TW201414480A - 由高劑量輻射誘發之抗腫瘤t細胞免疫力 - Google Patents
由高劑量輻射誘發之抗腫瘤t細胞免疫力 Download PDFInfo
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Abstract
本發明提供癌症之治療,其係藉由在個體原發性腫瘤位置經定位投與高單一劑量或短期劑量處理;在一段足以激活抗腫瘤反應之時間後,從該個體收集T細胞;利用有效劑量之化療劑量治療該個體;及將該T細胞群再引入該個體內。
Description
癌症(亦稱為惡性腫瘤)具有細胞異常生長的特徵,其鄰近組織會呈現失控的細胞分裂、細胞侵入及細胞破壞,且有時候會轉移至身體的其他部位。癌症有100多種類型,包括乳癌、皮膚癌、肺癌、結腸癌、前列腺癌及淋巴癌。癌症在美國是第二位主要的死亡原因,且其會導致約13%之總死亡數。癌症會侵襲所有年齡層的人,甚至是胎兒,但大多數類型之癌症的風險是隨年齡增加。癌症會侵襲所有的動物。
軀體立體定位輻射療法(Stereotactic body radiation therapy;SBRT)是利用一種三維座標系統以達到精確的輻射傳送。利用SBRT,可以讓為解決治療方案不確定性之輻射治療計畫範圍達到最小化。此考量到以較高劑量-體積限制不傷害週圍正常組織,而能夠傳送較高及較少分次的輻射劑量(低分次)。利用SBRT,可以用可達最大化局部控制(類似於切除術)及最小化毒性之主要目標處理個別分離的腫瘤。SBRT定義為一種輻射治療計畫及傳送技術,其中係用三維定向系統增加靶向精確性,典型地係為低分次(1至5分次)方案。
雖然有這些新穎性藥劑及經改進的組合,但目前的治療對於多種類型的癌症或不同時期的癌症仍是無效的。經改善的治療方案及治療對於癌症療法是大大有需要的。
本發明係提供用以治療個體中癌症之方法。本發明方法提供先在個體腫瘤位置定位投與高單一劑量或短期高劑量之輻射;經一段足以激活抗腫瘤反應的時間後(例如約2週至約5週),從該個體收集T細胞;給予該個體化療劑量,其可為常規劑量或清髓劑量;繼之將該T細胞群再輸注回該個體。本發明方法可提供原發性腫瘤持久性完全的緩解。本發明方法亦可預防轉移性腫瘤在輻射位置以外之位置的生長。
在一些實施例中,該癌症為實體腫瘤,該實體腫瘤可以是處於晚期狀態、達到轉移狀態及包括轉移狀態。關注的腫瘤包括在身體某處的至少一種腫瘤,該等腫瘤是承受經集中高劑量輻射之彼等,包括但不限於肝癌、肺癌、腦癌、胰癌、黑色素瘤、乳癌及類似癌症。
T細胞典型地係從血液樣本中藉由血漿析離術收集的。該等細胞收集之後視需要進行挑選處理,例如挑選T細胞、清除癌細胞等。該等細胞在收集之後,可(例如)藉由技術中已知的冷凍等技術加以儲存或培養。
在治療其中化療為清髓化療之個體時,細胞收集物及再輸注物可另外包括除T細胞以外之造血幹細胞收集物及再輸注物,例如利用流通外週血液作為細胞源。或者,該經激活T細胞與造血幹細胞組合使用,該等造血幹細胞為自體性的或來自同種供體。
定義
為便於理解本發明,規定下列定義。應理解,一般而言,除非另有定義,該等術語具有技術中一般經接受的含義。
本說明書中所述之所有公開案、專利及專利申請案係藉由引用之方式併入本文,其程度如同各單一公開案、專利及專利申請案明確地及單個地表明通過引用之方式併入般。
熟習此項技術者從本說明書的考量或本發明所揭示之實務即可明瞭本發明其他實施例。本說明書及實例只欲視為示例性的,本發明實際範圍係藉由附加請求項說明。
為了本發明目的,個體係指經診斷患有癌症及需要治療的個體。該個體通常為哺乳動物,其中哺乳動物係指任何經分類為哺乳動物的動物,包括人類、家養及農場動物,及動物園中之動物、體育用動物或寵物,諸如狗、馬、貓、乳牛等。該哺乳動物較佳係人類。
預後及預測資訊。如文中所用,預後及預測資訊可相互交換使用,係指任何可用於預見未經治療或經治療之疾病或病症過程的任何態樣的資訊。該資訊包括但不限於患者之平均壽命預期、患者存活某
特定時間(例如6個月、1年、5年等)之可能性、患者可治癒疾病的可能性、患者疾病對特定療法具有反應性的可能性(其中反應可以多種方法中任一種加以界定)。預後及預測資訊包括診斷資訊之廣泛分類中。
反應。如文中所用,對治療具有反應性係指個體病症因治療所發生的任何有利之改變。該改變包括病症之穩定(例如可以預防當沒有該治療時可能發生的惡化)、紓緩該病症之症狀、在治癒該病症之前景方面的改進等。反應性係指個體之反應或腫瘤之反應。一般而言,該等概念在文中可互換使用。
可根據各種廣泛性標準(包括臨床標準及客觀性標準)測量腫瘤或個體反應。用以評估反應之技術包括但不限於臨床檢查、胸部X光、CT掃描、MRI、超音波、內視鏡檢查、腹腔鏡檢、獲自個體樣本中腫瘤標誌物之存在或含量、細胞學、組織學。該等技術中有許多技術試圖用來測定腫瘤大小或不然用來測定總腫瘤負擔。可以任何適當的方式選擇準確的反應標準,條件是當與腫瘤組別及/或患者組別比較時,待比較組別係以測定反應速率之相同的或相當的標準為基礎。一般技術者能夠選擇適當的標準。
可藉由技術中已知的任何方法測定臨床效能。在一些實施例中,個體治療方法之臨床效能係藉由測量臨床受益率(clinical benefit rate;CBR)加以測定的。臨床受益率係藉由在距離療法結束至少6個月時間點測定完全緩解(complete remission;CR)患者、部份緩解(partial remission;PR)患者數及具有穩定疾病(stable disease;SD)患者數之百分比的總和加以測定的。該公式簡寫為CBR=CR+PR+SD月。在一些實施例中,個體治療方法之CBR至少約50%。在一些實施例中,個體治療方法之CBR至少約55%、60%、65%、70%、75%、80%、85%、90%、95%或更高。
樣本。如文中所用,獲自個體之樣本包括但不限於下列之任何
一種或全部:一個細胞或多個細胞、一部份組織、血液、血清、腹水、尿液、唾液及其他體液、內分泌物或外分泌物。術語「樣本」亦包括藉由處理該樣本所獲得之任何物質。衍生性樣本包括萃取自該樣本或藉由將樣本進行諸如擴增或mRNA反轉錄等的技術而獲得之核酸分子或多肽。
腫瘤樣本。文中所用之術語「腫瘤樣本」廣泛地用於包括移除自一腫瘤之細胞或組織樣本、衍生自位於身體他處之腫瘤的細胞(或其子代)(例如血流中的細胞或轉移性腫瘤位置的細胞),或藉由處理該樣本所獲得之任何物質。衍生性腫瘤樣本包括萃取自該樣本或藉由將樣本進行諸如擴增或mRNA反轉錄等的技術而獲得之核酸或蛋白質。
高劑量輻射。如文中所用,高劑量輻射係指其中在一段短暫時間內以少次劑量方式傳送高量輻射之局部性傳送輻射劑量。一般而言,因為輻射量足以傷害正常組織,所以輻射係以軀體立體定位輻射療法(SBRT)傳送。
靶向位置之輻射總劑量通常係於一段短於1週的時間內(例如)以單一劑量、於一段1至3天的時間內以3次分次劑量、於一段1至5天的時間內以2次分次劑量等方式傳送至少約20Gy、至少25Gy、至少30Gy,及不超過60Gy、通常不超過40Gy。在分次劑量中,每次劑量可相同或不同,但總和不超過以上說明之總劑量。在一些組織中,具有使單一劑量小於20Gy、小於15Gy、小於10Gy之分次劑量是令人滿意的。
SBRT需要一種能偵測及處理三維陣列之裝置。可使用不同的三維座標系統,包括內部基準點、外部標示及/或影像導引。配備每日CT成像、超音波及/或正交X射線之影像導引輻射療法(image guided radiation therapy;IGRT)可幫助靶向精準度。若干其他工具可用以改進固定,包括軀體立體定位框、縮腹裝置及真空袋。當呼吸動作致使
目標物置於預定定位參數之外時可以讓輻射束關閉且當目標物再次落到接受對準範圍內時可回復輻射照射之呼吸調控閘門可以幫助靶向。一些SBRT系統(諸如Cyberknife®)可即時追蹤三維座標,同時加速器頭會即時性地自身校準以適應靶向位置之波動。
SBRT之規劃及傳送一般是使用多個指向輻射目標物之非共平面及/或弧形場。因此,儘管低劑量區包含較大體積且呈不規則形狀,但劑量傾斜度比常規輻射更為陡峭。利用SBRT之劑量一般係分配至包含該目標物之等中心點及/或等劑量線,此會導致其中該等中心點接受較目標物週圍更大劑量之非均質性劑量傳送。為減少到達週圍組織之劑量,選擇較低的等中心點劑量及/或將該劑量分配至更高的等劑量線。利用相對常規輻射之低分次SBRT,該絕對經分配輻射劑量更低(因為使用更大、更具生物有效性的劑量分次)。
SBRT相當適合用於保留涉及或鄰接類似功能組織(例如腎、肺柔軟組織及肝臟柔軟組織)之腫瘤,在該等組織中的功能亞單元是連續的分散實體。由於SBRT會減少器官體積,且類似功能亞單元的絕對數目會因此被輻射破壞。因為器官保留多餘的功能,因此未受破壞之功能亞單元可維持器官功能及/或再生新的器官亞單元(一如發生在肝臟中)。其中功能性亞單元未有界定範圍之連續型功能性組織(諸如脊髓、食道、支氣管、肝管及腸)之線型或具有分支狀的器官亦會因減少高劑量體積的暴露而受益。
骨髓移植術已是惡性病症治療中建立完善的技術。利用造血幹細胞支持物之高劑量化療法廣泛地用於大多數血液性惡性腫瘤及一些實體腫瘤。鑒於最近在血液母細胞收集物之發展,特定言之,藉由顆粒細胞群落刺激因子移動及藉由白血球分離術收集之大量血液幹細胞之可利用性,克服HLA錯配患者的組織相合性屏障是具有可能性的。其他最近的發展包括但不限於血液母細胞移動之新方法、母細胞及免
疫細胞之活體外擴增、臍帶血作為幹細胞之替代性來源的用途及其他分子技術可透由造血及免疫細胞之自體性或同種移植作用而能支持癌症有效的治療。
自體性HSCT需要從患者萃取(血漿析離術)造血幹細胞(HSC)並將所收集細胞儲存在冷凍庫中。該病患一般是接受包括或不包括放射療法之高劑量化療治療,在付出部份或完全的骨髓剝蝕(破壞患者骨髓生長新的血細胞之功能)的代價下達到消除患者惡性細胞群的目的。接著將該患者自己已儲存的幹細胞送回他/她身體內,其中該等細胞會替換掉被破壞的組織,並讓患者恢復製造正常血液細胞。由於免疫功能迅速地恢復,自體移植物在治療中免疫功能低下期間具有較低感染風險的優點。另外,由於提供者與接受者為同一個體,出現排斥(移植物抗宿主疾病)的發病患者極少。該等優點已經確立自體性HSCT為一種可用於諸如淋巴癌疾病的標準二線治療(Canellos,George(1997)The Oncologist 2(3):181-183)。
圖1A-1C。藉由高劑量輻射治療晚期CT26腫瘤會導致完全的緩解,及會發展出可由T細胞過繼轉移之長期性系統免疫力。A,實驗方案。小鼠以皮下方式建立晚期CT26結腸腫瘤21天,並接受單一劑量之局部腫瘤輻射(local tumor irradiation;LTI)。所示是經過15、20及30Gy之單一輻射劑量之後,或未經輻射處理,或利用每日10次每
次3Gy之每日劑量所顯示之腫瘤生長曲線及治癒小鼠分量及存活的百分比。藉由Mantel-Cox檢定,在未經治療腫瘤組別相對以15Gy(p<0.05)或10x3Gy之治療腫瘤組別之間、或在經以30Gy相對15Gy之治療組別之間(p<0.05)或在經以30Gy相對10x3Gy之治療組別之間(p<0.05)的存活期具有顯著差異。B,實驗方案。挑選出帶有21天腫瘤小鼠經過30Gy LTI治療後完全緩解的彼等(n=12)。以皮下方式將1x106經輻射處理腫瘤細胞(50Gy,活體外)及30μg CpG接種至一組正常小鼠(n=10)作為對照組。經接種或經輻射處理的小鼠在治療後的100-150天以皮下方式激發挑戰5x106 CT26細胞。所示是腫瘤生長曲線、經保護小鼠分量及存活的百分比。在經接種或未經治療小鼠相對經輻射處理小鼠之間的存活有顯著差異(p<0.05)。C,實驗方案。從經以30Gy治癒達至少100天之小鼠收集T細胞(6x106)及經去除T細胞(TCD)骨髓細胞(1x107),並轉移至經以8Gy總體輻射(total body irradiation;TBI)調整之同基因型帶有腫瘤的小鼠(7天腫瘤)。從未經治療小鼠所得之T細胞及TCD骨髓移植物係作為對照組。所示是100天的存活。無移植物程序之組別相對來自LTI供體之移植物之間(p<0.05)的存活有顯著差異,而非與來自天然小鼠之移植物之間(p>0.1)的存活有顯著差異。
圖2A-2E。LTI誘發對腫瘤激發挑戰之抗性的動力學、T細胞缺乏宿主之疾病緩解的解除及T細胞注射後之疾病緩解的恢復。A,在實驗第0天建立原發性CT26腫瘤。在第21天,帶腫瘤動物在腫瘤對側以5x106 CT26細胞進行激發挑戰。所示是第二次腫瘤之生長曲線及具有進展性第二次腫瘤生長之小鼠的分量(n=5)。B,在第21天,施予原發性腫瘤30Gy LTI,及在原發性腫瘤植入後的第21天或第51天,在腫瘤對側以5x106 CT26細胞激發挑戰小鼠。經以LTI處理之組別中在第21天相對第51天激發挑戰之無腫瘤生長的分量有顯著差異(藉由Chi
Square檢定,p<0.05)。C,帶有21天CT26腫瘤之野生型動物接受30Gy LTI及抗-CD8或CD4除去抗體或ATS。在僅給予LTI之組別相對給予LTI+CD8除去之組別(p<0.001)或相對給予LTI+CD4除去之組別(p<0.01),或相對給予ATS之組別(p<0.001)或相對未治療之組別(p<0.001)之間的存活有顯著差異。D,帶腫瘤的BALB/C RAG2-/-小鼠在第21天僅接受30Gy LTI,或在注射CY(在LTI之後立即以i.p.方式投與500mg/kg)或不注射CY的情況下於第23天接受LTI+6x106 BALB/c脾臟T細胞。所示是帶腫瘤動物的存活。在僅給予LTI之組別相對給予LTI+CY+T細胞之組別(p<0.001)、或給予LTI+T細胞之組別相對給予LTI+T細胞+CY之組別(p<0.05)、或給予LTI+CY而無T細胞之組別相對給予LTI+CY+T細胞之組別(p<0.01)之間的存活有顯著差異。E,在第21天給予30Gy LTI+CY(恰好在LTI之後以i.p.方式投予500mg/kg),或LTI+CY+6x106 BALB/c脾臟T細胞(第23天)之帶CT26 luc+之RAG2-/-小鼠之生物發光成像(bioluminescence imaging;BLI)。空盒子表示老鼠死亡。
圖3A-3C。腫瘤中及有或無腫瘤小鼠之脾臟中的浸潤單核細胞之比較。A,在CT26腫瘤移植之後,在第21天,分析腫瘤浸潤細胞及脾細胞關於CD4+及CD8+ T細胞之CD25、PD-1及Tim-3之表現,及MDSC(Mac-1+ Gr1+)及TAM(Mac-1+ Gr1-)。所示是代表性雙色分析板框中各子集細胞的百分比,而箭頭係確認經門控(qated)的子集細胞。針對所用單核門控Mac-1、Gr-1、CD4及CD8加以染色。B,細胞子集(CD8+、CD4+、Mac-1+Gr-1+及Mac-1+Gr-1-)係以腫瘤移植後第21天之腫瘤及脾臟中單核細胞中的平均百分比+/- SE,及在總CD8+ T細胞中所顯示之「耗竭型」Tim-3+ PD-1+細胞的平均百分比表示。C,顯示腫瘤及脾臟中Treg細胞及Treg細胞之PD-1+表現的平均百分比。N=5,*-p<0.05,**-p<0.01,***-p<0.001,NS p>0.05。
圖4A-4E。單一劑量之30Gy LTI會改變腫瘤浸潤細胞朝向有利於CD8+ T細胞之方向平衡,且會減少MDSC、TAM及Treg。A,患有晚期21天腫瘤小鼠接受單一劑量之LTI(30Gy)或經分次每日劑量LTI(3Gyx10)。從完成LTI之後的14天腫瘤製備單細胞懸浮液。對照組之帶腫瘤小鼠未接受LTI並在第35天分析細胞。所示是CD4+及CD8+T細胞、MDSC及TAM之代表性染色情況及PD-1及Tim-3之表現。B,所示是腫瘤浸潤細胞在單核細胞門控中的平均百分比+/- SE。C,在腫瘤浸潤CD8+ T細胞中之Tim-3+PD-1+細胞的平均百分比。D,在單核細胞中CD4+CD25+ Foxp3+細胞的平均百分比及在CD4+CD25+Foxp3+細胞中PD-1+細胞的平均百分比。E,在未治療動物及接受LTI(30Gy)或經分次LTI(3Gyx10)治療動物中之腫瘤的CD8/MDSC、CD8/TAM及CD8/Treg比例。所示是平均比例+/- SE。*-p<0.05,**-p<0.01,***-P<0.001,NS p>0.05。
圖5。當T細胞療法與放射療法及化療組合使用時,可促進4T1腫瘤轉移之完全緩解。A,以皮下注射方式給予1x104 4T1野生型腫瘤細胞及4T1 luc+腫瘤細胞小鼠的存活與帶4T1 WT或4T1 luc+腫瘤細胞小鼠在第14、15、16天給予60Gy(3次各20Gy之每日劑量)的存活之比較。B,經注射4T1 luc+腫瘤細胞後在系列時間點時之小鼠的生物發光成像(bioluminescence imaging;BLI)。應注意第21及28天時橫膈膜上的信號。C,顯示未經治療小鼠中具有腫瘤細胞叢肺部之代表性組織切片(H&E,x放大)。D,小鼠給予4T1 luc+腫瘤細胞經在第14、15、16天以及在第21、22、23天給予60Gy(3次各20Gy之每日劑量)LTI後之BLI。空白區域表示小鼠死亡。E,給予4T1 luc+細胞、60Gy(3次各20Gy之每日劑量)LTI及在第23天以i.p.方式注射CY(500mg/kg)之小鼠的BLI。F,小鼠按照E所述給予4T1 luc+細胞及LTI及CY,並恰好在第23天之CY注射之前收集Thy 1.2+ T細胞。冷凍保存T
細胞,接著解凍及在注射CY之後48小時以i.v.方式注射(5X106)。所示是在系列時間點之BLI,以及未經治療組別及實驗組別之存活。僅給予LTI或LTI+CY腫瘤組別相對LTI+CY+T細胞組別(p<0.05)之間的存活有顯著差異,而LTI+CY組別相對僅LTI組別(p>0.05)之間的存活則沒有顯著差異。
圖6。腫瘤浸潤細胞之PDL-1及CD62L表現。腫瘤浸潤細胞係在CT26腫瘤移植後第21天分析,而在未經治療動物或在第21天接受LTI 30Gy之動物係在第35天分析。分析在MDSC(Mac-1+ Gr1+)、TAM(Mac-1+ Gr1-)抑制細胞以及DC(CD11c+)上的PDL-1表現。分析在CD8+腫瘤浸潤細胞上的CD44及CD62L表現。所示是代表性染色。
本發明係提供用於治療個體中癌症之方法。本發明方法可提供先在個體原發性腫瘤位置定位投與高單一劑量或短期高劑量之輻射;經一段足以激活抗腫瘤反應之時間後(例如約2週至約6週),從該個體收集T細胞;給予該個體化療劑量,該化療劑量可為常規或清髓劑量;繼之將該T細胞群再輸注回該個體。本發明方法係在未接種腫瘤細胞之疫苗下進行。
本發明方法可以提供原發性腫瘤持久性完全緩解。本發明方法亦可預防轉移性腫瘤在輻射位置以外之位置的生長。
癌症免疫療法是利用免疫系統來排斥癌症。該等方法會刺激患者免疫系統以攻擊會導致疾病之惡性腫瘤細胞,此可以透過控制患者自身的免疫系統辨識欲破壞的標的腫瘤細胞。許多腫瘤細胞類型會表
現出非尋常的抗原,該等抗原對該細胞類型及/或其環境並不適當,或正常情況下僅會在生物體發展期間存在(例如胎兒抗原)。此等抗原的實例包括但不限於糖原鞘脂GD2,其是一種正常情況下在神經元細胞之外表面膜上才會以顯著量表現的雙唾液酸神經節苷脂,其中其與免疫系統之接觸會受到血腦屏障的限制。GD2會在包括神經母細胞瘤、神經管母細胞瘤、星形細胞瘤、黑色素瘤、小細胞肺癌、骨肉瘤及其他軟組織肉瘤的許多腫瘤細胞的表面上表現。其他腫瘤細胞類型會表現健康細胞表面上很少存在或不存在的細胞表面受體,而該等表面受體係負責激活會導致腫瘤細胞失調的生長及分裂之細胞訊號轉導路徑。實例包括ErbB2,其是一種會在乳癌腫瘤細胞表面上異常性產生高含量之基本性活性細胞表面受體。
然而,癌細胞會利用多種免疫抑制機制以避開T細胞反應,這些機制不是避免免疫辨識就是讓效應子T細胞失能。該等機制包括抗原展現機制系統之組分的改變、基底TCR發出信號之缺陷、免疫抑制因子及促凋亡因子的分泌、負性調控路徑之激活作用及調控細胞群特定的補充。該等機制會限制免疫系統約束癌症之能力及成功地消除惡性細胞之免疫療法策略的有效性。
藉由APC之腫瘤抗原處理及展現是腫瘤抗原特異性CD4+ T細胞耐受性在發展下的主要機制。特定言之,樹突細胞(dendritic cell;DC)在決定導致活體內產生相對於T細胞初敏(T-cell priming)之T細胞耐受性上扮演關鍵的作用。該結果大大地受到其中經偶遇DC的抗原之環境背景所影響。儘管抗原在發炎環境中偶遇DC會驅使其成熟作用而成為能夠產生強力免疫反應的表型,但在非發炎環境中被DC所捕獲之抗原則不能引發生產性T細胞反應,而代之的是導致T細胞耐受性之發展。隨著腫瘤進展,其微觀環境不僅無法提供有效的DC激活所需之發炎信號,而且會產生諸如IL-10及血管內皮生長因子(vascular
endothelial growth factor;VEGF)之額外免疫抑制機制,該機制對DC之成熟作用及/或功能會進一步產生負面衝擊。
在不受限於理論下,據信定位至腫瘤位置之高輻射劑量可透由殺死不合要求的調控細胞、改變腫瘤位置所存在之抗原展現細胞及類似機制進而改變腫瘤之免疫抑制環境。在具有免疫功能的動物中,高劑量腫瘤輻射會朝向有利於CD8+效應子T細胞方向改變CD8+效應子細胞及T調控細胞、骨髓來源抑制細胞(myeloid derived suppressor cell;MDSC)、腫瘤相關巨噬細胞(tumor-associated macrophage;TAM)之平衡,並促進免疫學上所介導之腫瘤排斥作用。然而,因為化療會耗損初期想要的反應,因此當化療後宿主T細胞對腫瘤所增加的反應是無效果的。本發明方法係藉由在化療之前先收集這些經激活抗腫瘤T細胞並完成化療之後再輸注回該患者而保護該等經激活抗腫瘤T細胞。以此方式,可獲得對抗癌症具持久性免疫反應。對於消除腫瘤而言,無需特異性腫瘤抗原免疫化作用。本發明方法藉由在放射療法後收集T細胞及在化療後再輸注的作法,晚期實體腫瘤經高劑量放射療法之後可顯著地提高存活。
治療方法
在本發明方法中,治療的是經診斷為罹癌個體。利用本發明方法可治療之癌症類型包括但不限於腎上腺皮層癌、肛門癌、再生障礙性貧血、膽管癌、膀胱癌、骨癌、骨轉移、腦癌、中樞神經系統(CNS)癌、週圍神經系(PNS)癌、乳癌、子宮頸癌、兒童期非何傑金淋巴瘤(Non-Hodgkin's lymphoma)、結腸及直腸癌、子宮內膜癌、食道癌、尤因氏腫瘤族(例如尤因氏肉瘤(Ewing's sarcoma))、眼睛癌、膽囊癌、胃腸道類癌腫瘤、胃腸基質腫瘤、妊娠期滋養層疾病、何傑金淋巴瘤、卡波西氏肉瘤(Kaposi’s sarcoma)、腎癌、喉癌及下咽癌、肝癌、肺癌、肺類癌腫瘤、非何傑金淋巴瘤、男性乳癌、惡性間皮瘤、
多發性骨髓瘤、脊髓發育不良症候群、脊髓增生病、鼻腔及鼻側癌、鼻咽癌、神經母細胞瘤、口腔及口咽癌、骨肉瘤、卵巢癌、胰癌、陰莖癌、垂體瘤、前列腺癌、視網膜母細胞瘤、橫紋肌肉瘤、唾液腺癌、肉瘤、黑色素瘤皮膚癌、非黑色素瘤皮膚癌、胃癌、睾丸癌、胸腺癌、甲狀腺癌、子宮癌(例如子宮肉瘤)、轉移細胞癌、陰道癌、外陰癌、間皮瘤、扁平細胞或表皮樣癌、支氣管腺瘤、惡性蛻膜瘤、頭及頸癌、畸胎癌,或華氏巨球蛋白血症(Waldenstrom's macroglobulinemia)。
在一個較佳實施例中,本發明方法係用於治療可承受高劑量輻射之實體腫瘤,例如肺癌、肝癌、乳癌、前列腺癌、卵巢癌或胰癌;包括但不限於晚期及/或轉移癌。
該個體係以如上定義之高劑量定位輻射加以治療。該個體接著以原位方式進行一段用於將T細胞激活之適當時間,通常至少1週、至少2週、至少3週,而不超過6週、不超過5週、不超過4週。
經激活T細胞之收集
在T細胞激活之後,利用技術中已知的方法收集週圍T細胞。例如可使用白血球分離術、全血收集等。收集之後,藉由包括流式細胞儀、等滲Percoll密度梯度;利用抗體或磁性珠塗布抗體之免疫磁性分離技術等之常規方法,將T細胞視需要與其他細胞分離。當進行親和性挑選的情形下,該挑選可以是正向的,例如分離出可表現關注標誌物(例如CD4+、CD8+、CD3+等)之細胞,或可為負向的挑選,例如挑選出對抗不合要求的調控細胞,例如CD25+細胞。
在一些實施例中,造血幹細胞及/或母細胞(諸如CD34+細胞)可與T細胞一起收集以用於自體性重構作用。在其他實施例中,係自同種供體收集造血幹細胞及/或母細胞以用於造血性重構作用。
為了收集造血幹細胞/母細胞,可利用粒細胞群落刺激因子
(granulocyte colony-stimulating factor;G-CSF)移動該等細胞。G-CSF是一種可將HSC從骨髓移動至血流中之潛在誘發劑,並可在藉由白血球分離術收集用於造血幹細胞移植之前用於增加供體血液中造血幹細胞的數目。其亦可投與給接受者以補償調理治療方案。
在一些實施例中,CD34+造血母細胞係經過富集。技術中已知的方法可用於富集CD34+造血母細胞。例如,可利用免疫磁性或免疫螢光法從血液樣本分離出CD34+細胞。抗體可用於定量及純化用於臨床骨髓移植之造血母幹細胞。在一個實施例中,等滲Percoll密度梯度可用於富集CD34+細胞。在另一實施例中,利用抗CD34抗體或經抗CD34抗體塗布之磁性珠之免疫磁性分離技術可用於富集CD34+細胞。
化療
在收集T細胞及視需要之造血幹細胞/母細胞之後,該個體以抗腫瘤藥劑或其醫藥上可接受的鹽或前藥加以治療。該劑量可為常規劑量或清髓劑量。在一些實施例中,該抗腫瘤藥劑包括但不限於抗腫瘤烷基化藥劑、抗腫瘤抗代謝物、抗腫瘤抗生素、植物衍生抗腫瘤藥劑、抗腫瘤有機鉑化合物、抗腫瘤喜樹鹼衍生物、抗腫瘤酪胺酸激酶抑制劑及其他具有抗腫瘤活性之藥劑或其醫藥上可接受的鹽。
已知烷基化藥劑是透過將大分子(諸如癌細胞之DNA)烷基化而作用的,通常是強力的親電子物質,此活性可中斷DNA合成及細胞分裂。本文所用適合之烷基化藥劑的實例包括氮芥類(nitrogen mustards)及其類似物及衍生物,其包括環磷醯胺(cyclophosphamide)、異環磷醯胺(ifosfamide)、苯丁酸氮芥(chlorambucil)、雌氮芥(estramustine)、二氯甲二乙胺氫氯化物(mechlorethamine hydrochloride)、苯丙氨酸氮芥(melphalan)及尿嘧啶氮芥(uracil mustard)。烷基化藥劑之其他實例包括磺酸烷基酯(例如白消安(busulfan))、亞硝基脲(nitrosoureas)(例如亞硝脲氮芥(carmustine)、環己亞硝脲(lomustine),及鏈脲黴素
(streptozocin))、三氮烯(triazenes)(例如氮烯唑胺(dacarbazine)及替莫唑胺(temozolomide))、氮丙啶(ethylenimines)/甲基三聚氰胺(methylmelamines)(例如六甲嘧胺(altretamine)及硫替派(thiotepa)),及甲肼(methylhydrazine)衍生物(例如甲基苄肼(procarbazine))。包含於烷基化藥劑群組的是類似烷基化之含鉑藥物,其包括卡鉑(carboplatin)、順鉑(cisplatin),及奧沙利鉑(oxaliplatin)。
抗代謝抗腫瘤藥劑在結構上類似天然代謝物,並可參與癌細胞一般代謝過程,諸如核酸及蛋白質之合成作用。其等藥劑與天然代謝物相當具有差異性,因此其等會干擾癌細胞之代謝過程。用於本發明之適宜抗腫瘤藥劑可按照其影響之代謝過程加以分類,及包括但不限於葉酸、嘧啶、嘌呤,及胞嘧啶核苷之類似物及衍生物。本文所用適合之葉酸群組之成員的藥劑包括但不限於甲胺喋呤(methotrexate(amethopterin))、培美曲唑(pemetrexed)及其類似物及衍生物。本文所用適合之嘧啶藥劑包括但不限於阿糖胞苷(cytarabine)、氟尿苷(floxuridine)、氟尿嘧啶(fluorouracil)(5-氟尿嘧啶(5-fluorouracil))、卡培他濱(capecitabine)、吉西他濱(gemcitabine)及其類似物及衍生物。本文所用適合之嘌呤藥劑包括但不限於巰基嘌呤(6-巰基嘌呤)、噴托他丁(pentostatin)、硫鳥嘌呤(thioguanine)、克拉屈濱(cladribine)及其類似物及衍生物。本文所用適合之胞嘧啶核苷藥劑包括但不限於阿糖胞苷(cytarabine(cytosine arabinodside))、阿札胞苷(azacitidine)(5-氮胞苷)及其類似物及衍生物。
天然抗腫瘤藥劑包括抗有絲分裂藥劑、抗菌性抗腫瘤藥劑、喜樹鹼(camptothecin)類似物及酶。本文所用適合之抗有絲分裂藥劑包括但不限於長春花屬生物鹼(vinca alkaloids),諸如長春花鹼(vinblastine)、長春新鹼(vincristine)、長春地辛(vindesine)、長春瑞濱(vinorelbine)及其類似物及衍生物。其等係來自長春花(Madagascar
periwinkle)植物且通常對於細胞週期M階段具有特異性,可以結合至癌細胞微管中之微管蛋白。本文所用適合之其他抗有絲分裂藥劑為鬼臼素(podophyllotoxins),其包括但不限於依託泊苷(etoposide)、替尼泊苷(teniposide)及其類似物及衍生物。該等藥劑主要地靶向細胞週期之G2及晚期S階段。
在天然抗腫瘤藥劑中亦包括抗菌性抗腫瘤藥劑:抗菌性抗腫瘤藥劑通常是透過與癌細胞DNA相互作用而具有抗腫瘤性的抗菌藥。本文所用適合之抗菌性抗腫瘤藥劑包括但不限於博來黴素(belomycin)、放線菌素(dactinomycin)、阿黴素(doxorubicin)、艾達魯比辛(idarubicin)、泛艾黴素(epirubicin)、絲裂黴素(mitomycin)、邁杜蔥酮(mitoxantrone)、噴司他丁(pentostatin)、普卡黴素(plicamycin)及其類似物及衍生物。
天然抗腫瘤藥劑分類亦包括本文所用適合之喜樹鹼的類似物及衍生物及包括喜樹鹼、拓撲替康(topotecan)及伊立替康(irinotecan)。該等藥劑主要是藉由靶向核酶拓撲異構酶I而起作用。在天然抗腫瘤藥劑下之另一亞類為酵素、L-天冬醯胺酸酶(L-asparaginase)及其變體。L-天冬醯胺酸酶係藉由透過將循環性天冬醯胺催化水解成天冬胺酸及氨而作用去除某些癌細胞之L-天冬醯胺。
激素抗腫瘤藥劑主要是作用在與前列腺組織、乳房組織、子宮內膜組織及卵巢組織有關的激素依賴性癌細胞、淋巴瘤及白血病。該等組織對於諸如糖皮質激素(glucocorticoids)、助孕素(progestins)、雌激素(estrogens)及雄激素(androgens)之該等藥劑類別具有反應性且可依賴該等藥劑類別。作為激動劑或拮抗劑之類似物及衍生物適合用於本發明中以治療腫瘤。本文所用適合之糖皮質激素激動劑/拮抗劑的實例為地塞米松(dexamethasone)、皮質醇(cortisol)、皮質酮(corticosterone)、強的松(prednisone)、米非司酮(mifepristone
(RU486))、其類似物及衍生物。本文所用適合之助孕素激動劑/拮抗劑亞類的藥劑包括但不限於17-羥孕酮(hydroxyprogesterone)、甲羥孕酮(medroxyprogesterone)、醋酸甲地孕酮(megestrol acetate)、米非司酮(mifepristone;RU486)、ZK98299、其類似物及衍生物。本文所用適合之雌激素激動劑/拮抗劑亞類的藥劑的實例包括但不限於雌激素、它莫西芬(tamoxifen)、托瑞米芬(toremifene)、RU58668、SR16234、ZD164384、ZK191703、氟維司群(fulvestrant),其類似物及衍生物。本文所用適合而可抑制雌激素產生之芳族酶抑制劑的實例包括但不限於雄烯二酮(androstenedione)、福美斯坦(formestane)、依西美坦(exemestane)、氨魯米特(aminoglutethimide)、阿他美坦(anastrozole)、來曲唑(letrozole)、其類似物及衍生物。本文所用適合之雄激素激動劑/拮抗劑亞類的藥劑的實例包括但不限於睪酮(testosterone)、雙氫睾酮(dihydrotestosterone)、氟羥甲睾酮(fluoxymesterone)、睾丸激素(testolactone)、庚酸睾固酮酯(testosterone enanthate)、丙酸睾固酮酯(testosterone propionate)、促性腺激素釋放激素(gonadotropin-releasing hormone)激動劑/拮抗劑(例如亮丙瑞林(leuprolide)、戈舍瑞林(goserelin)、曲普瑞林(triptorelin)、布舍瑞林(buserelin))、己烯雌酚(diethylstilbestrol)、阿巴瑞克(abarelix)、環丙孕酮(cyproterone)、氟利坦(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide),其類似物及衍生物。
血管生成抑制劑係藉由抑制腫瘤之血管生成而起作用的。血管生成抑制劑包含多種藥劑,包括靶向RNA功能之小分子藥劑、抗體藥劑及藥劑。本文所用適合之血管生成抑制劑的實例包括但不限於蘭尼單抗(ranibizumab)、貝伐單抗(bevacizumab)、SU11248、PTK787、ZK222584、CEP-7055、安奇羅然(angiozyme)、達肝素(dalteparin)、撒利多胺(thalidomide)、蘇拉明(suramin)、CC-5013、磷酸康布瑞塔
卡汀A4(combretastatin A4 Phosphate)、LY317615、大豆異黃酮(soy isoflavones)、AE-941、α干擾素(interferon alpha)、PTK787/ZK 222584、ZD6474、EMD 121974、ZD6474、BAY 543-9006、塞利西蔔(celecoxib)、氫溴酸鹵夫酮(halofuginone hydrobromide)、貝伐單抗(bevacizumab),其類似物、變體或衍生物。
T細胞再輸注
藉由可富集所要細胞之技術,將收集自該個體之T細胞從細胞混合物中分離出來。適宜的溶液可用於進行分散或懸浮。該溶液一般為平衡的鹽溶液,例如生理鹽水、PBS、Hank氏平衡鹽溶液等,通常該等溶液經補充胎牛血清或其他天然存在的因子,並結合低濃度(一般而言5-25mM)之可接受的緩衝劑。常規緩衝劑包括HEPES、磷酸鹽緩衝劑、乳酸鹽緩衝劑等。
親和性分離技術包括利用經抗體塗布之磁性珠的磁性分離、親和性層析法、結合至單株抗體或與單株抗體結合併用之細胞毒性藥劑(例如補體及細胞毒素),及利用附接至固體基質(例如板)之抗體「裝盤」,或其他常用技術。可提供準確分離的技術包括螢光激活細胞分選儀,其具有不同程度的精密度,諸如多色通道、低角度及鈍角光散射偵測通道、阻抗通道等。藉由利用可與死細胞結合的染料(例如碘化丙啶(propidium iodide))而挑選出對比死細胞之該等細胞。可採用不會不當地傷害經挑選細胞之存活率的任何技術。該親和性藥劑可為以上闡明之細胞表面分子的特異性受體或配體。除了抗體藥劑外,可使用肽-MHC抗原及T細胞受體對;肽配體及受體;效應子及受體分子及類似物。
經分離細胞係收集在可維持細胞生命力的適當介質中,通常在收集管底部具有血清墊。不同的介質可市售購得並可按照細胞之性質加以使用,包括dMEM、HBSS、dPBS、RPMI、Iscove培養基等,通
常補充有胎牛血清。
經收集及視需要經富集之細胞群可立即使用,或可在液氮溫度下冷凍及儲存,經解凍並能再使用。細胞通常是儲存在10% DMSO、50% FCS、40% RPMI 1640介質中。
該等T細胞係含於生理學上可接受介質中,依慣常經血管內方式再輸注回該個體體內,但該等細胞亦可引至該等細胞可以在其中找到適合生長位置之骨或其他適當的位置。通常係投與至少1x106個細胞/kg、至少1x107個細胞/kg、至少1x108個細胞/kg、至少1x109個細胞/kg、至少1x1010個細胞/kg或更多,通常受限於收集期間所獲得之T細胞數目。
商業方法
本發明亦提供一種將本發明經純化腫瘤細胞提供給第三方之商業方法。如文中所述,術語「客戶」或「潛在客戶」係指可利用T細胞純化業務之方法或服務的個體或實體。文中所述之T細胞純化方法及服務的潛在客戶包括例如患者、個體、醫師、細胞學實驗室、保健提供者、研究員、保險公司、政府實體(諸如醫療救助機構)、雇主,或任何對達成診斷、監測及治療癌症之系統感興趣的其他實體。
以下為本發明之方法及組合物的實例。應理解,依據以上提供之綜述,可進行各種其他的實施例。
實例1
藉由高劑量低分次輻射誘發之抗腫瘤T細胞免疫力可作為晚期腫瘤的治癒性療法
以下研究係用以評估現在臨床上可採用之例外性單一高劑量輻射對小鼠之晚期實體腫瘤的效果。吾人發現之結果顯示,該等高劑量可治癒罹患晚期結腸腫瘤的小鼠,且效能係取決於具有功能的免疫系統。該輻射治療不僅會導致腫瘤浸潤抑制細胞相對於效應子免疫細胞
之間平衡的急劇偏移,而且會誘發全身性抗腫瘤免疫力,該免疫力可預防在遠處激發挑戰後之腫瘤生長,並可藉由T細胞轉移至過繼接收宿主體中。轉移性乳癌經原發性腫瘤輻射及灌注經輻射激活T細胞之後,會誘發完全的緩解。該等發現結果顯示,相較於利用多次小劑量之常規輻射,單一高劑量輻射在針對腫瘤的全身性免疫力上具有不同性質的效果。
以3維靶向腫瘤但對鄰近正常組織造成最小輻射之共焦輻射束(軀體立體定位輻射療法;SBRT)之應用的進展在最近的臨床研究中可投與30Gy之單一劑量或多達3次每次20Gy之每日劑量(Chang,B.K.& Timmerman,R.D.Stereotactic body radiation therapy:a comprehensive review.Am.J.Clin.Oncol.30,637-644,2007;Brown,J.M.& Koong,A.C.High-dose single-fraction radiotherapy:exploiting a new biology?Int.J.Radiat.Oncol.Biol.Phys.71,324-325,2008)。SBRT誘發癌症緩解的效能是大於利用多次小輻射劑量之常規療法的彼等。SBRT其中一個優點是利用常規放射療法無法達到之腫瘤免疫力的誘發。
輻射可藉由刺激抗原展現細胞而增加腫瘤免疫原性,並可促進T細胞遷移及進入至腫瘤中。在一些研究中,在小鼠中將腫瘤輻射結合免疫療法可誘發系統性免疫力,從而減緩遠處的腫瘤生長。然而,除非腫瘤小(<1公分)且不具轉移性,否則利用該組合不能獲得弱免疫原性腫瘤之持久性完全緩解。
晚期腫瘤會藉由補充腫瘤浸潤單核細胞的不平衡而發展出一種可抑制腫瘤免疫力的微觀環境,該等腫瘤浸潤單核細胞在常規CD8+T細胞方面係有利於骨髓來源抑制細胞(MDSC)及腫瘤相關之巨噬細胞(TAM),而在CD8+T細胞方面係有利於CD4+CD25+FoxP3+ Treg細胞。此外,CD8+T細胞上負性共刺激分子(諸如PD-1及Tim-3)的表現會導致與相關免疫功能障礙的「耗竭型」表型。臨床研究已經證明,腫瘤切
片中含有大量免疫抑制MDSC及Treg細胞或在T細胞上負性共刺激受體具有經增加表現係與不良預後有關聯性,而大量常見的CD8+T細胞則係與較佳的預後有關聯性。
文中所述之研究可以測定投與至小鼠中具不良免疫原性晚期CT26結腸及4T1乳房腫瘤之類似於SBRT所用之彼等的高輻射劑量是否可誘發經激發挑戰之後預防遠處腫瘤生長之治癒性系統性免疫反應,及抗腫瘤免疫力是否可藉由經輻射激活T細胞轉移。此外,研究輻射對腫瘤浸潤單核分子之影響以測定該免疫抑制性微觀環境是否會被高劑量輻射療法逆轉。
結果
利用放射療法治療CT26腫瘤可誘發完全的緩解,且系統性免疫力可藉由T細胞轉移:圖1A顯示,CT26腫瘤細胞(2.5x104細胞)以皮下方式注射至野生型BALB/c小鼠後軀中的生長。腫瘤體積會逐漸的增加,但沒有腫瘤會自發性地退化。第21天,腫瘤持續的惡化,且結節直徑達至少1公分。當利用開發用於僅靶向1.0-1.5公分直徑腫瘤結節之鉛夾具在第21天對腫瘤投與15Gy局部腫瘤輻射(local tumor irradiation;LTI)之單一劑量時,觀察到8隻小鼠中有7隻小鼠的腫瘤生長會產生暫時性減緩。8隻小鼠中有1隻小鼠的腫瘤生長會完全持續性緩解。當劑量增加至20Gy時,則5隻小鼠中有3隻會發展到完全腫瘤緩解,而當劑量增加至30Gy時,則15隻小鼠中有13隻會達到完全緩解,且小鼠存活至少100天(圖1A)。進一步觀察顯示,在長達180天中沒有腫瘤再發生。儘管30Gy之單一劑量在治療腫瘤上極為有效,但10次每次3Gy之每日劑量僅會使8個腫瘤中的1個產生誘發性緩解,且帶腫瘤小鼠的存活期則類似以15Gy單一劑量的彼等(圖1A;p>0.05)。
另以皮下注射方式(5.0x105 CT26腫瘤細胞)激發挑戰經觀察100-
150天之經治癒野生型小鼠,及在體積略微增加之後,12個腫瘤中有9個會消退掉。12個腫瘤中有3個會逐漸地生長(圖1B),且後者帶腫瘤的小鼠會在100天內死亡(圖1B)。在此前的研究(Filatenkov等人,J.Immunol.1;183(11):7196-203,2009)中,吾人證明,以皮下方式單劑接種經以50Gy於試管內輻射照射的1x106 CT26腫瘤細胞混與佐劑CpG之疫苗可以保護約50%之BALB/c小鼠免於隨後經以2.5x104腫瘤細胞的激發挑戰。然而,當經接種疫苗之小鼠係經5.0x105腫瘤細胞激發挑戰時,則大多數的腫瘤會逐漸地生長,且約90%經激發挑戰的宿主會死亡(圖1B)。因此,由單一LTI劑量所提供之保護係比針對該微弱免疫原性腫瘤之疫苗接種程序更為有效(p=0.01)。
為了測定LTI治療後達至少100天具腫瘤完全緩解之小鼠的T細胞是否可授受性轉移有效治療CT26腫瘤的能力,吾人使用圖1C中所簡繪之方案。利用抗-Thy1.2管柱純化來自治癒小鼠脾臟之T細胞,並與來自供體經去除T細胞之骨髓細胞組合。將骨髓細胞及T細胞以i.v.方式注射至業已經皮下注射CT26腫瘤細胞的經輻射照射的授受接受者,及接著7天後以TBI方式給予8Gy單一劑量。該帶腫瘤接受者均會發展出完全緩解且存活達至少100天(圖1C)。當利用來自未治療正常小鼠脾臟之T細胞組合經去除T細胞之骨髓細胞重複該實驗時,則授受性轉移並不會誘發腫瘤生長的緩解,且所有接受者會第40天前死亡(圖1C)。後者接受者之存活期類似於給予腫瘤但隨後沒有輻射及移植的接受者之彼等。
圖2A顯示帶21天腫瘤之小鼠對抗在第21天於腫瘤對側之腫瘤激發挑戰沒有保護力,且所有第二次腫瘤均會逐漸地生長。類似地情況,當帶21天腫瘤之小鼠在第21天時給予30Gy LTI連同同一天於腫瘤對側之腫瘤激發挑戰時,所有第二次腫瘤均會逐漸地生長(圖2B)。相反地,若延遲挑戰直到在LTI之後30天,則5個第二次腫瘤中只有1
個會逐漸地生長。這表示腫瘤免疫力並非在LTI之後立即形成,而是在數週之後開始表現。在其他研究中,測定去除T細胞或免疫細胞不足對於LTI誘發完全腫瘤緩解的影響。圖2C顯示,約90%帶21天腫瘤之小鼠經LTI之後可存活100天以上。然而,藉由注射抗-CD8mAb而將CD8+T細胞去除之小鼠則存活未超過100天(p<0.0001)。約40%去除CD4+T細胞之小鼠相較未以mAb處理之小鼠則可存活至少100天(p<0.01)。利用抗-胸腺細胞血清(anti-thymocyte serum;ATS)去除CD4+T細胞及CD8+T細胞兩者則會使所有小鼠之存活期減至短於62天。該後者小鼠之存活相較僅去除CD4+或CD8+ T細胞而言明顯地更短(p<0.01)。
在一些實驗中,將CT26細胞以皮下方式注射至免疫力不足的RAG-2-/-小鼠中,及接著在第21天以30Gy LTI治療。圖2D顯示,在該等小鼠中之腫瘤會逐漸地生長,而帶腫瘤小鼠的存活期不超過70天。吾人將來自正常野生型BALB/c小鼠脾臟的T細胞以i.v.方式注射至立即經LTI處理之帶腫瘤RAG-2-/-小鼠中。注射T細胞會顯著地增加存活期(p<0.05),但僅20%小鼠存活超過100天(圖2D)。吾人將單一劑量環磷醯胺(cyclophosphamide;CY)注射給經LTI處理後之小鼠,而之後注射野生型T細胞。LTI、CY及T細胞之組合相較僅以LTI處理者會顯著地增加小鼠存活期(p<0.001),使得60%小鼠可存活至少100天(圖2D)。給予LTI及CY但無T細胞之小鼠則存活不超過80天,而加入T細胞則會顯著地增加存活(p<0.001)。藉由螢光素酶基因轉染之CT26腫瘤細胞之生物發光成像(bioluminescence imaging;BLI)評估T細胞注射對給予LTI及CY之RAG2-/-小鼠中之CT26腫瘤生長的效果。圖2E顯示實驗方案及從第21天起每週間隔之BLI結果、LTI之時間。在第23天注射CY,在第25天注射或未注射T細胞。第21天,在注射及未注射T細胞之組別中,癌症會有相當地擴散。第28天,大多數小鼠會產生向
橫隔膜上方延伸與肺中形成腫瘤結節有關之腫瘤。第35天,在有或沒有T細胞之RAG2-/-小鼠組別中存在著明顯差異;後者組別中5隻小鼠中有2隻死亡,當時段經T細胞注射組別中則所有的小鼠均存活且顯示腫瘤信號明顯的減少。在經T細胞注射組別中,腫瘤清除會持續進行,並在第42天時,8隻小鼠中有6隻顯示沒有腫瘤信號。相反地,沒有T細胞注射的組別則會顯示持續性腫瘤生長,且所有小鼠均會在第107天前死亡。
CT26腫瘤浸潤單核細胞之分析:檢測野生型小鼠中未經治療之21天CT26腫瘤之浸潤單核細胞的組成。切除皮下腫瘤並將單細胞懸浮物針對T細胞標誌物以及骨髓來源抑制細胞(MDSC)及腫瘤相關巨噬細胞(TAM)之CD11b及Gr-1標誌物進行染色。CD8+T細胞及CD4+T細胞在代表性的雙色FACS圖案中分別佔單核細胞約12及9%(圖3A)。在門控CD8+細胞中,約74%會表現出已述於患有腫瘤或經慢性病毒感染之小鼠中之「耗竭型」細胞之PD-1+Tim-3+表型(Sakuishi等人J.Exp.Med.207,2187-2194,2010)。在CD4+細胞中,約33%為CD25+,而在後者細胞中,約60%為FoxP3+ Treg細胞。此外,大多數CD4+CD25+及CD4+CD25- T細胞會表現負性共刺激受體PD-1,之前有報導PD-1對於腫瘤浸潤T細胞具有上調性。有意思地,該腫瘤單核細胞包含約10%具有MDSC表型之CD11b+Gr-1+細胞,及34%為CD11b+Gr-1- TAM。MDSC及TAM可表現高含量的PDL-1(圖5)。
在檢測腫瘤浸潤細胞的同時,亦檢測來自該等小鼠的脾臟(圖3A及B)。CD8+T細胞及CD4+T細胞分別佔單核細胞約5及13%,且約13%CD4+細胞為CD25+,而僅5% CD8+細胞為PD-1+Tim-3+。在正常脾臟中,CD4+細胞中CD25+細胞的平均百分比為約11%,及在CD8+細胞中PD-1+Tim-3+細胞的平均百分比約1%(圖3B)。然而,在圖3A所示之流式細胞儀圖中,腫瘤中大多數為PD-1+,脾臟中僅約10-13%為PD-1+。
脾臟中CD11b+Gr-1+及CD11b+Gr-1-細胞分別佔單核細胞約8%。圖3B比較腫瘤及來自帶腫瘤及正常小鼠中之CD8+T細胞、CD4+T細胞、MDSC,及TAM的平均百分比。T細胞及MDSC平均百分比在腫瘤中沒有顯著差異,而TAM平均百分比相較CD4+T細胞或CD8+T細胞及MDSC之彼等則增加約2倍。相反地,CD4+T細胞及CD8+T細胞百分比相較正常脾臟中之MDSC或TAM高得多。腫瘤中MDSC平均百分比相較帶腫瘤小鼠之脾臟係增加的(p<0.01),且兩種組織中之MDSC平均百分比相較正常脾臟係增加的(p<0.001)。
圖3C比較腫瘤及脾臟中CD8+T細胞的PD-1+Tim-3+細胞的平均百分比。儘管腫瘤中百分比為約80%,但帶腫瘤或不帶腫瘤小鼠中之脾臟中的彼等則小於5%。類似地,腫瘤中CD4+CD25+FoxP3+Treg細胞之PD-1+細胞平均百分比為約80%,而脾臟中則小於10%。腫瘤中CD4+T細胞中之Treg平均百分比相較脾臟係顯著增加的。
放射療法改變腫瘤浸潤細胞之組成:以30Gy之單一劑量輻射21天腫瘤並在第35天檢測浸潤細胞。對照組未接受輻射或各接受10次3Gy的劑量。圖4A顯示在第35天未經輻射處理之小鼠中的浸潤細胞組成。T細胞、MDSC及TAM之間的平衡類似於在21天腫瘤輻射前所觀察到之彼等(圖3)。然而,如圖4A及4B之代表性流式細胞儀圖及柱狀圖所示,經輻射腫瘤在CD8+T細胞百分比上會從沒有輻射之約15%平均值明顯增加至給予輻射之約65%(p<0.01)。CD8+T細胞幾乎全為效應子記憶(CD62L-CD44+)表型(圖5),但仍表現出「耗竭型」表型。有趣地是,MDSC及TAM之組合百分比在輻射之後會從約46%顯著降低至約7%(p<0.001)(圖4A及B)。Treg之百分比亦顯著降低(p<0.001),而在CD4+ Tcon及Treg細胞一直表現大量的PD-1(p>0.05)(圖4 D)。細胞類型之百分比的變化會導致CD8+T細胞與MDSC、與TAM,及與Treg之比例明顯增加(p<0.0001)(圖4E)。儘管30Gy之單一劑量會誘發
細胞組成之劇烈變化,但給予10次每次3Gy劑量後之組成則類似於沒有輻射之腫瘤(圖4)。
T細胞療法在放射療法之後於預防4T1乳房腫瘤轉移之進展的用途:在另外的實驗中,吾人研究高劑量輻射對BALB/c小鼠中之4T1乳房腫瘤以皮下注射之後轉移至肺之另一腫瘤的效果。圖5A顯示,皮下方式將螢光素酶基因轉染之4T1腫瘤注射至後軀後利用BLI檢測的生長。不論腫瘤細胞是否利用螢光素酶基因轉染,所有小鼠均會在55天內死於腫瘤進展(圖5A),且生長類似於針對原位注射所記錄之彼等。在第21天之BLI及組織病理學分析顯示截止到該時間,腫瘤已經擴散至肺部(圖5B及C)。當投與30Gy給14天腫瘤時,可觀察到腫瘤生長的減緩,但未發展完全的緩解。然而,3次每次20Gy之每日劑量在5隻小鼠中有2隻會產生完全的緩解,其存活期超過100天。因此,4T1腫瘤相較CT26腫瘤要求更高的總劑量以達到完全的緩解。在其他研究中,如在利用CT26腫瘤之實驗中,讓腫瘤在治療前生長21天。30Gy LTI之單一劑量僅會表現局部腫瘤生長之中度減緩,而對腫瘤之轉移擴散及存活期幾乎無影響。當該腫瘤係以3次每次20Gy之每日劑量輻射時,則皮下腫瘤會明顯地退化,但由BLI判斷擴散至遠位點。8隻小鼠中有7隻會在第84天前死亡,其中8隻中有1隻處於緩解中(圖5D)。當在第三次LTI劑量之後給予CY之單一劑量時,可減慢腫瘤生長之進展,但8隻小鼠中有6隻會在第84天前死亡而有1隻在第98天復發(圖5E)。
基於在上述RAG-2-/-實驗中應用CY及繼之以T細胞輸注,一組小鼠經以LTI治療後於24小時內進行脾切除術治療(圖5F)。利用抗-Thy1.2mAb管柱富集脾臟T細胞,並冷凍保存。在脾切除術之後即給予老鼠單一劑量之CY,48小時之後以i.v.方式輸注2.5x106T細胞。在該組別中,7隻小鼠中有4隻在第84天及第98天表現無腫瘤之現象。給
予LTI+CY+T細胞之組別的存活期相較給予LTI+CY而無T細胞之組別係顯著地增加(p<0.01)(圖5F)。因此,LTI、CY,及T細胞療法之組合相較僅給予LTI或與CY之組合更為有效。
這些數據顯示類似於當前人類所使用之SBRT(參見Chang & Timmerman Am.J.Clin.Oncol.30,637-644,2007;Brown & Koong Int.J.Radiat.Oncol.Biol.Phys.71,324-325,2008)的高劑量低分次腫瘤輻射可誘發完全的緩解及可誘發經以T細胞轉移之有效的系統性免疫力。第二個目的在於測定T細胞療法是否可提高治療轉移性腫瘤之放射療法的效能。為了最佳化局部輻射生長在BALB/c小鼠中之大的(>1公分直徑)皮下CT26結腸腫瘤的治療效能,將靶向腫瘤之單一輻射劑量從15 cGy升至30 cGy。在最高劑量下,約85%帶腫瘤小鼠在長達6個月中會發展出持久性完全的緩解。在至少100天中具有完全的緩解的幾乎所有小鼠可保護在腫瘤對側利用CT26腫瘤細胞之第二次激發挑戰而不受影響。由於係與輻射之同一天,在遠處之腫瘤激發挑戰會產生所有第二次腫瘤的進展性生長,而與原發性腫瘤之消除無關,輻射之後的保護不會立即出現,除非腫瘤激發挑戰係在輻射之後延遲30天。結果顯示,藉由輻射對輻射區之腫瘤細胞及基質之直接的細胞毒性效果的組合結合之後所發展出的系統性免疫力可最佳地解釋原發性腫瘤之消除。
獲自腫瘤輻射之後完全的緩解100天以上的小鼠之脾臟T細胞能夠將抗腫瘤免疫力移轉至帶CT26腫瘤之授受性宿主。在經去除T細胞之野生型小鼠或免疫力不足RAG-2-/-小鼠中之腫瘤輻射無法誘發完全的緩解。出人意料地,以靜胍內方式注射來自正常野生型小鼠之T細胞不會重建RAG-2-/-小鼠中之輻射的效能,但在輻射之後及恰好在注射T細胞之前投與CY單一劑量卻可產生緩解且存活期明顯增加。投與之CY可殺死腫瘤細胞,藉由改變樹突細胞子集之組成而增加抗原表
現細胞的功能,及選擇性地去除Treg細胞。LTI、CY,及T細胞療法之組合在預防RAG2-/-小鼠中腫瘤廣泛性傳播係有效的。
在輻射之前及之後研究浸潤CT26腫瘤之單核細胞的組成,以闡明免疫變化的機制。如在此前的研究中,腫瘤內單核細胞在輻射之前相較正常的脾臟中之彼等,存在有三個重要的變化:1)單核細胞(TAM)與骨髓(MDSC)抑制細胞相對CD8+ T細胞百分比係朝向有利於抑制細胞的不平衡狀態,2)相較於CD8+T細胞,係朝向有利於CD4+CD25+FoxP3+ Treg細胞的不平衡狀態,及3)CD8+T細胞會表現PD-1+Tim-3+「耗竭型」表型而Treg會表現經激活之PD-1+表型。30Gy單一劑量會降低TAM及MDSC相對CD8+T細胞之比例,及Treg相對CD8+T細胞之比例。相對抑制細胞而朝向有利於CD8+T細胞的平衡在人類腫瘤研究中與有利的預後具有關聯性。
在經設計以擴展該方法至乳房腫瘤的其他實驗中,以皮下方式注射4T1腫瘤細胞會導致局部性的生長,繼之會在肺中形成轉移。該4T1腫瘤需要3次每次20Gy之每日劑量以逆轉原發性腫瘤的生長,但無法控制轉移。基於具CT26腫瘤之RAG-/-結果,在4T1腫瘤輻射之後,立即切除小鼠脾臟並收集及冷凍保存脾臟T細胞。之後投與CY單一劑量,並在化療之後2天輸注冷凍保存的T細胞。此組合會誘發持久性完全的緩解。儘管在先前研究中,放射療法與以抗-CTLA4抗體之免疫療法組合時相較僅單一療法會導致在帶4T1腫瘤小鼠之存活期顯著的增加,但卻沒有經持性完全的緩解。
總之,該等研究顯示,高劑量低分次腫瘤輻射能夠誘發針對腫瘤的系統性免疫力,而該系統性免疫力可以利用T細胞轉移。當T細胞療法與輻射及化療組合使用時,可有效地治療轉移疾病。由於所有三種療法可以臨床應用,類似的組合在患有晚期實體腫瘤的患者是有效的。
材料及方法
動物。從傑克遜實驗室(Jackson Laboratories)(Bar Harbor,ME)購買野生型雄性BALB/c(H-2d)小鼠及雄性BALB/c RAG2-/-小鼠。小鼠為5-8週大。史丹福大學動物福利委員會(Stanford University Committee on Animal Welfare)(實驗動物關愛管理組(Administration Panel of Laboratory Animal Care))批准本研究所使用之所有小鼠方案。
細胞系。從ATCC(Manassas,VA)購買CT26細胞系(N-硝基-N-胺基甲酸甲酯-誘發之BALB/c鼠科結腸癌)。(自發性產生之)4T1細胞系亦獲自ATCC。4T1-LUC/GFP及CT26-LUC/GFP細胞系係經慢病毒轉導。慢病毒介體pHR-IG係由Yoshitaka Akagi博士製得。GFP-螢火蟲螢光素酶融合(GLF)基因係從pJW.GFP-yLuc(係由M.H.Bachmann博士友好提供)次選殖至pHR2以產生pHR2-GLF。按前述之方式製備可表現GLF之慢病毒顆粒。簡而言之,將293T細胞置於175cm2燒瓶中,並在次日,幾近匯合細胞在25μM氯奎(chloroquine)(Sigma)存在下,以45μg慢病毒介體連同封裝介體及VSV-G-表現介體(比例為3:2:1)進行共轉染。將WT 4T1及CT26細胞以0.25x106細胞/孔接種在6孔板中並在37℃培養箱中隔夜培養。接著,經滴定病毒在硫酸魚精蛋白(protamine sulfate)(10μg/ml)存在下用於轉染細胞系以增進轉導效率。然後利用FACS DIVA細胞分選儀將穩定的慢病毒轉導物以GFP螢光(100%純度)分選4次。經分選細胞經擴增及利用Xenogen IVIS光譜(Caliper Life Sciences;Hopkinton,MA)以及GFP進行生物發光的篩選。將細胞系維持補充有10%胎牛血清、L-穀胺醯胺、2-巰基乙醇、鏈黴素及青黴素之RPMI-1640完全培養基中。
疫苗接種。按前述之方式33進行腫瘤疫苗接種。5週大的雄性BALB/c小鼠以皮下方式注射1x106經輻射(50Gy)之CT26細胞及30μg CpG進行免疫。藉由Invivogen(San Diego,CA)合成包含未甲基化之
CG基序(CpG)(TCCATGACGTTCCTGACGTT)寡核酸並經硫代磷酸鹽穩定化。
輻射。利用Philips X射線裝置(200kV,10mA;Philips Electronic Instruments Inc.,Rahway,NJ),在84 cGy/min之速率下,利用0.5mm Cu過濾器進行全身輻射。對於局部腫瘤輻射而言,將未麻醉小鼠置於鉛夾具中,透過該夾具後軀中已確立的腫瘤會突出供輻射約2公分直徑的面積。利用在200kV下操作之Phillips X射線單元,以1.21Gy/min之劑量速率進行輻射(20mÅ,具附加濾器0.5mm銅,X射線源與目標之距離31公分,及半值層為1.3mm銅)。
細胞製備、脾切除術及T細胞之收集供自體的移植。根據前述程序製備骨髓及脾臟之單細胞懸浮液。利用MidiMACS體系(Miltenyi Biotech,Auburn,CA),分別以抗-Thy1.2-生物素單株抗體(mAb)(5a-8;Caltag,Burlingame,CA)及鏈黴抗生物素蛋白(streptavidin)-磁性珠(Miltenyi Biotech)富集某些樣本中的Thy1.2+細胞。利用抗-TCR-別藻藍蛋白(allophycocyanin)(APC)及抗-CD4或抗-CD8-異硫氰酸螢光素(FITC)mAb將富集細胞染色以檢查純度,而製劑均一地具有至少95%的純度。
FACS Aria(Becton Dickinson,Mountain View,CA)用於與FlowJo軟體(TreeStar,Ashland,OR)分析。在分選之後,細胞係藉由FACS再分析檢查及測定為>99%的純度。經收集T細胞係利用10% DMSO冷凍保存並在液氮中冷凍。在異氟烷麻醉下進行脾切除術。在開腹術之後,結紮脾臟器,及除去脾臟。利用單針(絲線5-0)縫合腹壁。在脾切除術之後的76小時內進行腹膜內注射500mg/kg環磷醯胺(Sigma Aldrich)。
活體內BLI成像。根據Edinger等人之方法進行活體內BLI。簡而言之,利用螢光素(10μg/g體重)以腹膜內方式注射小鼠。10分鐘之
後,利用IVIS100電荷偶聯裝置成像系統(Xenogen)對小鼠攝像5分鐘。分析成像數據及利用Living Image軟體(Xenogen)量化。
活體內T細胞之去除。從服務於La Jolla Institute for Allergy and Immunology(La Jolla,CA)的S.Schoenberger博士處獲得抗-CD4、抗CD8單株抗體。在輻射之後的第1、3、5天以腹膜內方式投與150mg GK1.5抗體進行活體內CD4細胞之去除。小鼠在輻射之後的第1、3、5天藉由i.p.方式注射100mg單株抗-CD8抗體以去除CD8 T細胞。
兔抗胸腺細胞血清(ATS)係購自Accurate Chemical and Scientific(Westbury,NY)。BALB/c接受者在輻射之後的第0、2、4天以腹膜內方式注射含於0.5mL鹽水中之0.05mL ATS。
組織病理學。按照史丹福動物福利協議指導(Stanford Animal Welfare protocol guidelines),當動物垂死時,或在移植之後100天,其仍存活而未死,則將動物進行安樂死。從宿主之肺及肝臟獲得組織病理學樣本。將組織固定在10%福爾馬林中,利用蘇木清(hematoxylin)及曙紅(eosin)染色及利用前述之Eclipse E1000M顯微鏡(Nikon,Melville,NY,USA)獲得圖像。
藉由著色及流式細胞儀分析腫瘤及脾臟單核細胞。從BALB/c接受者之脾臟及腫瘤結節製備單細胞懸浮液。下列mAb用於流式細胞儀分析:未共軛之抗-CD16/32(2.4G2 BD Biosciences)、抗-CD4-FITC(RM4-5 BD Biosciences)、抗-TCR-APC(H57-597 BD Biosciences)、抗-CD8-APC-Cy7,(53-6.7 BD Biosciences)、抗-PD-1 FITC(29F.1A12,Biolegend)、抗-Tim-3 PE(B8.2C12 Biolegend)、抗-FoxP 3 APC(FJK-16s,eBioscience)、抗-Gr-1 PE(RB6-8C5,Biolegend)、抗-CD11b FITC(M1/70,Biolegend)、抗-CD62L(MEL-14,Biolegend)、抗CD44 PerCP-Cy5(IM-7,eBioscience)、抗-Thy1.1PE-Cy7(HIS51,eBioscience)、抗-Thy1.2-生物素(5a-8;Caltag)。鏈黴抗生物素蛋白-PE係來自Beckton
Dickenson。所有染色係在經純化抗-CD16/32mAb之存在下於PBS/1%胎牛血清中進行。
統計分析。利用Prism軟體(SAS Institute Inc.,Cary,NC)產生出Kaplan-Meier存活曲線,並利用對數等級(Mantel-Cox)檢定分析統計差異。利用平均值之雙尾史都華氏t檢定(two-tailed Student's t-test of means)分析脾臟及腫瘤中細胞平均百分比的差異之統計顯著性。
Claims (17)
- 一種治療個體中癌症之方法,該方法包括:讓該個體之腫瘤位置接受高劑量輻射;在一段足以激活T細胞之時間之後,從該個體收集包括T細胞之細胞群;利用有效的化療劑量治療該個體;及將所收集細胞群再引入該個體,以便持久性緩解該癌症。
- 如請求項1之方法,其中該高劑量輻射為20至40Gy總劑量。
- 如請求項2之方法,其中該輻射係以單一劑量傳送。
- 如請求項2之方法,其中該輻射係於不超過一週的時間內以分次劑量方式傳送。
- 如請求項4之方法,其中該輻射係於不超過三天的時間內以分次劑量方式傳送。
- 如請求項1之方法,其中該足以激活T細胞之時間為2至6週。
- 如請求項6之方法,其中該等T細胞係從所收集的細胞群加以富集。
- 如請求項1之方法,其中該有效的化療劑量為非清髓劑量。
- 如請求項1之方法,其中該有效的化療劑量為清髓劑量。
- 如請求項9之方法,其進一步包括在化療之後將有效劑量的造血幹細胞/母細胞引入該個體內。
- 如請求項10之方法,其中該造血幹細胞/母細胞為同種細胞。
- 如請求項10之方法,其中該造血幹細胞/母細胞為自體性細胞。
- 如請求項1之方法,其中該癌症是可承受集中高劑量輻射之實體腫瘤。
- 如請求項13之方法,其中該腫瘤係選自肝癌、肺癌、腦癌、胰 癌、黑色素瘤及乳癌。
- 如請求項14之方法,其中該癌症係處於晚期狀態。
- 如請求項15之方法,其中該癌症係轉移性。
- 如請求項6之方法,其中該等細胞群係藉由血漿析離術收集。
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