 10 mg/kg for both induction and maintenance therapy. A significant lymphocytic infiltrate has occasionally been demonstrated in primary tumors of the CNS.[8] Dendritic-cell vaccination strategies in animal models of melanoma and in patients with glioblastoma multiforme have resulted in the intratumoral infiltration of immune effector cells, thus, suggesting a new way to approach the treatment of CNS malignancies.[9,10] Although data are promising, it is becoming apparent that additional problems need to be addressed, such as the role of tumor-infiltrating immune regulatory cells in the CNS.[11,12] An effective, systemic therapy that gives durable responses or disease stabilization simultaneously in CNS and non-CNS sites is needed. The enthusiasm for evaluating immune therapies for these patients, however, has been limited by the postulation/assumption that the CNS is an immune-privileged site. The blood-brain barrier offers mechanical protection and controls molecular transport between the vasculature and CNS.[13] Even when systemic therapies are effective, the CNS is a frequent site of treatment failure.[14] It is, therefore, not expected that immune components will reach brain metastases successfully and elicit a meaningful response. Ipilimumab is under investigation to treat several types of cancers, with a particular focus on melanoma. In preclinical murine studies, CTLA-4 blockade using monoclonal antibodies has demonstrated antitumor activity.[2] Results of early trials in patients with metastatic melanoma show that ipilimumab alone or with other therapies (i.e. vaccines or chemotherapy) is generally well tolerated and results in objective responses and disease stabilization.[15-17] Pathology analysis from a subset of patients whose pre-existing metastases were biopsied following treatment with ipilimumab revealed infiltrates of CD4+, CD8+, and CD20+ lymphocytes, neutrophils, and extensive (>90%) tumor necrosis.[14] Potential effects of CTLA-4 blockade on melanoma metastases to the CNS have been unclear; however, this case suggests that the antitumor effect may be executed via CNS tumor infiltration by CD8+ lymphocytes. Conclusions This case describes pathological evidence of immune-mediated inflammation and edema with extensive tumor disruption and evidence of foci of necrosis within the CNS in response to ipilimumab therapy in a patient with advanced melanoma. Investigation of CTLA-4 blockade and other immune therapies to treat CNS metastases should be a focus of further clinical investigation. Supplementary information in the form of a figure is available on the Nature Clinical Practice Oncology website.

重點翻譯一下 因為有血腦障壁 許多藥品都進不到腦裡 醫界以前認為 腦是特權區域 不期待免疫細胞可以進入腦 這報告說明這個假設是錯誤的 (我讀過另一篇報告 研究免疫細胞如何進入腦內 方法大致是 免疫細胞分泌促進發炎的細胞介素 讓血腦障壁細胞間的細縫張開 從細縫間專鑽入腦內 這方法與當你皮膚割傷後 免疫細胞如何重鑽出微血管 到受傷的皮膚層一樣) The enthusiasm for evaluating immune therapies for these patients, however, has been limited by the postulation/assumption that the CNS is an immune-privileged site. The blood-brain barrier offers mechanical protection and controls molecular transport between the vasculature and CNS.[13] Even when systemic therapies are effective, the CNS is a frequent site of treatment failure.[14] It is, therefore, not expected that immune components will reach brain metastases successfully and elicit a meaningful response. 病人打了anti CTLA4 藥品後 抑制免疫反應的regulatory T cells減少 毒殺型(CD8+) T cells 增加 免疫反應能有效的破壞腫瘤 The tumor destruction associated with this immune response correlated with the radiographic findings. The paucity of regulatory T cells in the infiltrate, as assayed by FoxP3 immunohistochemistry, also supports the mechanism for effective immune recognition of tumor. This is consistent with experimental findings that suggest that anti-CTLA-4 blockade causes a relative decrease in the frequency of regulatory T cells through preferential expansion of cytotoxic CD8+ T cells2 or by abrogating the function of regulatory T cells. 這個病例記錄anti CTLA4藥品引起免疫反應 造成的發炎水腫和大規模腫瘤破壞 This case describes pathological evidence of immune-mediated inflammation and edema with extensive tumor disruption and evidence of foci of necrosis within the CNS in response to ipilimumab therapy in a patient with advanced melanoma.

仔細看這個病例會發現病人是先做放療(電腦刀) 再打Yervoy 放療破壞腫瘤 同時死去的癌細胞會激起免疫反應 Yervoy讓毒殺型(CD8+) T cells 順利繁衍增生 不受腫瘤抑制免疫反應的regulatory T cells影響 唯一遺憾的是當時Anti PD1藥品尚未出現 少了Anti PD1藥品 免疫反應無法持續下去 最後腫瘤反撲 病人於兩年後辭世

免疫治療要有效 一定要包括 Anti PD1藥品 放療可以破壞腫瘤 同時死去的癌細胞會激起免疫反應 放療是很好的輔助免疫治療的方式

請問肝癌標把藥物雷莎瓦的費用、副作用、療效如何?已做過載藥微球肝動脈化療栓塞，再搭配雷莎瓦成效又如何?

Cincia(星希亞)

這問題我沒辦法回答耶！ 你要不要去FB戰友會問問看阿～也許有戰友可以分享經驗！

2015-09-04 18:33

2015: The Year of Anti-PD-1/PD-L1s Against Melanoma and Beyond The history of clinical oncology has witnessed several revolutionary therapeutic advances that have significantly improved cancer care. These have included the introduction of cisplatin in the 1970s for testicular and ovarian cancers, the taxanes in the 1990s for breast and other solid tumors, targeted therapy with anti-HER2 for breast cancer and c-Kit inhibitors for chronic myeloid leukemia and other cancers at the start of this millennium. Each of these treatments has revolutionized outcomes for patients with various types of cancer. Today, we are at the start of a new era in cancer care — that of immunotherapy. The approval of sipuleucel-T for the treatment of prostate cancer in 2010 and ipilimumab (anti-CTLA-4) for advanced melanoma in 2011 was the first notable success in the immunotherapy of cancer. After almost three years from the approval of the first checkpoint inhibitor (ipilimumab), the good news is not over. Quite the contrary, we are only at the beginning and, notably, these advances do not relate just to the treatment of melanoma. Immunotherapy has become the fourth pillar of cancer treatment alongside surgery, radiotherapy and chemotherapy (including targeted therapy). This can be attributed primarily to the impact that another group of checkpoint inhibitors, the anti-PD-1/PD-L1 agents, is having on the treatment of various malignancies. As with anti-CTLA-4, the anti-PD-1/PD-L1 story starts with melanoma. Data from a large phase I study with pembrolizumab (Robert et al., 2014a , Robert et al., 2014b ) led to its approval by the US Food and Drug Administration (FDA) in September 2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This study of 411 patients showed that pembrolizumab resulted in an overall response rate (ORR) of 34%, a median progression-free survival (PFS) of 5.5 months, and overall survival (OS) rates of 69% at one year and 62% at 18 months. Moreover, a randomized phase II trial with pembrolizumab at two different dosages (2 mg/kg or 10 mg/kg every three weeks) in advanced melanoma refractory to previous ipilimumab therapy showed that both doses improved PFS compared with investigator choice chemotherapy (Ribas et al., 2014 ). In fact, the 6-month PFS was 34% with pembrolizumab 2 mg/kg, 38% with pembrolizumab 10 mg/kg and 16% with chemotherapy, while the 9-month PFS was 24%, 29% and 8% respectively. The ORR in the three groups was 21%, 25% and 4%, respectively. More recently, in December 2014, another anti-PD-1, nivolumab, was approved by the FDA for patients with advanced melanoma with the same indication as pembrolizumab. Data from a large phase I trial with nivolumab showed an ORR of 32% and 1, 2, 3, and 4-year OS rates of 63%, 48%, 42%, and 32%, respectively. In addition, data from a phase III study in patients with metastatic melanoma previously treated with ipilimumab reported that nivolumab had an ORR of 32% compared with 11% with the chemotherapy control arm (D'Angelo et al., 2014 ). Nivolumab was also compared to chemotherapy in another randomized phase III trial in which untreated patients with advanced BRAF wild-type melanoma received either nivolumab or dacarbazine. The ORR was 40.0% in the nivolumab group versus 13.9% in the dacarbazine group. At 1 year, the OS was 73.0% in the nivolumab group compared with 42.1% in the dacarbazine group. Median PFS was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (Robert et al., 2014a , Robert et al., 2014b ). Considering historical data with a typical median OS of 6.2 months and 1-year OS rate of 25.5% and 1 and 2-year OS rates of 45% and 24% obtained with ipilimumab therapy in the treatment of advanced melanoma, the results achieved with anti-PD-1 therapy represent a terrific improvement in clinical benefit for these patients. Moreover, these data obtained in melanoma patients are just the start. OS data from a phase I study of nivolumab in solid tumors were particularly encouraging, even in patients with non-small-cell lung cancer (NSCLC), with a median OS of 9.6 months, 1-year OS of 42% and 2-year OS of 24%. Moreover, in a phase II study in patients with advanced, refractory NSCLC, nivolumab was associated with an ORR of 15% and a median OS of 8.2 months (Ramalingam et al., 2014 ). Historically, these patients have ORRs of between 2 and 8% and a median OS of about 5 months. The estimated 1-year survival rate was 41%, which also compares favorably with historical data for patients with third-line squamous cell NSCLC of 1-year OS rates of 5.5–18%. Pembrolizumab has also shown interesting results in NSCLC. In the NSCLC expansion cohort of a phase I trial, pembrolizumab treatment resulted in an ORR of 21%. The median PFS in treatment-naïve patients was 27 weeks and 6-months OS was 86%, while in pretreated patients median PFS was 10 weeks and 6-months OS was 59% (Garon et al., 2014 ). Interesting preliminary results have also been reported for urothelial bladder cancer (UBC) and triple negative breast cancer (TNBC). In patients with platinum-pretreated, metastatic UBC, the ORR obtained with an anti-PD-L1 antibody (MPDLA3280) was between 11% and 43%, depending on the level of PD-L1 (Powles et al., 2014 ). In patients with heavily pretreated advanced TNBC, pembrolizumab achieved an ORR of 18.5% with a durable response (median response duration was not reached) (Nanda et al., 2014 ). Anti-PD-1 therapy has also achieved interesting results in patients with hematological malignancies. In a small phase I study that enrolled 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated, nivolumab resulted in a clinical benefit in all patients; the ORR was 87% (20/23), with 17% having a complete response and 70% a partial response. The remaining three patients (13%) all had stable disease (Ansell et al., 2014 ). PFS at 6 months was 86%. In another phase Ib study, pembrolizumab also demonstrated promising antitumor activity in patients with heavily pretreated Hodgkin's lymphoma, with a 21% complete remission rate and an ORR of 65% (Craig et al., 2014 ). What can we expect during 2015? New data in other types of cancer are surely expected. Studies with anti-PD-1/PD-L1 are ongoing in gastric cancer, small-cell lung cancer, glioblastoma, colorectal cancer, Merkel cell carcinoma and others. There are also likely to be more data concerning the role of PD-L1 as a predictive marker, even though data from phase III studies in melanoma seem to refute such a role. We will also see more important news on the potential of anti-PD-1/PD-L1s in combination with other approaches, including other immunotherapies (e.g. checkpoint inhibitors), radiotherapy, chemotherapy and targeted agents. We are observing the beginning of another new era in the fight against cancer: that of anti-PD-1/PD-L1 therapy. Source: http://www.ebiomedicine.com/article/S2352-3964(15)00034-1/fulltext

在美國政府癌症機構(NCI) 推廣的T細胞療法(CAR-T) 已經進步到用基因改造在T細胞加上能辨識癌症的受體 因為是基因改造 T細胞繁衍的世世代代代都能辨識癌症 NCI 稱它為 “A Living Drug” 幾家biotech 公司已經在NCI 的技術 上改良 第三代CAR-T已經在雸研究中 這將是癌症歷史上為最客制化也是最昂貴的癌症治療技術 CAR T-Cell Therapy: Engineering Patients’ Immune Cells to Treat Their Cancers For years, the cornerstones of cancer treatment have been surgery, chemotherapy, and radiation therapy. Over the last decade, targeted therapies like imatinib (Gleevec®) and trastuzumab (Herceptin®)—drugs that target cancer cells by homing in on specific molecular changes seen primarily in those cells—have also emerged as standard treatments for a number of cancers. And now, despite years of starts and stutter steps, excitement is growing for immunotherapy—therapies that harness the power of a patient’s immune system to combat their disease, or what some in the research community are calling the “fifth pillar” of cancer treatment. One approach to immunotherapy involves engineering patients’ own immune cells to recognize and attack their tumors. And although this approach, called adoptive cell transfer (ACT), has been restricted to small clinical trials so far, treatments using these engineered immune cells have generated some remarkable responses in patients with advanced cancer. For example, in several early-stage trials testing ACT in patients with advanced acute lymphoblastic leukemia (ALL) who had few if any remaining treatment options, many patients’ cancers have disappeared entirely. Several of these patients have remained cancer free for extended periods. Equally promising results have been reported in several small trials involving patients with lymphoma. These are small clinical trials, their lead investigators cautioned, and much more research is needed. But the results from the trials performed thus far “are proof of principle that we can successfully alter patients’ T cells so that they attack their cancer cells,” said one of the trial's leaders, Renier J. Brentjens, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center (MSKCC) in New York. “A Living Drug” Adoptive cell transfer is like “giving patients a living drug,” continued Dr. Brentjens. That’s because ACT’s building blocks are T cells, a type of immune cell collected from the patient’s own blood. After collection, the T cells are genetically engineered to produce special receptors on their surface called chimeric antigen receptors (CARs). CARs are proteins that allow the T cells to recognize a specific protein (antigen) on tumor cells. These engineered CAR T cells are then grown in the laboratory until they number in the billions. The expanded population of CAR T cells is then infused into the patient. After the infusion, if all goes as planned, the T cells multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill cancer cells that harbor the antigen on their surfaces. This process builds on a similar form of ACT pioneered by Steven Rosenberg, M.D., Ph.D., and his colleagues from NCI’s Surgery Branch for patients with advanced melanoma. The CAR T cells are “much more potent than anything we can achieve” with other immune-based treatments being studied, said Crystal Mackall, M.D., of NCI’s Pediatric Oncology Branch (POB). Even so, investigators working in this field caution that there is still much to learn about CAR T-cell therapy. But the early results from trials like these have generated considerable optimism. CAR T-cell therapy eventually may “become a standard therapy for some B-cell malignancies” like ALL and chronic lymphocytic leukemia, Dr. Rosenberg wrote in a Nature Reviews Clinical Oncology article. A Possible Option Where None Had Existed More than 80 percent of children who are diagnosed with ALL that arises in B cells—the predominant type of pediatric ALL—will be cured by intensive chemotherapy. For patients whose cancers return after intensive chemotherapy or a stem cell transplant, the remaining treatment options are “close to none,” said Stephan Grupp, M.D., Ph.D., of the Children’s Hospital of Philadelphia (CHOP) and the lead investigator of a trial testing CAR T cells primarily in children with ALL. This treatment may represent a much-needed new option for such patients, he said. Trials of CAR T cells in adults and children with leukemia and lymphoma have used T cells engineered to target the CD19 antigen, which is present on the surface of nearly all B cells, both normal and cancerous. In the CHOP trial, which is being conducted in collaboration with researchers from the University of Pennsylvania, all signs of cancer disappeared (a complete response) in 27 of the 30 patients treated in the study, according to findings published October 16 in the New England Journal of Medicine. Nineteen of the 27 patients with complete responses have remained in remission, the study authors reported, with 15 of these patients receiving no further therapy and 4 patients withdrawing from the trial to receive other therapy. According to the most recent dataExit Disclaimer from a POB trial that included children with ALL, 14 of 20 patients had a complete response. And of the 12 patients who had no evidence of leukemic cells, called blasts, in their bone marrow after CAR T-cell treatment, 10 have gone on to receive a stem cell transplant and remain cancer free, reported the study’s lead investigator, Daniel W. Lee, M.D., also of the POB. Even so, investigators working in this field caution that there is still much to learn about CAR T-cell therapy. But the early results from trials like these have generated considerable optimism. CAR T-cell therapy eventually may “become a standard therapy for some B-cell malignancies” like ALL and chronic lymphocytic leukemia, Dr. Rosenberg wrote in a Nature Reviews Clinical Oncology article. A Possible Option Where None Had Existed More than 80 percent of children who are diagnosed with ALL that arises in B cells—the predominant type of pediatric ALL—will be cured by intensive chemotherapy. For patients whose cancers return after intensive chemotherapy or a stem cell transplant, the remaining treatment options are “close to none,” said Stephan Grupp, M.D., Ph.D., of the Children’s Hospital of Philadelphia (CHOP) and the lead investigator of a trial testing CAR T cells primarily in children with ALL. This treatment may represent a much-needed new option for such patients, he said. Trials of CAR T cells in adults and children with leukemia and lymphoma have used T cells engineered to target the CD19 antigen, which is present on the surface of nearly all B cells, both normal and cancerous. In the CHOP trial, which is being conducted in collaboration with researchers from the University of Pennsylvania, all signs of cancer disappeared (a complete response) in 27 of the 30 patients treated in the study, according to findings published October 16 in the New England Journal of Medicine. Nineteen of the 27 patients with complete responses have remained in remission, the study authors reported, with 15 of these patients receiving no further therapy and 4 patients withdrawing from the trial to receive other therapy. According to the most recent dataExit Disclaimer from a POB trial that included children with ALL, 14 of 20 patients had a complete response. And of the 12 patients who had no evidence of leukemic cells, called blasts, in their bone marrow after CAR T-cell treatment, 10 have gone on to receive a stem cell transplant and remain cancer free, reported the study’s lead investigator, Daniel W. Lee, M.D., also of the POB. “Our findings strongly suggest that CAR T-cell therapy is a useful bridge to bone marrow transplant for patients who are no longer responding to chemotherapy,” Dr. Lee said. Similar results have been seen in phase I trials of adult patients conducted at MSKCC and NCI. In findings published in February 2014, 14 of the 16 participants in the MSKCC trial treated to that point had experienced complete responses, which in some cases occurred 2 weeks or sooner after treatment began. Of those patients who were eligible, 7 underwent a stem cell transplant and are still cancer free. The NCI-led trial of CAR T cells included 15 adult patients, the majority of whom had advanced diffuse large B-cell lymphoma. Most patients in the trial had either complete or partial responses, reported James Kochenderfer, M.D., and his NCI colleagues. “Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that, until this point, were virtually untreatable,” Dr. Kochenderfer said. [NCI Surgery Branch researchers have also reported promising resultsExit Disclaimer from one of the first trials testing CAR T cells derived from donors, rather than the patients themselves, to treat leukemia and lymphoma.] Other findings from the trials have been encouraging, as well. For example, the number of CAR T cells increased dramatically after infusion into patients, as much as 1,000-fold in some individuals. In addition, after infusion, CAR T cells were detected in the central nervous system, a so-called sanctuary site where solitary cancer cells that have evaded chemotherapy or radiation may hide. In two patients in the NCI pediatric trial, the CAR T-cell treatment eradicated cancer that had spread to the central nervous system. If CAR T cells can persist at these sites, it could help fend off relapses, Dr. Mackall noted. Managing Unique Side Effects CAR T-cell therapy can cause several worrisome side effects, perhaps the most troublesome being cytokine-release syndrome. The infused T cells release cytokines, which are chemical messengers that help the T cells carry out their duties. With cytokine-release syndrome, there is a rapid and massive release of cytokines into the bloodstream, which can lead to dangerously high fevers and precipitous drops in blood pressure. Cytokine-release syndrome is a common problem in patients treated with CAR T cells. In the POB and CHOP trials, patients with the most extensive disease prior to receiving the CAR T cells were more likely to experience severe cases of cytokine-release syndrome. For most patients, trial investigators have reported, the side effects are mild enough that they can be managed with standard supportive therapies, including steroids. The research team at CHOP noticed that patients experiencing severe reactions all had particularly high levels of IL-6, a cytokine that is secreted by T cells and macrophages in response to inflammation. So they turned to two drugs that are approved to treat inflammatory conditions like juvenile arthritis: etanercept (Enbrel®) and tocilizumab (Actemra®), the latter of which blocks IL-6 activity. The patients had “excellent responses” to the treatment, Dr. Grupp said. “We believe that [these drugs] will be a major part of toxicity management for these patients.” The other two teams subsequently used tocilizumab in several patients. Dr. Brentjens agreed that both drugs could become a useful way to help manage cytokine-release syndrome because, unlike steroids, they don’t appear to affect the infused CAR T cells’ activity or proliferation. Improving the Process Even with these encouraging preliminary findings, more research is needed before CAR T-cell therapy becomes a routine option for patients with ALL. “We need to treat more patients and have longer follow-up to really say what the impact of this therapy is [and] to understand its true performance characteristics,” Dr. Grupp said. Several other trials testing CAR T cells in children and adults are ongoing and, with greater interest and involvement from the pharmaceutical and biotechnology sector, more trials testing CAR T cells are being planned. Researchers are also studying ways to improve on the positive results obtained to date, including refining the process by which the CAR T cells are produced. Research groups like Dr. Brentjens’ are also working to make a superior CAR T cell, including developing a better receptor and identifying better targets. For example, Dr. Lee and his colleagues at NCI have developed CAR T cells that target the CD22 antigen, which is also present on most B cells, although in smaller quantities than CD19. The CD22-targeted T cells, he believes, could be used in concert with CD19-targeted T cells as a one-two punch in ALL and other B-cell cancers. NCI researchers hope to begin the first clinical trial testing the CD22-targeted CAR T cells in November 2014. Based on the success thus far, several research groups across the country are turning their attention to developing engineered T cells for other cancers, including solid tumors like pancreatic and brain cancers. The stage has now been set for greater progress, Dr. Lee believes. NCI investigators, for example, “now have a platform to plug and play better CARs into that system, without a lot of additional R&D time,” he continued. “Everything else should now come more rapidly.” Updated: October 16, 2014 http://www.cancer.gov/about-cancer/treatment/research/car-t-cells

在看到病友一次次化放療無法阻止癌細胞擴散 當一線藥二線藥用盡 醫生想的不再是怎樣治癒疾病 而是怎樣讓病人不受病痛之苦 當藥廠比的是誰的藥能延長病人生命3個月 當標靶藥一個月要價是20萬至80萬 病人狀況越來越差 你不覺得那裡出錯了? 醫生沒有錯 醫生遵照著現行的醫療SOP 照顧病人 醫生盡力了 癌細胞是生命體 是很難趕盡殺絕的 但是癌細胞有個天敵 就是人的免疫系統 但是如果醫生治療的重點放 怎樣引起 病人(抗癌症)免疫反應 怎樣讓(抗癌症)免疫反應持續下去 病人情況可能不會越來越糟 像一部份用過Anti PD1, Anti CTLA4的病人 病情穩定 甚至腫瘤奇蹟似的消失 只要能引起病人(抗癌症)免疫反應 而且能讓免疫反應持續下去 不受腫瘤干擾 控制癌細胞的數量 與癌症共存是有可能的 免疫治療不應該是只有特定醫院做的一個特定項目 免疫治療應該是癌症治療的重點

Cincia(星希亞)

David, 感謝你一直分享免疫相關的消息，造福了我和不少戰友。 只是Anti PD1, Anti CTLA4的反應率畢竟不高(肺癌30％)，費用又相當昂貴，這才是讓人怯步的主要原因。 如果價格親民的話大家當然很願意去嘗試，誰想要接受化療的摧殘呢？你說是吧！

2015-09-17 10:00

Studies: Merck drug Keytruda effective against 3 cancers April 19, 2015 by By Linda A. Johnson One of the hot new cancer immunotherapy drugs, Merck & Co.'s Keytruda, strongly benefited patients with melanoma, lung cancer and mesothelioma, according to three studies presented Sunday at the American Association for Cancer Research conference in Philadelphia. One study, comparing Keytruda to Bristol-Myers Squibb Co.'s Yervoy, could give Merck a temporary advantage as the rivals battle for market supremacy and billions of dollars in annual sales from this new generation of drugs, which help the immune system destroy cancer cells. While research continues, the pace is quickening and big improvements in patient care regimens are likely fairly soon. Here's a look at the studies: MELANOMA: Merck ran the first head-to-head comparison of two approved "immune checkpoint inhibitors," its Keytruda and Yervoy, as initial therapy for patients with advanced melanoma. Of 834 participants, one-third each got Keytruda every two weeks, Keytruda every three weeks or Yervoy every three weeks. KEY FINDINGS: Confirming partial results disclosed previously, compared to Yervoy, Keytruda boosted survival without cancer worsening by 42 percent after 6 months and boosted overall survival more than 30 percent after a year. About 33 percent of patients on Keytruda responded, meaning their tumors shrank or disappeared, versus 12 percent getting Yervoy. Serious side effects occurred a bit sooner and more commonly in the Yervoy group. ANALYSIS: Dr. Michael Postow, a melanoma and immunotherapeutics specialist at Memorial Sloan-Kettering Cancer Center in New York, said Keytruda was clearly better. "I don't think there's much debate," Postow said, adding doctors expect "this survival benefit will be continued over the long haul." Longer follow-up of patients is needed to confirm that, he stressed. Some Yervoy studies have followed patients for five years, finding the Bristol-Myers drug, combined with standard chemotherapy, increased survival about 18 percent over chemotherapy alone. THE RIVALRY: Melanoma is the deadliest skin cancer, each year killing about 10,000 Americans and striking about 73,000. Yervoy, from a class of immunotherapy drugs called CTLA-4 inhibitors, is approved as initial treatment for advanced melanoma. Keytruda, from the PD-1 inhibitors class, is approved as second-line treatment, for use after Yervoy or another drug. Based on these results, Merck will seek FDA approval of Keytruda as initial therapy. Postow said the study shows PD-1 inhibitors should be an initial treatment. Keytruda costs $12,500 per month, and Yervoy about $11,000. LUNG CANCER: In an early-stage study, Merck tested Keytruda in patients with advanced non-small cell lung cancer, on Sunday reporting results for all 495 patients for the first time. KEY RESULTS: On average, patients survived for 12 months, including nearly 4 months without the cancer worsening, and 20 percent responded, meaning their tumors shrank or disappeared. Among the subset of patients who had a protein called PD-L1 on at least half their tumor cells, results were stronger because Keytruda targets PD-L1. On average 45 percent responded, they survived more than six months without tumors worsening, and they're living long enough that average overall survival hasn't been reached yet. There was no comparison group getting a different treatment or placebo. ANALYSIS: Dr. Hossein Borghaei, a lung cancer and mesothelioma specialist at Fox Chase Cancer Center in Philadelphia, called the results "great news." He noted it's important to find "patients that have the best chance of responding to a drug," to help them—and to spare others the side effects and expense of a treatment less likely to work. Still, he noted even in patients with PD-L1 on fewer tumor cells, Keytruda extended survival about as much as standard chemotherapy. THE RIVALRY: This is a much bigger market than melanoma, so more money is at stake. Non-small cell lung cancer causes about 85 percent of lung cancer, killing about 158,000 Americans and striking about 221,000 each year. On Sunday, Merck said it applied to the FDA for Keytruda's approval in this use. Bristol-Myers already has run four non-small cell lung cancer studies of its own PD-L1 inhibitor, Opdivo. Opdivo costs $12,500 per month. MESOTHELIOMA: Merck for the first time reported results of Keytruda treatment for mesothelioma, a rare but tough-to-treat cancer caused by asbestos exposure that mainly affects the lungs. KEY RESULTS: In a study of 25 patients not helped by chemotherapy—a group for whom there's no approved second-line treatment—after 5 ½ months' treatment on average, 76 percent were helped. The patients all had tumors with the PD-L1 protein. Altogether, 28 percent had tumors shrink and 48 percent had tumors stop growing, though 10 patients were still taking the drug and two haven't been assessed yet. ANALYSIS: Normally, only 10 percent of mesothelioma patients who have relapsed after initial treatment respond to a second type of chemotherapy. "For an early-stage investigation into this terrible disease, it's very encouraging to have the kind of results that the investigators are reporting," said Fox Chase's Borghaei, adding that Keytruda's side effects were more tolerable than those of chemotherapy. http://medicalxpress.com/news/2015-04-merck-drug-keytruda-effective-cancers.html

Keytruda showing remarkable results in the fight against lung cancer UNDATED (WJRT) - (07/24/2015) - More than 200,000 people will be diagnosed with lung cancer this year, and almost 160,000 people with the disease will die from it. The good news is a new drug may be a game-changer. A new drug called Keytruda is showing incredible results in treating lung cancer, and has doctors more hopeful than ever in the fight to find a cure. "It truly is a transformative treatment," said Dr. Amita Patnaik, MD, the START Center associate director of clinical research. Those are not words many doctors would use lightly, but a clinical trial for treating lung cancer with Keytruda has shown remarkable results. Abelardo Torres has gone from being wheelchair-bound and on oxygen full time to an almost full recovery. Before the trial began, doctors weren't sure how things would go, but a year and a half later, treated with Keytruda, the tumors on his lungs and liver are virtually gone. Here's how Keytruda works: Cancer suppresses the immune system. Keytruda blocks communication between cancer cells and certain proteins, allowing the immune system to kick in. "This allows for our bodies to essentially mount natural anti-tumor immunity against cancer," Patnaik said. Scans of Torres' lungs show on the left, the tumor obscures the lung, on the right, after Keytruda, the lung is clear - the tumor is gone. "He's had about a 97 percent reduction in the extent of his tumor, so, the future for him looks very optimistic," Patnaik said. Taking Torres from near death to hopeful and giving doctors a new tool to fight lung cancer. "It truly is something that will change the way we practice and think about cancer," Patnaik said. The FDA has assigned a priority review designation to Keytruda as a treatment for patients with advanced non-small cell lung cancer. A final decision is expected in October. Last year, the FDA approved the use of Keytruda for treating melanoma, and data suggests it could also be used for treating triple negative breast cancer, bladder and kidney cancer. Tests on these cancers are currently underway. http://www.abc12.com/news/healthsource/headlines/Keytruda-showing-remarkable-results-in-the-fight-against-lung-cancer-318486771.html?device=phone&c=y

我之前讀到的報告 anti pd1治療大腸癌反應率在20%左右 剛好基因修復缺陷病人發生率為15% 至20%左右 Merck這份6月在ASCO發表的研究 確定基因修復(MMR)缺陷 可以用來做 anti pd1治療是否有效的genomic marker 大腸癌病人如果癌症起因於基因修復(MMR)缺陷 使用Keytruda 反應率(ORR)高達62% 疾病控制率(DCR)高達92% 但若是沒有此缺陷 反應率是0% 疾病控制率(DCR)為16% 48位臨床實驗大腸癌病人 每位都接受過多次化放療 其中13位有基因修復缺陷 在用Keytruda 治療後 8位腫瘤縮小 反應率為62% 其他25位沒有基因修復缺陷的病人 沒有一位有反應 反應率為0% in 48 evaluable, heavily pre-treated patients with advanced colorectal cancer and other solid tumors. In the colorectal cancer group with MMR-deficient tumors, an objective response rate (ORR) of 62 percent was observed (n=8/13). In contrast, no responses were observed in the colorectal cancer group with MMR-proficient tumors (n=0/25). 醫學的Overall Response Rate (ORR) 我翻譯為反應率 是有嚴謹定義的 ORR是指腫瘤有縮小的比率 還有一群人有免疫反應 但是因為種種原因 (像是基因突變數量 見下文) 免疫反應不足以讓腫瘤縮小 但是病人病情穩定 病情沒有繼續惡化 醫學用 disease control rate (DCR) 來區別 Keytruda 在有基因修補缺陷的大腸癌病人ORR是62% DCR 是92% Keytruda 在沒有基因修補缺陷的大腸癌病人ORR是0% DCR 是16% In the group with MMR-deficient colorectal cancer, the ORR was 62 percent and the disease control rate (DCR) was 92 percent. No responses were observed in the colorectal cancer group with MMR-proficient tumors and the DCR was 16 percent. ORR 62% DCR 92%是讓人驚喜的數字 相信是有基因修復(MMR)缺陷的病友的福音 如果你的醫師太忙還沒注意到這消息 底下這網頁是ASCO的官網 ASCO 2015: Mismatch Repair Deficiency Predicts Response to Pembrolizumab Among Patients With Colorectal and Other Cancers http://www.ascopost.com/ViewNews.aspx?nid=27670 我不是在談未來 anti pd1藥已經有了 MMR缺陷測試是很普遍的測試 大腸癌病友應該都要測驗一下有沒有MMR缺陷 MMR 缺陷的病人 平均有1782個突變 沒有MMR 缺陷的病人平均有73個突變 越多突變免疫系統越容易辨識癌細胞 免疫反應也越大 Keytruda 效果也越明顯 In this study, mismatch repair–deficient tumors had an average of 1,782 mutations, compared to 73 mutations in mismatch repair–proficient tumors. Higher numbers of mutations were linked to better response to pembrolizumab.

Cincia(星希亞)

感謝David分享的實用資訊，希望大腸癌的朋友可以讀到。

2015-09-24 18:07

Imunotherapy update for NSCLC (not squamous cell) Posted on April 20, 2015 by admin On April 17 it was announced that a large study of Bristol-Myers Squibb Co’s Opdivo treatment has been halted after proving the drug is effective against the most common form of lung cancer, non-small cell lung cancer (NSCLC). When a similar thing happened in January 2015, it took about two months for the FDA to grant approval for OPdivo to be sold for squamous cell lung cancer. Merck announced on April 19 it has filed for U.S. Food and Drug Administration approval of its similar imunotherapy drug Keytruda as a treatment for patients with NSCLC whose disease has worsened despite previous treatment. Merck’s Phase 1 study of 495 patients with NSCLC found that 45% of patients with levels over 49% of PD-L1 responded to Keytruda, compared with 16.5 percent of patients with PD-L1 levels of 1% to 49%. http://www.reuters.com/article/2015/04/19/us-merck-co-cancer-lung-idUSKBN0NA0JS20150419

Cincia(星希亞)

thank for sharing, David. 我下次回診問問醫師台大是否可以先檢驗" PD-L1 levels"，感謝！

2015-09-24 18:24

Alectinib approval by the FDA is expected by the end of October. Back in May 14, 2015, Roche announced its plans to file a new drug application for Alectinib in 2015. http://www.roche.com/media/store/releases/med-cor-2015-05-14.htm According to several postings on Inspire.com by patients, Alectinib approval by the FDA is expected by the end of October. https://www.inspire.com/groups/american-lung-association-lung-cancer-survivors/discussion/anyone-on-pf-02341066-crizotinib-alk-gene-part-3/?reply_sort=desc

ALK Inhibitors News. http://alkinhibitors.com/

Cincia(星希亞)

thanks~

2015-09-24 18:28

Comparison of 3 ALK inhibitors’ phase 2 trials Posted on June 1, 2015 by admin All of these results are based on 5 phase 2 trials. However the conditions of each trial may differ in important ways. For example, it is my understanding that the trial for brigatinib was limited to healthier patients while the trial for ceritinib included almost every available patient. There may be other differences as well. Definitions for the acronyms are at the bottom. While the data is similar to previously posted data, this data is more complete and up to date. They are also easier to compare. Ceritinib 2 trials, one all Crizotinib resistant, the other all ALK inhibitor naive Crizotinib resistant patients 140 ORR 38.6% DCR 77.1% CNS ORR 33% PFS 5.7 months DOR 9.7 months ALK inhibitor naive patients patients 124 ORR 63.7% DCR 89.5% CNS ORR 58% PFS 11.1 months DOR 9.3 months CNS metastases “the ORR, DOR, and PFS for patients with brain metastases at baseline were similar with those reported for the overall population of these studies Alectinib 2 studies both all Crizotinib resistant patients . global U.S. & Canada patients 138 87 ORR 50.0%. 47.8% DCR 79.5% 79.7% CNS ORR 57.1%. 68.8% PFS 8.9 months 6.3 months DOR 11.2 months 7.5 months Brigatinib One trial of 78 patients Only healthier patients Last patient enrolled July 2014 Median time on treatment = 12.6 months Crizotinib resistant patients patients 70 ORR 71% PFS 13.4 months DOR 9.3 months ALK inhibitor naive patients patients 8 ORR 100% PFS not available yet DOR not available yet All patients with CNS metastases ORR 53% of measurable CNS PFS 15.6 months CNS = central nervous system = the brain and spine CNS ORR = objective response of tumors in CNS DCR = disease control rate = ORR plus stable patients DOR = duration of response = time from documentation of tumor response to disease progression ORR = objective response rate = average shrinkage of 30% on longest dimensions of measured tumors in a CT or MRI scan PFS = progression free survival = Time from randomization or study enrollment until disease progression or death

人能生存在世界上不被微生物腐食 是因為人有免疫系統 人有37萬兆細胞 每天有5萬個細胞要更新 每天都會有細胞分裂時出錯 出錯的細胞卻不是那麼容易變成癌症 是因為人有免疫系統的監視 人會得癌症 是因為腫瘤能夠利用免疫系統壓制免疫反應 西醫發明一堆化學毒藥 放射線來治病 同時也傷害病人的身體 也傷害病人的免疫系統 喚醒對癌症的免疫反應 並讓免疫反應長久持續下去 也許免疫治療反應率也許沒有標靶化療來的好 但是** 起動身體抗癌的機制 是人能不能存活下去的關鍵 ** 妳的醫師也是人 不是神 醫師沒有所有病的答案 特別是難治的癌症

Cincia(星希亞)

我現在的打算是先繼續吃標靶，Anti-PD1的藥物台灣可以專案購買，但因為反應率差醫師也不是很推薦，我目前就邊觀察邊收集相關資訊囉！

2015-09-24 17:24

許多神的巧妙設計 不是物競天擇就可以解釋的 推薦這本"免疫兵團 抗病大作戰" 是我免疫起蒙的書 見證神的巧妙設計 推薦給大家 　　如果病毒、細菌是入侵人體的恐怖份子，那麼免疫系統就是對抗這群外敵的大軍。免疫系統除了攸關我們的身體如何抵抗疾病，此外舉凡流感大流行、令人難受的過敏、愛滋病如何危害人體、到底要不要注射疫苗、器官移植能不能成功、癌症如何治療，全都涉及免疫系統的運作。 　　從辨識敵我、排斥異族、發動攻勢，到劫後餘生，這一連串的過程中，我們見識到免疫兵團不僅武器精良，更是戰略高手；來自胸腺及骨髓所製造的各式淋巴細胞，在全身各處布下天羅地網，隨時準備迎戰侵略者。 　　這支免疫兵團，包括了龐大免疫家族的各個支系：T細胞（狙擊手）、B細胞（機動兵工廠）、巨噬細胞及顆粒白血球（圍剿部隊）、抗原呈現細胞（斥候營）等。它們各司所長又彼此合作，藉由各種細胞介素（傳令兵）連絡訊息，靠著抗體與補體（武器）共同打擊外來者，竭心戮力的護衛我們的身體。 　　我們平日若能保持飲食好、睡眠佳、常運動、好心情，珍惜、善待這群優異的精兵，才能擁有健全的免疫力，享受美好的生活！

Thanks for the introduction,David

1) 癌症是突變極快的生命體 藥物根本不可能永遠控制癌症 2) 癌症突變極快 但是免疫系統能夠偵測新的突變而產生新的免疫反應 3) 只要免疫反應能長久持續下去 癌症最終會被免疫系統控制的 這是抗癌的秘密 你的主治醫師不會告訴你的抗癌的方法

Cincia(星希亞)

我真的也很期待免疫治療，希望有朝一日可以擺脫癌症，哈哈～

2015-09-25 18:12

To David, 其實，這不是抗癌的秘密，主治醫師也不是不知道。 我上週去旁聽癌症醫學會的免疫腫瘤菁英論壇，出席的多半是這一個領域的專家。 其實，他們都懂喔~~ 而且簡報的內容，幾乎跟美國同步了。 特別是上午場，因為有請外國葯廠的專家，全程是以英文進行的。 所以，台灣的醫生，其實還是很厲害的，包括星希亞的廖醫師也是。 他們也才剛去美國，開完肺癌大會回來哩!

Hi, Gary, 好久不見 上文我是為幾位重症病友寫的 文中的主治醫師沒有特別指誰 大多數病友的主治醫師都認為免疫效果差 效果短 治療方式以化放療標靶為主 癌症還是繼續漫延 病友也很無助 主治認為免疫效果差 效果短 病友也只能相信醫師 相信藥物 即使這些治療的目的只是延長病人的生命而已 讓病人少些痛苦 神的恩惠讓我理解化放療不是抗癌唯一的路 有另一條抗癌的路在人瓜瓜落地前 就已經為人準備好了

台灣是因為對新藥的開放流程緩慢，並不是沒有pd-1相關的免疫藥物，醫師本來就要跟病人說明每種治療的成效是多少，病人還是可以自己選擇治療方式，據我所知，台灣已經有些人轉案申請pd-1相關的免疫治療。

Cincia(星希亞)

感謝Andrew兄說明。:)

2015-09-28 20:07

謝謝Andrew指正 病人懂的不多 還是聽醫生的意見 醫生治病通常是看效果 但是如果只注重短期效果 也許會讓病人走上不歸路 化療標靶很有效 免疫治療效果慢效果差 那麼醫生病人大多會選擇有效的標靶化療 等到病人自己察覺這些藥品沒辦法阻止癌症蔓延 才會想試試免疫 但那時身體已經很差 免疫效果慢 可能又走回化療或走入安寧病房 醫生還是主導病人治療的結果的人 醫生的意見左右病人治療的結果

腫瘤如何經由CTLA-4抑制免疫反應 我的瞭解是在腫瘤微環境有許多抑制免疫反應的樹突細胞和巨嗜細胞 腫瘤經由抑制免疫反應的樹突細胞和巨嗜細胞間接阻礙T細胞活化 細節我就不說了 大家只要知道T細胞細胞膜上有兩個開關可以讓活化的T細胞失去攻擊力 一個開關叫做CTLA-4另一個開關叫做 PD1 腫瘤就是透過這兩個開關來抑制免疫反應的 因為各種癌症突變量不一 治療黑色素瘤的效果不一定能適用於各型癌症上 要有實驗數據才能確定

Hi David 一樣都是用激起人體免疫系統產生的自癒力，我想知道您對"葛森療法"的看法如何？ 認識了一些台灣人是完全沒作化療或吃標靶（國外的成功案例更多，因為國外的自然療法較為興盛），完全嚴格的執行2-3年(當然這兩三年很辛苦)，便恢復至比一般人還健康的狀態。 我自己是只有取其精神，參考內容只選擇一部分來施行，得到的幫助就很大了（一些良性腫瘤長久以來聞風不動，但我只做了半年，就縮小了），所以完全可以想像那些用完整葛森療法來治療的癌症病人，最後抗癌成功並不是奇蹟，而是有理可尋，也知道某些西醫師有開始接觸，或甚至到國外受訓。（是哪些醫生我不方便直接公開，怕他們任職的醫院會找他們麻煩。）

anti PD1和anti CTLA4藥物要有效的前提是病人已經對癌症已有免疫反應 所謂已有免疫反應是指病人已經有抗癌症的 毒殺型T細胞 anti PD1藥物 目的是阻礙癌症透過PD1抑制T細胞攻擊 校 消滅免疫反應 癌細胞在受到毒殺型T細胞攻擊 時 在死亡前 會釋放出細胞間傳遞訊息的介白素(interleukin) 讓附近的癌細胞知道它受到正在遭受T細胞攻擊 附近的癌細胞收到信號 會武裝自己 在細胞膜上生出PDL1 PDL1能結合T細胞PD1讓T細胞 失去攻擊力 同時也讓T細胞自然死亡(PD1 = programmed Death 1) 如果沒有anti PD1藥物 的幫助 腫瘤最後會成功消滅大部份T細胞 到那時又要再做一次免疫療法 anti PD1藥物 讓腫瘤無法抵抗T細胞攻擊 讓T細胞 變成不死的Terminator 這是為什麼握我建議所有做免疫治療的朋友 一定要加上anti PD1藥物 效果才會長久 讓T細胞存活下去 才有機會完全清理身體裡的癌細胞 anti PD1藥物 雖然貴但是只要打7次 者左右 效果長久 不像同樣很貴的標靶藥 幾天不吃就無效 ** 癌症是突變極快的生命體 藥物根本不可能永遠控制癌症 ** 癌症突變極快 但是免疫系統能夠偵測新的突變而產生新的免疫反應 ** 只要免疫反應能長久持續下去 癌症最終會被免疫系統控制的 anti PD1藥物是目前少數能讓免疫反應能長久持續下去的方法

JESS 蔬果 有許多植化素有幫助身體抵制自由機傷害 預防癌症發生 女生一日7份蔬果 男生一日9份蔬果 可以維持身體正常運作 加上充足的睡眠和有氧運動 讓免疫系統能正常運作 在治療過程也有較多的本錢與癌症搏鬥 Cincia 就是個模範生 葛森療法應該比較正確的說是葛森生機飲食發法 多吃蔬果我相信是有至助於抗癌的 但是效果如何我不清楚 多吃蔬果種總是好事 我個人還是習慣食物煮熟吃 一日至少吃到7份蔬果 我爸媽不喜歡燒飯 天天買外面餐廳食物吃 現在都得癌症 我相信與飲食有密切關係

卡斯柏在千葉大學所做的是在體外培養T細胞 再回輸病人體內 腫瘤起初有縮小 但是後來腫瘤經由PD1成功的抑制T細胞攻擊 讓打入的T細胞自然死亡 卡斯柏在久留米大學所做的是樹突細胞療法 樹突細胞是免疫系統的哨兵 是抗原承現細胞 把癌細胞的抗原(胜肽) 帶給T細胞B細胞辨識 激起免疫反應 因此先做樹突細胞療法再打anti PD1可以得到持久的免疫反應 此外如果病人免疫系統正常 不一定要做樹突細胞或T細胞療法 直接對腫瘤放療可以破壞腫瘤微環境 消弱腫瘤抑制免疫反應的力量 (腫瘤越大 抑制免疫反應的力量越強) 大量死亡的癌細胞 內部流出的不正常的蛋白質 會被巨嗜細胞樹突細胞吞噬 把癌細胞的抗原帶給T細胞B細胞辨識 激起免疫反應 花醫生有建議用電腦刀(放療一種) 卡斯柏因為腫瘤包覆動脈 有動脈纖維化危險 無法做放療 其他朋友若有多處擴散 針對一處放療即可引起自發性免疫反應 癌細胞通常有數十種到數百種突變 突變越多 免疫反應越多 活化的T細胞 種類越多 越容易辨識攻擊腫瘤 治療效果越好 先做放療 再做anti PD1治療效果會更好

to David ＆ Cincia 其實葛森療法的生機飲食只是一部分而已，除了有規定劑量的超大量蔬果汁之外跟有機咖啡灌腸，它牽扯到蠻多分子矯正的輔助應用(有很多營養補充劑要服用，比如維生素C、D、胰酵素、菸酸、B12、硒等等等)，每個月的服用劑量都要跟著血液報告來作調整。 因為我自己也是學理工的，過去學到的領域也有相關。它的原理有說服我，再加上這療法的創始人葛森自己就是名西醫（順帶一提，他用這療法的前身醫治了史懷哲），所以很多操作是架構在藥理上。日本有個星野醫師就是用葛森療法治好了他復發的大腸癌還出了書，台灣有翻譯。 就算不想當成正規療法來治療，也很建議癌症病人在一般西醫療法治療後、有慢性病的、或是一般健康人，參考其中精神拿來當保養身體的方式（為什麼說用參考"精神"就好，是因為若要完全100%施行這療法真的很嚴謹也很累人...)，來增強自身的免疫、自癒力。 如果有興趣的話，可以多查一些資料，盡量國內外的文章都查（因為中文的話，很多是錯誤的資訊，且不夠完整），深入研究之後覺得完全可以了解為什麼有效。（當然打壓的文章也不少。） 因為知道Cincia的blog很多網友都有在追蹤，所以才介紹比較多，希望Cincia多多見諒，也希望能拋磚引玉，讓每個人在結束治療之後，能夠用一些對的方式保養身體，不會再害怕復發。 PS. 台灣人有個叫Jesse的男生（不是我，我不認識他本人，而且我是女的..），他用葛森治療黑色素瘤的過程的演講(死亡率最高也發展最快的皮膚癌)，有發表到youtube，可以在youtube搜尋 "Jesse 棄手術,採自然療法,戰勝病魔"，影片2個小時。

Cincia(星希亞)

感謝Jess的分享，晚上回家來看看。:)

2015-10-01 12:46

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台灣臨床試驗 http://www1.cde.org.tw/ct_taiwan/archive.html 以pembrolizumab (keytruda) 收尋有3項實驗: 1) 未曾接受過治療且PD-L1陽性的晚期或轉移性非小細胞肺癌 2) 復發性或轉移性頭頸部鱗狀細胞癌 3) 晚期胃部或胃食道交界處腺癌 以 nivolumab (opdivo) 收尋有4項實驗: 1) 頭頸部鱗狀細胞癌 2) 腎細胞癌 3) 晚期肝細胞癌 4) 黑色素瘤

JESS 我爸也是黑色素瘤 而且是長在鼻腔內 葛森療法有一定的幫助 輔助傳統治療 但是我不建議放棄傳統治療 因為癌症不治療會變的很可怕

to David 葛森療法本身就是一整套完整"治療"的療法，並不是一定要採取一般傳統西醫體制的療法才算積極治療，真的很建議先去深入了解一下完整系統，而不要把它當成吃吃蔬菜喝喝果汁所以身體才改善的"養生"的生機飲食而已＠＠ 養生跟可以治療癌症的自然療法是不一樣的。 大部分的癌症，葛森療法可以完全不經手術或放療便能完全治癒，但碰到部分癌症或是腫瘤長的地方較棘手(比如腦部)，在腫瘤過大時，也會推薦病人要先動手術，但化療幾乎都不讓病人作（化療跟葛森療法基本上是互斥的）。同時葛森也對腦癌/腦部腫瘤效果比較差，如果是腦癌病患又不想要用傳統治療或是已經被宣告末期，可以去位於New York 的Dr. Gonzalez，他用改良式的葛森療法加入自己的許多元素，成功治好很多癌症病人，葛森官方在遇到腦癌或胰臟癌病人時，常會轉介病人至這位醫師。這位美國醫生很會治腦癌，他的成功機率蠻高，葛森官方也都是向腦癌病人介紹這位醫生。診所資料可參考 www。burzynskiclinic。com 有時間的話建議可以去看一下我上述留言的youtube「Jesse 棄手術,採自然療法,戰勝病魔」，這影片因為剛好這位黑色素瘤病人，也是理工背景的，所以他用葛森治療康復後，找了非常多的醫學資料來講解（有少部分要有點生物背景、或一直都有在注意相關研究的會比較可以看得懂），雖然對於療法本身沒有介紹到完全詳盡，但因為剛好跟你父親是同癌型，你看了應該會比較能代入、理解。 我自己也是因為之前癌症指數有異常，和身體各器官突然跑出很多良性腫瘤/囊腫，在台大和其他醫院給各科最權威的醫師們作過各項的血液檢查、MRI、切片都查不出原因跟病灶，最後都只得到了一句等你再惡化(腫瘤超過X公分)我們再來看該怎麼辦。也是因為這契機讓我發現現在的傳統醫學體制根本沒辦法完全預防、在病灶微小的時候就能找出原因加以治療，大部分檢查到真的是惡性腫瘤時，都已經是好久之後的事了。因此才開始對很多自然療法、替代療法、分子矯正學、免疫學、營養學有更深入的研究跟了解，自然療法有些只能當作輔助，有些甚至對重症、癌症是幾乎無效只著重在心理層面，少部份如葛森療法便是對"治療"癌症有極大的效果。 PS. 我雖然打了很多，但不代表我覺得傳統西醫治療就完全不好（除了化療。我高中同學有1/4都是醫生，當家人碰到癌症時，沒有一個同學同意讓他們的家人去作化療..因為她們知道化療對人體的影響力有多嚴重），或是葛森療法就一定是最好什麼都能治療。我認為要作什麼治療方式都是自己的選擇，但在選擇之前，可以多"深入"了解不同的治療方式，這樣在做選擇的時候，才能找到最適合自己的。

上面的是我，暱稱忘記打了:P

謝謝JESS 我會多瞭解葛森療法的

真的佷感谢星希亚的版面，还有许多人的分享。 我不是医学院生，但的确从你们得了不少抗癌知识。 谢谢你David， 无数次分享免疫治療，虽然无法记牢那些医学名称，至少你一再分享的同时，新的癌友和家属上了一堂课，而我们也再做了一次的免疫治療复习.Thanks ! 佷多时候，最后的选择都在病人手上。病人得到的资讯和实例的分享会提升判断力和智慧来和主治医师决定以后的疗程。 再次谢谢你们大家的资讯和分享。 愿神的恩典与你们同在。

NSCLC anti PD1免疫藥品除了Opdivo外 又多了新選擇 FDA 於3天前批准 Keytruda 治療4期NSCLC http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm465650.htm 參與實驗的病人都有PDL1 表象 41% (ORR) 病人腫瘤縮小 84% (DCR) 病人病情穩定無惡化

更正: 刪除這句”84% (DCR) 病人病情穩定無惡化” 我誤會原文意思 原文沒有DCR資料

癌細胞基因突變數量決定anti PD1藥品反應率 https://www.mskcc.org/blog/why-new-immunotherapy-lung-works-only-some-people

Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer - Science Magazine http://www.sciencemag.org/content/348/6230/124.full

上篇 Science Magazine 的報導揭開下列問題的答案: 為什麼 有些病人對anti PD1有反應 有些病人對anti PD1沒有反應? 腫瘤基因突變的數量才是決定anti PD1藥品的反應率 基因突變的數量越多 免疫系統越容易辨識攻擊癌細胞 anti PD1藥品的反應率越高 這點在大腸癌特別明顯 Keytruda 用於有MMR基因修補缺陷的大腸癌病人 反應率ORR是62% Keytruda 用於沒有MMR基因修補缺陷的大腸癌病人 反應率ORR是0% 原因是有MMR基因修補缺陷的大腸癌病人 通常以有上千種基因突變 沒有MMR基因修補缺陷的大腸癌病人通常有數十種基因突變 腫瘤有PDL1表象不是決定anti PD1藥品的反應率的決定因素 臨床實驗發現 1) 有些病人腫瘤有PDL1表象 卻對anti PD1沒有反應 2) 有些病人腫瘤沒有PDL1表象 卻對anti PD1有反應 雖然如此PDL1測試還是有其價值 腫瘤有PDL1表象的NSCLC病人對anti PD1藥品的反應率是41% 腫瘤缺乏PDL1表象的NSCLC病人對anti PD1藥品的反應率是16%

Cincia(星希亞)

感謝David整理的資料，非常受用。

2015-10-15 10:51

Science Magazine editor's summary More mutations predict better efficacy Despite the remarkable success of cancer immunotherapies, many patients do not respond to treatment. Rizvi et al. studied the tumors of patients with non–small-cell lung cancer undergoing immunotherapy. In two independent cohorts, treatment efficacy was associated with a higher number of mutations in the tumors. In one patient, a tumor-specific T cell response paralleled tumor regression.

免疫系統的驚人真相 http://m.life.com.tw/?app=view&no=344569 本文作者為陳昭妃博士，著名美國華裔科學家，「營養免疫學」的創始人。1997年，她榮獲「美國十大傑出青年獎」，是59年來首位獲此殊榮的華人，也是獲此獎項唯一的女性。 尋找疾病的真正病因 1928年，抗生素誕生了，我們向世人宣稱能夠控制所有感染性的疾病。但我們沒有想到，抗生素會給人類帶來一系列疾病。過去，醫學人員認為是病毒、細菌製造了疾病。但是現代研究發現，有10％的病人感染依波拉病毒，但並沒有死於這種病，原因在於他們身體裡有抵抗力；同樣，有30％的肺結核病人並沒有出現嚴重的症狀，而且還可以自行恢復。科學家認識到，是否患肺結核取決於自身免疫系統；艾滋病，有5％的人感染後5年甚至10年也不發病。在各種宣傳資料上，都提到HIV病毒，但我沒有在任何的醫學報告上看到實驗證明是HIV病毒製造的艾滋病。我們所看到的實驗報告上是這樣寫的：所有的艾滋病人體內都有HIV病毒的存在。這兩種意思是完全不同的。 我舉個通俗的例子：這裡有一堆垃圾，有垃圾的地方自然會有蒼蠅，但這並不表示說，是蒼蠅製造了垃圾。而以前我們認為蒼蠅就是病因，然後趕快發明一種化學武器出來，將蒼蠅消滅掉；殺死蒼蠅以後，垃圾裡又跑出蚊子，我們又趕快把蚊子消滅掉；之後，垃圾裡又跑出蟑螂，殺死蟑螂，垃圾裡又會跑出老鼠，總而言之，是永無止境的。因為真正的原因並不在於蒼蠅、蚊子，而在於這堆垃圾。得到健康的關鍵是要把垃圾消滅掉。所以現在的科學家開始研究基礎免疫學。 免疫系統涉及不計其數的細胞、特殊物質及器官之間的高度紛繁複雜的相互作用。它隨時處於戰備狀態，能夠預防疾病，並能明確地知道應該什麼時候、在哪裡、怎樣採取適當行動摧毀入侵的物質，而不會傷害人體其他細胞。任何藥物也無法取代人體內與生俱來的、兼具防禦和修復雙重功能的免疫系統。 認識我們的免疫系統 免疫系統最重要的功能是清除體內各種垃圾。舉個例子，紅細胞的壽命只有120天，之後，就會死去變成垃圾，這就需要自身的免疫系統把它清除。 第二大功能，就是抵禦疾病。科學家認為，免疫功能是獲得健康的一把鑰匙。當垃圾裡產生蚊子時，蚊子就會到處飛，但是如果沒有垃圾的話，它是無法繁殖下去的。換言之，病毒、細菌或骯髒的東西侵入人體，如果人的抵抗能力強，它就沒有辦法繁殖下去。 我曾受邀於美國最大的一個醫學研究機構。在和科學家們一起討論的時候，得到一個統一的結論，99％的疾病都和免疫系統失調有關。當然有的疾病和免疫系統疾病無關，如基因、遺傳類的疾病。以前，我們對免疫學沒有這麼重視，一直認為還是化學藥物的作用比較強，治病效果比較明顯。有人會說，既然免疫系統這樣強，為什麼還要用化學藥品呢？事實上，免疫系統的功能本身是很強的，但正是由於化學藥品的副作用而使免疫系統的功能下降。我曾經做過10年的癌症研究，看到許多被醫生宣佈只有兩三個星期可以活的病人，過了幾年以後，又回來找我們，奇妙的是，我們居然已經發現不到任何癌細胞的存在。這種藥物無法治癒的疾病，我們的自身免疫系統卻會將其治癒，這就證明，自身的免疫力是比化學藥品要強的。 過去，我們沒有認識到化學藥品的副作用會那麼大。到了如今，美國醫學會不得不警告所有醫學人員：醫生的責任不在於開藥單，而在於其指導的職責，他有責任告訴病人藥品進入人體後，會有什麼樣的功能，會帶來什麼樣的副作用。90％的感冒是由病毒引起的，但人們往往習慣向醫生索要僅有抗菌作用的抗生素。所以美國醫學會發出通知，醫生不可以隨意給病人開抗生素，除非已做過實驗檢查，證實其感冒是由細菌引起的。醫生如果違反這一規定的話，其行醫資格可能被吊銷。 據美國醫學統計報告，美國每年有960萬人因為服用化學藥品而必須住院；每年有2.8萬人因服用一種心臟病藥而死於心臟病；每年有3300人因為吃了治關節炎的藥物而死亡（而原來人們想不出關節炎和死亡有什麼關係）；每年有16.3萬人因藥物的副作用而導致大腦記憶力衰退；有3.8萬人得了老年痴呆症；有2.8萬人因藥品而導致骨質疏鬆症。總而言之，這個統計結果還是非常保守的，有很多醫院不在調查之列，實際情況只會更為嚴重。 從微觀角度來看免疫系統，自身的免疫系統就像一個軍隊，裡面有空軍、海軍、陸軍各類軍人，一旦有敵人侵入身體，就會將其消滅掉。 在免疫系統裡幾個最重要的器官 骨髓生產各類血細胞。從骨髓裡產生的細胞，會被送到胸腺裡。 胸腺就像一個訓練營，兒童時期，沒有訓練出足夠的軍隊，所以很容易胸腺腫大。當人慢慢長大以後，訓練出一批「軍人」後，胸腺慢慢萎縮下來，但並不表示它沒有功能了。 扁桃腺也是免疫系統的一部分，不應輕意地被割掉。 脾臟裡面有很多V細胞，產生各類抗體。當人感冒或小孩注射疫苗以後，脾臟會稍微地腫大，這是很自然的現象，它是在拚命地生成武器來抵禦外來的敵人。 淋巴就像一個過濾器，將所有的敵人集中起來，然後免疫細胞就會將其消滅。所以，感冒時淋巴摸起來會硬硬的，這說明身體裡的免疫系統正在打仗，感冒過後，就會自然而然軟下去了。 盲腸是免疫系統很重要的一部分，抵抗下腹部各種各樣的感染。 血液裡的白細胞都是免疫細胞。白細胞分為兩大類，第一類稱為T細胞，另一類稱為V細胞。V細胞功能在於產生各種抗體，而這相當於軍隊裡的武器、子彈。有戰爭，就會有死亡的軍人，就必須將死亡的細胞清除。這就需要依賴我們胸腺訓練出來的一批細胞。 對「死亡之吻」的研究 我在研究癌症的過程中，並沒有發現任何的藥物、化療、電療能夠真正治療癌症。化療只是賭博，成功率在1％左右，用作化療的藥品無法識別哪一個細胞是癌細胞，哪一個細胞是身體裡的好細胞。所以我最終放棄研究這些化學藥品，而轉向研究免疫細胞中一個被稱為「死亡之吻」的細胞。這個細胞一接觸癌細胞，癌細胞就破裂了，被消滅掉了。 免疫學是一門非常年輕的科學，是有待研究的科學。沒有任何一種化學藥物能夠代替免疫系統，也不可以用化學藥物來刺激免疫系統，否則可能會造成各種副作用。既然不能用化學藥品來提升免疫系統，那麼只能依靠「營養」。 人體的三道防線 免疫器官對人體至關重要 免疫學是一門新學科。在美國，我是第一批的免疫學家，在這之前根本就沒有人學習免疫學，對免疫的瞭解僅限於各種疫苗而已。但如今免疫學已經變成一門很受重視的學科了。舉幾個例子，在1960年以前，我們甚至不知道胸腺的功能，認為胸腺是一個沒有用的器官。而根據後來的跟蹤調查發現，所有胸腺被毀的人都得了癌症，因為他們喪失了最重要的免疫器官；現在很多人認為扁桃體沒有用，就把它割了；有些人在做手術時，順便將盲腸割掉了，認為可以預防盲腸炎。可是您知道嗎？盲腸是由免疫細胞充塞而成的，能夠抵抗各類的感染。如果有人認為可以用摘掉某些器官的方法來預防疾病的話，那麼是否可以用割掉心臟的方法來預防心臟病呢？實際上，如果您的免疫系統不工作的話，您只有24小時可以活。 營養來自於完整的食物 談到營養，每一個人對營養的定義是不一樣的。我有一位很要好的女朋友，她每天給她的兒子兩個雞蛋，兩個雞腿，兩杯牛奶，如果兒子沒有吃下這些東西，她會很著急。我問她，為什麼要給孩子吃這麼多肉類呢？她說，因為孩子身體不好，別人一感冒，他就感冒，別人一咳嗽，他就咳嗽。我對她說，肉類並不代表營養。當人們吃到很多肉類，身體裡就會產生荷爾蒙，整個免疫系統就會下降。在美國，以前小學裡有一個食品金字塔量表，它把最重要的營養劃為肉類、牛奶製品，如今，這個量表已經被禁用了。研究發現這種教導導致今天美國各種癌症、心臟病不斷地上升。 關於牛奶的問題。 牛奶和人奶是完全不一樣的蛋白質，人類只能消化50％的牛奶蛋白質，消化吸收90％的母奶蛋白質。有一部分人喝牛奶會肚子痛，喝母奶則不，因為其蛋白質不同。一隻小牛生下來以後大約90磅，而兩年以後大約成長到1000磅；人生下來是8磅，而十幾年才成長到100多磅。換言之，我們是屬於不同種類的，所需的營養也是不一樣的。牛奶裡含有很多的荷爾蒙，它可以刺激小牛快速地成長，但這種荷爾蒙到孩子身體裡面，會產生不同的效果。現在已有研究表明，牛奶會阻止小孩大腦的發育。 關於咖啡的問題。兩種咖啡，一種沒有咖啡因，一種有，喝哪一種好呢？不要多喝有咖啡因的咖啡，因為它會加速中樞神經系統的刺激，也有實驗報告表明，它會製造皺紋；但是沒有咖啡因的咖啡更不能喝，因為將咖啡因從咖啡中提取出來需要一種化學藥品，而這種藥品是致癌藥品，美國衛生局已禁止使用了。所以，問題並不在於咖啡因的好壞，而在於咖啡因是如何被提取的。同理，我們不是說維生素不好，而關鍵在於維生素是如何提取出來的。 維生素與營養的關係 芬蘭政府曾做過一個世界最大的維生素實驗，可以說是比較公正的實驗，出資4300萬美元，總共2.9萬人參與被試，長達5-8年時間。分為兩組，一組是吸菸的人，讓他們每天吃維生素A和維生素E；另外一組的人員什麼都沒有吃。過了5年、8年，吃維生素A和維生素E的這組人員死於癌症的比例要比另一組高出18％。更重要的一點，吃維生素E的人得心臟病、死於心臟病的人要高出另一組50％。當科學家聽到這個消息的時候，真是很羞愧。一直以來，所有科研工作者在小型實驗裡面得到的結論，都是維生素E可以防止血管硬化，防止心臟病，這麼大的實驗，為什麼會得出一個相反結論呢？ 美國的衛生局研究報告表明，當維生素C存在於橘子等整體時，被稱為抗氧化劑，能防止心臟病、癌症。當維生素C離開橘子後，能製造上億的自由基，相反會造成心臟病、癌症。對於這個問題，我把它看得很簡單。我認為，橘子是自然生成的，維生素C是人造的，人造的不可能比自然的要好。我們根本沒有能力創造一個橘子或蕃茄出來。蕃茄裡面含有一萬多種營養素，這些營養素是什麼我們都還搞不清楚，哪裡來的智慧和權力對大眾說，裡面最重要的是維生素呢？所以一個完整的食品才代表著真正的營養。 美國衛生局希望把所有的維生素製品列為藥品，不讓人們隨意在市場上買到。服用維生素不當會帶來很多副作用。美國有3萬多兒童，因服用維生素而出現中毒的現象。小孩吃下過量的維生素，血液裡的鐵質就會上升，就比較容易得癌症；過食維生素E會造成關節炎；過食維生素D會造成肝功能的損傷。 結論 一個人經過化療，免疫系統需要一年的時間才能恢復正常，但給他比較有營養的植物的話，免疫系統6個月以後就恢復正常了。一系列的研究報告表明，免疫系統和植物營養是分不開的。 人的健康不是一天就會得到，疾病也是一樣。要得癌症也很不容易，人體裡必須有100多種錯誤，才會產生一個癌細胞。我們的生命就像一棵小樹，需要精心地澆灌、呵護才會茁壯起來。這裡，我談三點重要的結論： 第一，營養。 完整的植物，多種類的植物，代表著營養。人如果比較喜歡吃蔬果，少吃肉類，就會比較健康。美國現在提倡素食的漢堡，就是這個道理。 第二，保持一種很平靜的心情。 因為一旦有壓力或生氣、緊張，半小時以內身體免疫功能就會下降。 第三，適當的運動和休息。 很激烈的運動對身體是絕對沒有好處的。奧林匹克的運動模式是自我犧牲的一種表現。適當地休息，免疫系統在白天會比較弱一點，晚上的時候才做修補工作。舉個例子，兩個學生一個在運動讀書，一個在睡覺，旁邊有人咳嗽，哪個有可能被感染呢？當然是那個又運動又讀書的學生。 我希望大家都能把這樣的智慧帶給自己的親戚、朋友，共同創造一個更美好，更健康的明天。

> 而轉向研究免疫細胞中一個被稱為「死亡之吻」的細胞。 The “kiss of death” 細胞就是T細胞 T細胞24小時在血液淋巴液巡邏 在辨識細胞是否正常時 會接觸受檢驗細胞表面的的蛋白質片段是否正常 遇到突變的細胞 或是被病毒入侵成為制造病毒工廠的細胞 會分泌能融解細胞膜的酵素 破壞殺死突變的細胞 可惜癌細胞知道如何抵抗T細胞的攻擊 癌細胞在死亡前 會分泌一種介白素 告知附近的癌細胞遭到T細胞攻擊 附近的癌細胞收到介白素的訊息 會在細胞表面生出PDL1 抵抗T細胞的攻擊

>白細胞分為兩大類，第一類稱為T細胞，另一類稱為V細胞。V細胞功能在於產生各種抗體 更正: B細胞功能在於產生各種抗體 腫瘤能夠作大和擴散 在於癌症能成功的 1) 蒙蔽免疫系統 (即免疫系統無法辨識癌細胞) 2) 抵抗免疫系統攻擊 (via PDL1 和調節型T細胞) Anti PD1解決了第2個問題 讓一部份病人的自然抗癌力量顯現出來 Anti PD1用於乳癌治療 有20%的病人腫瘤縮小 20%還是少數 我們希望看到的是更多病人受惠 我認為只要解決第一個問題會有更多病人受惠 癌細胞基因突變數量少的 免疫系統較難辨識 (這是為什麼腫瘤可以在5到10年默默成型 發展出抑制免疫反應的機制) 好消息只要科學家明白問題的原因 就有希望發展出解決問題的方法 譬如在澳洲正在進行的臨床實驗 把Herceptin 與anti PD1併用 Herceptin可以標記癌細胞 讓免疫系統辨識原本無法辨識的癌細胞 Anti PD1 解決腫瘤與癌細胞的武裝 讓身體自然的免疫力量展現出來

> 一個人經過化療，免疫系統需要一年的時間才能恢復正常 這個問題我之前有報告過 免疫系統在化療停止一個月就能恢復大部份功能 但很不幸的 化療對免疫系統的傷害是不可逆的 免疫反應還是會有 大多數人促進免疫反應的介素都會分泌不足 造成T細胞 數量不足 或B細胞抗體不足 你要知道化療是否傷害免疫系統 可以看看 感冒是不是比較久才會好

>感冒時淋巴摸起來會硬硬的，這說明身體裡的免疫系統正在打仗 淋巴結是T細胞B細胞(又名漿細胞)的大本營 在感染或有癌症免疫反應時 漿細胞生產大量的抗體 淋巴結會硬 若沒有感染現象 淋巴結一直硬 醫師會懷疑是癌症 淋巴結硬是免疫反應 如果淋巴結因為癌症而硬 那麼表示你對癌症有免疫反應

有位版友問我一些問題 我覺得問的很好 在此與大家分享 1.卡斯柏去久留米做的免疫細胞治療（樹突），是否有針對特定的癌較有效呢？有些戰友遠赴日本治療，但回來後效果不如預期，甚至說只是延緩一點惡化程度而已，這樣是屬正常情況嗎？ 樹突細胞療法目的是激起免疫反應 即使是同是NSCLC 每個病人癌症突變都不同 日本醫院的作法是要先驗腫瘤檢體 找到特定的腫瘤抗原(胜肽) 在病人抽血分離出樹突細胞 在實驗室培養到數十萬再打回病人體內 對於多次接受化療的病人 可以幫助病人激起對癌症的免疫反應 但是腫瘤成型後有許多抑制免疫反應的機制 這些我在Cincia 版有寫過許多 激起的免疫反應在一段時間後 還是會被腫瘤抑制 就算是T細胞療法也是同樣的受到癌症抑制 逐漸失去效果 2.PD1 PDL-1 CTLA4，您認為是三種都必須注射嗎？還是擇一即可呢？我記得您在卡斯柏部格上給的建議是應該先注射PD1然後再進行免疫細胞療法（樹突），但我發現有些戰友注射PD1後，效果仍不如預期，是因為自身免疫力已受損所以不能發揮效用的關係嗎？ 許多癌症都是以PDL1 來抵抗免疫系統Ｔ的細胞的攻擊 anti PD1 是目前少數能夠瓦解癌症抵抗免疫系統的攻擊　 破壞癌症抑制免疫反應的機制 化療會殺死大部份免疫細胞　破壞骨瓍　造成不可逆轉的傷害 化療結束　免疫系統還是會對癌症起反應　 只是促進免疫反應的各種介白素都大幅減少 對癌症免疫反應不足　沒有足夠軍隊　而效果不彰 但是癌細胞突變的數量才是真正決定anti PD1效果 以大腸癌為例　一般大腸癌只有數十種基因突變 anti PD1效果不彰　反應率（腫瘤縮小）是０％　 但是有基因修補缺陷的ＭＭＲ型大腸癌　反應率高達６０％ 原因是ＭＭＲ型大腸癌的突變上千 突變越多　免疫反應越多　免疫反應越強　anti PD1效果越好　 以你所關心的ＮＳＣＬＣ而言　抽煙者的腫瘤突變要比非抽煙者多 使用anti PD1效果會比非抽煙者好　 3.目前在台灣已經有部份醫生在使用keythuda（pd1）,但價格是屬於天價，且使用過的人效果好像都不佳，依您的見解，pd1會再降價嗎？如果只注射pd1而沒赴日做免疫細胞治療，這樣效果會打折甚或無效嗎？再次感謝您十分熱心的幫忙及回覆喔！ anti PD1效果如何還是要看腫瘤突變的數量 anti PD1治療ＮＳＣＬＣ反應率在２０％ Objective Response Rate (ORR)反應率是醫學界測量一種藥品是否有效的方式 腫瘤要縮小才算有反應 然而對許多病人和家屬只要腫瘤沒變大擴散就很高興了 所以我們在意的是Disease Control Rate (DCR) anti PD1的DCR肯定高於ＯＲＲ只是我沒有找到數據 anti PD1的作用在破壞腫瘤抑制免疫反應 幫助免疫系統抑制癌症　讓身體自然抗癌的力量眼顯現出來 你想想除了標靶　醫界還有什麼方法能控制癌症？ 一直化療　病人遲早會虛弱到連普通感冒都致命 標靶是有效　但健保不給付　標靶也會讓人付傾家蕩產 anti PD1每３週注射一次　注射８次　有效無效都不需要一直注射 我覺得只要經濟許可　值得一試 赴日做免疫細胞治療有機會　有經費　還是值得一試

A novel clinical trial: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death in men and women in the United States. Despite advances in the treatment of advanced NSCLC in the last decade, survival outcomes remain poor. Treatment benefit from cytotoxic chemotherapy has reached a plateau and further progress will depend upon identifying novel methods to target tumor cells. Harnessing the human immune system to target lung cancer could result in the development of effective treatment options against lung cancer and potentially enhance the effect of cytotoxic chemotherapy. Lung cancer cells produce a number of abnormal proteins or abnormal amounts of certain proteins found in normal lung cells. In some cancers, the abnormal protein expression may lead to an immune response against the cancer cells much in the way the immune system responds to an infection. In progressive lung cancer however, the immune system fails to identify or respond to these abnormalities and the cancer cells are not attacked or destroyed for reasons not yet fully understood. This clinical trial proposes a novel method to stimulate the immune system to recognize the abnormal components found in lung cancer cells and to stimulate an immune response that destroys or blocks the growth of the cancer. This new method of treatment helps the immune system of lung cancer patients to "identify" and target the cancerous tissue. As an example, patients who receive an organ transplant to replace a damaged kidney or heart are treated with special drugs to supress their immune response from destroying or "rejecting" the transplanted organ. This "rejection" occurs when the patient's immune system responds to differences between the cells of the transplanted organ and their own immune system by attacking the foreign tissue in the same way as it would attack infected tissue. When the differences between foreign tissues and the patient's body are even larger, perhaps like differences between organs from pigs and the immune system cells of humans, the rejection is very rapid, highly destructive and the immunity it generates is long-lasting. This is called hyperacute rejection and the medicine used to immunize patients in this protocol tries to harness this response to teach a patient's immune system to fight their lung cancer just as the body would learn to reject a transplanted organ from an animal. To do this, we have placed a mouse gene into cultured human lung cancer cell lines. These cells will express a sugar that will stimulate a strong immune response in humans. These cancer cells are irradiated to prevent any growth and then injected along with chemotherapy to patients with lung cancer. The presence of the sugar will stimulate the patient's immune system to kill the injected immunotherapy cells. As part of the process of destroying the immunotherapy cells, the patient's immune system is stimulated to identify as many differences between these cancer cells and normal human cells. This extra stimulation is thought to encourage immune responses against the lung cancer in the patient based on shared abnormalities of lung cancer immunotherapy cells and the patient's lung cancer cells. In this experimental therapy, patients are given docetaxel or injections of an immunotherapy consisting of three types of modified lung cancer cells. We propose to test these treatments in patients with lung cancer who have progressed after initial chemotherapy to demonstrate that treatment of immunotherapy results in improved tumor stabilization or response and could potentially improve the patient's overall survival. Source: https://clinicaltrials.gov/ct2/show/study/NCT01774578?show_locs=Y#locn

After 9th infusion (of Keytruda), My dad's status update There is no sign of disease progression. One third of the tumor site has been replaced with fresh normal tissue. The tumor site also appear enclosed by normal tissue, suggesting the T cells are slowly eatting up the tumors. There is no doubt there are anti tumor response, even with my dad's age: 83. My dad also has new skin on his face and scalp. New skin replacing some of his old skin. He has a 大花臉 now. That is the most visible thing of Keytruda's effect. He experience no fatigue, no fever, nothing unusual. The UCLA doctor will continue Keytruda infusion.

I started my cancer research back in Oct 2014 when my Dad was diagnosed to have cancer. This is one of the earliest T-cell therapy I watched at that time. Although it talks about Melanoma, but its principle apply to many cancer types. In the beginning of the video, there is a clip of how a T-cell punch holes on a cancer cell and destroyed the cancer cell. In the end of the video, Dr. Hwu says "We are not after trying increase survival by 4 months. We are after getting patients 10 years and beyond." ** Not chemo, not target, not radiation, only your own immune system can get you there. ** https://www.youtube.com/watch?v=yGzJzzGj5Jw I learned much more beyond these basics and I believe many cancers can be controlled by the immune system (not chemo, not target, not radiation) over the long term. Most healthy people have anti-cancer immune response, but it's actively suppressed by the tumor. When tumor grows over a certain size, it develops complex mechanism to suppress immune response. Thus, the key is to arm your T-cells do they don't get killed by the tumor. The best time to revive your T-cell population is after chemo/surgery/radiotherapy when there is no detectable tumors or when the size of tumors are reduced.

Keytruda: 10th infusion My dad started Keytruda infusion in March, 2015. He has 10 infusions so far. Because he is on patience assistance program, so finance is not a concern. The doctor keeps the infusion going so far. The UCLA doctor was the one that did Keytruda clinical trial so he knows what he's doing. The medicine halted the disease progression early on. And it stayed that way for a long time. I thought my Dad had no response, but was glad that Keytruda halted the disease. It is strange that we rarely talk about his disease any more ever since he started the infusion... as if... he is cured. The subsequent CT-scans and MRI did not disappoint us. We become more concerned with his memory loss. My sister and I even thought the cancer somehow get into his brain. But MRI is negative. (Brain tumor has to be BIG to affect memory) Finally, the recent reports show part of the tumors are eaten up by T-cells. My dad also has new skin on his scalp and face. New skin like baby's. Nurse said that is the response. She saw it on other patients too. I could not figure out why. But there are many things I don't know and God has not revealed to me. But I do try my best to pass on the secret that God revealed to me to those who need it the most. I am sure my dad can live to the 90's.

As an engineer, I want to know "why things happen this way" and I won't give up until we understand the reasons behind it. Here are some of the things I've learned over the past two years. CTLA-4 pathway blocks the immune system from starting an immune response against cancer. How tumor employ this mechanism to block anti tumor response is still not completely known. What the scientists do know is when the dendritic cells present tumor antigens to an naive T-cell (a T cell which never been activated), it fails to activate the T-cell. PD-1 is more direct. Most cancer types use this mechanism to fend of T cell attack. PD-1 is a receptor on the T cells. It stands for Programmed Death-1. When attached by PDL1, the T cell become deactivated, and will die over a period of time. When cancer cells are under T cells attack, dying cancer cells secret substances to alert cancer cells nearby. These cancer cells will respond to the signal by presenting PDL1 on their cell surface. When T cells attack these cancer cells, T cells will become deactived and die gradually. This is why T cell therapy, DC cell therapy and cancer vaccine maybe only effective for a short time. My observation is anti PD1 is effective in preventing the disease from spreading. This is logical because T cells are based in lymph nodes and lymph nodes are body's check point for intruders**. Lymph system are interconnected to blood vessel system to form a complex network. All substances (virus, bacteria, cancer cells) flowing in the blood vessel are subject to examination of the T-cells (a white blood cell). In my opinion, it is easier to eliminate free flowing cancer cells. And this observation is back by medical data. In a recent Nivolumab clinical trial, Hodgkin lymphoma achieved a high response rate 87% (20/23). Solid tumors are harder to attack. Still using anti PD1 to treat various cancers, we still see an average of 20% response rate, which is remarkable in my opinion. Solid tumors are cluster of cancer cells. 1 cm of tumor packed with 1 billion cancer cells. Solid tumors have several defense mechanism to fend off immune system attack. 1) thick wall called vasculature. 2) regulatory T cells and Dentritic cells, macrophage, MSDC in the tumor micro environment, which can turn off anti tumor immune response. (All of above use PDL1 to turn off immune response, that is why anti PD1 is so critical in the fight with cancer). 3) PDL1 on cancer cells. Even armed with anti PD1, a T cell works on one cancer cell at a time. Patients who previously treated with chemo therapy generally have weaker anti tumor immune response. These could mean less number of cytotoxic T cells. If tumor grows faster than the T cells are able to eliminate them, the tumor may appear to be growing. Thus, anti PD1 works best when combined with radiotherapy or target therapy or even chemotherapy. Use traditional therapy to destroy as much tumors as possible, then start on anti PD1 to chase after remaining cancer population. **Many cancer patients have swollen lymph nodes, which indicates their immune system detected tumor cells and have activated immune response. These patients should try Anti PD1. On the other hand, if the cancer cells can sneak pass lymph nodes without being recognized, the immune system may not be able to recognize the cancer cells, thus, Anti PD1 may not be effective. The rule of thumb is the more mutation the cancer cells have, the easier the immune system is able to recognize and eliminate them.

The following excerpt explains why some patients have no Tumor reactive T cells. Conventional therapies (radiotherapy/chemo/target/surgery) are needed to remove as much tumor burden as possible before starting anti PD1 therapy. http://www.sciencedirect.com/science/article/pii/S1074761313002896 Generation of Tumor-Reactive T Cells Dendritic cells (DCs) are extremely important for the coordination of an anti-tumor immune response. As professional APCs, they present tumor antigens to both B cells and T cells, generating an antigen-specific antitumor response. Tumors have a profound effect on the functions of dendritic cells (Gabrilovich, 2004). Defective dendritic cell function is often combined with deregulation of DC maturation, and in humans as well as in mice, tumor-infiltrating cells expressing DC markers also express markers of macrophages and immature monocytes, indicating recruitment of myeloid precursors with incomplete differentiation (Conejo-Garcia et al., 2004). Dendritic cells can have significant heterogeneity both in vitro and in vivo (Hashimoto et al., 2011), and they include resident and bone-marrow-derived myeloid dendritic cells and plasmacytoid dendritic cells. These cells have different functional properties, and they might contribute differently to tumor tolerance or rejection (Kim et al., 2007). For example, although DCs are important APCs, depletion of CD11c+ cells (primarily DCs) can actually inhibit tumor growth (Huarte et al., 2008), an effect that reflects the role of tumor-coopted tolerogenic dendritic cells in establishing tumor tolerance and dissemination (Labidi-Galy et al., 2011 and Sawant et al., 2012). Most tumor myeloid DCs present a phenotype of partially mature DCs expressing intermediate amounts of MHC class I and II and costimulatory molecules, as well as high amounts of coinhibitory molecules and immunosuppressive cytokines. In the mouse, such cells are unable to elicit antigen-specific effector T cells (Conejo-Garcia et al., 2004). Human DCs isolated from breast, neck and/or head, and lung cancer patients were also functionally impaired in a mixed leukocyte reaction, and this functional impairment corresponded to a more severe (higher stage) cancer diagnosis (Almand et al., 2000). Immature or incompletely matured DCs might mediate tumor tolerance, inducing anergy of effector T cells and/or expansion of Treg cells in the lymph nodes or at tumor sites (Lutz and Schuler, 2002 and Mahnke et al., 2002). Gabrilovich and colleagues were the first to identify vascular endothelial growth factor (VEGF) as a tumor factor capable of impairing both dendritic cell function and maturation from CD34+ hematopoietic precursors (Gabrilovich et al., 1996). Similar observations of defective DCs have since been made in association with VEGF in cancer patients (Della Porta et al., 2005 and Takahashi et al., 2004). VEGF is an important regulator of hematopoiesis, and its artificial overexpression has led to widespread changes in the differentiation of multiple hematopoietic lineages. In patients, treatment with the VEGF-blocking antibody bevacizumab has been shown to reverse DC maturation defects (Almand et al., 2000, Fricke et al., 2007 and Osada et al., 2008). Defective DC maturation that is reversible with VEGF blockade was also found in mouse models (Gabrilovich et al., 1999, Nair et al., 2003, Roland et al., 2009 and Ishida et al., 1998). VEGF most likely exerts effects on dendritic cells beyond its role in the suppression of normal hematopoiesis. Programmed death ligand 1 (PD-L1) is a major negative regulatory ligand of the B7 family that engages the cognate programmed death-1 (PD-1) receptor that is expressed on activated T cells and which transduces a signal that inhibits T cell proliferation, cytokine production, and cytolytic function (Riley, 2009). PD-L1 is expressed on tumor cells, but it is also highly expressed on tumor-associated myeloid DCs in ovarian cancer patients (Curiel et al., 2003). Incubation of blood myeloid DCs with VEGF induced robust expression of PD-L1 on the cell surface, offering a potential mechanism by which VEGF might affect DC function (Curiel et al., 2003). A number of other tumor-derived soluble mediators can also disrupt DC function and play critical roles in defining the semi-mature, tolerogenic phenotype of tumor DCs. Such mediators include transforming growth factor β (TGFβ) (Geissmann et al., 1999), interleukin 10 (IL-10) (Steinbrink et al., 1999), macrophage colony-stimulating factor (M-CSF), and IL-6 (Menetrier-Caux et al., 1998). IL-10 also induces PD-L1 expression on DCs (Curiel et al., 2003). Additional mechanisms can contribute to a tolerogenic phenotype for DCs. Physiological stimuli such as hypoxia (Elia et al., 2008) and lactic acid (Gottfried et al., 2006) in the tumor microenvironment can also influence DC phenotype and function. In vitro, DCs differentiated under these exposures tend to have a less mature phenotype, express immunosuppressive molecules such as indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2), and fail to stimulate T cells efficiently (Elia et al., 2008, Gabrilovich et al., 2012 and Gottfried et al., 2006). In particular, PGE2 signaling on DCs can induce the expression of immunosuppressive molecules such as IL-10 (Kaliński et al., 1997) and IDO (Braun et al., 2005), suppress IL-12 production (Watchmaker et al., 2010), and inhibit chemokine expression (Muthuswamy et al., 2010). Thus, it is not surprising that in many patients there are no detectable tumor-reactive T cells. For example, in ovarian cancer, tumor-reactive T cells were detected in the peripheral blood of only half the patients tested (Schlienger et al., 2003). The defective phenotype of DCs might contribute further to deregulation of the T cell tumor attack; properly mature DCs that express costimulatory ligands might be required in the periphery at the inflammatory site to maintain an effective effector CD8+ T cell response (Dolfi et al., 2011), and these are typically absent in the tumor microenvironment. Finally, defective DCs fail to secrete appropriate chemokines that play a critical role in recruiting effector cells to tumors (Muthuswamy et al., 2012). As described above, disruption of normal DC function is an essential component of tumor-mediated immune suppression that leads to tumor immune tolerance, and strategies aimed at relieving this immune suppression or generating potent DC-vaccines ex vivo are an active area of research that has already enjoyed some early success.

上面的醫學報告 相信很難懂 簡單的說就是 在腫瘤附近的樹突細胞(myeloid DCs)都是抑制免疫反應的 腫瘤會分泌介白素M-CSF TGFβ IL-10 IL-6 影響腫瘤附近的樹突細胞的成熟 讓它們不但不能起動免疫反應 反而抑制免疫反應 你能夠想像這些樹型細胞表面長出PDL1嗎? 真的是異型! 造成免疫系統對癌症識而不見 有50%的卵巢癌患者測不出有抗癌的T細胞 原因就是腫瘤收買了樹突細胞 所以腫瘤都是抑制免疫反應的 若是病人沒有抗癌的免疫反應 第一步就是要用放化療標靶摧毀或縮小腫瘤 再用Anti PD1會比較能看到 效果 卡特總統 的 腦瘤是用放療除去的 Anti PD1幫助卡特總統 的免疫系統清除剩餘的癌細胞

在中時電子報(2016/1/12 下午 03:54:00 社群分享)看到的一日本免疫療法的新聞 : 日本山下弘子被診斷出肝癌晚期的時候，她只有19歲，是個大學一年級的小女生，還來不及過20歲的成人節便聽聞此噩耗。起初的她只是覺得右胸口疼痛，去醫院檢查後，醫生一句話也沒說，反而要她立即住院手術。而醫生則告訴她的母親：「女兒只剩下半年的生命了。」 2公斤的腫瘤摘取後不久，又發現癌細胞轉移到了肺部。肺部再動手術，隨後又發現轉移，轉移地方多達20多處。短短幾個月的時間裡，弘子動了11次手術，胸腔打開、縫上；再打開、再縫上，她則想著要如何才可以盡快死去。但是，半年過去了，弘子並沒過世，反而繼續痛苦地活著。 弘子長的一副圓圓的臉，說不出特別的美麗，但十分可愛。在家中，共有四姐妹，弘子是老大。小時候隨在中國工作的父親，在北京讀到小學3年級才回日本。 每一次的化療，讓弘子的頭髮一撮一撮地往下掉。雖然她把長頭髮給剪了，讓自己變成男孩一般，但是頭髮依然逐日減少當中。但弘子並不想變成光頭，愛美的女孩都會這麼想，於是讓她想起了高中一位待她如兒女般的班主任。她回到母校抱住班主任痛哭，班主任摸摸她的頭，說道：「我陪你好好地活下去！」第二天，班主任去醫院看她，弘子發現，班主任把長頭髮剪了，剪成了比她還短的男孩頭。那一刻，弘子有了活下去的勇氣。 醫生告訴她：「每一個人的身上都有各種的壞細胞，當免疫力很強時，好細胞遏制著壞細胞。而當免疫力下降時，壞細胞就要跑出來興風作浪。所以，只有提高免疫力，才能戰勝壞細胞。而提高免疫力的最好辦法，不是吃藥，而是快樂！」 弘子離開醫院後，回到了大學，重新拿起課本走進了課堂。她在自己的臉書上寫下了這麼一段話：「人生只有一次，不管是短還是長，都是一次。不管是哭也好笑也好，也都是一次。所以，哪怕是一天，哪怕是一瞬，都要毫無後悔地活好。」 課餘時間，弘子開始去學打高爾夫球，暑假時跑去澳大利亞學跳傘、跑到塞班島去學潛海。她不需要人陪，一個人來到巴黎、來到倫敦、來到布魯塞爾，把自己想看的城市、想走的地方都走一遍，並把自己的心得，通過臉書傳遞給關愛著自己的朋友們，共同分享生命的快樂。 雖然弘子服用了許多的抗癌藥，躲過了半年的死期。但一年過後，檢查結果顯示，吃了這麼多日子的抗癌藥，依然沒能阻止住癌細胞的擴散。 當醫生再度發出「餘命半年」的通告後，弘子開始寫書。她要把自己與死神搏鬥的故事寫出來，來鼓勵那些想自殺的人：「珍惜生命，相信未來」。弘子拖著傷痕累累的病軀，開始走上講台，給同齡人給癌症患者們，講述「人生不後悔」的故事。 也許上帝垂愛努力生活的人。在家人們絕望的時候，日本一家醫藥公司發明了一種抗癌新藥，並開始尋找試驗者。治療弘子癌症的近畿大學醫學部附屬醫院醫生在分析了這一新藥的成分後，覺得可以讓弘子一試。於是，弘子開始服用這一種新藥，結果奇蹟出現了，癌細胞開始得到控制，並出現了萎縮的趨勢。 弘子從立命館大學畢業後，像普通的大學生一樣走上了社會。她開始在母親經營的不動產中介公司開始工作，兼做中文翻譯。弘子成了小白領，下班後也和普通的上班族一樣去居酒屋喝酒，去KTV唱歌。休息天也去銀座逛街看電影，或者與姐妹們一起去泡溫泉，活潑、熱情，毫無病意。 醫生說，參加新藥臨床試驗的人當中，全世界共有200位，弘子是其中的一位。這一新藥新免疫療法並非人人有效，但弘子感覺很對頭，「病人找藥，藥也在找人，這是天意」。 弘子曾在她自己的紀錄片中說道：「現在這一刻，讓我們歡笑地活著，不要後悔每一天。精神比藥重要！」 山下弘子，今年23歲，她的目標，是要進入聯合國從事兒童教育工作，然後活到80歲。 文章來源：發現日本 (我是相信將來免疫療法會是所有患者都會有效)

Cincia(星希亞)

感謝分享，Cincia也有看到這篇報導，弘子真的很棒，自己一個人做了那麼多事情，相對之下自己感覺很不獨立，總喜歡有家人朋友作伴，哈哈XDDDDD 免疫療法我也好期待啊！癌症治癒就要靠它了～

2016-01-28 09:00

是沒錯 癌基因突變有可能有效 可是窮人呢 一個療程半年要200多萬 還是希望健保能幫忙

衛生福利部有在招收免疫治療的名額，請詢問一下自己治療的醫院。台南成大醫院名額已滿，這只是我目前所知道一點點情形。

腫瘤可以分為會發炎的腫瘤和不會發炎的腫瘤 會發炎 積水 發燒表示病人對腫瘤有免疫反應 通常可以在這類病人的腫瘤裡找到活化的T細胞 (TIL: tumor infiltrating lymphocytes) 醫界普遍認為有TIL的病人預後較佳 有TIL的病人適合直接用anti PD1治療 不會發炎的腫瘤 表示病人對腫瘤沒有免疫反應 或有TIL但被腫瘤抑制 (我爸的黑色素瘤就不會發炎) 表示腫瘤成功的抑制了免疫反應 這類病人應先用化療縮小破壞腫瘤 激起免疫反應 再使用anti PD1 An observation of two major phenotypes of MEL metastases, “inflamed” and “noninflamed,” provides a good conceptual framework for understanding immune escape mechanisms. Inflamed tumors are characterized by tumor-infiltrating immune cells; noninflamed tumors are characterized by the lack thereof. Source: http://www.cancernetwork.com/oncology-journal/prospects-targeting-pd-1-and-pd-l1-various-tumor-types/page/0/3

這段大致的意思是不發炎的腫瘤或沒PD-L1表象的病人用anti–PD-1/PD-L1或治療效果不佳 A biomarker biopsy study of the ongoing phase I study of MPDL3280A indicated that patients who responded to therapy had tumor-infiltrating lymphocytes and tumoral PD-L1 expression at baseline.[55] By contrast, in a PD-L1–negative patient not responding to therapy, very few CD8+ T cells were noted at the tumor periphery at baseline. Following therapy, there was minimal infiltration of T cells, and a gene expression study showed lack of cytotoxic T-cell marker expression. Similar observations have been reported with anti–CTLA-4 antibodies,[58,59] implying that noninflamed tumors may have a greater tendency to be resistant to this class of therapy. See more at: http://www.cancernetwork.com/oncology-journal/prospects-targeting-pd-1-and-pd-l1-various-tumor-types/page/0/3#sthash.sMYqHyo5.dpuf

Cincia(星希亞)

我有點困惑，不發炎的腫瘤或沒PD-L1表象的病人用anti–PD-1/PD-L1或治療效果不佳， 如David所寫的，黑色素瘤不會發炎， 但黑色素瘤對免疫療法的效果卻很好？這怎麼有點矛盾？

2016-01-29 09:20

照上篇報告 我爸的黑色素瘤沒發炎 醫生應該早就放棄用anti PD1治療我爸 開始打Keytruda 後我爸根本沒有反應 他還覺得醫生是不是只是給他打IV UCLA醫生不死心 繼續給他打 最後還是看到效果 我想到Cincia的書上寫的 因為堅持 而看到希望 聖徒也有類似的話 Faith is to believe what you do not yet see; the reward for this faith is to see what you believe.

Cincia(星希亞)

所以黑色素瘤也有分發炎和不發炎的嗎？ 謝謝David分享的聖經的話喔！

2016-01-29 09:34

#164 回Cincia Cincia 果然是聰明 我想原因是這篇文章是2014年11月寫的 是根據當時資料 而下的結論 後來anti PD1大腸癌實驗發現 癌症基因突變的數量決定anti PD1的效果 因為有定量關係 基因突變的數量可能成為anti PD1的bio marker 不過發炎性腫瘤的確意謂免疫反應這是顯而易見的 只是沒發炎也可能有免疫反應 有PD-L1表象 發炎與否不能當bio marker

#164 我再看一次原文 其他地方都是在講PDL1表像 問題出在這句話 Similar observations have been reported with anti–CTLA-4 antibodies,[58,59] implying that noninflamed tumors may have a greater tendency to be resistant to this class of therapy. 我想這句話是作者誤導

#165 我也沒聽過發炎的黑色素瘤

Non–Small-Cell Lung Cancer The PD-1/PD-L1 pathway appears to be a critical therapeutic target for advanced NSCLC. Multiple PD-1 and PD-L1 antibodies have demonstrated antitumor activities in both pre- and postsystemic therapy settings. The activity appears to be more pronounced in earlier disease settings. As shown in Table 5, in chemotherapy-naive, PD-L–positive patients, nivolumab[31] and pembrolizumab[32] demonstrated ORRs of 50% (95% CI, NR) and 26% (95% CI, 14–42), respectively. In pretreated patients, nivolumab,[33] pembrolizumab,[34] MPDL3280A, [35] and MEDI4736[36] have demonstrated ORRs ranging from 16% to 23%. Brahmer et al presented survival data of a phase Ib trial of nivolumab that included 129 heavily pretreated patients with advanced NSCLC, more than half of whom received > 3 prior therapies.[33] At a median follow-up of 27 months across all dose levels, 1- and 2-year OS rates were 42% (95% CI, 34–51) and 24% (95% CI, 16–32), respectively, and median OS was 9.9 months (95% CI, 9.8–12.4). Patients given the 3-mg/kg dose appeared to have superior survival data, with 1- and 2-year OS rates of 56% (95% CI, 38–71) and 45% (95% CI, 27–61), respectively, and a median OS of 14.9 months (95% CI, 7.3–NR). Unlike cytotoxic agents—and as seen in other settings, such as in mRCC[25]—nivolumab did not show a clear dose-response relationship in advanced NSCLC. The survival data are certainly encouraging in a disease where the median OS has been no more than 7 to 8 months. PD-L1 expression on NSCLC tumor cells or tumor-infiltrating immune cells was associated with higher response rates. Although not statistically powered to show this, some degree of correlation has been observed with most of the agents, including pembrolizumab, MPDL3280A, and MEDI-4736. As noted in Table 5, across all these agents, except nivolumab in pretreated patients, PD-L1 expression was associated with higher response rates. ORRs were 23% to 46% vs 3% to 15% in PD-L1–positive vs PD-L1–negative groups, respectively. As also noted, while PD-L1 expression was highly predictive of response to nivolumab in treatment-naive patients (50% in PD-L1–positive patients vs 0% in PD-L1–negative patients),[31] this was not the case for pretreated patients (15% in PD-L1–positive vs 14% in PD-L1–negative), using 5% as a PD-L1 expression cutoff.[33] This difference, despite the use of the same assay and the same drug, raises several questions, including questions of assay sensitivity, of archival tissue vs “fresh” pretreatment biopsy, and of whether the complexity of immune-mediated cytolysis is underestimated. Several ongoing phase III trials of nivolumab in advanced NSCLC require mandatory tissue samples and will explore the role of PD-L1 as a predictive biomarker for nivolumab, with its prespecified evaluation correlated to OS (see Table 7). Another important potential predictive biomarker is smoking status. Both MPDL3280A[35] and pembrolizumab[34] have demonstrated higher response rates among current or former smokers than among never-smokers. Among current/former smokers, ORRs by RECIST 1.1 were 25% (95% CI, NR) and 26% (95% CI, 19–35) with MPDL3280A and pembrolizumab, respectively. Among never-smokers, ORRs were 16% (95% CI, NR) and 8% (95% CI, 3–18) with MPDL3280A and pembrolizumab, respectively. It has been hypothesized that because lung cancers in smokers are associated with more genetic mutations, they generate new tumor-associated or tumor-specific antigens, which are rendered more susceptible to recognition by immune cells. Thus, when an immune checkpoint such as PD-L1 is blocked, these patients’ immune cells may be more likely to respond and induce immune-mediated tumor cell killing. Combination studies in NSCLC Several combination strategies are being tested in large, multicohort phase I trials. Nivolumab, pembrolizumab, MEDI-4736, and MPDL3280A are being evaluated in combination with chemotherapies, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, anti–CTLA-4 antibodies, or other targeted therapies. Nivolumab and ipilimumab in combination were tested in chemotherapy-naive advanced NSCLC in the ongoing CA209-012 study.[37] At the time of data analysis, 8 of 29 patients (16%) had objective responses. Six of these patients (75%) had ongoing responses at the time of analysis. Most of the responses were seen by the time of the first tumor assessment (10 weeks). In an exploratory analysis based on PD-L1 status, responses were seen in both PD-L1–positive and PD-L1–negative patients, with ORRs of 19% (3/16) and 14% (3/22), respectively. The CA209-012 study also tested nivolumab in combination with various platinum-doublet chemotherapy regimens, including gemcitabine/cisplatin, pemetrexed/cisplatin, and paclitaxel/carboplatin. The safety data showed an adverse event profile reflecting the additive toxicities of nivolumab and chemotherapy. No dose-limiting toxicities were seen during the first 6 weeks of treatment.[38] ORRs were 33% (95% CI, 10–65) to 47% (95% CI, 21–73) across all arms. One-year OS rates were 50% (95% CI, 21–74) to 87% (95% CI, 56–96). Nivolumab plus erlotinib was tested in 21 patients with chemotherapy-naive, EGFR-mutant, advanced NSCLC.[39] All except one patient had acquired resistance to the EGFR tyrosine kinase inhibitor. The overall ORR was 19% (95% CI, 5.4–41.9). Of 20 patients who had erlotinib resistance, 3 (15%) achieved a partial response. One erlotinib-naive patient achieved a near CR, and all responses were durable beyond 78+ weeks. Nine patients (45%) had stable disease. The most common treatment-related adverse events were rash, fatigue, paronychia, diarrhea, and skin fissures. No pneumonitis of any grade was observed. - See more at: http://www.cancernetwork.com/oncology-journal/prospects-targeting-pd-1-and-pd-l1-various-tumor-types/page/0/2#sthash.9gYBjF9v.dpuf

找到篇張景明醫師和張金堅教授寫的腫瘤微環境簡介 http://www.tma.tw/ltk/104580103.pdf 為什麼專家對腫瘤微環境有興趣? 原因很簡單 腫瘤微環境抑制對癌症的免疫反應 瞭解腫瘤如何抑制免疫反應 進而破壞腫瘤抑制免疫反應的機制 才能長期有效的抑制癌症 文章內容大概和我過去談的吻合 只是因為是醫學文章內容可能許多人看不懂 不過你有耐心仔細讀也是能夠瞭解大概的內容

之前我提到腫瘤附近的巨噬細胞都被腫瘤收買 研究顯示這些巨噬細胞會分泌許多蛋白酶和細胞激素抑制免疫反應 腫瘤相關巨噬細胞 腫瘤相關巨噬細胞(tumor-associated macrophage, TAM) 是一群多樣性的細胞， 主要來源來自腫瘤 周邊組織或骨髓，可以簡單分為兩種主要型態： M1 及M2。其中在腫瘤形成的早期主要是M1 腫 瘤相關巨噬細胞浸潤，它可以分泌促發炎細胞激素 (proinammatory cytokines)，即第一型細胞激素(type I cytokines)，進而抑制腫瘤生長。相反的，在腫瘤形 成晚期，則以M2 腫瘤相關巨噬細胞為主，它分泌 的第二型細胞激素(type II cytokines)，可以促進抗發 炎反應，因而促進腫瘤的生長( 圖1)(2)。然而M1 腫 瘤相關巨噬細胞何時會轉型為M2 腫瘤相關巨噬細 胞，目前仍不是非常清楚，但目前認為腫瘤缺氧狀 態(tumor hypoxia) 可能與這樣的轉變有關。M2 腫 瘤相關巨噬細胞會分泌許多蛋白酶( 如細胞自溶酶 cathepsin)、細胞激素( 如轉化生長因子transforming growth factor-beta, TGF-β、IL-10)、生長因子( 如表 皮生長因子epidermal growth factor, EGF、腫瘤衍生聚 落刺激因子tumor-derived colony stimulating factor-1, CSF-1)，使得腫瘤易於成長、血管新生，進而侵犯其 他組織。 臨床上，以乳癌為例，在128 名第一期或第二期 的病人，發現M2 腫瘤相關巨噬細胞較多者，組織學 較為高惡性度，血管新生較多，且整體存活較差，而 M1 腫瘤相關巨噬細胞較多者，則剛好相反(3)。 Source: http://www.tma.tw/ltk/104580103.pdf

除了腫瘤相關巨噬細胞 和腫瘤相關樹突細胞 腫瘤還會吸引不成熟骨髓細胞 MDSC MDSC是免疫抑制功能的骨髓細胞 此外腫瘤附近還有許多抑制免疫反應的調節型T細胞Treg 文中也提到若是病人有活化的T細胞(TIL) 預後狀況會比較好 免疫細胞與環境 腫瘤微環境中免疫機轉對於腫瘤生長、發展具 有舉足輕重的角色，許多細胞參與了免疫的調控，一 般而言，當腫瘤微環境的免疫作用受到逃避或抑制， 是腫瘤生成最重要的啟始步驟。其中骨髓來源抑制細 胞(marrow-derived suppressor cells, MDSCs) 為一很重 要的細胞，它來源自骨髓，本身是具有「免疫抑制 功能」的不成熟骨髓系細胞，在腫瘤生成時，從骨 髓移動出來並浸潤在發展中的腫瘤；其功能包含，促 進腫瘤血管生成、破壞樹突細胞的抗原呈現(antigen presentation)、抑制T 細胞活化、促進M1 腫瘤相關 巨噬細胞轉型為M2 腫瘤相關巨噬細胞、抑制NK 細 胞的細胞毒殺作用等。所以骨髓來源抑制細胞會促進 腫瘤的生長，這些都在臨床觀察中證實，在骨髓來源 抑制細胞數量較多的癌症病人，其疾病較為嚴重，其 藥物治療的效果也較差(8)。 另外一群很重要，也研究很多的就是腫瘤浸潤 淋巴球(tumor inltrating lymphocytes, TIL)。這些淋巴球大 多是CD3+ T 淋巴球，根據不同的功能，又可分為CD4+ helper 細胞( 包括1、2 次分型)、CD4+ regulatory 細胞( 又稱Treg， 主要為CD4+ CD25+ FOXP3+)、CD8+ cytotoxic 細胞等。其中又以Treg 最為重要，Treg 約佔 所有CD4+ 細胞的10%，細胞表面有forkhaed box P3 transcription factor(FOXP3) 的表現， 而FOXP3 可以 抑制IL-2 的生成，進而抑制T 細胞的活化，也可藉由 cytotoxic T lymphocyte antigen 4(CTLA-4) 與抗原呈現細 胞(antigen presenting cell, APC) 結合而產生免疫抑制， 或是分泌免疫抑制細胞激素，如IL-10、TGF-β，最 終產生免疫抑制的效果(9)，也因此癌症病人若是其腫 瘤浸潤淋巴球中Treg 比例較高者，常常對治療的反應 較差，預後也較差。然而另一方面，若是腫瘤浸潤淋 巴球中CD8+ cytotoxic 細胞數目較多時，則其存活狀 況會較好，這在乳癌病人中觀察到此現象(10)。

這段談到的我過去談過的T細胞活化過程 這段沒講明白的是anti PD1實際上可以克服上面各種抑制免疫反應的怪物 因為這些怪物都是用PDL1來消滅已活化的T細胞 這就是為什麼在免疫療法 anti PD1是如此關鍵 T 淋巴球的活化或抑制 T 淋巴球的活化，需要有2 個訊號，第一個訊號 是抗原呈現細胞藉由MHC 將抗原呈現給T 淋巴球表 面上的T 細胞接受器(T cell receptor, TCR)，同時需 要第二個訊號，也就是抗原呈現細胞表面上的B7-1、 B7-2 配體( 即CD80、CD86) 與T 淋巴球表面上的 CD28 結合( 圖2)，當這兩種訊號一起傳遞，則T 淋 巴球便被活化，進而執行它的任務，清除外來的微生 物、對抗並殺死腫瘤細胞等。然而在T 淋巴球活化 的同時，T 淋巴球有自己的回饋抑制機轉，會表現出 CTLA-4，當CTLA-4 與CD80、CD86 結合時，T 淋巴 球便受到抑制。同樣的，T 淋巴球、自然殺手細胞、 樹突細胞、活化的單核球會表現programmed death 1 (PD-1)，當T 淋巴球表面上的PD-1 與腫瘤細胞表面 上的PD-L1、PD-L2 結合時，T 淋巴球的作用便會受 抑制( 圖2)(11)。CTLA-4 和PD-1 路徑，我們稱為免疫 檢查點(immune checkpoint)，類似的路徑還有CD40 與CD40L、OX40 與OX40L、ICOS 與ICOSL 等(12)。 臨床應用，我們可以利用對抗CTLA-4 的抗體 (anti-CTLA-4) 或是對抗PD-1、PD-L1 的抗體(anti- PD-1、anti-PD-L1)，讓T 淋巴球再次活化，進而毒殺 腫瘤細胞。Ipilimumab 就是對抗CTLA-4 的抗體，已 經在大規模的第三期臨床試驗，看到可以增加黑色素 瘤整體存活的好處(13)，故早在2010 便得到美國FDA 的核可使用。同樣的，nivolumab 為對抗PD-1 的抗體， 在第一期臨床試驗，單獨使用nivolumab 對黑色素瘤 有31% 的反應率，對腎臟癌有29% 的反應率，甚至 對一般認為並非免疫性(immunogenic) 的腫瘤，非小 細胞肺癌，也有16% 的反應率(14)，這樣的結果令人 相當興奮與期待。

Green juices usually start with fresh vegetables such as spinach, kale, broccoli or others as your base. In a study published in the journal "Cell" in 2011, researchers at the Babraham Institute in Cambridge, England, reported that cruciferous vegetables such as bok choy and broccoli contain a compound that boosts immunity and provides an extra layer of protection to cells in the body. Timing Is Everything https://www.iorganifireviews.com/patriot-power-green-reviews/

Cincia(星希亞)

Thanks for sharing. I have been drinking vegetable juice for six years. :)

2018-11-28 08:29