CN109496155A - 用于治疗癌症的免疫检查点抑制剂和细胞毒性t细胞 - Google Patents
用于治疗癌症的免疫检查点抑制剂和细胞毒性t细胞 Download PDFInfo
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Abstract
本文提供用于治疗癌症的方法,所述方法包括联合施用免疫检查点抑制剂和包括细胞毒性T细胞(CTL)的组合物。
Description
相关申请
本申请要求于2016年5月25日提交的美国临时专利申请序列号62/341,402的优先权的权益,其特此通过引用被整体并入。
背景
鼻咽癌是一种开始于鼻咽中的头颈癌。最近,有新出现的证据表明,暴露于EB病毒(EBV)能够促成鼻咽癌的病理学。EB病毒相关性鼻咽癌(NPC)在东南亚地区是地方性的,其中中国南方每10万人发病率高达25-50个病例。虽然目前的标准疗法对于患有I期或II期疾病的子集通常是治愈性的,但是高比例的患者复发并且许多患者仍然最初被诊断患有晚期III期或IV期疾病,其中总体5年的存活率显著降低。因此,存在对于开发用于NPC的改进的疗法的需要。
概述
在某些方面,本文提供通过施用(例如,联合地)免疫检查点抑制剂和包括细胞毒性T细胞(CTL)的组合物来在受试者中治疗癌症(例如,NPC)的方法,所述细胞毒性T细胞(CTL)表达对于I类MHC上呈递的癌症相关性肽特异性的T细胞受体。
在一些实施方案中,免疫检查点抑制剂是与免疫检查点蛋白(如CTLA4、PD-1、PD-L1、PD-L2、A2AR、B7-H3、B7-H4、BTLA、KIR、LAG-3、TIM-3、IDO、TDO和VISTA)结合的蛋白质或多肽(例如,抗体或抗体的抗原结合片段)。在一些实施方案中,免疫检查点蛋白是CTLA4、PD-1、PD-L1、TIM-3或LAG-3。在一些实施方案中,免疫检查点抑制剂与免疫检查点蛋白结合,使得免疫检查点抑制剂抑制免疫检查点蛋白的活性。在一些实施方案中,免疫检查点抑制剂抑制免疫检查点蛋白与相关受体/配体之间的相互作用。在一些实施方案中,免疫检查点抑制剂是纳武单抗(nivolumab)、派姆单抗(pembrolizumab)、皮地利珠单抗(pidilizumab)、AMP-224、AMP-514、STI-A1110、TSR-042、RG-7446、BMS-936559、BMS-936558、MK-3475、CT O1 1、MPDL3280A、MEDI-4736、MSB-0020718C、AUR-012和STI-A1010。
在一些实施方案中,组合物中的细胞毒性T细胞可以对于I类MHC上呈递的任何癌症相关性肽(例如,由受试者中的肿瘤细胞和/或癌细胞表达的癌症相关性肽)是特异性的。在一些实施方案中,癌症相关性肽是病毒肽。在一些实施方案中(例如,当受试者患有EBV相关性NPC或另一种EBV相关性癌症时),病毒肽是EBV肽。在一些实施方案中,EBV肽包括LMP1肽、LMP2A肽、和/或EBNA1肽。
在一些实施方案中,CTL对于受试者是同种异体的(例如,从细胞库获得)。在一些实施方案中,CTL对于受试者是自体的。CTL和免疫检查点抑制剂可以被共同施用或顺序施用。在一些实施方案中,方法还包括向受试者施用化学治疗剂。
在一些方面,本文提供在受试者中治疗癌症(例如鼻咽癌)的方法,所述方法包括通过将包括CTL的样品与呈递CMV肽的抗原呈递细胞(APC)孵育、从而诱导样品中肽特异性CTL的增殖来生成肽特异性CTL,以及将肽特异性CTL与本文所描述的免疫检查点抑制剂组合施用至受试者。在一些实施方案中,通过将APC与编码EBV肽的核酸构建体(例如,AdE1-LMPpoly)孵育、从而诱导APC呈递EBV肽,来使APC呈递EBV肽。在一些实施方案中,APC可以是B细胞、抗原呈递T细胞、树突状细胞、或人工抗原呈递细胞(例如,表达CD80、CD83、41BB-L和/或CD86的细胞系(如aK562细胞))。在一些实施方案中,EBV肽包括LMP1肽或LMP1肽的片段、LMP2A肽或LMP2A肽的片段、和/或EBNA1肽或EBNA1肽的片段。在一些实施方案中,EBV肽包括表1中列出的序列。在一些实施方案中,一种或更多种免疫检查点抑制剂被施用。可以通过本领域已知的任何技术施用免疫检查点抑制剂。在一些实施方案中,免疫检查点抑制剂被瘤内施用。在一些实施方案中,样品包括一种或更多种细胞因子或外周血单核细胞(PBMC)。
附图的简要说明
图1具有两幅图片,所述图片示出免疫检查点分子(即,LAG-3、TIM-3、CTLA4、或PD-1)的表达。图片A描绘了表达PD-1、TIM-3、LAG-3和CTLA-4的HLA-多聚体阳性CD8阳性淋巴细胞的百分比。图片B描绘了在过继性T细胞疗法后显示出病情稳定(SD)或疾病进展(PD)的患有无/微小残留病变(N/MRD)和活动性复发性/转移性疾病(ARMD)的NPC患者中施用的CTL免疫疗法中PD-1阳性淋巴细胞、TIM-3阳性淋巴细胞、LAG-3阳性淋巴细胞和CTLA-4阳性淋巴细胞的百分比。
详细说明
概述
在某些方面,本文提供使用组合疗法在受试者中治疗癌症的方法,所述组合疗法包含与细胞毒性T细胞(CTL)免疫疗法组合的一种或更多种免疫检查点抑制剂的施用(例如,联合施用)。在一些实施方案中,癌症是EBV相关性NPC,并且施用至受试者的CTL表达T细胞受体,所述T细胞受体对于I类MHC上呈递的表达肽和EBV表位具有结合特异性。
定义
为了方便起见,此处收集了说明书、实施例和所附权利要求中采用的某些术语。
本文中使用冠词“一(a)”和“一(an)”指所述冠词的一个或多于一个(即,至少一个)语法对象。举例来说,“一要素”意指一个要素或多于一个要素。
如本文所使用的,术语“施用”意指向受试者提供药剂或药物组合物,并且包含(但不限于)由医疗技术人员施用和自我施用。这样的药剂可以含有例如本文所描述的肽、本文提供的抗原呈递细胞和/或本文提供的CTL。
术语“生物样品”、“组织样品”或简单地“样品”各自指从受试者的组织获得的细胞的集合。组织样品的来源可以是如来自新鲜、冷冻和/或保存的器官、组织样品、活组织检查、或抽出物的实体组织;血液或任何血液成分、血清、血液;体液,如脑脊液、羊水、腹膜液或间质液、尿液、唾液、粪便、眼泪;或来自受试者的妊娠或发育的任何时间的细胞。
术语“结合”或“相互作用”指由于例如生理条件下的静电相互作用、疏水相互作用、离子相互作用和/或氢键相互作用而在两个分子之间(例如,T细胞受体(TCR)和肽/MHC之间)的缔合(其可以是稳定的缔合)。
如本文所使用的,术语“癌症”包含(但不限于)实体肿瘤和血液传播肿瘤。术语癌症包含皮肤、组织、器官、骨骼、软骨、血液和血管的疾病。术语“癌症”还包含原发性癌症和转移性癌症。
术语“表位”意为能够与抗体特异性结合的蛋白决定簇。表位通常由分子的化学活性表面基团(如氨基酸或糖侧链)组成。某些表位可以由T细胞受体或抗体能够结合的特定氨基酸序列限定。
如本文所使用的,短语“药学上可接受的”指在合理的医学判断范围内适合于与人类和动物的组织接触,而没有过度毒性、刺激、过敏反应或其他问题或并发症,与合理的利益/风险比相称的那些药剂、化合物、材料、组合物和/或剂量。
如本文所使用的,短语“药学上可接受的载体”意为药学上可接受的材料、组合物或运载体(vehicle)(如液体或固体填充剂、稀释剂、赋形剂、或溶剂包封材料),其涉及将药剂从器官、或身体的一部分携带或转运至另一器官、或身体的一部分。每种载体在与制剂的其他成分相容并且对患者无害的意义上必须是“可接受的”。可以用作药学上可接受的载体的材料的一些实例包含:(1)糖(如乳糖、葡萄糖和蔗糖);(2)淀粉(如玉米淀粉和马铃薯淀粉);(3)纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素和乙酸纤维素);(4)粉状黄芪胶;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂(如可可脂和栓剂蜡);(9)油类(如花生油、棉籽油、红花子油、麻油、橄榄油、玉米油和大豆油);(10)二醇类(如丙二醇);(11)多元醇(如甘油、山梨糖醇、甘露糖醇和聚乙二醇);(12)酯类(如油酸乙酯和十二烷酸乙酯);(13)琼脂;(14)缓冲剂(如氢氧化镁和氢氧化铝);(15)藻酸;(16)无热原水;(17)等渗盐水;(18)林格溶液;(19)乙醇;(20)pH缓冲溶液;(21)聚酯、聚碳酸酯和/或聚酸酐;以及(22)药物制剂中采用的其他无毒相容物质。
如本文所使用的,“预防”病况的治疗剂指化合物,当在紊乱或病况的发作之前被施用至统计样品时,相对于未经处理的对照样品,所述化合物降低经处理的样品中的紊乱或病况的发生,或相对于未经处理的对照样品,所述化合物延迟紊乱或病况的一种或更多种症状的发作或降低紊乱或病况的一种或更多种症状的严重性。
如本文所使用的,术语“受试者”意为被选择用于治疗或疗法的人类或非人类动物。
如本文所使用的,短语“治疗有效量”和“有效量”意为以适用于任何医学治疗的合理的利益/风险比在受试者中的至少一个细胞亚群中对于产生期望的治疗效果有效的药剂的量。
在受试者中“治疗”疾病或“治疗”患有疾病的受试者指使受试者经受药物治疗(例如,施用药物),使得疾病的至少一种症状被减轻或防止恶化。
如本文所使用的,术语“联合施用”意为将两种或更多种药剂作为单一治疗方案的一部分施用至感兴趣的受试者。一次或多次施用可以是同时的或顺序的,即,施用一种药剂,随后在稍后的时间施用第二药剂(和/或第三药剂等),只要施用的药剂共存于正在被治疗的受试者中,或当所述靶组织仍处于所述其他药剂的影响下时,至少一种药剂将有机会作用于其他药剂的相同靶组织。在某一实施方案中,待施用的药剂可以包含在单一药物组合物中并且一起被施用。在某一实施方案中,药剂被同时施用(包含通过单独途径)。在某一实施方案中,一种或更多种药剂被连续施用,而其他药剂仅以预定间隔(如单次大剂量、或以较小剂量每周两次等)施用。
免疫检查点抑制剂
在某些方面,本文提供与通过向受试者施用组合疗法来在受试者中治疗癌症(例如,鼻咽癌)有关的方法,组合疗法包括向受试者施用免疫检查点抑制剂和包括细胞毒性T细胞(CTL)的组合物两者,所述细胞毒性T细胞(CTL)表达对于I类MHC上呈递的癌症相关性肽特异性的T细胞受体。
免疫检查点抑制剂和CTL组合物可以被一起施用或分别施用。其可以被同时施用或顺序施用。当被顺序施用时,在一些实施方案中,将在CTL组合物之前(例如,至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24小时之前、至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30天之前)施用免疫检查点抑制剂。当被顺序施用时,在一些实施方案中,将在免疫检查点抑制剂之前(例如,至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24小时之前、至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30天之前)施用CTL组合物。
免疫检查点抑制概括地指抑制用作检查点的生物学途径,以预防或下调免疫应答。这样的途径往往被癌细胞使用以避免抗肿瘤免疫应答。在某些实施方案中,方法包含向受试者施用靶向免疫检查点蛋白的一种或更多种免疫检查点抑制剂。免疫检查点蛋白包含(但不限于)CTLA4、PD-1、PD-L1、PD-L2、A2AR、B7-H3、B7-H4、BTLA、KIR、LAG-3、TIM-3、IDO、TDO和VISTA。在一些实施方案中,一种或更多种免疫检查点抑制剂可以靶向一种或更多种免疫检查点蛋白。
在一些实施方案中,免疫检查点抑制剂是蛋白质(如可溶性融合蛋白)。在一些实施方案中,这样的蛋白质包括CTLA4、PD-1、PD-L1、PD-L2、A2AR、B7-H3、B7-H4、BTLA、KIR、LAG-3、TIM-3、IDO、TDO或VISTA的受体/配体结合域(例如,胞外域)。在一些实施方案中,受体/配体结合域被融合至免疫球蛋白Fc域。可以通过标准重组DNA技术产生这样的融合蛋白。例如,根据常规技术将编码不同肽序列的DNA片段在框内连接在一起,例如通过采用平端末端或交错端末端用于连接、限制酶消化以提供适当的末端、酌情补平粘性端、碱性磷酸酶处理以避免不期望的连接、以及酶促连接。在另一个实施方案中,可以通过常规技术(包含自动DNA合成仪)合成融合基因。可替代地,可以使用锚定引物进行基因片段的PCR扩增,所述锚定引物在两个连续基因片段之间产生互补突出端,其随后可以退火并且再扩增以生成嵌合基因序列(参见,例如,Current Protocols in Molecular Biology,Ausubel etal.,eds.,John Wiley&Sons:1992)。此外,许多表达运载体是商业可获得的,其已经编码融合部分。
在某些实施方案中,免疫检查点抑制剂是与免疫检查点蛋白(例如,CTLA4、PD-1、PD-L1、PD-L2、A2AR、B7-H3、B7-H4、BTLA、KIR、LAG-3、TIM-3、IDO、TDO或VISTA)结合并且抑制免疫检查点蛋白(例如,CTLA4、PD-1、PD-L1、PD-L2、A2AR、B7-H3、B7-H4、BTLA、KIR、LAG-3、TIM-3、IDO、TDO或VISTA)的抗体或所述抗体的抗原结合片段。如本文所使用的,术语“抗体”可以指完整抗体及所述完整抗体的抗原结合片段两者。术语“抗体”包含,例如,单克隆抗体、多克隆抗体、嵌合抗体、人源化抗体、人抗体、多特异性抗体(例如,双特异性抗体)、单链抗体和抗原结合抗体片段。抗体的抗原结合片段指保留与抗原结合的能力的抗体的一个或更多个片段。结合片段的实例包含Fab、Fab’、F(ab’)2、Fv、scFv、二硫键连接的Fv、Fd、双抗体、单链抗体、骆驼抗体、分离的CDRH3、以及保留完整抗体的可变区的至少一部分的其他抗体片段。可以使用常规重组技术和/或酶促技术获得这样的抗体片段,并且可以以与完整抗体相同的方式筛选抗原结合。
在一些实施方案中,免疫检查点抑制剂是与编码免疫检查点抑制剂(例如,CTLA4、PD-1、PD-L1、PD-L2、A2AR、B7-H3、B7-H4、BTLA、KIR、LAG-3、TIM-3、IDO、TDO或VISTA)的mRNA特异性结合的抑制性核酸(例如,siRNA分子、shRNA分子、反义RNA)。可以通过经由核糖核酸酶III或Dicer酶的化学合成、体外转录、或长dsRNA的消化来制备抑制性核酸分子。抑制性核酸分子可以被体外递送至细胞或体内递送至例如哺乳动物的肿瘤或缺氧组织。可以使用本领域已知的典型递送手段。例如,可以使用例如PCT申请号:PCT/US09/036223、PCT/US09/061381、PCT/US09/063927、PCT/US09/063931和PCT/US09/063933(其中的每个特此通过引用被整体并入)中描述的方法和组合物系统地递送干扰RNA。在某些实施方案中,抑制性核酸被局部递送。例如,当本文所描述的抑制性核酸被用于治疗癌症时,可以通过如例如Takahashi et al.,Journal of Controlled Release 116:90-95(2006)和Kim et al.,Journal of Controlled Release 129:107-116(2008)(其中的每个通过引用被整体并入)中所描述的肿瘤内注射完成向肿瘤的递送。
在其他实施方案中,免疫检查点抑制剂是小的有机分子(例如,具有低于约5kD、优选小于约2kD的分子量的分子),并且通常排除寡核苷酸和寡肽。小分子包含例如拟肽物、寡糖、类固醇等。WO 2016/041511、WO 2015/034820、WO 2010/005958、WO 2014/159248、美国公布申请2011/0318373、以及Weinmann,H.,Chem.Med.Chem.2016,11,450-466(及其中引用的参考文献)中描述了代表性的小分子检查点抑制剂。
各种免疫检查点抑制剂是本领域已知的。在一些实施方案中,免疫检查点抑制剂是纳武单抗、派姆单抗、皮地利珠单抗、AMP-224、AMP-514、STI-A1110、TSR-042、RG-7446、BMS-936559、BMS-936558、MK-3475、CT O11、MPDL3280A、MEDI-4736、MSB-0020718C、AUR-012和STI-A1010。
细胞毒性T淋巴细胞
在一些实施方案中,施用至受试者的CTL组合物中的CTL表达T细胞受体,所述T细胞受体与I类MHC上呈递的肽(例如,包括癌症相关性表位的肽)特异性结合。在一些实施方案中,I类MHC具有α链多肽,所述α链多肽是HLA-A、HLA-B、HLA-C、HLA-E、HLA-F、HLA-g、HLA-K或HLA-L。在一些实施方案中,肽是本文所描述的肽。在一些实施方案中,样品中的CTL表达对于I类MHC上呈递的EB病毒(EBV)肽(例如,LMP1肽、LMP2A肽或EBNA1肽)特异性的TCR。
可以通过将包括CTL的样品与抗原呈递细胞(APC)孵育从而诱导CTL增殖,来生成本文所描述的CTL组合物中的CTL。在一些实施方案中,APC呈递本文所描述的肽(例如,包括LMP1、LMP2A或EBNA1表位序列的肽)。在一些实施方案中,APC是B细胞、抗原呈递T细胞、树突状细胞、或人工抗原呈递细胞(例如,aK562细胞)。
可以通过从患者样品中取出外周血单核细胞(PBMC)并且将其粘附至塑料来制备用于在过程中使用的树突状细胞。通常,单核细胞群体粘着,并且全部其他细胞可以被清洗掉。然后用IL-4和GM-CSF分化粘附的群体以产生单核细胞来源的树突状细胞。这些细胞可以通过添加IL-1β、IL-6、PGE-1和TNF-α(其上调树突状细胞的表面上的重要的共刺激分子)来成熟化,并且然后用本文提供的肽中的一种或更多种转导。
可以通过使APC与包括CTL表位的肽和/或与编码包括CTL表位的肽的核酸接触来生成呈递一种或更多种本文所描述的肽的APC。在一些实施方案中,APC被照射。在一些实施方案中,APC呈递本文所描述的肽(例如,包括LMP1、LMP2A或EBNA1表位序列的肽)。可以通过本领域已知的标准技术产生呈递本文所描述的肽的细胞。例如,细胞可以被施以脉冲以促进肽摄取。在一些实施方案中,用编码本文提供的肽的核酸转染细胞。本文提供产生抗原呈递细胞(APC)的方法,所述方法包括用本文所描述的肽对细胞施以脉冲。产生抗原呈递细胞的示例性实例可以在WO2013088114(其特此被整体并入)中找到。
在一些实施方案中,本文提供的方法包含生成T细胞(例如,CTL)、激活T细胞(例如,CTL)和/或诱导T细胞(例如,CTL)的增殖的步骤,所述T细胞(例如,CTL)识别本文所描述的CTL表位中的一种或更多种。在一些实施方案中,将包括CTL的样品(即,PBMC样品)在培养基中与本文提供的APC(例如,呈递I类MHC复合体上的包括CTL表位(例如,EBV表位)的肽的APC)孵育。在一些实施方案中,APC对于从其获得T细胞的受试者是自体的。在一些实施方案中,APC对于从其获得T细胞的受试者不是自体的(即同种异体的)。在一些实施方案中,将含有T细胞的样品与本文提供的APC孵育两次或更多次。在一些实施方案中,在存在至少一种细胞因子的情况下将T细胞与APC孵育。在一些实施方案中,细胞因子是IL-4、IL-7和/或IL-15。例如,美国专利公开号2015/0017723(其特此通过引用被并入)中提供用于使用APC诱导T细胞增殖的示例性方法。
在一些方面,本文提供包括向受试者施用包括免疫检查点抑制剂和CTL的样品以便治疗和/或预防癌症的方法。在一些实施方案中,方法包含向受试者施用有效量的本文提供的包括CTL、一种或更多种免疫检查点抑制剂的组合物。在一些实施方案中,组合物包含本文提供的多种(例如,两种或更多种)CTL和/或免疫检查点抑制剂的组合。在一些实施方案中,T细胞对于受试者是自体的。在一些实施方案中,T细胞对于受试者是同种异体的。在一些实施方案中,在CTL被施用至受试者之前,其被储存在细胞库中。
在一些实施方案中,本文提供的方法包含通过测定CTL群体内生物标志物的表达水平,来从细胞库(例如,预生成的第三方供体来源的表位特异性CTL库)中选择同种异体CTL用于过继性免疫疗法。在一些实施方案中,测定两种或更多种生物标志物的表达水平。在一些实施方案中,方法还包含选择同种异体CTL,因为其表达受限制于I类MHC的TCR,所述I类MHC由存在于受试者中的HLA等位基因编码。在一些实施方案中,如果CTL和受试者共有至少2个(例如,至少3个、至少4个、至少5个、至少6个)HLA等位基因,并且CTL通过共有的HLA等位基因被限制,则选择CTL。在一些实施方案中,方法包括用流式细胞术测试预生成的第三方供体来源的表位特异性T细胞(即,同种异体T细胞)的TCR库。在一些实施方案中,使用四聚体测定、ELISA测定、免疫印迹测定、荧光显微术测定、埃德曼降解法测定和/或质谱测定(例如,蛋白质测序)检测表位特异性T细胞。在一些实施方案中,使用核酸探针、核酸扩增测定和/或测序测定分析TCR库。
肽
在一些实施方案中,本文提供的方法和组合物涉及肽特异性CTL。在一些实施方案中,方法包含这样的CTL的生成,例如,通过将包括CTL的样品(即,PBMC样品)与呈递本文所描述的CTL表位中的一种或更多种的抗原呈递细胞(APC)(例如,呈递I类MHC复合体上的包括CTL表位的本文所描述的肽的APC)孵育。
在一些实施方案中,本文提供的肽包括任何EBV病毒蛋白的序列(例如,任何EBV蛋白的至少5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个邻接的氨基酸的序列)。在一些实施方案中,本文提供的肽包括EBV病毒蛋白的不超过25、20、19、18、17、16、15、14、13、12、11或10个邻接的氨基酸。
在一些实施方案中,本文提供的肽包括LMP1的序列(例如,LMP1的至少5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个邻接的氨基酸的序列)。在一些实施方案中,本文提供的肽包括LMP1的不超过25、20、19、18、17、16、15、14、13、12、11或10个邻接的氨基酸。下文提供示例性LMP1氨基酸序列(SEQ ID NO:1):
在一些实施方案中,本文提供的肽包括LMP2A的序列(例如,LMP2A的至少5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个邻接的氨基酸的序列)。在一些实施方案中,本文提供的肽包括LMP2A的不超过25、20、19、18、17、16、15、14、13、12、11或10个邻接的氨基酸。下文提供示例性LMP2A氨基酸序列(SEQ ID NO:2):
在一些实施方案中,本文提供的肽包括EBNA1的序列(例如,EBNA1的至少5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个邻接的氨基酸的序列)。在一些实施方案中,本文提供的肽包括EBNA1的不超过25、20、19、18、17、16、15、14、13、12、11或10个邻接的氨基酸。下文提供示例性EBNA1氨基酸序列(SEQ ID NO:3):
在一些实施方案中,肽包括表1中列出的表位的序列。
表1.示例性EBV病毒蛋白表位
在一些实施方案中,本文提供的肽包括CTL表位(例如,病毒表位)中的两个或更多个。在一些实施方案中,本文提供的肽包括至少2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个CTL表位。例如,在一些实施方案中,本文提供的肽包括通过连接体(例如,多肽连接体)连接的CTL表位中的两个或更多个。
在一些实施方案中,除一个或更多个(例如,1、2、3、4、5、6、7、8、9、10或更多个)保守序列修饰之外,肽的序列包括病毒蛋白序列。如本文所使用的,术语“保守序列修饰”旨在指不显著地影响或改变T细胞受体(TCR)与MHC上呈递的含有氨基酸序列的肽之间的相互作用的氨基酸修饰。这样的保守修饰包含氨基酸置换、添加(例如,向肽的N末端或C末端添加氨基酸)和缺失(例如,从肽的N末端或C末端缺失氨基酸)。保守氨基酸置换是其中氨基酸残基被具有相似侧链的氨基酸残基替代的氨基酸置换。本领域中已经定义了具有相似侧链的氨基酸残基家族。这些家族包含具有碱性侧链的氨基酸(例如,赖氨酸、精氨酸、组氨酸)、具有酸性侧链的氨基酸(例如,天门冬氨酸、谷氨酸)、具有不带电荷的极性侧链的氨基酸(例如,甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、具有非极性侧链的氨基酸(例如,丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、具有β-支化侧链的氨基酸(例如,苏氨酸、缬氨酸、异亮氨酸)和具有芳香族侧链的氨基酸(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)。因此,本文所描述的肽的一个或更多个氨基酸残基可以被来自相同侧链家族的其他氨基酸残基替代,并且可以使用本领域已知的方法测试改变的肽的TCR结合的保留。可以通过本领域已知的标准技术(如定点诱变和PCR介导的诱变)将修饰引入抗体。
在一些实施方案中,本文提供的肽包括与蛋白质序列(例如,病毒蛋白的片段的序列)至少80%、85%、90%、95%或100%一致的序列。为了测定两个氨基酸序列的百分比一致性,序列被比对以用于最优比较目的(例如,可以在第一氨基酸序列和第二氨基酸序列中的一个或两个中引入空位以用于最优比对,并且可以忽略非一致序列以用于比较目的)。然后比较相应氨基酸位置处的氨基酸残基。当第一序列中的位置被与第二序列中的相应位置相同的氨基酸残基占据时,则分子在该位置处是一致的。考虑到空位的数量和每个空位的长度(其需要被引入以用于两个序列的最优比对),两个序列之间的百分比一致性是序列共有的一致位置的数量的函数。
本文提供的肽可以使用标准蛋白质纯化技术通过适当的纯化方案从细胞来源或组织来源分离,并且可以通过重组DNA技术产生,和/或可以使用标准肽合成技术以化学方法合成。可以通过编码本发明的一种或多种肽的核苷酸的表达,在原核宿主细胞或真核宿主细胞中产生本文所描述的肽。可替代地,可以通过化学方法合成这样的肽。用于在重组宿主中表达异源肽的方法、肽的化学合成的方法和体外翻译的方法是本领域公知的,并且被进一步在Maniatis et al.,Molecular Cloning:A Laboratory Manual(1989),2nd Ed.,Cold Spring Harbor,N.Y.;Berger and Kimmel,Methods in Enzymology,Volume 152,Guide to Molecular Cloning Techniques(1987),Academic Press,Inc.,San Diego,Calif.;Merrifield,J.(1969)J.Am.Chem.Soc.91:501;Chaiken I.M.(1981)CRCCrit.Rev.Biochem.11:255;Kaiser et al.(1989)Science 243:187;Merrifield,B.(1986)Science 232:342;Kent,S.B.H.(1988)Annu.Rev.Biochem.57:957;以及Offord,R.E.(1980)Semisynthetic Proteins,Wiley Publishing中描述,其通过引用被并入本文。
在某些方面,本文提供编码本文所描述的肽的核酸分子。在一些实施方案中,核酸分子是运载体。在一些实施方案中,核酸分子是病毒运载体(如基于腺病毒的表达运载体),所述病毒运载体包括本文所描述的核酸分子。在一些实施方案中,本文提供的运载体编码本文提供的多个表位(例如,如多表位)。在一些实施方案中,本文提供的运载体编码本文提供的至少2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个表位(例如,表1中提供的表位)。
在一些实施方案中,运载体是AdE1-LMPpoly。AdE1-LMPpoly运载体编码来自LMP1和LMP2的限定的CTL表位的多表位,所述LMP1和LMP2被融合至Gly-Ala重复缺失的EBNA1序列。AdE1-LMPpoly运载体描述于,例如,Smith et al.,Cancer Research 72:1116(2012);Duraiswamy et al.,Cancer Research 64:1483-9(2004);以及Smith et al.,J.Immunol117:4897-906中,其中的每个特此通过引用被并入。
如本文所使用的,术语“运载体”指能够转运已经与其连接的另一核酸的核酸分子。一种类型的运载体是“质粒”,其指环状双链DNA环,附加的DNA区段可以连接至所述环状双链DNA环中。另一种类型的运载体是病毒运载体,其中附加的DNA区段可以连接至病毒基因组中。某些运载体能够在其被引入的宿主细胞中自主复制(例如,具有细菌复制起点的细菌运载体、游离型哺乳动物运载体)。其他运载体(例如,非游离型哺乳动物运载体)在被引入宿主细胞时可以被整合到宿主细胞的基因组中,并且从而与宿主基因组一起被复制。此外,某些运载体能够指导基因的表达。这样的运载体在本文中被称为“重组表达运载体”(或简单地“表达运载体”)。在一些实施方案中,本文提供被可操作地连接至表达运载体中的一个或更多个调控序列(例如,启动子)的核酸。在一些实施方案中,细胞转录本文提供的核酸,并且从而表达本文所描述的肽。核酸分子可以被整合到细胞的基因组中,或其可以在染色体外。
在一些实施方案中,本文提供含有本文所描述的核酸(例如,编码本文所描述的肽的核酸)的细胞。细胞可以是,例如,原核的、真核的、哺乳动物的、禽的、鼠的和/或人的。在一些实施方案中,细胞是哺乳动物细胞。在一些实施方案中,细胞是APC(例如,抗原呈递T细胞、树突状细胞、B细胞或aK562细胞)。在本发明的方法中,本文所描述的核酸可以例如以核酸无需递送运载体(vehicle)被施用至细胞、与递送试剂组合被施用至细胞。在一些实施方案中,本领域已知的任何核酸递送方法可以被用于本文所描述的方法中。合适的递送试剂包含(但不限于)例如,Mirus Transit TKO亲脂性试剂;转化脂(lipofectin);阳离子脂质体(lipofectamine);细胞转染剂(cellfectin);聚阳离子(例如,聚赖氨酸)、缺端胶原、纳米颗粒系统(nanoplexe)和脂质体。在本文所描述的方法的一些实施方案中,脂质体被用于将核酸递送至细胞或受试者。适合于在本文所描述的方法中使用的脂质体可以由标准囊泡形成脂类形成,所述标准囊泡形成脂类通常包含中性的或带负电的磷脂和甾醇(如胆甾醇)。通常由考虑因素(如期望的脂质体尺寸和脂质体在血流中的半衰期)来指导脂类的选择。已知用于制备脂质体的各种各样的方法,例如,如Szoka et al.(1980),Ann.Rev.Biophys.Bioeng.9:467;和美国专利号4,235,871、4,501,728、4,837,028和5,019,369中所描述的,其全部公开内容通过引用被并入本文。
治疗方法
在一些实施方案中,本文提供通过向受试者施用本文所描述的组合疗法来在受试者中治疗癌症的方法。
在一些实施方案中,本文提供的方法可以被用于治疗任何癌症。例如,在一些实施方案中,本文所描述的方法和CTL可以被用于治疗任何癌性肿瘤或癌前期肿瘤。在一些实施方案中,癌症包含实体肿瘤。在一些实施方案中,可以通过本文提供的方法和组合物治疗的癌症包含,但不限于,来自膀胱、血液、骨骼、骨髓、脑、乳腺、结肠、食管、胃肠、牙龈、头部、肾脏、肝脏、肺、鼻咽、颈部、卵巢、前列腺、皮肤、胃、睾丸、舌或子宫的癌细胞。此外,癌症可能具体地是以下组织学类型,但不限于这些:恶性新生物;癌;未分化的癌;巨型梭形细胞癌;小细胞癌;乳头状癌;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛母质癌;移形细胞癌;乳头状移形细胞癌;腺癌;恶性胃泌素瘤;胆管癌;肝细胞癌;肝细胞癌合并胆管癌;小梁状腺癌;腺样囊性癌;腺瘤性息肉内腺癌;腺癌,家族性结肠息肉病;实体癌;恶性类癌瘤;细支气管肺泡腺癌;乳头状腺癌;嫌色细胞癌;嗜酸细胞癌;嗜酸性腺癌;嗜碱细胞癌;透明细胞腺癌;颗粒细胞型癌;滤泡性腺癌;乳头状和滤泡性腺癌;非包裹性硬化型癌(nonencapsulatingsclerosing carcinoma);肾上腺皮质癌;子宫内膜样癌;皮肤附属器癌;大汗腺腺癌;皮脂腺癌;盯聍腺腺癌;粘液表皮样癌;囊腺癌;乳头状囊腺癌;乳头状浆液性囊腺癌;粘液性囊腺癌;粘液性腺癌;印戒细胞癌;浸润性导管癌;髓样癌;小叶癌;炎性癌;乳腺派杰氏病;腺泡细胞癌;腺鳞状癌;腺癌伴鳞状上皮化生;恶性胸腺瘤;恶性卵巢间质肿瘤;恶性泡膜细胞瘤;恶性粒层细胞肿瘤;以及恶性成神经细胞瘤(malignant roblastoma);塞托利细胞癌;恶性莱迪希细胞肿瘤;恶性脂质细胞肿瘤;恶性副神经节瘤;恶性乳腺外副神经节瘤;嗜铬细胞瘤;血管球肉瘤;恶性黑素瘤;无黑素性黑素瘤;浅表扩张性黑素瘤;巨大色素痣内恶性黑素瘤;上皮样细胞黑素瘤;恶性蓝痣;肉瘤;纤维肉瘤;恶性皮肤纤维瘤;粘液肉瘤;脂肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎性横纹肌肉瘤;腺泡性横纹肌肉瘤;间质肉瘤;恶性混合瘤;苗勒混合肿瘤(mullerian mixed tumor);肾母细胞瘤;肝胚细胞瘤;癌肉瘤;恶性间充质瘤;恶性卵巢纤维上皮瘤;恶性叶状肿瘤;滑膜肉瘤;恶性间皮瘤;无性细胞瘤;胚胎性癌;恶性畸胎瘤;恶性甲状腺肿样卵巢瘤;绒毛膜癌;恶性中肾瘤;血管肉瘤;恶性血管内皮细胞瘤;卡波西肉瘤;恶性血管外皮细胞瘤;淋巴管肉瘤;骨肉瘤;皮质旁骨肉瘤;软骨肉瘤;恶性成软骨细胞瘤;间充质型软骨肉瘤;骨巨细胞瘤;尤因肉瘤;恶性牙源性肿瘤;成釉细胞牙肉瘤;恶性成釉细胞瘤;成釉细胞纤维肉瘤;恶性松果体瘤;脊索瘤;恶性神经胶质瘤;室管膜瘤;星形细胞瘤;原浆性星形细胞瘤;纤维性星形细胞瘤;成星形细胞瘤;成胶质细胞瘤;少突神经胶质瘤;成少突神经胶质细胞瘤;原始神经外胚层;小脑肉瘤;成神经节细胞瘤;成神经细胞瘤;成视网膜细胞瘤;嗅神经源性肿瘤;恶性脑脊膜瘤;神经纤维肉瘤;恶性神经鞘瘤;恶性颗粒细胞肿瘤;恶性淋巴瘤;霍奇金病;霍奇金淋巴瘤;类肉芽肿;小淋巴细胞恶性淋巴瘤;弥散性大细胞恶性淋巴瘤;滤泡性恶性淋巴瘤;蕈样肉芽肿病;其他规定的非霍奇金淋巴瘤;恶性组织细胞增多症;多发性骨髓瘤;肥大细胞肉瘤;免疫增生性小肠疾病;白血病;淋巴细胞白血病;血浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;髓细胞白血病;嗜碱细胞白血病;嗜酸细胞白血病;单核细胞白血病;肥大细胞白血病;巨核细胞白血病;髓系肉瘤;和毛细胞白血病。
在一些实施方案中,本文提供的方法被用于治疗EBV相关性癌症。在一些实施方案中,EBV相关性癌症是EBV相关性NPC。在一些实施方案中,EBV相关性癌症是移植后淋巴组织增生性紊乱(PTLD)、NK/T细胞淋巴瘤、EBV+胃癌、或EBV+平滑肌肉瘤。
在一些实施方案中,组合疗法还包括化学治疗剂(例如,烷基化剂或具有烷基化作用的药剂,如环磷酰胺(CTX;例如,)、苯丁酸氮芥(CHL;例如,)、顺铂(Cis P;例如)、白消安(例如,)、美法仑、卡莫司汀(BCNU)、链唑霉素(streptozotocin)、三亚胺嗪(TEM)、丝裂霉素C等;抗代谢物,如甲氨蝶呤(MTX)、依托泊苷(VP16;例如,)、6-巯嘌呤(6-mercaptopurine)(6MP)、6-硫鸟嘌呤(6-thiocguanine)(6TG)、阿糖胞苷(Ara-C)、5-氟尿嘧啶(5-FU)、卡培他滨(capecitabine)(例如)、达卡巴嗪(DTIC)等;抗生素,如放线菌素D、阿霉素(DXR;例如,)、柔红霉素(道诺霉素)、博来霉素、普卡霉素等;生物碱,如长春花生物碱(如长春新碱(VCR)、长春花碱等);以及其他抗肿瘤药剂,如紫杉酚(例如,)和紫杉酚衍生物、细胞生长抑制剂(cytostatic agent)、糖皮质激素(如地塞米松(DEX;例如,))和皮质类固醇(如泼尼松(prednisone))、核苷酶抑制剂(如羟基脲)、氨基酸消耗酶(如门冬酰胺酶)、亚叶酸和其他叶酸衍生物以及相似的不同种类的抗肿瘤药剂。下列药剂也可以被用作附加的药剂:阿米福汀(arnifostine)(例如,)、放线菌素D(dactinomycin)、二氯甲基二乙胺(氮芥(nitrogen mustard))、链佐星、环磷酰胺、罗氮芥(CCNU)、阿霉素脂(doxorubicin lipo)(例如,)、吉西他滨(gemcitabine)(例如,)、柔红霉素脂(例如,)、甲基苄肼、丝裂霉素、多西他赛(例如,)、阿德斯白细胞素、卡铂、奥沙利铂、克拉屈滨(cladribine)、喜树碱(camptothecin)、CPT 11(伊立替康(irinotecan))、10-羟基7-乙基-喜树碱(SN38)、氟尿苷(floxuridine)、氟达拉滨(fludarabine)、异环磷酰胺、伊达比星(idarubicin)、美司钠(mesna)、干扰素β、干扰素α、米托蒽醌(mitoxantrone)、拓扑替康(topotecan)、亮丙瑞林、甲地孕酮、美法仑、巯嘌呤(mercaptopurine)、普卡霉素、米托坦、培门冬酶(pegaspargase)、喷司他丁、溴丙哌嗪、普卡霉素、他莫昔芬、替尼泊甙、睾内酯(testolactone)、硫鸟嘌呤(thioguanine)、塞替派、尿嘧啶芥(uracil mustard)、长春瑞滨(vinorelbine)、苯丁酸氮芥。
本文提供的药物组合物中的活性成分的实际剂量水平可以变化,以便获得活性成分的量,所述活性成分的量对实现特定患者、组合物和施用模式的期望的治疗响应是有效的,而对患者没有毒性。
所选择的剂量水平将取决于各种各样的因素,所述因素包含所采用的特定药剂的活性、施用途径、施用时间、正在被采用的特定化合物的排泄或代谢的速率、治疗的持续时间、与所采用的特定化合物组合使用的其他药物、化合物和/或材料、正在被治疗的患者的年龄、性别、体重、病况、总体健康状况和先前的病史,以及医学领域中众所周知的类似因素。本文所描述的CTL和免疫检查点抑制剂可以共同施用或顺序施用。可以通过本领域已知的任何技术施用免疫检查点抑制剂。在一些实施方案中,免疫检查点抑制剂被瘤内施用。在一些实施方案中,免疫检查点抑制剂被静脉内施用。在一些实施方案中,免疫检查点抑制剂被肠胃外施用。
在一些实施方案中,受试者已经被暴露于病毒(例如EBV),使得病毒颗粒在受试者的血液中是可检测的。在一些实施方案中,方法还包括测量受试者中的病毒载量(例如,在向受试者施用肽特异性CTL之前或之后)。测定受试者中的病毒载量的操作可以是免疫疗法有效性的良好的预后标志物。在一些实施方案中,选择CTL的操作还包括测定受试者中(例如,组织或血液样品中)的病毒DNA拷贝的数量。在一些实施方案中,病毒载量被测量两次或更多次。
在一些实施方案中,方法还包含选择同种异体CTL用于组合疗法,因为其表达受限于I类MHC的TCR,所述TCR由存在于受试者中的HLA等位基因编码。在一些实施方案中,如果CTL和受试者共有至少2个(例如,至少3个、至少4个、至少5个、至少6个)HLA等位基因,并且CTL通过共有的HLA等位基因被限制,则选择CTL。在一些实施方案中,方法包括用流式细胞术测试预生成的第三方供体来源的表位特异性T细胞(即,同种异体T细胞)的TCR库。在一些实施方案中,使用四聚体测定、ELISA测定、免疫印迹测定、荧光显微术测定、埃德曼降解法测定和/或质谱法测定(例如,蛋白质测序)检测表位特异性T细胞。在一些实施方案中,使用核酸探针、核酸扩增测定和/或测序测定分析TCR库。在一些实施方案中,从细胞库获得同种异体CTL。
示例:
实施例1:NPC患者中的免疫检查点蛋白表达
应用LMP1&2和EBNA1特异性CTL免疫疗法用于治疗EBV相关性NPC的研究中招募了52个患者,其中41个患有姑息性化学疗法后的活动性进行性疾病,并且11个患者患有标准放射/化学疗法治疗后的微小或无残留病变(N/MRD)。
20个活动性疾病患者和9个N/MRD患者接受最少2剂量(范围2-8剂量)和中位数总计1.1×108个细胞(范围:5.7×107至2.4×108)。表1和表2中提供了接受过继性T细胞疗法的患者的临床特征。在剩余的23个患者中,1个患者在单剂量的施用之后死亡,T细胞疗法被制造以用于5个患者,但由于疾患而未被施用,12个由于低特异性或低细胞产量而未能满足缓解标准,并且5个在T细胞制造开始之前退出。
为了生成LMP/EBNA1特异性T细胞,收获100-300mL的外周血,并且用于生成外周血单核细胞(PBMC)。然后使用AdE1-LMPpoly运载体感染30%的PBMC(10:1的MOI),然后所述30%的PBMC(10:1的MOI)被照射,并且与剩余的PBMC共培养两周。每3-4天用新鲜的生长培养基和120IU/mL的重组IL-2补充培养基(Komtur Pharmaceuticals,Frieburg,Germany)。在释放用于输注之前,使用细胞内细胞因子分析和微生物污染测试经培养的T细胞的抗原特异性。
进行FACS分析以表征被施用至受试者的T细胞的免疫检查点蛋白的表达。在内部生成MHC四聚体。将T细胞在4℃与APC标记的MHC I类四聚体孵育20分钟,所述APC标记的MHCI类四聚体对于HLA A11限制性表位SSCSSCPLSKI(LMP2A)、HLAA24限制性表位TYGPVFMCL(LMP2A)和HLA Cw03限制性表位FVYGGSKTSL(EBNA1)是特异性的。然后将细胞与下列抗体中的一种或更多种孵育另外的30分钟:PE缀合的抗TIM-3、FITC缀合的抗LAG-3、BV786缀合的抗PD-1和BV421缀合的抗CTLA4。用FACSDiva软件(BD Biosciences)使用BD LSR Fortessa获取细胞,并且使用FlowJo软件(TreeStar)进行获取后分析。
图1显示出免疫检查点分子(即,LAG-3、TIM-3、CTLA4或PD-1)的表达。图片A描绘了表达PD-1、TIM-3、LAG-3和CTLA-4的HLA-多聚体阳性CD8阳性淋巴细胞的百分比。图片B描绘了在过继性T细胞疗法后显示出病情稳定(SD)或疾病进展(PD)的患有无/微小残留病变(N/MRD)和活动性复发性/转移性疾病(ARMD)的NPC患者中施用的CTL免疫疗法中PD-1阳性淋巴细胞、TIM-3阳性淋巴细胞、LAG-3阳性淋巴细胞和CTLA-4阳性淋巴细胞的百分比。
实施例2:NPC患者中EBV-CTL的过继性转移和检查点抑制剂疗法
用同种异体EB病毒细胞毒性T淋巴细胞(EBV-CTL)的过继性转移与检查点抑制剂(派姆单抗)组合治疗患有铂类耐药性或复发性EBV相关性鼻咽癌(NPC)的患者。研究中招募了多达总计48个患有转移性、铂类耐药性或复发性EBV相关性NPC的受试者。
研究方案和给药
研究具有两个部分:第1群组被招募作为研究的第1B阶段部分,以确定第2阶段剂量;第2群组被招募作为研究的第2阶段部分,以检查组合的过继性细胞疗法和检查点抑制剂疗法对NPC的临床益处。方案将招募总计48个受试者。第1B阶段(第1群组)将招募12个受试者(尽管先前的PD1抑制剂疗法,所述受试者的疾病仍进展),并且第2阶段(第2群组)将招募36个初始接受PD1抑制剂疗法的受试者。
基于EBV-CTL源材料(供体)与受试者之间共有的匹配的≥2个HLA等位基因(其中的至少一个是限制性HLA等位基因)从可用的EBV-CTL的库中针对每个受试者选择同种异体第三方EBV-CTL。在筛选过程中,将进行高分辨率HLA分型,以便利EBV-CTL细胞产物的选择。如果以高分辨率(基于DNA的血清学评估)进行,则历史HLA分型是可接受的。
在第1B阶段(第1群组)中,在21天周期的第1天、第8天和第15天以每次输注范围从500000至200000000个T细胞的剂量向6个患有晚期NPC的受试者静脉施用EBV-CTL。基于先前的第1阶段安全性和有效性数据(所述数据显示出患有晚期NPC的患者中足够的EBV CTL扩增和抗肿瘤活性)选择受试者群体。同样地,将派姆单抗施用至第1群组受试者(以200mgIV Q3周的剂量施用至成人(成人为大于或等于18岁)和以2mg/kg IV Q3周施用至儿科受试者(小于18岁))。
如果初始的6个第1B阶段第1群组受试者中的少于2个在第一个21天内经历剂量限制性毒性,则发生EBV-CTL的剂量降低,并且用EBV-CTL与派姆单抗的组合以推荐的剂量水平治疗随后的6个受试者。
在给药之前多达28天开始筛选(第1周期第1天)。将用EBV-CTL与派姆单抗组合治疗受试者,直至观察到疾病进展或不可接受的毒性。
研究参加者
受试者招募标准的概括如下:
纳入标准:如果满足下列纳入标准中的全部,则患者将被认为有资格参加本研究:
1.≥2岁的男性和女性
2.被认为是铂类难治性/耐药性的、被定义为具有至少一种先前的基于铂的化学疗法方案(具有随后的<12个月的无铂间隔)、在基于铂的疗法期间具有进展、或在基于铂的疗法之后患有持续性疾病的患有晚期NPC或转移性NPC的患者是合格的
3.其中已经在组织活检样本中证明EBV基因组或抗原的患有NPC的患者
4.组织学或细胞学证实的EBV相关性局部复发性、转移性或持续性NPC(WHO II/III型),并且满足他们将被招募到其中的研究的群组的下列相应要求:
a.第1B阶段(第1群组):已经接受用派姆单抗抗PD1的先前治疗、尚未接受用抗PD-L1抗体、抗PD-L2抗体、抗CD137抗体、抗OX-40抗体或抗CTLA-4抗体的先前治疗的患者
b.第2阶段(第2群组):尚未接受用派姆单抗或其他抗PD1抗体、抗PD-L1抗体、抗PD-L2抗体、抗CD137抗体、抗OX40抗体或抗CTLA 4抗体的先前治疗的患者
5.筛选时的预期寿命≥4个月
6.使用RECIST 1.1可测量的疾病。如果已经在位于先前照射区域中的肿瘤病变中证明了进展,则这样的病变被认为是可测量的
7.第1B阶段中的患者必须在基线处和转移性病变(其可以被活检具有可接受的临床风险(如由研究者判断的))的治疗中进行活检,并且必须同意经历活检。
8.患者必须同意提交先前的活检材料,用于生物标志物评估。
9.年龄>16岁的患者的≤1的东部肿瘤协作组(Eastern Cooperative OncologyGroup)(ECOG)体力状态;年龄≤16岁的患者的≥70的兰斯基评分(Lansky score)。
10.按照下列的充足的器官功能(除非被认为是由EBV-CTL意图治疗的潜在EBV驱动过程、或其先前的疗法引起的):
11.愿意并且能够提供书面知情同意书。
排除标准:如果满足下列标准中的任何一个,则患者将无资格参加研究:
1.患有适合于以治疗意图施用的局部疗法的疾病。
2.需要甲氨蝶呤或体外光分离置换法
3.需要血管加压药或呼吸机支持
4.在第1周期第1天之前,抗胸腺细胞球蛋白或类似的抗T细胞抗体疗法≤4周
5.在试验治疗的第一剂量之前7天内被诊断为免疫缺陷或正在接受系统性类固醇疗法或任何其他形式的免疫抑制疗法。在与赞助商协商之后,可以批准使用生理剂量的皮质类固醇。
6.具有间质性肺疾病史或迹象的患者
7.患有需要系统疗法的活动性感染的患者
8.具有需要类固醇的(非传染性)肺炎史或目前患有肺炎的患者
9.在研究第1天之前4周内已经接受血液制品(包含血小板或红细胞)的转输或集落刺激因子(包含G-CSF、GM-CSF或重组促红细胞生成素)的施用的患者。
10.妊娠或哺乳;有生育能力的女性必须进行阴性尿液或血清妊娠测试。如果尿液测试是阳性的或不能被证实为阴性的,则将需要血清妊娠测试。对于有资格的患者,必须在第一剂量的72小时内证实血清妊娠为阴性的。
11.在招募之前至少4周完全消除免疫疗法相关性不良反应并且没有针对这些不良事件(AE)的治疗
12.没有严重免疫疗法相关性不良反应史(CTCAE第4级;需要治疗>4周的CTCAE第3级)
13.已经在招募之前多达30天接受用于预防感染性疾病的任何非肿瘤疫苗疗法的患者。实例包含(但不限于):措施、腮腺炎、风疹、水痘、黄热病、狂犬病、BCG和伤寒疫苗。不含有活病毒的季节性流感疫苗是可接受的。
14.患有正在进展或需要积极治疗的已知的附加的恶性肿瘤。例外包含皮肤基底细胞癌、已经经历过潜在治愈性疗法的皮肤鳞状细胞癌、或原位宫颈癌。
15.在最后一次研究剂量之后120天内,在研究过程中不愿意使用高效避孕方法(禁欲是可接受的)的具有生育能力的女性或有具有生育能力的女性伴侣的男性。
16.无法遵守研究程序
17.在第1周期第1天的2周内化学疗法、靶向小分子疗法、激素疗法、或放射疗法,或由于先前施用的药剂,尚未从不良事件中恢复(即,≤第1级或在基线处)。患有≤第2级神经病变或≤第2级脱发的受试者是本标准的例外,并且可能有研究的资格。
18.在第1周期第1天的5个半衰期或4周(以较长者为准)内的抗体/生物疗法,或由于超过4周前施用的药剂,尚未从不良事件中恢复(即,≤第1级或在基线处)。
19.患有癌性脑膜炎和/或活动性中枢神经系统转移的患者,除非转移被治疗并且稳定并且患者不需要全身性类固醇。注意:患有先前经治疗的脑转移的患者可以参加,前提是他们是稳定的(在试验治疗的第一剂量之前至少四周没有依据成像(每个评估使用相同的成像模式(MRI或CT扫描))的进展迹象,并且任何神经症状已经恢复到基线),不具有新出现的或扩大的脑转移的迹象,并且在试验治疗之前至少7天没有使用类固醇。本例外不包含癌性脑膜炎,所述癌性脑膜炎被排除而不管临床稳定性。
20.具有任何病况、疗法或实验室异常史或当前迹象的患者,根据治疗研究者的意见,所述任何病况、疗法或实验室异常史或当前迹象可能混淆试验结果、在试验的整个持续时间内干扰受试者的参加、或不符合受试者参与的最佳利益。
21.患有会干扰与试验要求的协作的已知的精神障碍或药物滥用障碍。
22.已知的HIV史、已知的活动性乙型肝炎(例如HBsAg反应性)、丙型肝炎(例如检测到HCV RNA)。
23.在第1周期第1天的4周内用任何研究产品的先前治疗
24.在研究第1天之前的4周内已经具有先前的抗癌单克隆抗体(mAb),或由于超过4周前施用的药剂,尚未从不良事件中恢复(即,≤第1级或在基线处)。
25.用EBV T细胞的先前治疗。
下列是治疗功效的指标:
1)如通过完全缓解(CR)率、缓解持续时间(DOR)、无进展生存期(PFS)和总生存期(OS)测量的NPC疾病进展和其他临床相关结果的变化。
2)免疫应答率(irRR=irCR+irPR)和/或应答持续时间(DOirR)的增加。
本文提到的全部出版物、专利、专利申请和序列登录号通过引用被整体并入,犹如每个单独的出版物、专利或专利申请被具体地和单独地表明通过引用被并入。在冲突的情况下,本申请(包含本文中的任何定义)将受约束。
本领域技术人员将认识到或能够使用仅仅常规实验来确定本文中描述的本发明的具体的实施方案的许多等同物。这样的等同物旨在由以下权利要求涵盖。
Claims (34)
1.一种在受试者中治疗癌症的方法,所述方法包括向所述受试者施用免疫检查点抑制剂和包括细胞毒性T细胞(CTL)的组合物,所述细胞毒性T细胞(CTL)表达对于I类MHC上呈递的癌症相关性肽特异性的T细胞受体。
2.如权利要求1所述的方法,其中所述免疫检查点抑制剂是与免疫检查点蛋白结合的蛋白质或多肽。
3.如权利要求2所述的方法,其中所述免疫检查点蛋白是CTLA4、PD-1、PD-L1、PD-L2、A2AR、B7-H3、B7-H4、BTLA、KIR、LAG-3、TIM-3、IDO、TDO或VISTA。
4.如权利要求3所述的方法,其中所述免疫检查点蛋白是PD-1、PD-L1、TIM-3、LAG-3或CTLA4。
5.如权利要求1所述的方法,其中所述免疫检查点抑制剂是与免疫检查点蛋白结合的抗体或所述抗体的抗原结合片段。
6.如权利要求5所述的方法,其中所述免疫检查点蛋白是CTLA4、PD-1、PD-L1、PD-L2、A2AR、B7-H3、B7-H4、BTLA、KIR、LAG-3、TIM-3、IDO、TDO或VISTA。
7.如权利要求6所述的方法,其中所述免疫检查点蛋白是PD-1、PD-L1、TIM-3、LAG-3或CTLA4。
8.如权利要求1所述的方法,其中所述免疫检查点抑制剂是纳武单抗、派姆单抗、皮地利珠单抗、AMP-224、AMP-514、STI-A1110、TSR-042、RG-7446、BMS-936559、BMS-936558、MK-3475、CT O11、MPDL3280A、MEDI-4736、MSB-0020718C、AUR-012和STI-A1010。
9.如权利要求1至8中任一项所述的方法,其中所述癌症相关性肽是病毒肽。
10.如权利要求9所述的方法,其中所述病毒肽是EB病毒(EBV)肽。
11.如权利要求10所述的方法,其中所述EBV肽包括LMP1肽。
12.如权利要求10所述的方法,其中所述EBV肽包括LMP2A肽。
13.如权利要求10所述的方法,其中所述EBV肽包括EBNA1肽。
14.如权利要求1至13中任一项所述的方法,其中所述癌症是鼻咽癌(NPC)。
15.如权利要求1至14中任一项所述的方法,其中所述CTL对于所述受试者是自体的。
16.如权利要求1至14中任一项所述的方法,其中所述CTL对于所述受试者是同种异体的。
17.如权利要求16所述的方法,其中所述CTL从细胞库获得。
18.如前述权利要求中任一项所述的方法,其中所述CTL和所述免疫检查点抑制剂被共同施用。
19.如前述权利要求中任一项所述的方法,其中所述CTL和所述免疫检查点抑制剂被顺序施用。
20.如权利要求1至19中任一项所述的方法,所述方法还包括向所述受试者施用化学治疗剂。
21.一种在受试者中治疗或预防癌症的方法,所述方法包括:
(a)将包括CTL的样品与呈递CMV肽的抗原呈递细胞(APC)孵育,从而诱导所述样品中肽特异性CTL的增殖,
(b)将所述肽特异性CTL与免疫检查点抑制剂组合施用至所述受试者。
22.如权利要求21所述的方法,其中核酸构建体是病毒运载体。
23.如权利要求22所述的方法,其中所述病毒运载体是AdE1-LMPpoly。
24.如权利要求21至23中任一项所述的方法,其中所述癌症是鼻咽癌(NPC)。
25.如权利要求21至24中任一项所述的方法,其中免疫检查点蛋白是CTLA4、PD-1、PD-L1、PD-L2、A2AR、B7-H3、B7-H4、BTLA、KIR、LAG-3、TIM-3、IDO、TDO或VISTA。
26.如权利要求25所述的方法,其中所述免疫检查点蛋白是PD-1、PD-L1、TIM-3、LAG-3或CTLA4。
27.如权利要求21至26中任一项所述的方法,其中所述免疫检查点抑制剂是纳武单抗、派姆单抗、皮地利珠单抗、AMP-224、AMP-514、STI-A1110、TSR-042、RG-7446、BMS-936559、BMS-936558、MK-3475、CT Ol l、MPDL3280A、MEDI-4736、MSB-0020718C、AUR-012和STI-A1010。
28.如权利要求21至27中任一项所述的方法,其中所述CTL和所述免疫检查点抑制剂被共同施用。
29.如权利要求21至27中任一项所述的方法,其中所述CTL和所述免疫检查点抑制剂被顺序施用。
30.如权利要求21至29中任一项所述的方法,其中所述APC是B细胞。
31.如权利要求21至29中任一项所述的方法,其中所述APC是抗原呈递T细胞。
32.如权利要求21至29中任一项所述的方法,其中所述APC是树突状细胞。
33.如权利要求21至29中任一项所述的方法,其中所述APC是aK562细胞。
34.如权利要求21至33中任一项所述的方法,其中所述样品包括外周血单核细胞(PBMC)。
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SMITH ET AL.: "Adoptive therapy for EBV-induced cancers: driving success with post-transplant lymphoproliferative disorder to other EBV-derived tumors", 《IMMUNOTHERAPY》 * |
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CN111961648A (zh) * | 2019-05-20 | 2020-11-20 | 河南省肿瘤医院 | 一种肿瘤特异性t细胞的分离培养方法及由其获得的产品 |
CN114981413A (zh) * | 2019-10-23 | 2022-08-30 | 昆士兰医学研究所理事会 | 过继免疫治疗 |
Also Published As
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KR20190028664A (ko) | 2019-03-19 |
JP2019516768A (ja) | 2019-06-20 |
AU2017271128A1 (en) | 2019-01-03 |
WO2017203362A1 (en) | 2017-11-30 |
EP3463398A1 (en) | 2019-04-10 |
EP3463398A4 (en) | 2020-03-11 |
CA3023845A1 (en) | 2017-11-30 |
SG11201809541UA (en) | 2018-12-28 |
AR108624A1 (es) | 2018-09-12 |
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