CN112638428A - 嵌合抗原受体肿瘤浸润淋巴细胞 - Google Patents
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Abstract
公开了用于靶向治疗感染和表达癌症的组合物和方法。特别地,肿瘤浸润淋巴细胞(TIL)被遗传工程化以表达嵌合抗原受体(CAR)多肽,从而产生CAR‑TIL,其可以与过继性细胞转移一起使用,以靶向、穿透和杀伤实体肿瘤块。因此,还公开了在患有感染或癌症的受试者中提供免疫疗法的方法,其涉及所公开的CAR‑TIL的过继性转移。
Description
相关申请的交叉引用
本申请要求2018年6月12日提交的美国临时申请号62/683,792和2019年6月4日提交的申请序列号62/857,054的优先权,其全部内容通过引用并入本文。
背景技术
手术、放射疗法和化学疗法已经是治疗癌症包括白血病、实体瘤和转移(metastasis)的标准公认方法。多年来,已经研究了直接或间接使用身体免疫系统来缩小或根除癌症的免疫疗法(有时称为生物疗法(biological therapy/biotherapy)或生物反应调节剂疗法)作为常规癌症疗法的辅助。人们相信,人类免疫系统是癌症治疗的未开发资源,并且一旦免疫系统的组分被适当利用,就可开发有效的治疗。
嵌合抗原受体(CAR)是工程化的受体,其与免疫细胞组合新的特异性以靶向癌细胞。CAR-T细胞设计的基本原理涉及组合抗原结合和T细胞激活功能的重组受体。迄今为止,所有CAR-T细胞都涉及激活的外周血淋巴细胞(PBL)作为CAR的载体以消除造血(液体)癌。然而,激活的PBL在生物学上不能穿透实体肿瘤块。
发明内容
与PBL不同,肿瘤浸润淋巴细胞(TIL)具有穿透肿瘤块的能力。因此,公开了表达CAR多肽的TIL(本文中称为“CAR-TIL”),其可以与过继性细胞转移(adoptive celltransfer,ACT)一起使用以靶向和杀伤受试者中的癌症,包括实体瘤。
首先使用标准方法从手术切除的肿瘤离体扩增TIL。这可以包括选择具有最佳肿瘤反应性的TIL,然后用快速扩增方案(REP)进一步扩增这些TIL。然后可以遗传工程化TIL以表达一个或多个CAR用于表面表达。这种遗传操作可以发生在快速扩增方案(REP)阶段或REP前阶段。
通过用CAR工程化TIL,TIL被再靶向至不同的肿瘤抗原。在一些实施方案中,可以通过标准方法(例如CRISPR-Cas9;shRNA等)使CAR-TIL表达的内源性TcRs或其它分子沉默,以改善CAR识别的肿瘤抗原的靶向。
CAR多肽在胞外结构域中含有可结合癌细胞上的肿瘤抗原的靶向剂。与其它CAR一样,所公开的多肽也可含有跨膜结构域和能够激活免疫效应细胞的胞内结构域。例如,所述胞内结构域可以含有信号传导结构域和/或一个或多个共刺激信号传导区。
还公开了含有至少两种结合不同配体结合靶标的CAR的双CAR-TIL。在这些实施方案中,一个CAR可以仅包括CD3ζ结构域,并且另一个CAR可以仅包括一个或多个共刺激结构域。在这些实施方式中,双CAR-TIL激活需要两种靶向到靶细胞上共表达。
还公开了在患有癌症的受试者中提供抗肿瘤免疫的方法,其涉及向受试者施用有效量的所公开的CAR-TIL。
在附图和下面的描述中阐述了本发明的一个或多个实施例的细节。本发明的其它特征、目的和优点将从说明书和附图以及权利要求书中显而易见。
附图说明
图1A显示了针对MC-38的TIL的Cr51释放测定。图1B显示接受TIL的小鼠中MC-38肿瘤体积。图1C显示了通过CD45.2染色追踪的TIL优先再运输回MC-38肿瘤。
图2显示了在肿瘤中过继性转移7天后TIL的富集。
图3显示了7天后检测受体小鼠的脾、淋巴结和骨髓中的TIL。
图4显示了7天后肿瘤中幼稚T细胞和效应记忆细胞以及终末分化的效应细胞的比例。
图5是显示TIL中CAR表达的直方图。开放直方图显示CAR表达。浅灰色直方图显示染色的、未转导的T细胞。深灰色直方图显示未染色的细胞。
具体实施方式
本文公开了人肿瘤相关淋巴细胞(TIL),其被工程化以表达嵌合抗原受体(CAR)(本文中称为“CAR-TIL”),所述嵌合抗原受体可特异性识别诱导自身(induced-self)或外源蛋白质,这些蛋白质在正常细胞表面上完全不存在或仅以低水平存在,但被感染、转化、衰老和应激的细胞过表达(overexpressed)。因此,还公开了使用所公开的CAR-TIL在受试者中提供免疫疗法的方法。
CAR通常由三个结构域组成:胞外结构域、跨膜结构域和胞内结构域。胞外结构域包含靶向剂并且负责结合肿瘤抗原。它还任选地含有信号肽(SP),使得CAR可以被糖基化并锚定在免疫效应细胞的细胞膜中。跨膜结构域(TD)如其名字所暗示的那样,将胞外结构域连接到胞内结构域,并且当由细胞表达时位于细胞膜内。胞内结构域是CAR的工作端,其在抗原识别后将激活信号传输至免疫效应细胞。例如,所述胞内结构域可以含有信号传导结构域(ISD)和共刺激信号传导区(CSR)。由于所公开的CAR旨在与第二CAR组合,CAR可以具有需要第二CAR用于激活的不完全胞内结构域。
“信号传导结构域(SD)”通常含有免疫受体基于酪氨酸的激活基序(ITAM),当ITAM被磷酸化时,ITAM激活信号传导级联。术语“共刺激信号传导区(CSR)”是指来自共刺激蛋白受体,例如CD28、41BB和ICOS的胞内信号传导结构域,其能够增强T细胞受体对T细胞的激活。
其它CAR构建体描述于例如Fresnak AD等人Engineered T cells:the promiseand challenges of cancer immunotherapy.Nat Rev Cancer.2016 Aug 23;16(9):566-81中,其全部内容通过引用并入本文,以教导这些CAR模型。
例如,CAR可以是TRUCK、通用CAR、自驱动CAR、装甲CAR、自毁CAR、条件性CAR、标记CAR、TenCAR、双CAR或sCAR。
TRUCK(通用细胞因子杀伤重定向T细胞)共表达嵌合抗原受体(CAR)和抗肿瘤细胞因子。细胞因子表达可以是组成性的或由T细胞激活诱导。以CAR特异性为靶标,促炎性细胞因子的局部产生将内源性免疫细胞招募到肿瘤位点,并且可以增强抗肿瘤应答。
通用的同种异体CAR T细胞被工程化以不再表达内源性T细胞受体(TCR)和/或主要组织相容性复合体(MHC)分子,从而分别防止移植物抗宿主病(GVHD)或排斥。
自驱动CAR共表达CAR和趋化因子受体,所述趋化因子受体结合肿瘤配体,从而增强肿瘤归巢。
经过工程化以抵抗免疫抑制的CAR T细胞(装甲CAR)可以进行基因修饰,以不再表达各种免疫检查点分子(例如细胞毒性T淋巴细胞相关抗原4(CTLA4)或程序性细胞死亡蛋白1(PD1)),具有免疫检查点转换受体,或者可以与阻断免疫检查点信号传导的单克隆抗体一起施用。
可以使用通过电穿孔递送的RNA实现瞬时CAR表达。或者,可基于更昔洛韦与基因修饰的淋巴细胞中的胸苷激酶结合或最近描述的通过小分子二聚体激活人胱天蛋白酶9的系统,来实现TIL细胞的诱导性凋亡。
条件性CAR T细胞默认为无反应的,或“关闭”,直到加入小分子以完成回路,使得信号1和信号2两者能够完全转导,从而激活CAR T细胞。或者,T细胞可以被工程化以表达对随后施用的针对靶抗原的二级抗体具有亲和力的衔接子特异性受体。
标记CAR T细胞表达CAR加上现有单克隆抗体试剂结合的肿瘤表位。在无法忍受的副作用的情况下,施用单克隆抗体清除CAR T细胞并减轻症状,而没有另外的肿瘤外效应。
串联CAR(TanCAR)T细胞表达由两个连接的单链可变片段(scFv)组成的单个CAR,所述单链可变片段具有融合至胞内共刺激结构域和CD3ζ结构域的不同亲和力。仅当靶细胞共表达两种靶标时,才实现TanCAR T细胞激活。
双CAR T细胞表达具有不同配体结合靶标的两个单独CAR;一个CAR仅包括CD3ζ结构域,并且另一个CAR仅包括共刺激结构域。双CAR T细胞激活需要两种靶标在肿瘤上共表达。
安全CAR(sCAR)由与胞内抑制结构域融合的胞外scFv组成。共表达标准CAR的sCART细胞仅在遇到具有标准CAR靶标但缺乏sCAR靶标的靶细胞时才被激活。
胞外结构域包含靶向剂并且负责结合肿瘤抗原。它还任选地含有信号肽(SP),使得CAR可以被糖基化并锚定在免疫效应细胞的细胞膜中。肿瘤抗原是由肿瘤细胞产生的蛋白质,其引发免疫应答,特别是T细胞介导的免疫应答。抗原结合结构域可以是抗体或肿瘤抗原的天然配体。额外抗原结合结构域的选择将取决于待治疗的癌症的特定类型。
可以使用CAR靶向的抗原的例子包括CD19、CD22、CD123、CD38、CLL-1、TEM8/ANTXR1、CD56、NKG2D、B7H6、CD4、Gp120、Erb-B、SLAMF7、CD7、EGFR、TAG-72、MMG49、整联蛋白β7、FLT3、MESO、CD70、FOLR1、CD33、CD171、CD20、GD2、HER2、EGFRvIII、CSPG4、DNAX、BCMA、LeY、CD30、GPC3、CS1、CD138、Nectin4/FAP、CEA、EpCAM、PSCA、MUC1、CD80、CD86、CTLA-4、PD-1、CD10、EGFR806、IL12、TLR-9、CD83、CLEC12A、CD99、IL13Rα2、SSTR2和GPC3。
肿瘤抗原的其它非限制性实例包括以下:分化抗原,如酪氨酸酶、TRP-1、TRP-2和肿瘤特异性多向抗原,如MAGE-1、MAGE-3、BAGE、GAGE-1、GAGE-2、pi5;过表达的胚胎抗原,如CEA;过表达的癌基因和突变的肿瘤抑制基因,例如p53、Ras、HER-2/neu;染色体易位产生的独特肿瘤抗原;例如BCR-ABL、E2A-PRL、H4-RET、IGH-IGK、MYL-RAR;和病毒抗原,例如Epstein Barr病毒抗原EBVA和人乳头瘤病毒(HPV)抗原E6和E7。其它大的基于蛋白质的抗原包括TSP-180、MAGE-4、MAGE-5、MAGE-6、RAGE、NY-ESO、pl85erbB2、pl80erbB-3、c-met、nm-23H1、PSA、CA19-9、CA72-4、CAM17.1、NuMa、K-ras、β-连环蛋白、CDK4、Mum-1、p15、p16、43-9F、5T4、791Tgp72、α-甲胎蛋白、β-HCG、BCA225、BTAA、CA125、CA15-3\CA27.29\BCAA、CA195、CA242、CA-50、CAM43、CD68\P1、CO-029、FGF-5、G250、Ga733\EpCAM、HTgp-175、M344、MA-50、MG7-Ag、MOV18、NB/70K、NY-CO-1、RCASl、SDCCAG1 6、TA-90\Mac-2结合蛋白质\环孢素C相关蛋白、TAAL6、TAG72、TLP、TPS、GPC3、MUC16、LMP1、EBMA-1、BARF-1、CS1、CD319、HER1、B7H6、L1CAM、IL6和MET。肿瘤抗原包括例如神经胶质瘤相关抗原、癌胚抗原(CEA)、EGFRvIII、IL-llRa、IL-13Ra、EGFR、FAP、B7H3、Kit、CA LX、CS-1、MUC1、BCMA、bcr-abl、HER2、β-人绒毛膜促性腺激素、甲胎蛋白(AFP)、ALK、CD19、细胞周期蛋白Bl、凝集素反应性AFP、Fos相关抗原1、ADRB3、甲状腺球蛋白、EphA2、RAGE-1、RUl、RU2、SSX2、AKAP-4、LCK、OY-TESl、PAX5、SART3、CLL-1、岩藻糖基GM1、GloboH、MN-CA IX、EPCAM、EVT6-AML、TGS5、人端粒酶逆转录酶、聚唾液酸、PLAC1、RUl、RU2(AS)、肠道羧酸酯酶、lewisY、sLe、LY6K、mut hsp70-2、M-CSF、MYCN、RhoC、TRP-2、CYPIBI、BORIS、prostase、前列腺特异性抗原(PSA)、PAX3、PAP、NY-ESO-1、LAGE-la、LMP2、NCAM、p53、p53突变体、Ras突变体、gplOO、prostein、OR51E2、PANX3、PSMA、PSCA、Her2/neu、hTERT、HMWMAA、HAVCR1、VEGFR2、PDGFR-beta、存活素和端粒酶、天冬酰胺内肽酶(legumain)、HPV E6、E7、精子蛋白17、SSEA-4、酪氨酸酶、TARP、WT1、前列腺癌肿瘤抗原-1(PCTA-1)、ML-IAP、MAGE、MAGE-A1、MAD-CT-1、MAD-CT-2、MelanA/MART 1、XAGE1、ELF2M、ERG(TMPRSS2 ETS融合基因)、NA17、中性粒细胞弹性蛋白酶、肉瘤易位断点、NY-BR-1、ephnnB2、CD20、CD22、CD24、CD30、CD33、CD38、CD44v6、CD97、CD171、CD179a、雄激素受体、FAP、胰岛素生长因子(IGF)-I、IGFII、IGF-I受体、GD2、o-乙酰基-GD2、GD3、GM3、GPRC5D、GPR20、CXORF61、叶酸受体(FRa)、叶酸受体beta、ROR1、Flt3、TAG72、TN Ag、Tie2、TEM1、TEM7R、CLDN6、TSHR、UPK2、间皮素、RPSA、HPV、HPV E7、BING-4、CLCA2、9D7、SAP-1、BAGE家族(BAGE1)、CAGE家族(CAGE1)、GAGE家族(GAGE1-8)、LAGE家族(LAGE1-2)、MAGE家族(MAGEA1-A12、MAGEB1-B2、MAGEC2、MAGED4)、SAGE家族(SAGE1)、XAGE家族(包括XAGE1)、PRAME、Pme117、OCA2、BRCA1/2、CML66、FN1、MART-2、TGF-βRII、TCR、细胞周期蛋白-A1、D393-CD20n、GnTV、HERV-K-MEL、KK-LC-1、KM-HN-1、MUC1、NA88-A、SSX-4、TAG-1、TAG-2、TRAG-3、TRP2-INT2、MCC、CLPP、IGF2B3、KLK4、KIF20A、LGSN、MELOE-1和-2、MUC5AC、Gp100、EBV、ERBB2IP、CD62E、CD63、CD99、CD104、CD107b、CD164、CD175s、CD178、CD243、CD248、CD261、CD262、CD263、CD264、CD318及其任意组合。
在一些实施方式中,靶向剂是包含NKG2D蛋白的NKG2D诱饵,或包含NKG2D的胞外结构域的至少一部分的多肽,其能够结合来自MIC和RAET1/ULBP家族的诱导自身蛋白。
胞内结构域是CAR的工作端,其在抗原识别后将信号传输至免疫效应细胞,激活免疫效应细胞的至少一种正常效应子功能。T细胞的效应子功能例如可以是溶细胞活性或辅助活性,包括细胞因子的分泌。因此,所述胞内结构域可以包含T细胞受体(TCR)和任选的共受体的“胞内信号传导结构域”。虽然通常可以使用整个胞内信号传导结构域,但是在许多情况下,不必使用整个链。就使用胞内信号传导结构域的截短部分而言,只要它转导效应子功能信号,就可以使用这样的截短部分代替完整链。
调节以刺激方式作用的TCR复合体的初次激活的胞质信号传导序列可以含有称为基于免疫受体酪氨酸的激活基序(ITAM)的信号传导基序。含有胞质信号传导序列的ITAM的例子包括那些来源于CD8、CD3ζ、CD3δ、CD3γ、CD3ε、CD32(FcγRIIa)、DAP10、DAP12、CD79a、CD79b、FcγRIγ、FcγRIIIγ、FcεRIβ(FCERIB)和FcεRIγ(FCERIG)的ITAM。
在具体实施方案中,胞内信号传导结构域源自CD3 zeta(CD3ζ)(TCR zeta,基因库登陆号BAG36664.1)。T细胞表面糖蛋白CD3 Zeta(CD3ζ)链,也称为T细胞受体T3ζ链或CD247(分化簇247),是在人体中由CD247基因编码的蛋白质。
第一代CAR通常具有来自CD3ζ链的胞内结构域,其是来自内源性TCR的信号的主要传输者。第二代CAR将来自各种共刺激蛋白受体(例如,CD28、41BB、ICOS)的胞内信号传导结构域添加到CAR的胞内结构域以向T细胞提供另外的信号。临床前研究已经表明,第二代CAR设计改善T细胞的抗肿瘤活性。最近,第三代CAR组合多个信号传导结构域以进一步增强效能。用这些CAR移植的T细胞已证明不依赖于共刺激受体/配体相互作用的改善的扩增、激活、持久性和肿瘤根除效率(Imai C等人,Leukemia 2004 18:676-84;Maher J等人,NatBiotechnol 2002 20:70-5)。
例如,CAR的胞内结构域可被设计为包含CD3ζ信号传导结构域本身或与在本发明的CAR的上下文中有用的任何其他期望的胞质结构域组合。例如,CAR的胞质结构域可包含CD3ζ链部分和共刺激信号传导区。共刺激信号传导区是指CAR的包含共刺激分子的胞内结构域的部分。共刺激分子是淋巴细胞对抗原有效应答所需的除抗原受体或其配体之外的细胞表面分子。这些分子的实例包括CD27、CD28、4-1BB(CD137)、OX40、CD30、CD40、ICOS、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3,以及与CD83、CD8、CD4、b2c、CD80、CD86、DAP10、DAP12、MyD88、BTNL3和NKG2D特异性结合的配体。因此,虽然CAR主要以CD28作为共刺激信号传导元件来举例说明,但是其他共刺激元件可以单独使用或与其他共刺激信号传导元件组合使用。
在一些实施方案中,CAR包含铰链序列。铰链序列是促进抗体柔性的短氨基酸序列(参见,例如,Woof等人,Nat Rev Immunol,4(2):89-99(2004))。铰链序列可位于抗原识别部分(例如抗NKG2D scFv)和跨膜结构域之间。铰链序列可以是源自任何合适的分子或从任何合适的分子获得的任何合适的序列。在一些实施方案中,例如,铰链序列源自CD8α分子或CD28分子。
跨膜结构域可以源自天然来源或合成来源。当来源是天然的情况下,结构域可以源自任何膜结合蛋白或跨膜蛋白。例如,跨膜区可以源自(即至少包含以下的跨膜区)T细胞受体的α、β或ζ链、CD28、CD3ε、CD45、CD4、CD5、CD8(例如CD8α、CD8β)、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137或CD154、KIRDS2、OX40、CD2、CD27、LFA-1(CD11a、CD18)、ICOS(CD278)、4-1BB(CD137)、GITR、CD40、BAFFR、HVEM(LIGHTR)、SLAMF7、NKp80(KLRF1)、CD160、CD19、IL2Rβ、IL2Rγ、IL7Rα、ITGA1、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD11a、LFA-1、ITGAM、CD11b、ITGAX、CD11c、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、TNFR2、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(触觉)、CEACAM1、CRTAM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、SLAMF6(NTB-A、Ly108)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、和PAG/Cbp。或者,跨膜结构域可以是合成的,在这种情况下,它将主要包含疏水性残基,例如亮氨酸和缬氨酸。在一些情况下,在合成跨膜结构域的每个末端将发现苯丙氨酸、色氨酸和缬氨酸的三联体。短的寡肽或多肽接头,例如长度为2-10个氨基酸之间,可以形成CAR的跨膜结构域和内质结构域之间的连接。
在一些实施方案中,CAR具有多于一个跨膜结构域,其可以是相同跨膜结构域的重复,或可以是不同的跨膜结构域。
在一些实施方案中,CAR是多链CAR,如WO2015/039523中所述,其通过引用并入本文以用于本教导。多链CAR可以在不同的跨膜多肽中包含分开的胞外配体结合和信号传导结构域。信号传导结构域可被设计成在近膜位置组装,其形成更接近天然受体的柔性结构,其赋予最佳的信号转导。例如,多链CAR可包含部分FCERIα链和部分FCERIβ链,使得FCERI链自发地二聚在一起形成CAR。
还公开了结合至少两种靶抗原的双特异性CAR。还公开了设计为仅与结合不同抗原的另一种CAR联合作用的CAR。例如,在这些实施方案中,所公开的CAR的胞内结构域可以仅含有信号传导结构域(SD)或共刺激信号传导区(CSR),但不含有两者。如果第二CAR(或内源性T细胞)被激活,则其提供缺失的信号。例如,如果所公开的CAR含有SD而不是CSR,则只有在含有CSR的另一CAR(或T细胞)结合其相应抗原的情况下才激活含有此CAR的免疫效应细胞。同样,如果所公开的CAR含有CSR而不是SD,则只有在含有SD的另一个CAR(或T细胞)结合其相应抗原的情况下才激活含有此CAR的免疫效应细胞。
制备CAR TIL的方法
肿瘤浸润淋巴细胞(TIL)的产生为2步法:1)REP前(快速扩增)阶段,其中将新鲜肿瘤的片段或单细胞悬浮液在标准实验室培养基中用白介素-2铺板。然后选择在这些REP前培养物中生长的T细胞,并且2)在REP阶段用试剂如经辐射的饲养细胞和抗CD3抗体扩增至大量以实现期望的效果;即以足够大的培养量扩增TIL以治疗患者。REP阶段需要cGMP级试剂和30-40L培养基。然而,REP前阶段可以利用实验室级试剂(假设在REP阶段期间实验室级试剂被稀释),使得更容易引入用于改善TIL产生的替代策略。
自体TIL可以从切除的新鲜肿瘤的薄壁组织(parenchyma)获得。从患者获得肿瘤样品,并制备解剖刀切割碎片或单细胞悬浮液。单细胞悬液可以以任何合适的方式获得,例如机械方式(使用例如gentleMACSTM分离器(Miltenyi Biotec,Auburn,加利福尼亚)分解肿瘤)或酶促方式(例如胶原酶或DNase)。
淋巴细胞(包括肿瘤浸润淋巴细胞,如T细胞)的扩增可以通过本领域已知的许多方法中的任何一种来完成。例如,在存在饲养淋巴细胞和白介素-2(IL-2)、IL-7、IL-15、IL-21或其组合的情况下,使用非特异性T细胞受体刺激,T细胞可以快速扩增。非特异性T细胞受体刺激物可以包括例如约30ng/ml OKT3,一种小鼠单克隆抗CD3抗体(可从Raritan,新泽西或Miltenyi Biotec,Bergisch Gladbach,德国获得)。
扩增的TIL的特异肿瘤反应性可通过本领域已知的任何方法检测,例如,通过测量细胞因子释放(例如,干扰素-γ)或与肿瘤细胞共培养后的细胞毒性。在一个实施方案中,在细胞快速扩增之前,富集培养的TIL的CD8+或CD4+T细胞。在IL-2中培养TIL后,可以耗尽T细胞的CD4+细胞或CD8+细胞,并使用例如CD8/CD4微珠分离(例如,使用CliniMACS<plus>CD8/CD4微珠系统(Miltenyi Biotec))富集CD4+或CD8+细胞。在一些实施方案中,将促进自体TIL生长和激活的T细胞生长因子与自体TIL同时或在自体TIL后向哺乳类施用。T细胞生长因子可以是促进自体TIL生长和激活的任何合适的生长因子。合适的T细胞生长因子的例子包括白介素(IL)-2、IL-7、IL-15、IL-12和IL-21,它们可以单独使用或以各种组合使用,例如IL-2和IL-7、IL-2和IL-15、IL-7和IL-15、IL-2、IL-7和IL-15、IL-12和IL-7、IL-12和IL-15、或IL-12和IL2。IL-12是优选的T细胞生长因子。
TIL被遗传工程化以表达CAR。这可在REP前阶段期间、REP阶段期间、或REP阶段之后发生。编码所公开的CAR的核酸序列及其区域可以使用本领域已知的重组方法获得,例如通过从表达基因的细胞筛选文库,通过从已知包括相同基因的运载体衍生基因,或通过使用标准技术直接从含有相同基因的细胞和组织分离。或者,感兴趣的基因可以合成产生,而不是克隆。
编码CAR的核酸的表达通常通过将编码CAR多肽的核酸与启动子可操作地连接,并将构建体并入表达运载体中来实现。典型的克隆运载体含有转录和翻译终止子、起始序列和可用于调节所需核酸序列表达的启动子。
所公开的核酸可以克隆到多种类型的运载体中。例如,核酸可被克隆到包括但不限于质粒、噬菌粒、噬菌体衍生物、动物病毒和黏粒的运载体中。特别感兴趣的运载体包括表达运载体、复制运载体、探针生成运载体和测序运载体。
此外,表达运载体可以以病毒运载体的形式提供给细胞。病毒运载体技术是本领域公知的,并且描述于例如Sambrook等人(2001,分子克隆:实验室手册,冷泉港实验室,纽约)和其它病毒学和分子生物学手册中。可用作运载体的病毒包括但不限于逆转录病毒、腺病毒、腺相关病毒、疱疹病毒和慢病毒。通常,合适的运载体含有在至少一种生物体中有功能的复制起点、启动子序列、方便的限制性核酸内切酶位点和一个或多个选择性标记。在一些实施方案中,多核苷酸运载体是慢病毒或逆转录病毒运载体。
已经开发了许多基于病毒的系统用于将基因转移到哺乳类细胞中。例如,逆转录病毒为基因递送系统提供了方便的平台。可以使用本领域已知的技术将选择的基因插入运载体并包装在逆转录病毒颗粒中。然后可分离重组病毒并将其体内或离体递送到受试者的细胞中。
合适的启动子的一个实例是即刻早期巨细胞病毒(CMV)启动子序列。该启动子序列是强组成性启动子序列,其能够驱动与其可操作地连接的任何多核苷酸序列的高水平表达。合适的启动子的另一个实例是伸长生长因子-1α(EF-1α)。然而,也可以使用其它组成性启动子序列,包括但不限于猿猴病毒40(SV40)早期启动子、MND(骨髓增生性肉瘤病毒)启动子、小鼠乳腺肿瘤病毒(MMTV)、人免疫缺陷病毒(HIV)长末端重复序列(LTR)启动子、MoMuLV启动子、禽白血病病毒启动子、Epstein-Barr病毒即刻早期启动子、Rous肉瘤病毒启动子,以及人类基因启动子,例如但不限于肌动蛋白启动子、肌球蛋白启动子、血红蛋白启动子和肌酸激酶启动子。或者,启动子可以是诱导性启动子。诱导性启动子的实例包括但不限于金属硫蛋白启动子、糖皮质激素启动子、孕酮启动子和四环素启动子。
另外的启动子元件,例如增强子,调节转录起始的频率。通常,这些启动子位于起始位点上游30-110bp的区域,尽管最近已显示许多启动子也含有起始位点下游的功能元件。启动子元件之间的间隔通常是柔性的,以便当元件相对于彼此反转或移动时,启动子功能得以保留。
为了评估CAR多肽或其部分的表达,待导入TIL的表达运载体也可含有选择性标记基因或报道基因或两者,以促进从试图通过病毒运载体转染或感染的细胞群体中鉴定和选择表达细胞。在其它方面,选择性标记可以携带在单独的DNA片上并用于共转染程序中。选择性标记和报告基因两者的侧翼都可以有适当的调节序列,以便能够在宿主细胞中表达。有用的选择性标记包括例如抗生素抗性基因。
报告基因用于鉴定潜在转染的细胞和用于评估调节序列的功能性。通常,报告基因是不存在于受体生物体或组织中或不被受体生物体或组织表达的基因并且其编码多肽,所述多肽的表达通过一些容易检测的特性例如酶活性来表现。在DNA导入受体细胞后的合适时间测定报告基因的表达。合适的报告基因可以包括编码萤光素酶、β-半乳糖苷酶、氯霉素乙酰转移酶、分泌性碱性磷酸酶或绿色荧光蛋白基因的基因。合适的表达系统是公知的,可以使用已知技术制备或商业获得。通常,具有最小5'侧翼区的显示报告基因表达最高水平的构建体鉴定为启动子。这种启动子区可与报告基因连接,并用于评估试剂调控启动子驱动的转录的能力。
将基因导入细胞并在细胞中表达的方法是本领域已知的。在表达运载体的情况下,运载体可通过本领域的任何方法容易地导入宿主细胞,例如哺乳类、细菌、酵母菌或昆虫细胞。例如,可通过物理、化学或生物手段将表达运载体转移到宿主细胞中。
将多核苷酸导入宿主细胞的物理方法包括磷酸钙沉淀、脂转染、粒子轰击、显微注射、电穿孔等。用于产生包含运载体和/或外源性核酸的细胞的方法是本领域众所周知的。参见,例如,Sambrook等人(2001,分子克隆:实验室手册,冷泉港实验室,纽约)。
将感兴趣的多核苷酸导入宿主细胞的生物学方法包括使用DNA和RNA运载体。病毒运载体,特别是逆转录病毒运载体,已经成为将基因插入哺乳类,例如人细胞的最广泛使用的方法。
将多核苷酸导入宿主细胞的化学手段包括胶体分散系统,例如大分子复合体、纳米胶囊、微球、珠和基于脂质的系统,包括水包油乳液、胶束、混合胶束和脂质体。用作体外和体内递送媒剂的示例性胶体系统是脂质体(例如人工膜囊泡)。
在使用非病毒递送系统的情况下,示例性递送媒剂是脂质体。在另一个方面,核酸可以与脂质缔合。与脂质缔合的核酸可以包封在脂质体的含水内部,散布在脂质体的脂质双层内,通过与脂质体和寡核苷酸都缔合的连接分子附着于脂质体,包封在脂质体中,与脂质体复合,分散在含有脂质的溶液中,与脂质混合,与脂质组合,作为悬浮液包含在脂质中,包含或与胶束复合,或者以其它方式与脂质缔合。与脂质、脂质/DNA或脂质/表达运载体缔合的组合物不限于溶液中的任何特定结构。例如,它们可以以双层结构、作为胶束或以“塌陷”结构呈现。它们也可以简单地散布在溶液中,可能形成大小或形状不一致的聚集体。脂质是脂肪物质,其可以是天然存在的或合成的脂质。例如,脂质包括天然存在于细胞质中的脂肪滴以及含有长链脂族烃及其衍生物的化合物类,例如脂肪酸、醇、胺、氨基醇和醛。适合使用的脂质可以从商业来源获得。例如,二巯基磷脂酰胆碱(“DMPC”)可以从Sigma,St.Louis,Mo.获得;二乙酰基磷酸酯(“DCP”)可以从K&K Laboratories(纽约州普莱恩维尤)获得;胆固醇(“Choi”)可从Calbiochem-Behring获得;二巯基磷脂酰甘油(“DMPG”)和其它脂质可以从Avanti Polar Lipids,Inc(阿拉巴马州伯明翰)获得。
治疗方法
CAR-TIL可引发抗肿瘤细胞的抗肿瘤免疫应答。由公开的CAR-TIL引发的抗肿瘤免疫应答可以是主动或被动免疫应答。此外,CAR-TIL可以是过继性免疫疗法方法的一部分,其中CAR-TIL诱导免疫应答。
所公开的CAR-TIL可单独施用,或作为药物组合物与稀释剂和/或与其他组分如IL-2、IL-15或其他细胞因子或细胞群体组合施用。简言之,药物组合物可包含如本文所述的靶细胞群体,以及一种或多种药学上或生理学上可接受的载体、稀释剂或赋形剂组合。这样的组合物可以包含缓冲液,例如中性缓冲盐水、磷酸盐缓冲盐水等;碳水化合物,例如葡萄糖、甘露糖、蔗糖或葡聚糖、甘露醇;蛋白质;多肽或氨基酸,例如甘氨酸;抗氧化剂;螯合剂,例如EDTA或谷胱甘肽;助剂(例如,氢氧化铝);和防腐剂。在一些实施方案中,用于所公开的方法的组合物被配制用于静脉内施用。药物组合物可以以任何适当的方式施用以治疗癌症。施用的量和频率将由诸如患者的状况和患者疾病的严重程度的因素决定,尽管适当的剂量可以通过临床试验来决定。
当指出“免疫有效量”、“抗肿瘤有效量”、“肿瘤抑制有效量”或“治疗量”时,待施用的本发明组合物的精确量可由医师考虑患者(受试者)的年龄、体重、肿瘤大小、感染或转移(metastasis)程度和状况的个体差异来确定。通常可以说,包含本文所述CAR-TIL细胞的药物组合物可以104至109个细胞/kg体重的剂量施用,例如105至106个细胞/kg体重,包括那些范围内的所有整数值。CAR-TIL细胞组合物也可以以这些剂量多次施用。细胞可以通过使用免疫疗法中公知的输注技术施用(参见,例如Rosenberg等人,New Eng.J.of Med.319:1676,1988)。对于特定患者的最佳剂量和治疗方案可以由医学领域的技术人员通过监测患者的疾病症状并相应地调整治疗而容易地确定。
所公开的组合物的施用可以以任何方便的方式进行,包括通过注射、输血或植入。本文所述的组合物可皮下、皮内、瘤内、结节内、髓内、肌内、通过静脉内注射或腹膜内施用给患者。在一些实施方案中,通过皮内或皮下注射将所公开的组合物施用给患者。在一些实施方案中,所公开的组合物通过静脉内注射施用。该组合物也可直接注射到肿瘤、淋巴结或感染部位。
在某些实施方案中,将所公开的CAR-TIL与任何数量的相关治疗模式联合(例如,在此之前、同时或之后)施用于患者,所述治疗模式包括但不限于沙利度胺、地塞米松、硼替佐米和来那度胺。在进一步的实施方案中,CAR修饰的免疫效应细胞可以与化学疗法、放射、免疫抑制剂(如环孢菌素、硫唑嘌呤、甲氨蝶呤、霉酚酸酯和FK506)、抗体或其它免疫消融剂(如CAM PATH)、抗CD3抗体或其它抗体疗法、环磷酰胺、氟达拉滨、环孢菌素、FK506、雷帕霉素、霉酚酸、类固醇、FR901228、细胞因子和辐射组合使用。在一些实施方案中,CAR-TIL与骨髓移植、使用化疗剂如氟达拉滨、外束放射疗法(XRT)、环磷酰胺或抗体如OKT3或CAMPATH的T细胞消融疗法联合(例如,在此之前、同时或之后)向患者施用。在另一个实施方案中,本发明的细胞组合物在B细胞消融疗法(例如与CD20反应的试剂,例如Rituxan)后施用。例如,在一些实施方案中,受试者可经历高剂量化学疗法的标准治疗,随后进行外周血干细胞移植。在某些实施方案中,在移植后,受试者接受本发明的扩增的免疫细胞的输注。在另外的实施方案中,在手术之前或之后施用扩增的细胞。
所公开的方法的癌症可以是经历不受控制的生长、侵袭或转移(metastasis)的受试者中的任何细胞。癌症包括前列腺癌、卵巢癌、肺腺癌、乳腺癌、子宫内膜癌、胃癌、结肠癌和胰腺癌。在一些情况下,癌症包含骨髓增生异常综合征、急性髓细胞白血病或双表型白血病。
在一些方面,癌症可以是目前使用放射疗法的任何赘生物或肿瘤。或者,癌症可以是对使用标准方法的放射疗法不够敏感的赘生物或肿瘤。因此,癌症可以是肉瘤、淋巴瘤、白血病、癌、母细胞瘤或生殖细胞瘤。所公开的组合物可以用于治疗的癌症的代表性但非限制性的列表包括淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、蕈样肉芽肿、霍奇金病、髓细胞白血病、膀胱癌、脑癌、神经系统癌、头颈癌(head and neck cancer)、头颈鳞状细胞癌、肾癌、肺癌(lung cancer)(如小细胞肺癌和非小细胞肺癌)、神经母细胞瘤/成胶质细胞瘤、卵巢癌、胰腺癌、前列腺癌(prostate cancer)、皮肤癌、肝癌、黑色素瘤、口腔、喉、喉头和肺的鳞状细胞癌、子宫内膜癌、宫颈癌(cervical cancer)、宫颈癌(cervical carcinoma)、乳腺癌、上皮癌、肾脏癌、泌尿生殖癌、肺癌(pulmonary cancer)、食道癌、头颈癌(head and neckcarcinoma)、大肠癌、造血系统癌;睾丸癌;结肠和直肠癌、前列腺癌(prostatic cancer)和胰腺癌。
所公开的CAR-TIL可以与具有细胞毒性或细胞抑制作用的任何化合物、部分或基团组合使用。药物部分包括化疗剂,其可以作为微管蛋白抑制剂、有丝分裂抑制剂、拓扑异构酶抑制剂或DNA嵌入剂,特别是用于癌症疗法的那些化疗剂。
所公开的CAR-TIL可以与检查点抑制剂组合使用。两种已知的抑制性检查点通路涉及通过细胞毒性T淋巴细胞抗原-4(CTLA-4)和程序性死亡1(PD-1)受体的信号传导。这些蛋白是共信号传导(cosignaling)分子的CD28-B7家族的成员,在T细胞功能的所有阶段都发挥重要作用。PD-1受体(也称为CD279)在激活的T细胞表面表达。其配体PD-L1(B7-H1;CD274)和PD-L2(B7-DC;CD273)在APC如树突状细胞或巨噬细胞的表面上表达。PD-L1是主要的配体,而PD-L2具有更受限制的表达模式。当配体与PD-1结合时,抑制信号被传输到T细胞中,这减少了细胞因子的产生并抑制了T细胞增殖。检查点抑制剂包括但不限于阻断PD-1(纳武单抗(BMS-936558或MDX1106)、CT-011、MK-3475)、PD-L1(MDX-1105(BMS-936559)、MPDL3280A、MSB0010718C)、PD-L2(rHIgM12B7)、CTLA-4(艾匹利木单抗(MDX-010)、曲美利木单抗(CP-675,206))、IDO、B7-H3(MGA271)、B7-H4、TIM3、LAG-3(BMS-986016)的抗体。
程序性死亡1(PD-1)的人单克隆抗体和单独使用抗PD-1抗体或与其它免疫治疗剂组合使用治疗癌症的方法描述于美国专利号8,008,449中,所述专利出于这些抗体的目的通过引用并入。抗PD-L1抗体及其用途描述于美国专利号8,552,154中,所述专利出于这些抗体的目的通过引用并入。包含抗PD-1抗体或抗PD-L1抗体的抗癌剂描述于美国专利号8,617,546中,所述专利出于这些抗体的目的通过引用并入。
在一些实施方案中,PDL1抑制剂包含特异性结合PDL1的抗体,例如BMS-936559(Bristol-Myers Squibb)或MPDL3280A(Roche)。在一些实施方案中,PD1抑制剂包含特异性结合PD1的抗体,例如派姆单抗(Merck)、纳武单抗(Bristol-Myers Squibb)或MEDI4736(AstraZeneca)。PD-1的人单克隆抗体和单独使用抗PD-1抗体或与其它免疫治疗剂组合使用治疗癌症的方法描述于美国专利号8,008,449中,所述专利出于这些抗体的目的通过引用并入。抗PD-L1抗体及其用途描述于美国专利号8,552,154中,所述专利出于这些抗体的目的通过引用并入。包含抗PD-1抗体或抗PD-L1抗体的抗癌剂描述于美国专利号8,617,546中,所述专利出于这些抗体的目的通过引用并入。
所公开的CAR-TIL可以与其他癌症免疫疗法组合使用。有两种不同类型的免疫疗法:被动免疫疗法使用免疫系统的组分来指导针对癌细胞的靶向细胞毒性活性,而不必在患者中引发免疫应答,而主动免疫疗法主动触发内源性免疫应答。被动策略包括使用由B细胞响应于特定抗原而产生的单克隆抗体(mAb)。1970年代杂交瘤技术的发展和肿瘤特异性抗原的鉴定允许mAb的药物开发,所述mAb可以特异性靶向肿瘤细胞以被免疫系统破坏。迄今为止,mAb一直是免疫疗法的最大成功案例;2012年,头三种最畅销的抗癌药物是mAb。其中有利妥昔单抗(Rituxan,Genentech),其与在B细胞恶性肿瘤如非霍奇金淋巴瘤(NHL)表面上高度表达的CD20蛋白结合。FDA批准利妥昔单抗用于与化学疗法组合治疗NHL和慢性淋巴细胞性白血病(CLL)。另一种重要的mAb是曲妥珠单抗(Herceptin;Genentech),它通过靶向HER2的表达而彻底改变了HER2(人表皮生长因子受体2)阳性乳腺癌的治疗。
产生最佳“杀伤”CD8 TIL应答还可需要T细胞受体激活加共刺激,这可通过连接肿瘤坏死因子受体家族成员包括OX40(CD134)和4-1BB(CD137)来提供。OX40特别令人感兴趣,因为用激活(激动剂)抗OX40 mAb进行治疗增强T细胞分化和溶细胞功能,从而增强了针对多种肿瘤的抗肿瘤免疫。
在一些实施方案中,这样的另外的治疗剂可以选自抗代谢物,例如甲氨蝶呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷、氟达拉滨、5-氟尿嘧啶、癸基嘧啶、羟基脲、天冬酰胺酶、吉西他滨或克拉屈滨。
在一些实施方案中,这种另外的治疗剂可以选自烷化剂,例如甲氯雷他敏、thioepa、苯丁酸氮芥、美法仑、卡莫司汀(BSNU)、洛莫司汀(CCNU)、环磷酰胺、白消安、二溴甘露醇、链脲佐菌素、达卡巴嗪(DTIC)、丙卡巴嗪、丝裂霉素C、顺铂和其它铂衍生物,例如卡铂。
在一些实施方案中,这种另外的治疗剂可选自抗有丝分裂剂,诸如紫杉烷类,例如多西他赛和紫杉醇,以及长春花生物碱类,例如长春地辛、长春新碱、长春碱和长春瑞滨。
在一些实施方案中,这样的另外的治疗剂可以选自拓扑异构酶抑制剂,例如拓扑替康或伊立替康,或细胞抑制药物,例如依托泊苷和替尼泊苷。
在一些实施方案中,这种另外的治疗剂可以选自生长因子抑制剂,例如ErbB1(EGFR)抑制剂(例如EGFR抗体,例如扎鲁图单抗、西妥昔单抗、帕尼图单抗或尼妥珠单抗或其它EGFR抑制剂,例如吉非替尼或厄洛替尼),另一种ErbB2(HER2/neu)抑制剂(例如HER2抗体,例如曲妥珠单抗、曲妥珠单抗-DM l或培图珠单抗)或EGFR和HER2两者的抑制剂,例如拉帕替尼)。
在一些实施方案中,这样的另外的治疗剂可以选自酪氨酸激酶抑制剂,例如伊马替尼(Glivec,Gleevec STI571)或拉帕替尼。
因此,在一些实施方案中,所公开的抗体与奥法木单抗、扎木单抗、达雷木单抗、雷珠单抗、尼妥珠单抗、帕尼单抗、hu806、达利珠单抗(Zenapax)、巴利昔单抗(Simulect)、英夫利西单抗(Remicade)、阿达木单抗(Humira)、那他利珠单抗(Tysabri)、奥马珠单抗(Xolair)、依法利珠单抗(Raptiva)和/或利妥昔单抗组合使用。
在一些实施方案中,与CAR-TIL组合使用用于治疗上述病症的治疗剂可以是抗癌细胞因子、趋化因子或其组合。合适的细胞因子和生长因子的例子包括IFNγ、IL-2、IL-4、IL-6、IL-7、IL-10、IL-12、IL-13、IL-15、IL-18、IL-23、IL-24、IL-27、IL-28a、IL-28b、IL-29、KGF、IFNα(例如INFa2b)、IFN、GM-CSF、CD40L、Flt3配体、干细胞因子、安塞司亭和TNFa。合适的趋化因子可以包括Glu-Leu-Arg(ELR)-阴性趋化因子,如来自人CXC和C-C趋化因子家族的IP-10、MCP-3、MIG和SDF-la。合适的细胞因子包括细胞因子衍生物、细胞因子变体、细胞因子片段和细胞因子融合蛋白。
在一些实施方案中,与CAR-TIL组合用于治疗上述癌症的治疗剂可以是细胞周期控制/凋亡调节剂(regulator)(或“调节剂(regulating agent)”)。细胞周期控制/凋亡调节剂可以包括靶向和调控细胞周期控制/凋亡调节剂的分子,例如(i)cdc-25(例如NSC663284),(ii)过刺激细胞周期的细胞周期蛋白依赖性激酶(例如黄嘌呤核苷(L868275,HMR1275),7-羟基星形孢菌素(UCN-01,KW-2401)和roscovitine(R-roscovitine,CYC202)),和(iii)端粒酶调控剂(例如BIBR1532,SOT-095,GRN163和例如US6,440,735和US6,713,055中所述的组合物)。干扰凋亡通路的分子的非限制性实例包括TNF相关的凋亡诱导配体(TRAIL)/凋亡-2配体(apo-2L)、激活TRAIL受体的抗体、IFN和反义Bcl-2。
在一些实施方案中,与CAR-TIL组合使用用于治疗上述癌症的治疗剂可以是激素调节剂,例如用于抗雄激素和抗雌激素疗法的试剂。这种激素调节剂的实例是他莫昔芬、伊多昔芬、氟维司群、羟洛昔芬、托瑞米芬、雷洛昔芬、己烯雌酚、乙炔雌二醇/炔雌醇、抗雄激素(例如氟他胺/尤乐欣)、孕激素(例如己酸羟孕酮、甲羟孕酮/普维拉、甲地孕酮/美格司他)、肾上腺皮质类固醇(例如氢化可的松、泼尼松)、促黄体生成激素释放激素(及其类似物和其它LHRH激动剂例如布舍瑞林和戈舍瑞林)、芳香酶抑制剂(例如阿那曲唑/阿立米得、氨基谷酰胺/胞苷、依西美坦)或激素抑制剂(例如奥曲肽/善得定)。
在一些实施方案中,与CAR-TIL组合用于治疗上述癌症的治疗剂可以是抗癌核酸或抗癌抑制性RNA分子。
如上所述,联合给药可以是同时施用、单独施用或依次施用。对于同时施用,所述试剂可以作为一种组合物或作为单独的组合物适当地施用。
在一些实施方案中,所公开的CAR-TIL与放射疗法组合施用。放射疗法可以包含向患者提供放射或者放射性药物的相关施用。放射源可以在被治疗的患者的外部或内部(放射治疗可以是例如外束放射疗法(EBRT)或近距离放射疗法(BT)的形式)。可用于实践这些方法的放射性元素包括例如镭、铯-137、铱-192、镅-241、金-198、钴-57、铜-67、锝-99、碘化物-123、碘化物-131和铟-111。
在一些实施方案中,所公开的CAR-TIL与外科手术组合施用。
可以使用用于CAR表达的几种不同的方法,包括逆转录病毒转导(包括γ-逆转录病毒)、慢病毒转导、转座子/转座酶(Sleeping Beauty和PiggyBac系统)和信使RNA转移介导的基因表达。基因编辑(基因插入或基因缺失/破坏)对于工程化CAR-T细胞的可能性也变得越来越重要。CRISPR-Cas9、ZFN(锌指核酸酶)和TALEN(转录激活因子样效应子核酸酶)系统是三种潜在的方法,通过它们可以产生CAR-TIL。
定义
术语“氨基酸序列”是指表示氨基酸残基的缩写、字母、字符或单词的列表。本文所用的氨基酸缩写是氨基酸的常规单字母代码,表示如下:A,丙氨酸;B,天冬酰胺或天冬氨酸;C,半胱氨酸;D,天冬氨酸;E,谷氨酸(glutamate)、谷氨酸(glutamic acid);F,苯丙氨酸;G,甘氨酸;H,组氨酸;I,异亮氨酸;K,赖氨酸;L,亮氨酸;M,蛋氨酸;N,天冬酰胺;P,脯氨酸;Q,谷氨酰胺;R,精氨酸;S,丝氨酸;T,苏氨酸;V,缬氨酸;W,色氨酸;Y,酪氨酸;Z,谷氨酰胺或谷氨酸。
术语“抗体”是指免疫球蛋白、其保持特异性结合能力的衍生物、以及具有与免疫球蛋白结合结构域同源或大部分同源的结合结构域的蛋白质。这些蛋白质可能源自天然来源,或者部分或全部合成产生。抗体可以是单克隆或多克隆的。抗体可以是来自任何物种的任何免疫球蛋白类别的成员,包括任何人类类别:IgG、IgM、IgA、IgD和IgE。在示例性实施方案中,本文所述方法和组合物所用的抗体是IgG类别的衍生物。除了完整的免疫球蛋白分子,术语“抗体”中还包括那些免疫球蛋白分子的片段或聚合物,以及选择性结合靶抗原的人或人源化形式的免疫球蛋白分子。
术语“抗体片段”指小于全长的抗体的任何衍生物。在示例性实施方案中,抗体片段至少保留全长抗体的特异性结合能力的显著部分。抗体片段的实例包括但不限于Fab、Fab'、F(ab')2、scFv、Fv、dsFv双抗体、Fc和Fd片段。抗体片段可以通过任何手段产生。例如,抗体片段可以通过完整抗体的片段化来以酶的方式或者以化学的方式产生,其可以从编码部分抗体序列的基因重组产生,或者其可以全部或部分合成产生。抗体片段可以任选地是单链抗体片段。或者,片段可包含例如通过二硫键连接在一起的多个链。片段也可以任选地是多分子复合体。功能性抗体片段通常包含至少约50个氨基酸,更通常包含至少约200个氨基酸。
术语“抗原结合位点”是指与抗原上的表位特异性结合的抗体区。
术语“适配体”指结合特定靶分子的寡核酸或肽分子。这些分子通常选自随机序列库。所选适配体能够适应独特的三级结构并以高亲和力和特异性识别靶分子。“核酸适配体”是通过其构象与靶分子结合,从而抑制或阻止这种分子的功能的DNA或RNA寡核酸。核酸适配体可由DNA、RNA或其组合构成。“肽适配体”是具有插入恒定支架蛋白内的可变肽序列的组合蛋白分子。肽适配体的鉴定通常在严格的酵母双杂交条件下进行,这增加了所选肽适配体在胞内环境中稳定表达和正确折叠的可能性。
术语“载体”是指化合物、组合物、物质或结构,其当与化合物或组合物组合时,其有助于或促进化合物或组合物的制备、储存、施用、递送、有效性、选择性或任何其它特征以用于其预期用途或目的。例如,可选择载体以使活性成分的任何降解最小化并使受试者中的任何不良副作用最小化。
术语“嵌合分子”是指通过接合以其天然状态分开存在的两个或更多个分子而创造的单个分子。该单个嵌合分子具有其所有组成分子的所需功能性。一种类型的嵌合分子是融合蛋白。
术语“工程化抗体”指至少包含抗体片段的重组分子,所述抗体片段包含源自抗体重链和/或轻链的可变结构域的抗原结合位点,并且可以任选地包含来自任何Ig类(例如IgA、IgD、IgE、IgG、IgM和IgY)的抗体的全部或部分的可变和/或恒定结构域。
术语“表位”是指抗体优先和特异性结合的抗原区。单克隆抗体优先结合分子的单个特定表位,所述表位可以是分子定义的。在本发明中,多特异性抗体可以识别多个表位。
术语“融合蛋白”是指通过借助在一个多肽的氨基端和另一个多肽的羧基端之间形成的肽键接合两个或多个多肽而形成的多肽。融合蛋白可以通过化学偶联组成多肽形成,或者它可以作为来自编码单个连续融合蛋白的核酸序列的单个多肽表达。单链融合蛋白是具有单个连续多肽主链的融合蛋白。融合蛋白可以使用分子生物学中的常规技术制备,以将两个基因按读框接合成单个核酸,然后在产生融合蛋白的条件下在适当的宿主细胞中表达核酸。
术语“Fab片段"指包含通过用木瓜蛋白酶切割抗体生成的抗原结合位点的抗体片段,所述木瓜蛋白酶在H链间二硫键的N端的铰链区处切割,并从一个抗体分子生成两个Fab片段。
术语“F(ab')2片段”指含有两个抗原结合位点的抗体片段,所述片段是通过用胃蛋白酶切割抗体分子生成,所述胃蛋白酶在H链间二硫键的C端铰链区处切割。
术语“Fc片段”指包含其重链恒定结构域的抗体片段。
术语“Fv片段”是指包含其重链和轻链的可变结构域的抗体片段。
“基因构建体”是指核酸,例如运载体、质粒、病毒基因组等,其包括多肽的“编码序列”或以其他方式可转录为生物活性RNA(例如反义、诱饵、核酶等)的核酸,所述核酸可以转染到细胞中,例如在某些实施方案中为哺乳类细胞,并且可以导致编码序列在用构建体转染的细胞中表达。基因构建体可以包括与编码序列以及内含子序列、多腺苷酸化位点、复制起点、标记基因等可操作地连接的一个或多个调节元件。
术语“同一性”是指两个核酸分子或多肽之间的序列同一性。同一性可以通过比较每个序列中的位置来确定,所述位置可以为了比较的目的而比对。当被比较序列中的一个位置被相同碱基占据时,则分子在该位置是相同的。核酸或氨基酸序列之间的相似性或同一性程度是核酸序列共有位置处相同或匹配核苷酸数目的函数。可以使用各种比对算法和/或程序来计算两个序列之间的同一性,包括FASTA或BLAST,它们可作为GCG序列分析程序包(威斯康星大学麦迪逊分校,威斯康星州)的一部分获得,并且可以与例如默认设置一起使用。例如,预期与本文所述的特异性多肽具有至少70%、85%、90%、95%、98%或99%同一性并且优选表现出基本上相同功能的多肽,以及编码此类多肽的多核苷酸。除非另有说明,否则相似性得分将基于BLOSUM62的使用。当使用BLASTP时,相似性百分比基于BLASTP阳性得分,序列同一性百分比基于BLASTP同一性得分。BLASTP“同一性”表示高得分序列对中相同的总残基的数目和分数;BLASTP“阳性”表示比对得分为正值且彼此相似的残基的数目和分数。与本文公开的氨基酸序列具有这些同一性或相似性程度或任何中等同一性或相似性程度的氨基酸序列被本公开预期和涵盖。相似多肽的多核苷酸序列是使用遗传密码推导的,并且可以通过常规手段获得,特别是通过使用遗传密码反向翻译其氨基酸序列。
术语“接头”是本领域公认的,并且是指连结两个化合物(诸如两个多肽)的分子或分子组。接头可以由单个连接分子组成,或者可以包含连接分子和间隔子分子,旨在将连接分子和化合物分开特定距离。
术语“多价抗体”指包含多于一个抗原识别位点的抗体或工程化抗体。例如,“二价”抗体具有两个抗原识别位点,而“四价”抗体具有四个抗原识别位点。术语“单特异性”、“双特异性”、“三特异性”、“四特异性”等是指存在于多价抗体中的不同抗原识别位点特异性的数量(与抗原识别位点的数量相对)。例如,“单特异性”抗体的抗原识别位点都结合相同的表位。“双特异性”抗体具有至少一个结合第一表位的抗原识别位点和至少一个结合不同于第一表位的第二表位的抗原识别位点。“多价单特异性”抗体具有多个抗原识别位点,它们都结合相同的表位。“多价双特异性”抗体具有多个抗原识别位点,其中一些结合第一表位,一些结合不同于第一表位的第二表位。
术语“核酸”指天然或合成的分子,其包含单个核苷酸或两个或更多个核苷酸,所述核苷酸通过一个核苷酸的3'位置处的磷酸基团与另一个核苷酸的5'端连接。核酸不受长度限制,因此核酸可以包括脱氧核糖核酸(DNA)或核糖核酸(RNA)。
术语“可操作地连接”是指核酸与另一核酸序列的功能关系。启动子、增强子、转录和翻译终止位点和其它信号序列是与其它序列可操作地连接的核酸序列的实例。例如,DNA与转录控制元件的可操作连接是指DNA和启动子之间的物理和功能关系,使得通过RNA聚合酶从启动子起始这种DNA的转录,所述RNA聚合酶特异性识别、结合和转录DNA。
术语“肽”、“蛋白质”和“多肽”可互换使用,是指包含两个或更多个氨基酸的天然或合成分子,所述氨基酸通过一个氨基酸的羧基连接至另一个氨基酸的α氨基。
术语“药学上可接受的”是指在合理的医学判断范围内,适用于与人类和动物的组织接触而没有过度的毒性、刺激性、过敏反应或其它问题或并发症,与合理的效益/风险比相称的那些化合物、材料、组合物和/或剂型。
术语“多肽片段”或“片段”当用于指特定多肽时,是指与参考多肽本身相比氨基酸残基缺失的多肽,但其中剩余的氨基酸序列通常与参考多肽的氨基酸序列相同。这种缺失可以发生在参考多肽的氨基端或羧基端,或者两者。片段通常为至少约5、6、8或10个氨基酸长、至少约14个氨基酸长、至少约20、30、40或50个氨基酸长、至少约75个氨基酸长、或至少约100、150、200、300、500或更多个氨基酸长。片段可保留参考多肽的一种或多种生物活性。在各种实施方案中,片段可以包含参考多肽的酶活性和/或相互作用位点。在另一个实施方案中,片段可具有免疫原性性质。
术语“蛋白质结构域”是指蛋白质的一部分、蛋白质的多个部分或显示结构完整性的整个蛋白质;这种确定可以基于蛋白质的一部分、蛋白质的多个部分或整个蛋白质的氨基酸组成。
术语“单链可变片段或scFv”指其中重链结构域和轻链结构域连接的Fv片段。一个或多个scFv片段可与其它抗体片段(例如重链或轻链的恒定结构域)连接以形成具有一个或多个抗原识别位点的抗体构建体。
本文所用的“间隔子”是指接合包含融合蛋白的蛋白质的肽。通常,间隔子除了接合蛋白质或保持它们之间的一些最小距离或其它空间关系之外没有特定的生物学活性。然而,可以选择间隔子的组成氨基酸以影响分子的一些性质,例如分子的折叠、净电荷或疏水性。
当涉及多肽(包括抗体)或受体时,本文所用的术语“特异性结合”是指决定蛋白质或多肽或受体在蛋白质和其它生物制剂的异质群体中存在的结合反应。因此,在指定条件(例如,在抗体的情况下的免疫测定条件)下,当特异性配体或抗体不以显著量结合样品中存在的其它蛋白质或与配体或抗体在生物体中可能接触的其他蛋白质时,所述配体或抗体“特异性结合”其特定“靶标”(例如,抗体特异性结合内皮抗原)。通常,“特异性结合”第二分子的第一分子与该第二分子具有大于约105M-1(例如106M-1、107M-1、108M-1、109M-1、1010M-1、1011M-1和1012M-1或更高)的亲和力常数(Ka)。
本文所用的术语“特异性递送”是指分子与带有特定靶分子或标记物的细胞或组织的优先缔合,而不是与缺乏该靶分子的细胞或组织的优先缔合。当然,识别到在分子和非靶细胞或组织之间可能发生一定程度的非特异性相互作用。然而,特异性递送可以被区分为通过特异性识别靶分子介导。通常,特异性递送导致递送的分子与带有靶分子的细胞之间的缔合比递送的分子与缺乏靶分子的细胞之间的缔合强得多。
术语“受试者”是指作为施用或治疗目标的任何个体。受试者可以是脊椎动物,例如哺乳类。因此,受试者可以是人类或动物患者。术语“患者”是指在临床医生例如医师治疗下的受试者。
术语“治疗有效”是指所用组合物的量足以缓解疾病或病症的一种或多种原因或症状的量。这种缓解仅需要减少或改变,而不必消除。
术语“转化”和“转染”是指将核酸例如表达运载体导入受体细胞,包括将核酸导入所述细胞的染色体DNA。
术语“治疗”是指旨在治愈、缓解、稳定或预防疾病、病理状况或病症的患者的医学管理。该术语包括积极治疗,即专门针对疾病、病理状况或病症的改善的治疗,并且还包括因果治疗,即针对移除相关疾病、病理状况或病症的原因的治疗。此外,该术语包括姑息治疗,即设计用于减轻症状而不是治愈疾病、病理状况或病症的治疗;预防性治疗,即旨在最小化或部分或完全抑制相关疾病、病理状况或病症的发展的治疗;和支持性治疗,即用于补充针对相关疾病、病理状况或病症的改善的另一种特定疗法的治疗。
术语“变体”指具有保守氨基酸取代、非保守氨基酸取代(即简并变体)、编码氨基酸的每个密码子(即DNA和RNA)的摆动位置中的取代、添加至肽的C端的氨基酸、或与参考序列具有60%、70%、80%、90%、95%、96%、97%、98%、99%序列同一性的肽的氨基酸或肽序列。
术语“运载体”指能够将与运载体序列连接的另一种核酸转运到细胞中的核酸序列。术语“表达运载体”包括含有适合于细胞表达的形式的基因构建体(例如,与转录控制元件连接)的任何运载体(例如,质粒、黏粒或噬菌体染色体)。
已经描述了本发明的多个实施例。然而,应当理解,在不脱离本发明的精神和范围的情况下,可以进行各种修改。因此,其它实施例也在所附权利要求的范围内。
实施例
实施例1:
图1A显示了针对MC-38的TIL的Cr51释放测定。图1B显示接受TIL的小鼠中MC-38肿瘤体积。图1C显示了通过CD45.2染色追踪的TIL优先再运输回MC-38肿瘤。
实施例2:
通过皮下注射肿瘤细胞悬浮液在供体小鼠(CD45.2+)中生成MC38肿瘤。一旦肿瘤形成,分离CD45.2+TIL并在IL-2存在下离体扩增。将这些注射到带有肿瘤的受体小鼠(CD45.1+)中。过继性转移的TIL的组织分布由于CD45.2的表达而通过流式细胞术追踪。
用这种方法,观察到过继性转移的TIL(CD3+CD45.2+)在一周的过程中逐渐富集在肿瘤中(图2)。重新定位于受体小鼠肿瘤的大部分转移的TIL是CD8+T细胞(图2)。
尽管在第1天在受体小鼠的脾、淋巴结和骨髓中瞬时检测到一小部分过继性转移的TIL;到输注后第7天,几乎所有转移的TIL(和所有CD8+转移的TIL)都运输到肿瘤(图3)。结果表明TIL具有肿瘤趋向性。几乎所有的TIL都直接进入肿瘤。
小鼠T细胞的分化状态可以通过某些表面标记的表达来确定。例如,幼稚和Tscm淋巴细胞是CD62L+CD44-;中枢记忆T淋巴细胞是CD62L+CD44+;效应记忆T细胞是CD62L-CD44+;终末分化的T细胞是CD62L-CD44-。
基于对T细胞分化表现型随时间的分析,观察到过继性TIL转移后幼稚T细胞的比例降低,而效应记忆(EM)和终末分化效应子(EF)的比例增加(图4)。这一观察结果表明,在运输到受体小鼠的肿瘤后,TIL由于抗原刺激获得效应表现型。换句话说,TIL不仅能够在输注后有效运输至肿瘤,而且当它们遇到肿瘤细胞时,它们能主动识别肿瘤抗原。
有趣的是,在第1-3天注射TIL后,几乎所有的TIL都具有幼稚表现型。之后,肿瘤中效应记忆细胞的比例增加。
实施例3:
按照标准程序,在IL-2存在下扩增来自黑色素瘤患者的肿瘤浸润淋巴细胞。在REP后四十八小时,用编码抗IL13RA2 CAR(Hu07-28z)的逆转录病毒运载体转导细胞。一天后重复转导,并在用生物素化的蛋白-L和PE-缀合的链霉抗生物素蛋白染色后通过流式细胞术评估CAR表达(图5)。
除非另有定义,本文所用的所有技术和科学术语具有与所公开的发明所属领域的技术人员通常理解的相同的含义。本文引用的出版物和它们所引用的材料具体引入作为参考。
本领域技术人员将认识到或能够使用不超过常规实验确定本文所述的本发明的具体实施方案的许多等同方案。这些等同方案旨在被包括在所附权利要求中。
Claims (7)
1.一种重组淋巴细胞,其通过包含以下步骤的方法产生:
(a)从哺乳类受试者获得并扩增肿瘤浸润淋巴细胞;以及
(b)遗传工程化自体肿瘤浸润淋巴细胞以表达嵌合抗原受体CAR,其中所述CAR包含胞外结构域、跨膜结构域、胞内信号传导结构域和共刺激信号传导区,和
其中所述胞外结构域包含肿瘤抗原结合剂。
2.如权利要求1所述的重组淋巴细胞,其中所述肿瘤浸润淋巴细胞的内源性T细胞受体TcRs已经缺失或沉默。
3.如权利要求1或2所述的重组淋巴细胞,其中所述共刺激信号传导区包含选自由CD27、CD28、4-1BB、OX40、CD30、CD40、PD-1、ICOS、淋巴细胞功能相关抗原-1LFA-1、CD2、CD7、LIGHT、NKG2C、B7-H3、与CD83特异性结合的配体及其任何组合组成的组的共刺激分子的胞质结构域。
4.如权利要求1至3中任一项所述的多肽,其中所述胞内信号传导结构域包括CD3ζ信号传导结构域。
5.一种在受试者中提供抗肿瘤或抗病毒免疫的方法,所述方法包含向所述受试者施用有效量的如权利要求1至4中任一项所述的重组淋巴细胞,从而在所述哺乳类中提供抗肿瘤或抗病毒免疫。
6.如权利要求5所述的方法,其还包含向所述受试者施用检查点抑制剂。
7.如权利要求6所述的方法,其中所述检查点抑制剂包含抗PD-1抗体、抗PD-L1抗体、抗CTLA-4抗体或其组合。
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