CN113574171A - 治疗癌症的组合物和方法 - Google Patents
治疗癌症的组合物和方法 Download PDFInfo
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- CN113574171A CN113574171A CN201980087969.8A CN201980087969A CN113574171A CN 113574171 A CN113574171 A CN 113574171A CN 201980087969 A CN201980087969 A CN 201980087969A CN 113574171 A CN113574171 A CN 113574171A
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Abstract
本发明提供了用于治疗癌症的组合疗法,其包括γδT细胞免疫疗法联合DDR抑制剂的组合物和方法,所述DDR抑制剂包括但不限于PARP抑制剂。优选地,用于治疗癌症的γδT细胞免疫疗法和PARP抑制剂的组合还包括与其他免疫疗法例如免疫检查点(ICP)阻断疗法和/或DNA损伤剂例如细胞毒性化学治疗剂的组合。优选地,当γδT细胞免疫疗法和DDR抑制剂疗法的组合还包括化学治疗剂时,对γδT细胞进行基因修饰以赋予对所述化学治疗剂的抗性。
Description
相关申请
本申请要求2018年11月8日提交的美国临时申请No.62/757383的权益。上述申请的全部内容通过引用并入本文。
背景技术
Gamma-delta(γδ)T细胞是T淋巴细胞的重要亚群,因为它们可以识别多种抗原,且无需抗原启动和主要组织相容性复合体(MHC)分子的存在。它们可以通过细胞毒活性直接攻击靶细胞,也可以通过激活其他免疫细胞间接攻击靶细胞。γδT细胞的功能反应是由多种因素引起的,包括应激抗原的识别,其促进细胞因子的产生,调节病原体的清除、炎症以及组织内稳态的应激。
人γδT细胞亚群都表现出细胞毒性潜能,其通过例如细胞表面受体[即γδTCR(T细胞受体)和NKG2D(自然杀伤组2D)的表达而被诱导,且其部分由可溶性介质(即穿孔素和颗粒酶)的释放被介导。γδT细胞能产生颗粒溶素(一种有效的抗菌蛋白),并能表达配体如CD95L和肿瘤坏死因子相关的凋亡诱导配体,这些配体与靶细胞上的多种死亡受体结合。此外,γδT细胞通过在CD16依赖机制中的抗体依赖性细胞毒性(ADCC) 间接杀伤靶细胞。其他分子如DNAM-1(DNAX辅助分子-1)、白细胞功能相关抗原-1和共刺激受体CD27也参与了γδT细胞活化和细胞毒性的过程。
人γδT细胞也可以表现出抗原呈递能力。与树突状细胞(DC)相似,血Vγ9Vδ2T 细胞能够对来自微生物和肿瘤的信号作出反应,并启动CD4+和CD8+T细胞。γδT-APC 被认为直接交叉呈递抗原到CD8+T细胞。与单核细胞来源的DC对比,γδT细胞的细胞内蛋白质降解和核内酸化明显延迟。抗原由IRAP(胰岛素调节的氨基肽酶)阳性的早期和晚期胞内体运输,并且其加工过程包括在导入MHC-I装载室之前,通过蛋白酶体输出到细胞质进行降解。活化的γδT细胞可能通过C/EBPα(CCAAT/增强子结合蛋白α)依赖机制中的清道夫受体CD36吞噬肿瘤抗原和凋亡的或活的癌细胞,并且增强肿瘤抗原特异性CD8+T细胞应答。γδT细胞还可以通过TNF-α的产生诱导DC成熟。总的来说,γδT细胞可以处理多种抗原用于呈递并刺激其他免疫细胞。因此,可以利用γδT细胞对感染或癌症的反应来设计新的策略,以改善基于人γδT细胞的免疫疗法的临床反应。
聚(ADP-核糖)聚合酶-1(PARP-1)涉及多种细胞过程,例如DNA损伤修复(DDR)、细胞凋亡和基因组稳定性。DDR抑制剂(包括但不限于PARP抑制剂)会导致遗传毒性应激、局部抗原释放和其他免疫机制,从而导致全身抗肿瘤反应,包括募集自然杀伤(NK) 细胞和CD8+细胞以及γδT细胞。据信,使用如PARP抑制剂等试剂的DDR修复抑制导致的遗传毒性应激和停滞的DNA复制叉能诱导NKG2D受体的配体表达。还认为由DDR 修复抑制引起的基因组不稳定性导致肿瘤突变负荷增加、新抗原和/或干扰素基因(STING) 途径刺激的激活以及肿瘤免疫原性的总体增加。
由DDR抑制引起的肿瘤免疫原性增加(例如NKG2D受体配体的上调增加)特别地有利于γδT细胞介导的肿瘤免疫监视,以及最终由γδT细胞引起的肿瘤细胞杀伤。DDR 抑制与基于免疫疗法的人γδT细胞的联合作用提供了其他多种临床优势。例如,通过口服或静脉内向患者施用PARP抑制剂与如恶心和疲劳的症状相关,这可能格外麻烦且影响生活质量。并且可能需要停用PARP抑制剂。基于人γδT细胞的免疫疗法与PARP抑制剂相结合,通过降低PARP抑制剂所需的剂量避免与其相关的毒性,同时增强肿瘤杀伤作用。
发明内容
本发明提供了用于治疗癌症的组合疗法,包括γδT细胞免疫疗法联合DDR抑制剂(包括但不限于PARP抑制剂)的组合物和方法。优选地,用于治疗癌症的γδT细胞免疫疗法和PARP抑制剂的组合还包括与其他免疫疗法,例如免疫检查点(ICP)阻断疗法和/或DNA损伤剂例如细胞毒性化学治疗剂的组合。优选地,当γδT细胞免疫疗法和 DDR抑制剂疗法的组合还包括化学治疗剂时,对γδT细胞进行基因修饰以赋予对所述化学治疗剂的抗性。
优选地,本发明提供治疗有需要的患者的癌症的方法,包括:i)向所述患者施用包含治疗上有效量的γδT细胞的组合物,所述γδT细胞为对至少一种化学治疗剂具有抗性的基因工程γδT细胞;ii)向所述患者施用治疗上有效量的化学治疗剂;和iii)向所述患者施用治疗上有效量的DDR抑制剂。优选地,所述DDR抑制剂为PARP抑制剂。优选地,在施用所述化学治疗剂之前和在施用包含所述基因工程γδT细胞的所述组合物之前施用所述PARP抑制剂。优选地,在施用所述化学治疗剂之前约1天至约21天施用所述 PARP抑制剂。优选地,在施用化学治疗剂后约8小时至约72小时施用基因工程γδT细胞。优选地,在施用化学治疗剂后约12小时至约36小时施用基因工程γδT细胞。优选地,在施用化学治疗剂后约24小时施用基因工程γδT细胞。优选地,所述化学治疗剂为烷基化剂;代谢拮抗剂;DNA脱甲基剂;取代的核苷酸;取代的核苷;抗肿瘤抗生素;植物来源的抗肿瘤剂或亚硝基脲。优选地,所述化学治疗剂选自顺铂;卡铂;依托泊苷;甲氨蝶呤(MTX);三甲氧苯甲酸酯(TMTX);替莫唑胺;达卡巴嗪(DTIC);雷替曲塞; S-(4-硝基苄基)-6-硫肌苷(NBMPR);6-苄胍(6-BG);亚硝基脲(rabinopyranosyl-N-甲基 -N-亚硝基脲(Aranose)、卡莫司汀(BCNU,BiCNU)、氯唑霉素、乙基亚硝脲(ENU)、福特莫司汀、洛莫司汀(CCNU)、尼莫司汀、N-亚硝基-N-甲基脲(NMU)、雷莫司汀 (MCNU)、司莫司汀、链脲霉素(链脲菌素));阿糖胞苷;喜树碱;以及其任一的治疗衍生物。优选地,所述γδT细胞已被基因修饰为编码烷基鸟嘌呤转移酶(AGT)、 P140KMGMT、O6甲基鸟嘌呤DNA甲基转移酶(MGMT)、L22Y-DHFR、胸苷酸合成酶、二氢叶酸还原酶或多药耐药-1蛋白(MDR1)。优选地,所述γδT细胞已被基因修饰为对至少两种化学治疗剂具有抗性,所述化学治疗剂选自:烷基化剂;代谢拮抗剂;DNA脱甲基剂;取代的核苷酸;取代的核苷;抗肿瘤抗生素;植物来源的抗肿瘤剂或亚硝基脲。优选地,所述γδT细胞已被基因修饰为对至少两种化学治疗剂具有抗性,所述化学治疗剂选自顺铂;卡铂;依托泊苷;甲氨蝶呤(MTX);三甲氧苯甲酸酯(TMTX);替莫唑胺;达卡巴嗪(DTIC);雷替曲塞;S-(4-硝基苄基)-6-硫肌苷(NBMPR);6-苄胍(6-BG);亚硝基脲(rabinopyranosyl-N-甲基-N-亚硝基脲(Aranose)、卡莫司汀(BCNU,BiCNU)、氯唑霉素、乙基亚硝脲(ENU)、福特莫司汀、洛莫司汀(CCNU)、尼莫司汀、N-亚硝基 -N-甲基脲(NMU)、雷莫司汀(MCNU)、司莫司汀、链脲霉素(链脲菌素));阿糖胞苷;喜树碱;以及其任一的治疗衍生物。优选地,所述化学治疗剂为TMZ、甲氨蝶呤、DTIC、 BCNU、CCNU、MCNU、NMU或ENU。
附图说明
图1显示了四个折线图,比较了LN229胶质母细胞瘤细胞系上的自然杀伤组2D配体(NKG2DL)于选定时间点在以下条件下的表达:单独暴露于奥拉帕尼(5或10mM)、奥拉帕尼(示例性PARP抑制剂)+200mg/mL TMZ、或单独的培养基(RPMI+10%FBS 培养基)4小时,并在开始时和处理后8、16、24和36小时测量活力。
图2显示了两个折线图,比较了U138胶质母细胞瘤细胞系上的自然杀伤组2D配体(NKG2DL)于选定时间点在以下条件下的表达:单独暴露于奥拉帕尼(5或10mM)、奥拉帕尼(示例性PARP抑制剂)+200mg/mL TMZ、或单独的培养基(RPMI+10%FBS 培养基)4小时,并在开始时和处理8、16、24和36小时测量活力。
图3显示了三个折线图,比较了U251胶质母细胞瘤细胞系上的自然杀伤组2D配体(NKG2DL)于选定时间点在以下条件下的表达:单独暴露于奥拉帕尼(5或10mM)、奥拉帕尼(示例性PARP抑制剂)+200mg/mL TMZ、或单独的培养基(RPMI+10%FBS 培养基)4小时,并在开始时和处理8、16、24和36小时测量活力。
发明详述
定义
除非另有定义,否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。尽管与本文所述类似或等同的任何方法和材料也可用于本发明的实践或测试,但现在描述优选的方法和材料。
如本说明书和所附权利要求中所使用的,单数形式“一个”包括复数指称,除非上下文另有明确规定。因此,例如,关于“一个支持”的引用包括多个支持。在本说明书和随后的权利要求中,除非明显有相反的意思表示,否则提及的若干术语将被定义为具有以下含义。
应该注意的是,比率、浓度、量和其他数值数据可以在本文中以范围形式表示。应该理解的是,为了方便和简洁起见使用这种范围形式,因此,应该以灵活的方式解释,不仅包括明确列举为范围限制的数值,而且还包括在该范围内涵盖的所有单个数值或子范围,就像明确列举了每个数值和子范围一样。举例说明,“约0.1%至约5%”的浓度范围应解释为不仅包括明确列举的约0.1wt%至约5wt%的浓度,而且还包括在指定范围内的各个浓度(例如1%,2%,3%和4%)和子范围(例如0.5%,1.1%,2.2%,3.3%和4.4%)。术语“约”可以包括±1%、±2%、±3%、±4%、±5%、±6%、±7%、±8%、±9%、或者±10%,或更多修改的数值。另外,“约‘x’到‘y’”的短语包括“约‘x’到约‘y’”。
“施用”是指将本发明的化合物、包括细胞群的生物材料或其组合引入人或动物受试者。化合物的一种优选施用途径为静脉注射。化合物的其他优选施用途径可以为腹膜内给药或胸膜内给药,或通过导管进入大脑。然而,可以使用任一施用途径,例如口服、局部、皮下、腹膜、动脉内、吸入、阴道、直肠、鼻腔、引入脑脊液或滴入体腔给药。还考虑直接注射到靶组织部位如实体瘤中。
如本文所用,术语“癌症”应具有其一般含义,即作为异常细胞无控制地分裂的疾病的一般术语。癌细胞可以侵入附近的组织,并可以通过血液和淋巴系统扩散到身体的其他部位。当正常细胞失去表现为指定的、受控的和协调的单位的能力时,肿瘤就形成了。通常地,实体瘤是通常不包含囊肿或液体区域的异常组织块(一些脑肿瘤确实具有充满液体的囊肿和中心坏死区域)。单个肿瘤中甚至可能具有不同的细胞群,具有已经出错的不同的进程。实体瘤可以是良性的(非癌性的)或恶性的(癌性的)。不同类型的实体瘤因其形成的细胞类型来命名。实体瘤的例子为肉瘤、癌和淋巴瘤。白血病(血液癌症)通常不形成实体瘤。
如本文所用,术语“减少肿瘤”是指肿瘤块的大小或体积减小、受试者中转移的肿瘤数量减少、癌细胞的增殖状态(癌细胞增加的程度)降低等。
如本文所用,术语“化学治疗剂”是指可以与癌细胞相互作用,从而降低细胞的增殖状态和/或杀死细胞的化合物或其衍生物,例如通过损害细胞分裂或DNA合成,或通过破坏DNA有效地靶向快速分裂的细胞。化学治疗剂的实例包括但不限于烷基化剂(例如环磷酰胺、异环磷酰胺);代谢拮抗剂(例如甲氨蝶呤(MTX)、5-氟尿嘧啶或其衍生物);取代的核苷酸;取代的核苷;DNA去甲基化剂(也称为抗代谢物),如阿扎胞苷);抗肿瘤抗生素(如丝裂霉素、阿霉素);植物来源的抗肿瘤剂(例如长春新碱、长春地辛、紫杉醇、Abraxane);顺铂;卡铂;依托泊苷等等。这些药剂可以进一步包括但不限于抗癌剂三甲氧苯甲酸酯(TMTX);替莫唑胺;雷替曲塞;S-(4-硝基苄基)-6-硫肌苷(NBMPR);6-苄胍(6-BG);亚硝基脲(rabinopyranosyl-N-甲基-N-亚硝基脲(Aranose)、卡莫司汀(BCNU,BiCNU)、氯唑霉素、乙基亚硝脲(ENU)、福特莫司汀、洛莫司汀 (CCNU)、尼莫司汀、N-亚硝基-N-甲基脲(NMU)、雷莫司汀(MCNU)、司莫司汀、链脲霉素(链脲菌素));阿糖胞苷;喜树碱;以及其任一的治疗衍生物。
短语“治疗上有效量”或“有效量”是指向受试者施用药剂、单独或作为药物组合物的一部分并且以单剂量或作为一系列剂量的一部分向受试者施用药剂,其量能够对疾病、紊乱或病症的任一症状、方面或特征产生任一可检测的积极影响。治疗上有效量可以通过测量相关的生理效应来确定,并且可以结合给药方案和受试者病情的诊断分析等来调整。举例来说,给药后产生的炎性细胞因子量的测量可以指示是否使用了治疗上有效量。关于与未调节的细胞分裂相关的癌症或病理学,治疗上有效量是指具有以下作用的量: (1)减小肿瘤的大小(即肿瘤消退),(2)抑制(即在某种程度上减慢,优选地停止)异常细胞分裂,例如癌细胞分裂,(3)预防或减少癌细胞的转移,和/或(4)在一定程度上减轻(或优选地消除)与未调节或异常细胞分裂有关或部分由其引起的病理学相关的一种或多种症状,包括例如癌症。“有效量”也是在施用本发明的治疗活性组合物时导致期望的PD和PK曲线以及期望的免疫细胞谱的量。
本文所用疾病(或病症或紊乱)的“治疗”术语是指防止疾病在人类受试者或动物受试者中发生,所述受试者可能易患该疾病但尚未经历或表现出该疾病症状(预防性治疗)、抑制疾病(减缓或阻止其发展)、缓解疾病的症状或副作用(包括姑息治疗)以及导致疾病消退。关于癌症,这些术语还意味着受癌症影响的个体的预期寿命可能会延长,或者该疾病的一种或多种症状会减轻。关于癌症,“治疗”还包括增强或延长受试者的抗肿瘤反应。
如本文所使用,“组合”、“组合疗法”和/或“组合治疗方案”的任何给药形式是指至少两种治疗活性药物或组合物,其可以以单独或组合的制剂同时给药,或在不同的时间,间隔几分钟,数小时或数天按顺序给药,但以某种方式共同作用以提供所需的治疗反应。
如本文所用,术语“增强”是指允许受试者或肿瘤细胞提升其响应本文公开的治疗的能力。例如,增强的响应可以包括至少5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或98%以上的响应能力。如本文所用,“增强”还可以指增强对治疗例如包含化学疗法、耐药免疫活性细胞和免疫检查点抑制剂的组合疗法有响应的受试者的数量。例如,增强的响应可以指对治疗有反应的受试者的总百分比,其中百分比至少为5%、10%、15%、20%、25%、30%、 35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或98%以上。
本文使用的术语“受试者”和“患者”包括人、哺乳动物(例如猫、狗、马等)、活细胞和其他活生物体。活生物体可以与例如单个真核细胞一样简单或与哺乳动物一样复杂。典型的患者是哺乳动物,特别是灵长类动物,尤其是人类。对于兽医应用,各种各样的主题将是合适的,例如牲畜如牛、绵羊、山羊、母牛,猪等;家禽如鸡、鸭、鹅、火鸡等;以及家养动物,特别是狗和猫等宠物。对于诊断或研究应用,合适的受试者将是各种各样的哺乳动物,包括啮齿动物(例如,小鼠、大鼠、仓鼠)、兔、灵长类动物和猪,例如近交猪等。优选地,一个系统包括一个样品和一个受试者。术语“活宿主”是指存活且未死亡的上述宿主或生物体。术语“活宿主”指整个宿主或生物体,而不仅仅是从活宿主切除的部分(例如肝脏或其他器官)。
如本文所用,术语“γδT细胞(gamma delta T细胞)”是指在其表面表达独特的T细胞受体(TCR)的T细胞的亚群。大多数T细胞的TCR由两条称为α-和β-TCR链的糖蛋白链组成。相反,在γδT细胞中,TCR由一条γ链和一条δ链组成。这组T细胞通常不如αβT细胞常见。γδT细胞在T细胞类型中是独特的,因为它们不需要抗原加工和肽表位的MHC呈递。此外,据信γδT细胞在识别脂质抗原中具有重要作用,并且能响应应激相关抗原如MIC-A和MIC-B以及NKG2D受体的其他配体。
术语“耐药免疫疗法”或DRI是基于基因的治疗癌症的策略,其中抗癌免疫细胞(优选为γδT细胞)经过基因工程改造,可以抵抗化学疗法药物的毒性作用,从而可以将化学疗法和免疫疗法联合给药。
如本文所用,术语“富集的”是指相对于如本文所公开的富集前相同的一种或多种细胞类型的总百分比,增加样品中存在的一种或多种细胞毒性免疫细胞类型(例如,γδT细胞和/或NK细胞)l的总百分比。例如,针对一种或多种类型的细胞毒性免疫细胞“富集”的样品可占样品中一种或多种细胞毒性免疫细胞类型的约10%-100%,而富集前样品中一种或多种细胞毒性免疫细胞的总百分比为例如0%至10%,优选地,富集的样品包含至少10%、15%、20%、25%、30%、35%、40%、50%、60%、70%、80%、90%或100%的一种或多种细胞毒性免疫细胞类型。使用标准技术,例如流式细胞仪技术,可以富集一种或多种细胞类型的样品。
如本文所用,术语“高度富集的”是指增加样品中一种或多种细胞毒性免疫细胞类型的总百分比,使得一种或多种细胞毒性免疫细胞类型可占该样品中细胞毒性免疫细胞类型的至少约70%至约100%之间。而在富集前相同类型的细胞毒性免疫细胞的总百分比为例如0%至10%。优选地,高度富集的样品包含至少一种或多种类型的细胞毒性免疫细胞的60%、65%、70%、75%、80%、85%、90%、95%、99%或更多。使用标准技术,例如流式细胞仪技术,样品可以高度富集一种或多种细胞类型。
如本文所用,关于样品中一种或多种细胞毒性免疫细胞的扩增的术语“扩增”是指将样品中一种或多种细胞毒性免疫细胞的数目增加例如至少约2倍,优选约5倍,优选至少10倍,优选约至少50倍或更多。细胞毒性免疫细胞群的扩增可以通过本领域已知的许多方法来完成。例如,在饲养淋巴细胞和白介素2(IL-2)或白介素15(IL-15),优选IL-2存在的情况下,可以通过非特异性T细胞受体刺激快速扩增T细胞。非特异性T 细胞受体刺激可包括约30ng/ml的小鼠单克隆抗CD3抗体OKT3(可从ORTHO- Raritan,N.J获得)。备选地,在T细胞生长因子的存在下,可以通过用癌症的一种或多种抗原(包括其抗原性部分,例如表位或细胞)刺激体外外周血单核细胞(PBMC) 来快速扩增T细胞,其可任选地从载体上表达,例如人白细胞抗原A2(HLA-A2)结合肽,例如0.3μM MART-1:26-35(27L)或gp100:209-217(210M),例如300IU/ml IL-2 或IL-15,优选IL-2。
如本文所用,术语“分离的”和“分离的细胞群”是指从受试者体内发现的组织或状态中移除一个或多个细胞。该术语可以进一步包括已经根据以下参数分离的细胞:比如但不限于细胞表面标记、报告标记(例如染料或标记)之类。
如本文所用,术语“表达的”或“表达”是指从基因上转录以产生RNA核酸分子,该RNA核酸分子至少部分地与基因的两条核酸链之一的区域互补。如本文所用,术语“表达的”或“表达的”还指翻译所述RNA核酸分子以产生蛋白质、多肽或其部分或片段。
术语“重组细胞”是指具有在本质上彼此不共价连接的核酸片段的新组合的细胞。可使用本领域技术人员可获得的多种核酸处理技术将核酸片段的新组合引入生物体。重组细胞可以是单个真核细胞、单个原核细胞或哺乳动物细胞。重组细胞可能含有一种基因组外的载体。基因组外的核酸载体不能插入细胞基因组。重组细胞可进一步含有载体或其基因组内的一部分。术语“基因组内的”定义了整合在重组细胞基因组中的核酸构建体。
本文所使用的术语“重组核酸”和“重组DNA”是指在真核或原核细胞中未天然存在的至少两个核酸序列的组合。核酸序列包括但不限于核酸载体、基因表达调控元件、复制起点、表达时赋予抗生素抗性的合适基因序列、蛋白质编码序列等。术语“重组多肽”意指包括通过重组DNA技术产生的多肽,使得其在位置、纯度或结构上与天然存在的多肽不同。一般来说,这种重组多肽在细胞中的存在量与通常在自然界中观察到的不同。
如本文所使用的术语“靶向治疗”是指靶向免疫系统的任何方面的任何治疗分子。
术语“转化”和“转导”都表示将多核苷酸导入受体细胞。
“免疫检查点蛋白”调节免疫系统中的T细胞功能。T细胞在细胞介导的免疫中起核心作用。检查点蛋白与特定配体相互作用,这些配体向T细胞发送信号,本质上关闭或抑制T细胞功能。癌细胞利用这一系统在其表面高水平表达检查点蛋白,从而控制进入肿瘤微环境的T细胞表面表达检查点蛋白的T细胞,从而抑制抗癌免疫反应。因此,通过本文中称为“免疫检查点蛋白(ICP)抑制剂”的试剂抑制检查点蛋白将导致T细胞功能的恢复和对癌细胞的免疫应答。检查点蛋白质的实例包括但不限于:CTLA-4、PDL1、 PDL2、PD1、B7-H3、B7-H4、BTLA、HVEM、TIM3、GAL9、LAG3、VISTA、KIR、 2B4、CD160、CGEN-15049、CHK 1、CHK2、A2aR、OX40、B-7家族配体或其组合。优选地,免疫检查点抑制剂与检查点蛋白的配体相互作用,该配体可以是CTLA-4、PDL1、 PDL2、PD1、B7-H3、B7-H4、BTLA、HVEM、TIM3、GAL9、LAG3、VISTA、KIR、 2B4、CD160、CGEN-15049、CHK 1、CHK2、OX40、A2aR、B-7家族配体或其组合。优选地,检查点抑制剂是生物治疗剂或小分子。优选地,检查点抑制剂为单克隆抗体、人源化抗体、全人抗体、融合蛋白或其组合。目前有几种PD-1和CTLA-4抑制剂正在进行临床试验。CT-011是一种抗PD-1的人源化IgG1单克隆抗体,BMS 936558是一种针对PD- 1试剂的全人IgG4单克隆抗体。BMS 936559是一种针对PD-1配体PD-L1的全人IgG4 单克隆抗体。MK 3475是一种人源化IgG4抗PD-1单克隆抗体,其为一项由五部分组成的研究中I期进展中使用,该研究对进展性、局部晚期或转移性癌、黑色素瘤或NSCLC 患者的剂量、安全性和耐受性进行了评估。MPDL l3280A是一种单克隆抗体。AMP 224 是第二PD-1配体PD-L2和IgG1胞外区的融合蛋白,其具有阻断PD-L2/PD-1相互作用的潜力。Medi 4736是一种抗PD-L1抗体,用于晚期恶性黑色素瘤、肾细胞癌、NSCLC 和结直肠癌患者的I期临床试验。一种首创的免疫疗法伊普利单抗为一种针对T细胞表面CTLA-4的单克隆抗体,其用于治疗黑色素瘤。
γδT细胞组合免疫治疗
本发明提供用于在患者中减少肿瘤和治疗癌症的组合疗法,其包括将γδT细胞免疫疗法和DDR抑制剂(包括但不限于PARP抑制剂)联合的组合物和方法,其进一步还结合化学治疗剂(包括但不限于替莫唑胺(TMZ))。优选地,用于治疗癌症的γδT细胞免疫疗法和PARP抑制剂的组合还包括与其他免疫疗法例如免疫检查点(ICP)阻断疗法和 /或其他免疫刺激剂的组合。
本发明提供治疗患者癌症的方法,包括:i)施用包含任选富集和/或任选扩增的γδT 细胞群的组合物;ii)向有需要的患者施用(i)的组合物;向患者施用有效量的至少一种DDR抑制剂;和iii)任选地施用化学治疗剂,从而治疗患者的癌症。
优选地,γδT细胞源自人诱导多能干细胞(hiPSC)。优选地,多能干细胞可以从患有癌症的患者中分离。优选地,多能干细胞可以从癌症患者以外的来源分离。优选地,包含γδT细胞的任选富集和/或任选扩增的组合物还包含自然杀伤(NK)细胞并且任选地进一步包含其他免疫活性细胞,包括但不限于:单核细胞、巨噬细胞和树突细胞。
优选地,包含任选富集和/或任选扩增的γδT细胞群的组合物包含至少约50%、至少约60%、至少约70%或更多的γδT细胞。优选地,包含任选富集和/或任选扩增的γδT 细胞群的组合物包含少于约35%的自然杀伤(NK)细胞。优选地,包含任选富集和/或任选扩增的γδT细胞群的组合物包含小于约10%、小于约5%的αβT细胞。
优选地,用于向患者施用包含任选富集和/或任选扩增的γδT细胞群的治疗组合物包含约5×108γδT细胞/kg或更小患者体重。优选地,用于向患者施用包含任选富集和/或任选扩增的γδT细胞群的治疗组合物包含约5×107γδT细胞/kg或更小患者体重。优选地,用于向患者施用包含任选富集和/或任选扩增的γδT细胞群的治疗组合物包含约5×106γδT细胞/kg或更小患者体重。
用于从待治疗的患者或其他来源中分离的γδT细胞的方法,例如LambL.S.U.S.Pat. No.7,078,034中的描述,其通过引用全部并入本文。
适用于本文所述方法的DDR抑制剂可以是任何化合物或实体,例如小有机分子、肽或核酸,其抑制、降低或消除DNA损伤修复途径的一种或多种组分的活性。这些途径包括碱基切除修复(BER)同源重组(HR)依赖的DNA双链断裂(DSB)修复、非同源末端连接(NHEJ)、核苷酸切除修复(NER)、碱基切除修复(BER)和错配修复(MMR)。
优选地,DDR抑制剂降低或消除酶聚(ADP-核糖)聚合酶(PARP)的活性。优选的PARP抑制剂包括但不限于均获FDA批准的:尼拉帕尼、奥拉帕尼和芦卡帕尼。奥拉帕尼和芦卡帕尼已经FDA批准用于治疗复发性BRCA相关卵巢癌。最近,这两种和第三种PARP抑制剂尼拉帕尼经FDA批准作为复发性卵巢癌铂类化学疗法后的维持疗法。
其他优选的PARP抑制剂包括但不限于:他拉唑帕尼(Talazoparib)(Pfizer)、维利帕尼(veliparib)(Abbvie)、E7016(Eisai)、CEP-9722(Teva)和BGB-290(Pamiparib,BeiGene)。
已知的PARP抑制剂和可依照本发明使用的化合物的其他实例包括:
1.烟酰胺类,如5-甲基烟酰胺和O-(2-羟基-3-哌啶基-丙基)-3-羧酸胺肟及其类似物和衍生物;
2.苯甲酰胺类,包括3-取代的苯甲酰胺,例如3-氨基苯甲酰胺、3-羟基苯甲酰胺、3-亚硝基苯甲酰胺、3-甲氧基苯甲酰胺和地氯普胺,以及4-氨基苯甲酰胺、1,5-二[(3-氨基甲酰基苯基)氨基羰氧基]戊烷,及其类似物和衍生物;
3.异喹啉酮和二氢异喹啉酮类,包括2H-异喹啉-1-酮;3H-喹唑啉-4-酮;5-取代的二氢异喹啉酮,例如5-羟基二氢异喹啉酮、5-甲基二氢异喹啉酮和5-羟基异喹啉酮、5-氨基异喹啉-1-酮、5-二羟基异喹啉酮;3,4二氢异喹啉-1(2H)-酮,例如3,4二氢-5-甲氧基异喹啉-1(2H)-酮和3,4-二氢-5-甲基-1(2H)异喹啉酮;异喹啉-1(2H)-酮;4,5-二氢咪唑并 [4,5,1-ij]喹啉-6-酮;1,6-萘啶-5(6H)-酮;1,8-萘酰亚胺,例如4-氨基-1,8-萘酰亚胺;异喹啉酮;3,4-二氢-5-[4-1(1-哌啶基)丁氧基]-1(2H)-异喹啉酮;2,3-二氢苯并[de]异喹啉-1-酮;1- 11b-二氢-[2H]苯并吡喃[4,3,2-de]异喹啉-3-酮;以及四环内酰胺,包括苯并吡喃异喹啉酮,例如苯并吡喃并[4,3,2-de]异喹啉酮;及其类似物和衍生物;
4.苯并咪唑和吲哚类,包括苯并恶唑-4-甲酰胺;苯并咪唑-4-甲酰胺,例如2-取代苯并恶唑-4-甲酰胺;和2-取代苯并咪唑-4-甲酰胺,例如2-芳基苯并咪唑-4-甲酰胺;和2-环烷基苯并咪唑-4-甲酰胺,包括2-(4-羟基苯基)苯并咪唑-4-甲酰胺、喹喔啉甲酰胺、咪唑吡啶甲酰胺;2-苯基吲哚;2-取代苯并恶唑,如2-苯基苯并恶唑和2-(3-甲氧基苯基)苯并恶唑;2-取代苯并咪唑,如2-苯基苯并咪唑和2-(3-甲氧基苯基)苯并咪唑;1,3,4,5-四氢氮杂氮[5,4,3-cd]吲哚-6-酮;氮杂吲哚和氮杂吲哚酮,例如1,5-二氢氮杂吲哚[4,5,6-cd]吲哚-6- 酮和二氢二氮杂吲哚酮;3-取代的二氢二氮杂吲哚酮,例如3-(4-三氟甲基苯基)-二氢二氮杂吲哚酮、四氢二氮杂吲哚酮和5,6-二氢咪唑并[4,5,1-j,k][1,4]苯并二氮杂吲哚-7(4H)-酮;2-苯基-5,6-二氢咪唑并[4,5,1-jk][1,4]苯二氮杂-7(4H)-酮;和2,3二氢异吲哚-1-酮;及其类似物和衍生物;
5.酞嗪-1(2H)-酮和喹唑啉酮,例如4-羟基喹唑啉;酞嗪酮;5-甲氧基-4-甲基-1(2) 酞嗪酮;4-取代酞嗪酮;4-(1-哌嗪基)-1(2H)-酞嗪酮;四环苯并吡喃并[4,3,2-de]酞嗪酮和四环茚并[1,2,3-de]酞嗪酮和2-取代喹唑啉,例如8-羟基-2-甲基喹唑啉-4-(3H)酮;三环酞嗪酮和2-氨基酞酰肼,及其类似物和衍生物;
6.异吲哚啉酮及其类似物和衍生物;
7.菲啶和菲酮类,例如5[H]菲-6-酮;取代的5[H]菲-6-酮,尤其是2-、3-取代5[H]菲-6-酮和6(5H)菲酮的磺酰胺/尿素衍生物;噻吩并[2,3-c]异喹诺酮类,例如9-氨基噻吩并[2,3-c]异喹诺酮类和9-羟基噻吩并[2,3-c]异喹诺酮类,9-甲氧基噻吩并[2,3-c]异喹诺酮和N-(6-氧代-5,6-二氢菲-2-基]-2-(N,N-二甲氨基)乙酰胺;取代的4,9-二氢环戊基[lmn] 菲-5-酮;及其类似物和衍生物;
8.苯并吡喃酮类,例如1,2-苯并吡喃酮6-硝基苯并吡喃酮、6-亚硝基1,2-苯并吡喃酮和5-碘-6-氨基苯并吡喃酮,及其类似物和衍生物;
9.不饱和羟肟酸衍生物类,例如O-(3-哌啶基-2-羟基-1-丙基)烟酰胺肟,及其类似物和衍生物;
10.哒嗪类,包括稠合的哒嗪及其类似物和衍生物;和
11.其他化合物,如咖啡因、茶碱、胸苷及其类似物和衍生物。
组合γδT细胞DRI和DDR抑制剂的组合治疗。
优选地,作为治疗方案的γδT细胞免疫疗法和DDR抑制剂疗法的组合进一步包括与化学治疗剂的组合,其中γδT细胞经基因修饰以产生对被称为耐药性免疫疗法(DRI) 的化学治疗剂的抗性。优选地,对γδT细胞进行基因修饰以使其对化学治疗剂的作用具有抗性,在存在或不存在化学治疗剂的情况下,不影响γδT细胞杀死靶癌细胞的能力。使用标准重组技术对γδT细胞进行基因修饰,例如在实施例和WO 2011/053750和Lamb 等人,PloSONE 8(1):e51805.doi:10.1371/journal.pone.0051805)中所描述的。
优选地,包含任选富集和/或任选扩增的基因工程γδT细胞群的组合物包含至少约 50%、至少约60%、至少约70%或更多的γδT细胞。优选地,包含任选富集和/或任选扩增的基因工程γδT细胞群体的组合物包含少于约35%的自然杀伤(NK)细胞。优选地,包含任选富集和/或任选扩增的基因工程γδT细胞群的组合物包含小于约10%、小于约 5%的αβT细胞。
优选地,用于向患者施用包含任选富集和/或任选扩增的基因工程γδT细胞群的治疗组合物包含约5×108γδT细胞/kg或更小患者体重。优选地,用于向患者施用包含任选富集和/或任选扩增的基因工程γδT细胞群的治疗组合物包含约5×107γδT细胞/kg或更小患者体重。优选地,用于向患者施用包含任选富集和/或任选扩增的基因工程γδT细胞群的治疗组合物包含约5×106γδT细胞/kg或更小患者体重。
癌症化学疗法的一个主要限制是药物诱导的免疫毒性,这会导致免疫活性细胞的死亡和有效免疫系统的丧失,而有效免疫系统原本会避免不良感染或提供针对癌细胞的防御。对抗化学疗法的严重毒性作用的一种策略是通过引入逆转录病毒载体选择性地基因修饰细胞毒性免疫细胞,引入逆转录病毒载体的目的为表达产生耐药性的cDNA序列,该序列可主动靶向那些能够抵抗同时施用的化学治疗剂的癌细胞。例如,Spencer H.T.等在US2015/0017137(也可参见WO 2011/053750和Lamb等.,PloS ONE 8(1):e51805. doi:10.1371/journal.pone.0051805)描述了使用基因工程γδT细胞免疫疗法的这种耐药性免疫疗法。
发明人先前已发现施用诸如TMZ的化学治疗剂可瞬时增加TMZ抗性细胞系中的应激相关抗原(例如NKG2D家族受体的配体,如MIC a/B和UL 16结合蛋白(ULBPs))。本发明通过将化学治疗剂与DDR抑制剂结合来增强这一先前发现。在不受任何理论限制的情况下,诸如PARP抑制剂之类的DDR抑制剂可增强和延长暴露于化学治疗剂引起的癌细胞上的应激相关抗原的上调。因此,通过长期将化学疗法和DDR抑制剂治疗结合增强了NKG2D配体在癌细胞上的强制表达,使得肿瘤细胞非常容易被γδT细胞杀死。修饰γδT细胞以抵抗化学治疗剂的破坏,使它们能够在化学治疗剂和DDR抑制剂联合作用的瞬时NKG2D上调的最佳和延长窗口期间、在化学治疗剂的存在下持续存在。
优选地,在向患者施用化学治疗剂前约1至约21天施用DDR抑制剂例如PARP抑制剂或先前描述的任何其他DDR抑制剂。优选地,在施用化学治疗剂前约1至约14天施用PARP抑制剂。优选地,在施用化学治疗剂之前约1至约7天施用PARP抑制剂。
优选地,在施用化学治疗剂后约8至约72小时施用具有基因工程的抗化学疗法的γδ T细胞的DRI。优选地,在施用化学治疗剂后约8至约36小时施用具有基因工程的抗化学疗法的γδT细胞的DRI。优选地,在施用化学治疗剂后约8至约24小时施用具有基因工程的抗化学疗法的γδT细胞的DRI。优选地,在施用化学治疗剂后约8至约12小时施用具有基因工程的抗化学疗法的γδT细胞的DRI。优选地,在施用化学治疗剂后约 12至约36小时施用具有基因工程的抗化学疗法的γδT细胞的DRI。优选地,在施用化学治疗剂后约12至约24小时施用具有基因工程的抗化学疗法的γδT细胞的DRI。优选地,在施用化学治疗剂后约24小时施用具有基因工程的抗化学疗法的γδT细胞的DRI。优选地,在施用化学治疗剂后约8、9、10、11、12、13、14、15、16、17、18、19、20、 21、22、23、24、25、26、27、28、29、30、31、32、33、34、35或36小时施用具有基因工程的抗化学疗法的γδT细胞的DRI。
DRI和DRR抑制剂联合检查点抑制剂(ICP)疗法
优选地,作为治疗方案的γδT细胞DRI和DDR抑制剂疗法的组合进一步包括与ICP抑制剂的组合。优选地,检查点抑制剂为PD-1抑制剂或CTLA-4抑制剂。优选地,免疫检查点抑制剂可以为生物治疗剂或小分子。优选地,检查点抑制剂为单克隆抗体、人源化抗体、全人抗体、融合蛋白、抗原结合片段或其组合。
优选地,免疫刺激剂、T细胞生长因子和白细胞介素可用于本发明的各种组合疗法。免疫刺激剂是通过诱导激活或增加其任何成分的活性来刺激免疫系统的物质(药物和营养素)。免疫刺激剂包括但不限于细菌疫苗、集落刺激因子、干扰素、白细胞介素、其他免疫刺激剂、治疗性疫苗、疫苗组合和病毒疫苗。T细胞生长因子是刺激T细胞增殖的蛋白质。T细胞生长因子的例子包括IL-2、IL-7、IL-15、IL-17、IL21和IL-33。
WIPO专利申请WO/2018/035413中描述了包括耐药性γδT细胞免疫疗法、化学治疗剂、ICP抑制剂任选的免疫刺激剂的组合疗法。结合PARP抑制剂与免疫检查点抑制剂的临床试验正在进行中,并已在文献中报道。
优选地,用于治疗癌症的包含耐药性γδT细胞免疫疗法和PARP抑制剂的组合疗法进一步包括免疫检查点(ICP)阻断疗法和/或用化学治疗剂和/或免疫刺激剂的疗法。可以以单独或组合的制剂同时给药,或在相隔几分钟、几小时或几天的不同时间顺序给药,但以某种方式共同作用以提供所需的治疗反应。γδT细胞免疫疗法与DDR抑制组合和任选进一步与化学疗法和ICP抑制剂组合的最佳时机将根据本领域已知的疾病设置而变化,但通常会在施用细胞疗法以诱导DNA损伤和增加免疫原性前看到PARP抑制和/或化学疗法。
优选地,检查点抑制剂的有效量是与DRI和DDR组合疗法组合有效引起肿瘤消退的量。优选地,检查点抑制剂以小于0.0001mg/kg、0.0001-0.001mg/kg、0.001-0.01mg/kg、0.01-0.05mg/kg、0.05-0.1mg/kg、0.1-0.2mg/kg、0.2-0.3mg/kg、0.3-0.5mg/kg、0.5-0.7mg/kg、 0.7-1mg/kg、1-2mg/kg、2-3mg/kg、3-4mg/kg、4-5mg/kg、5-6mg/kg、6-7mg/kg、7-8mg/kg、 8-9mg/kg、9-10mg/kg、至少10mg/kg、或其剂量的任意组合的剂量施用(以患者体重的 kg计)。优选地,检查点抑制剂至少每周一次、每周至少两次、每周至少三次、至少每两周一次、或至少每月或多个月一次施用。优选地,检查点抑制剂以单剂量、两剂量、三剂量、四剂量、五剂量或六剂量或更多剂量施用。
药物组合物和施用方法
优选地,本文公开的组合疗法可以通过各种途径施用于患者,包括例如口服或肠胃外,并且可以包括但不限于静脉注射、肌肉注射、皮下注射、眶内注射、囊内注射、腹腔注射、直肠内注射、脑池内注射、肿瘤内注射、鼻内注射(intravasally)、皮内注射、阴道内注射(如阴道栓剂),或局部注射(如粉末、软膏透皮贴片),或通过皮肤被动或促进吸收,例如分别使用皮肤贴片或透皮离子导入。
还可以将治疗剂、检查点抑制剂、生物治疗剂或药物组合物施用于病理状况的部位,例如静脉内或动脉内施用于供给肿瘤的血管。例如,包含γδT细胞、PARP抑制剂或其任何组合的组合物可以通过例如但不限于直接注射到肿瘤块中、递送到进入肿瘤块的血管中,或两者的结合来直接递送至靶向肿瘤。例如,预期可以通过插入肿瘤块中、切除后腔内、腹膜内或心室内的空心针或导管直接植入、将组合物递送至患者脑中的成胶质细胞瘤块。
优选地,在实施本发明的方法时可以将要施用的全部药剂通过以下方式施用于受试者,作为单一剂量、或者作为大剂量、或通过在相对较短的时间内输注,或者可以使用分次治疗方案施用,其中长时间内多次给药。本领域技术人员知晓,用于治疗受试者病理状况的组合物的量取决于多种因素,包括受试者的年龄和一般健康状况以及给药途径和要给药的治疗次数。鉴于这些因素,本领域技术人员将根据需要调整特定剂量。
本发明的药物组合物可以配制成与预期的给药方法或途径兼容的形式;示例性给药途径在本文中阐述。此外,药物组合物可以与本文所述的其他治疗活性剂或化合物组合使用,以治疗或预防本发明所预期的疾病,紊乱和病状。
药物组合物通常包含治疗有效量的一种或多种用于本发明组合疗法的药剂和一种或多种药学和生理学可接受的制剂。合适的药学上可接受或生理学上可接受的稀释剂,载体或赋形剂包括但不限于抗氧化剂(例如抗坏血酸和硫酸氢钠)、防腐剂(例如苯甲醇、对羟基苯甲酸甲酯、乙基或正丙基、对羟基苯甲酸酯)、乳化剂、悬浮剂、分散剂、溶剂、填充剂、填充剂、去污剂、缓冲剂、载体、稀释剂和/或佐剂。例如,合适的载体可以是生理盐水溶液或柠檬酸盐缓冲盐水,可能补充有用于肠胃外给药的药物组合物中常见的其他材料。中性缓冲盐水或与血清白蛋白混合的盐水是另外的示例性载体。本领域技术人员将容易识别可用于本文考虑的药物组合物和剂型中的多种缓冲剂。典型的缓冲剂包括但不限于药学上可接受的弱酸、弱碱或其混合物。例如,缓冲组分可以是水溶性材料,例如磷酸、酒石酸、乳酸、琥珀酸、柠檬酸、乙酸、抗坏血酸、天冬氨酸、谷氨酸及其盐。可接受的缓冲剂包括例如Tris缓冲剂、N-(2-羟乙基)哌嗪-N’-(2-乙磺酸)(HEPES)、2-(N- 吗啉基)乙磺酸(MES)、2-(N-吗啉基)乙磺酸钠盐(MES)、3-(N-吗啉基)丙磺酸(MOPS) 和N-三[羟甲基]甲基-3-氨基丙磺酸(TAPS)。
配制药物组合物后,可将其作为溶液、悬浮液、凝胶、乳液、固体或脱水或冻干粉末储存在无菌小瓶中。此类制剂可储为即用形式、使用前需要重组的冻干形式、使用前需要稀释的液体形式或其他可接受形式。优选地,将药物组合物放在一次性容器(例如,一次性小瓶、安瓿、注射器或自动注射器(类似于例如))中,然而,在其它实施例中提供了多用途容器(例如,多用途小瓶)。任何药物递送装置可用于递送IL-10,包括植入物(例如,可植入泵)和导管系统、慢注射泵和装置,所有这些都是本领域技术人员所熟知的。通常皮下或肌肉内施用的积存注射也可用于在限定时间段内释放本文公开的多肽。积存注射剂通常为固体或油基注射剂,并且通常包含本文所述的制剂组分中的至少一种。本领域的普通技术人员熟悉积存注射剂的可能配方和用途。
所述药物组合物可以是无菌可注射水溶液或油性悬浮液。该悬浮液可根据已知技术使用本文提及的那些合适的分散剂或润湿剂和悬浮剂来配制。无菌可注射制剂也可以是无菌可注射溶液或在无毒的肠外可接受的稀释剂或溶剂中的悬浮液,例如,作为1,3-丁烷二醇中的溶液。可采用的可接受的稀释剂、溶剂和分散介质包括水、林格溶液、等渗氯化钠溶液、Cremophor ELTM(BASF,Parsippany,N.J.)或磷酸盐缓冲盐水(PBS)、乙醇、多元醇(例如甘油、丙二醇和液态聚乙二醇)及其合适的混合物。此外,无菌固定油通常用作溶剂或悬浮介质。为此,可以使用任何温和的固定油,包括合成的单甘油酯或甘油二酯。此外,油酸等脂肪酸可用于制备注射剂。可通过包括延迟吸收的药剂(例如单硬脂酸铝或明胶)来实现特定可注射制剂的延长吸收。
药物组合物可以是适于口服的形式,例如片剂、胶囊剂、含片、锭剂、水悬浮液或油悬浮液、可分散粉末或颗粒、乳剂、硬胶囊或软胶囊、糖浆、溶液、微球或酏剂。拟用于口服的药物组合物可根据本领域已知的用于制造药物组合物的任何方法来制备,并且所述组合物可包含一种或多种药剂,例如甜味剂、调味剂、着色剂和防腐剂,以提供药学上美味可口的制剂。片剂、胶囊剂等含有活性成分与无毒的药学上可接受的赋形剂的混合物适用于片剂的制造。这些赋形剂可以为例如稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;制粒剂和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如淀粉、明胶或阿拉伯胶;以及润滑剂,例如硬脂酸镁、硬脂酸或滑石。
适用于口服施用的片剂、胶囊等可通过已知技术不包衣,或包衣以延迟在胃肠道中的崩解和吸收,从而提供持续作用。例如,可以使用诸如单硬脂酸甘油酯或双硬脂酸甘油酯之类的延时材料。它们也可以通过本领域已知的技术进行包衣以形成用于控制释放的渗透治疗片。附加试剂包括可生物降解或生物相容性粒子或聚合物质,例如聚酯、聚胺酸、水凝胶、聚乙烯吡咯烷酮、聚酸酐、聚乙醇酸、乙烯基乙酸乙烯酯、甲基纤维素、羧甲基纤维素、硫酸鱼精蛋白或丙交酯/乙交酯共聚物、聚乳酸/乙交酯共聚物,或乙烯基醋酸乙烯酯共聚物,以控制施用的组合物的递送。例如,口服制剂可分别通过使用羟甲基纤维素或明胶微胶囊或聚甲基丙烯酸甲酯微胶囊,或通过凝聚技术或界面聚合制备的微胶囊中包封,或在胶体药物递送系统中包封。胶体分散体系包括高分子复合物、纳米胶囊、微球、微珠和脂质体(包括水包油乳液、胶束、混合胶束和脂质体)。制备上述制剂的方法对于本领域技术人员来说将是显而易见的。
口服制剂也可呈现为硬明胶胶囊的形式,其中活性成分与惰性固体稀释剂(例如碳酸钙、磷酸钙、高岭土或微晶纤维素)混合,或呈现为软明胶胶囊的形式,其中活性成分与水或油介质(例如花生油、液体石蜡或橄榄油)混合。
水悬浮液含有活性材料和适合其制备的赋形剂的混合物。所述赋形剂可以是悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄芩胶和金合欢胶;分散剂或润湿剂,例如天然存在的磷脂(例如卵磷脂),或环氧乙烷与脂肪酸(例如硬脂酸聚氧乙烯酯)的缩合产物,或环氧乙烷与长链脂肪醇(例如十七烷氧基十六醇)的缩合产物,或环氧乙烷与来自脂肪酸和己糖醇(例如聚氧乙烯山梨醇单油酸酯)的部分酯的缩合产物,或环氧乙烷与来自脂肪酸和己醇酸酐(例如,聚乙烯山梨醇酐单油酸酯)的部分酯的缩合产物。水悬浮液还可以含有一种或多种防腐剂。
油性悬浮液可由将活性成分悬浮于植物油(例如花生油、橄榄油、芝麻油或椰子油) 或矿物油(例如液体石蜡)中来制备。油性悬浮液可含有增稠剂,例如蜂蜡、硬石蜡或十六醇,可添加甜味剂(如上文所述)和调味剂以提供可口的口服制剂。
适合通过添加水来制备水悬浮液的可分散粉末和颗粒在混合物中提供具有分散剂或润湿剂、悬浮剂和一种或多种防腐剂的活性成分。本文举例说明合适的分散剂或润湿剂和悬浮剂。
药物组合物也可以是水包油乳液的形式。油相可以是植物油,例如橄榄油或花生油,或矿物油,例如液体石蜡,或这些的混合物。合适的乳化剂可以是天然的树胶,例如金合欢树胶或黄芩树胶;天然存在的磷脂,例如大豆、卵磷脂和从脂肪酸衍生的酯或偏酯;己醇酐,例如山梨醇单油酸酯;以及偏酯与环氧乙烷的缩合产物,例如聚氧乙烯山梨醇酐单油酸酯。
制剂还可包括保护所述组合物不被快速降解或从体内消除的载体,例如控释制剂,包括植入物、脂质体、水凝胶、前药和微胶囊递送系统。例如,可以使用诸如单硬脂酸甘油酯或单硬脂酸甘油酯或与蜡结合的延迟材料。
栓剂可通过将药物与适当的无刺激性赋形剂混合来制备,该赋形剂在常温下为固体,但在直肠温度下为液体,因此将在直肠中熔化以释放药物。这些材料包括但不限于可可脂和聚乙二醇。
适用于根据本发明使用的药物组合物可以是当前已知或将来开发的任何形式(例如,用于鼻腔或吸入的喷雾剂)。
治疗适应症
本文所述的组合治疗方法特别适合于癌症的治疗。癌细胞可以侵入附近的组织,并可以通过血液和淋巴系统扩散到身体的其他部位。有几种主要类型的癌症,例如,癌是开始于皮肤或组织线或覆盖内脏器官的癌症。肉瘤是始于骨、软骨、脂肪、肌肉、血管或其他结缔组织或支持组织的癌症。白血病是从骨髓等造血组织开始的癌症,其会导致大量异常血细胞产生并进入血液。淋巴瘤是始于免疫系统细胞的癌症。
当正常细胞失去作为一个特定的、受控制的和协调的单位的能力时,肿瘤就形成了。一般来说,实体瘤是一种异常的组织肿块,其通常不包含囊肿或液体区域(一些脑肿瘤确实有囊肿和充满液体的中央坏死区域)。单个肿瘤内甚至可能有不同的细胞群,具有不同的已经出错的进程。实体瘤可以是良性的(不是癌变的),也可以是恶性的(癌变的)。不同类型的实体瘤因其形成细胞的类型而得名。实体瘤的例子有肉瘤、癌和淋巴瘤。白血病(血液癌症)一般不会形成实体瘤。
肿瘤可分为恶性肿瘤和良性肿瘤。在这两种情况下都有异常的细胞聚集和增殖。在恶性肿瘤的情况下,这些细胞表现得更具攻击性,具有更强的侵袭性。最终,肿瘤细胞甚至可能获得脱离其起源的微观环境的能力,扩散到身体的另一个区域(环境非常不同,通常不利于其生长),并在这个新的位置继续快速生长和分裂。这叫做转移。一旦恶性细胞发生转移,就很难治愈。良性肿瘤侵袭性较小,转移可能性较小。
可使用本文所述的组合治疗方法治疗的实体瘤癌的实例包括但不限于:胰腺癌、结直肠癌、非小细胞肺癌、肾细胞癌;头颈部鳞状细胞癌、膀胱癌、前列腺癌、宫颈癌、胃癌、子宫内膜癌、脑癌、肝癌、卵巢癌、睾丸癌、头癌、颈癌、皮肤癌(包括黑色素瘤和基底癌)、间皮衬里癌、食管癌、乳腺癌、肌肉癌、结缔组织癌、肺癌(包括小细胞肺癌和非小细胞癌),肾上腺癌、甲状腺癌、肾癌或骨癌;胶质母细胞瘤、间皮瘤、胃癌、肉瘤、绒毛膜癌、皮肤基底细胞癌和睾丸精原细胞瘤。在优选的方面,所述癌症为宫颈癌、非小细胞肺癌、肾细胞癌;头颈部鳞状细胞癌、膀胱癌、胰腺癌、黑色素瘤、淋巴瘤或胃癌。在更优选的方面,所述癌症为黑色素瘤、非小细胞肺癌、头颈部鳞状细胞癌、膀胱癌、肾细胞癌或胃癌。本发明的治疗方案特别适合于治疗实体瘤,包括但不限于:淋巴瘤、黑色素瘤、肾细胞癌(RCC)、晚期实体瘤、先前已用治疗疗法治疗但对先前治疗仍难治的肿瘤。
也可根据本发明治疗的癌症包括但不限于急性淋巴细胞白血病,成人期;急性淋巴细胞白血病,儿童期;急性髓系白血病,成人期;肾上腺皮质癌;肾上腺皮质癌,儿童期;艾滋病相关淋巴瘤;艾滋病相关恶性肿瘤;肛门癌;星形细胞瘤,儿童小脑;星形细胞瘤,儿童脑;肝外胆管癌;膀胱癌;膀胱癌,儿童期;骨癌、骨肉瘤/恶性纤维组织细胞瘤;胶质母细胞瘤,儿童期;胶质母细胞瘤,成人期;脑干胶质瘤,儿童期;脑肿瘤,成人期;脑肿瘤,脑干胶质瘤,儿童期;脑肿瘤,小脑星形细胞瘤,儿童期;脑肿瘤,脑星形细胞瘤/恶性胶质瘤,儿童期;脑肿瘤,室管膜瘤,儿童期;脑肿瘤,髓母细胞瘤,儿童期;脑肿瘤,幕上原始神经外胚层肿瘤,儿童期;脑肿瘤,视觉通路和下丘脑胶质瘤,儿童期;脑肿瘤,儿童期(其他);乳腺癌;乳腺癌和妊娠;乳腺癌,儿童期;乳腺癌,男性;支气管腺瘤/类癌,儿童期:类癌,儿童期;类癌,胃肠道;肾上腺皮质癌;癌,胰岛细胞;原发性不明癌;中枢神经系统淋巴瘤,原发性;小脑星形细胞瘤,儿童期;脑星形细胞瘤/恶性胶质瘤,儿童期;宫颈癌;儿童癌症;慢性淋巴细胞白血病;慢性粒细胞白血病;慢性骨髓增生性疾病;腱鞘透明细胞肉瘤;结肠癌;儿童结直肠癌;皮肤T细胞淋巴瘤;子宫内膜癌;室管膜瘤,儿童期;上皮癌,卵巢;食管癌;食管癌,儿童期;尤因肿瘤家族;颅外生殖细胞肿瘤,儿童期;性腺外生殖细胞瘤;肝外胆管癌;眼内黑色素瘤;眼癌、视网膜母细胞瘤;胆囊癌;胃癌;胃癌,儿童期;胃肠道类癌;生殖细胞瘤,颅外,儿童期;生殖细胞瘤,性腺外;生殖细胞瘤,卵巢;妊娠滋养细胞肿瘤;胶质瘤。儿童脑干;胶质瘤。儿童视觉通路与下丘脑;毛细胞白血病;头颈癌;肝细胞(肝)癌,成人(原发性);肝细胞(肝)癌,儿童期(原发性);霍奇金淋巴瘤,成人期;霍奇金淋巴瘤,儿童期;妊娠期霍奇金淋巴瘤;下咽癌;下丘脑和视觉通路胶质瘤,儿童期;眼内黑色素瘤;胰岛细胞癌(内分泌胰腺);卡波西肉瘤;肾癌;喉癌;喉癌,儿童期;白血病,急性淋巴细胞性,成人期;白血病,急性淋巴细胞性,儿童期;白血病,急性髓细胞性,成人期;白血病,急性髓细胞性,儿童期;白血病,慢性淋巴细胞性;白血病,慢性粒细胞性;白血病,毛细胞;唇、口腔癌;肝癌,成人期(原发性);肝癌,儿童期(原发性);肺癌,非小细胞肺癌;肺癌,小细胞;成人急性淋巴细胞白血病;淋巴细胞白血病,儿童急性;慢性淋巴细胞白血病;淋巴瘤,艾滋病相关;淋巴瘤,中枢神经系统(原发性);淋巴瘤,皮肤T细胞;淋巴瘤,霍奇金病,成人期;淋巴瘤,霍奇金病;儿童期;淋巴瘤,妊娠期霍奇金病;淋巴瘤,非霍奇金,成人期;淋巴瘤,非霍奇金,儿童期;淋巴瘤,妊娠期非霍奇金淋巴瘤;淋巴瘤,原发性中枢神经系统;巨球蛋白血症;男性乳腺癌;恶性间皮瘤,成人期;恶性间皮瘤,儿童期;恶性胸腺瘤;髓母细胞瘤,儿童期;黑色素瘤;黑色素瘤,眼内;梅克尔细胞癌;恶性间皮瘤;转移性颈鳞癌伴隐匿原发灶;多发性内分泌肿瘤综合征,儿童期;多发性骨髓瘤/浆细胞肿瘤;蕈样肉芽肿;骨髓增生异常综合征;慢性粒细胞白血病;儿童急性髓系白血病;骨髓瘤,多发性;骨髓增生性疾病,慢性;鼻腔鼻窦癌;鼻咽癌;鼻咽癌,儿童期;神经母细胞瘤;神经纤维瘤;非霍奇金淋巴瘤,成人期;非霍奇金淋巴瘤,儿童期;妊娠期非霍奇金淋巴瘤;非小细胞肺癌;口腔癌,儿童期;口腔和唇癌;口咽癌;骨肉瘤/骨恶性纤维组织细胞瘤;卵巢癌,儿童期;卵巢上皮癌;卵巢生殖细胞瘤;卵巢低恶性潜能肿瘤;胰腺癌;胰腺癌,儿童期,胰腺癌,胰岛细胞;鼻窦鼻腔癌;甲状旁腺癌;阴茎癌;嗜铬细胞瘤;松果体和幕上原始神经外胚层肿瘤,儿童期;垂体瘤;浆细胞肿瘤/多发性骨髓瘤;胸膜肺母细胞瘤;妊娠和乳腺癌;妊娠和霍奇金淋巴瘤;妊娠与非霍奇金淋巴瘤;原发性中枢神经系统淋巴瘤;原发性肝癌,成人期;原发性肝癌,儿童期;前列腺癌;直肠癌;肾细胞癌;肾细胞癌,儿童期;肾盂输尿管移行细胞癌;视网膜母细胞瘤;横纹肌肉瘤,儿童期;涎腺癌;涎腺癌,儿童期;肉瘤,尤因氏肿瘤家族;肉瘤,卡波西氏;骨肉瘤/恶性骨纤维组织细胞瘤;肉瘤,横纹肌肉瘤,儿童期;肉瘤,软组织,成人期;肉瘤,软组织,儿童期;塞扎里综合征;皮肤癌;皮肤癌,儿童期;皮肤癌(黑色素瘤);皮肤癌,默克尔细胞;小细胞肺癌;小肠癌;软组织肉瘤,成人期;软组织肉瘤,儿童期;颈鳞癌伴隐匿性原发性转移;胃癌;胃癌,儿童期;幕上原始神经外胚层肿瘤,儿童期;皮肤T细胞淋巴瘤;睾丸癌;胸腺瘤,儿童期;胸腺瘤,恶性;甲状腺癌;甲状腺癌,儿童期;肾盂输尿管移行细胞癌;滋养细胞肿瘤,妊娠期;原发部位不明,癌症,儿童期;儿童时期罕见的癌症;输尿管肾盂移行细胞癌;尿道癌;子宫肉瘤;阴道癌;视觉通路与下丘脑胶质瘤,儿童期;外阴癌;瓦尔登斯特罗姆巨球蛋白血症;还有威尔姆斯的肿瘤等等。
优选地,根据本发明治疗的癌症是CNS肿瘤,包括但不限于颅内和脊柱室管膜瘤(不包括室管膜下瘤);低级别浸润性幕上星形细胞瘤/少突胶质细胞瘤、髓母细胞瘤、间变性胶质瘤、胶质母细胞瘤、中枢神经系统转移灶和原发性中枢神经系统淋巴瘤。
优选地,所治疗的癌症是黑色素瘤。优选地,所治疗的癌症是葡萄膜黑色素瘤。
优选地,所治疗的癌症是神经内分泌或肾上腺肿瘤。示例包括但不限于支气管肺病、胃肠道、肺或胸腺、胰腺、副神经节瘤或嗜铬细胞瘤。
优选地,所治疗的癌症是非霍奇金淋巴瘤,包括但不限于蕈样肉芽肿和塞扎莱综合征(Sezary syndrome)。
优选地,所治疗的癌症是软组织肉瘤。例如血管肉瘤、不可切除或进行性腹膜后/腹腔内软组织肉瘤、横纹肌肉瘤、四肢/浅表干和/或头颈部癌症或孤立性纤维瘤/血管外皮细胞瘤。
优选地,所治疗的癌症是骨癌。例如尤因肉瘤和间叶软骨肉瘤。
优选地,所治疗的癌症是子宫肉瘤、小细胞肺癌(SCLC)或佐林格-埃利森综合征(Zollinger-Ellison syndrome)。
优选地,本发明治疗的癌症是妇科癌症(例如,女性生殖系统癌症),包括但不限于:卵巢癌、输卵管癌、腹膜癌和乳腺癌。优选地,本发明治疗的癌症是卵巢癌。
优选地,本发明治疗的癌症是胶质母细胞瘤。
脑肿瘤在脑内广泛扩散,但通常不会转移到脑外。胶质瘤在大脑内部侵袭性很强,甚至跨越大脑半球。不过,他们确实以一种不受控制的方式分裂。根据它们的位置,它们可能和恶性病变一样危及生命。这方面的一个例子是大脑中的良性肿瘤,它可以生长并占据颅骨内的空间,导致大脑压力增加。
试剂盒
还提供包含所述药物组合物的试剂盒,所述试剂盒通常包含在本文所述的本发明的组合疗法中使用的治疗上有效量的一种或多种药剂。试剂盒通常包括指示试剂盒内容物预期用途的标签和使用说明。
如下文所述,试剂盒通常为容纳各种组分的物理结构的形式,并且可以例如在实施上述方法时使用。试剂盒可包括包含一种或多种用于本发明的联合治疗(例如,基因工程γδ细胞或DRI抑制剂或ICP抑制剂))的治疗剂的组合物,例如,提供在一个或多个无菌容器中,其可以是适合给受试者施用的药物组合物的形式。所述药物组合物可以以准备好使用的形式提供,或者以例如在施用前需要重组或稀释的形式提供。当所述组合物以需要用户重组的形式呈现时,所述试剂盒还可包括缓冲液、药药上可接受的赋形剂等,其与所述治疗剂一起包装或单独包装。当考虑到联合治疗时,试剂盒可以单独包含几种药物,或者它们在试剂盒中可以已组合。
本发明的试剂盒可设计为用于适当地维持其中容纳的组件所必需的条件(例如,冷藏或冷冻)。试剂盒可包含标签或包装插页,包装插页包括试剂盒组分的识别信息和使用说明(例如,剂量参数、活性成分的临床药理学,包括作用机制、药代动力学和药效学、不良反应、禁忌症等)。
试剂盒的每个组件都可以封装在一个单独的容器中,所有不同的容器都可以封装在一个单独的包装中。标签或插页可以包括制造商信息,如批号和有效期。标签或包装插页可以例如集成到容纳组件的物理结构中,单独包含在物理结构中,或者附在组合物的组件(例如安瓿、注射器或小瓶)上。
标签或插页可另外包括或并入计算机可读介质,例如磁盘(例如,硬盘、卡、存储盘)、光盘,例如CD-或DVD-ROM/RAM、DVD、MP3、磁带,或电存储介质,例如RAM 和ROM,或这些介质的混合物,例如磁/光存储介质,闪存介质或存储卡。在一些实施方案中,试剂盒中不存在实际说明,但是提供了用于例如经由因特网站点从远程源获得说明的装置。
具体实施方式
以下以说明的方式提供实施例,并且以下实施例不应被解释为以任何方式限制所要求保护的发明。
实施例1-癌症治疗范例
一种包含化学治疗剂、耐药性γδT细胞、PARP-1抑制剂和免疫检查点抑制剂的组合疗法用于治疗癌症患者。对于卵巢癌的治疗,尼拉帕尼、奥拉帕尼或芦卡帕尼为PARP 抑制剂。对于胶质母细胞瘤的治疗,奥拉帕尼或尼拉帕尼作为PARP抑制剂。化学治疗剂选自烷化剂(如环磷酰胺、异环磷酰胺)、代谢拮抗剂(如甲氨蝶呤(MTX)、5-氟尿嘧啶或其衍生物)、抗肿瘤抗生素(如丝裂霉素、阿霉素)、植物来源的抗肿瘤剂(例如,长春新碱、长春地辛、紫杉醇、Abraxane)、顺铂、卡铂、依托泊苷等。此类药剂可进一步包括但不限于抗癌剂三甲氧苯甲酸酯(TMTX);替莫唑胺;雷替曲塞;S-(4- 硝基苄基)-6-硫肌苷(NBMPR);6-苄胍(6-BG)、双氯亚硝基脲(BCNU)、阿糖胞苷和喜树碱,或其任一的治疗衍生物。耐药的γδT细胞对化学治疗剂具有耐药性。免疫检查点抑制剂单独使用或与其他免疫检查点抑制剂联合使用,其选自以下免疫检查点蛋白的抑制剂:CTLA-4、PDL1(B7-H1、CD274)、PDL2(B7-DC、CD273)、PD1、B7-H3(CD276)、 B7-H4(B7-S1,B7x,VCTN1)、BTLA(CD272)、HVEM、TIM3(HAVcr2)、GAL9、LAG3 (CD223)、VISTA、KIR、2B4(CD244,属于CD2分子家族,在所有NK,γδ和记忆CD8 +(αβ)T细胞上表达)、CD160(也称为BY55)、CGEN-15049、CHK1和CHK2激酶、OX40、A2aR和各种B-7家族配体。
免疫治疗联合化学疗法的活性评估
反应评估标准包括基于实体瘤反应评估标准(WHO,World Health OrganizationOffset Publication No.48,1979)的评估;RECIST(实体瘤疗效评估标准;J Natl CancerInst 2000; 92:205-16;Eisenhauer EA et al.,Eur J Cancer 2009;45:228-47);免疫相关反应标准(Jedd WE et al.,Clin Cancer Res 2009;15(23),7412-7420);和iRANO(神经肿瘤学中的免疫治疗反应评估;Okada H et al.,Lancet Oncol 2015Nov;16(15):e534-42)。
结果
化学治疗作为一种联合疗法,另外包括耐药γδT细胞(和/或耐药自然杀伤细胞)、PARP-1抑制剂和免疫检查点蛋白抑制剂,该疗法导致增强或延长抗肿瘤反应;有益于医学的反应;与单纯化学治疗或化学治疗联合耐药γδT细胞(和/或耐药自然杀伤细胞)相比,有附加或协同抗肿瘤活性;基线病变缩小,无新病变;肿瘤消退;持久稳定的疾病的总肿瘤负荷可能稳步下降;肿瘤总负荷增加后的反应;以及在出现新的病变时的反应。其他临床发现可能包括如肿瘤大小的增加所测得的肿瘤浸润淋巴细胞的增加;和长期生存的提升。
例如,替莫唑胺(TMZ)治疗的肿瘤导致大量DNA加合物包括N-甲基嘌呤和O6-甲基鸟嘌呤的形成。这种加合物导致DNA损伤反应(DDR)和错配修复(MMR)机制的激活。对这些DNA加合物的抗性机制是通过碱基切除修复(BER)途径,该途径涉及 PARP-1去除N-甲基嘌呤加合物,或通过O6-甲基鸟嘌呤DNA甲基转移酶(MGMT)蛋白的存在。O6-甲基鸟嘌呤是TMZ抗性的主要机制,如果MGMT不存在或不活跃,MMR 过程的激活将导致交叉连接、复制分叉受阻和双链DNA断裂(DSB)的形成。DSB导致 MSH-2/MSH-6二聚体的形成以及共济失调毛细血管扩张Rad3相关(ATR)激酶和共济失调毛细血管扩张突变(ATM)激酶的激活。
这种级联反应的激活导致肿瘤细胞表面应激配体数量增加,如MICA、MICB、ULBP1-6和MSH-2。耐药γδT细胞和/或耐药自然杀伤细胞促进了对肿瘤细胞的杀伤,其受体 (例如NKG2D)识别肿瘤特异性应激配体。然而,肿瘤细胞可以通过酶促裂解MICA和 MICB,释放可溶性MICA和MICB。当与血浆中的效应细胞受体结合时,这会导致受体表达下调,从而导致免疫逃逸。已发现诸如TMZ之类的化学疗法可增加肿瘤组织上应激配体的细胞表面表达,而不会显著增加血浆中可溶性配体的浓度。PARP-1抑制剂,例如尼拉帕尼、奥拉帕尼或芦卡帕尼已经批准用于治疗卵巢癌。
方法
γδT细胞的离体扩增
从健康捐赠者处收集人体单采产品。对于静态培养:所有操作均在ISO-7分类洁净室环境包围的ISO-5层流罩中进行。产物用HBSS(Hank的平衡盐溶液)按照v/v稀释,单核细胞使用Ficoll(Sigma-Aldrich;St.Louis,MO)通过密度梯度分离而分离。收获中间相并在HBSS中洗涤两次。将细胞沉淀重悬于CTSTMOpTmizerTMT细胞扩增无血清培养基(ThermoFisher Scientific;Waltham,MA)中,并添加2mM唑来膦酸(Novartis;Basel HV)和100u/mL IL2(Miltenyi Biotec Ltd;Bergisch Gladbach,德国)。细胞在标准T150 或T75烧瓶中培养。对于封闭系统培养:所有操作,包括培养基、原液和缓冲液的制备,均在ISO-t洁净室环境下的生物安全柜下的ISO 7洁净室中使用GMP级试剂进行。在 CLINIMACS(Miltenyi Biotec Ltd;Bergisch Gladbach,Germany)生物反应器中使用定制的细胞处理程序和TS520管组进行产品的自动Ficoll分离和培养。然后在 OpTmizer无血清培养(Thermo Fisher Scientific;Waltham,MA)中使用唑来膦酸盐(Zometa;诺华,巴塞尔)和白细胞介素-2(Miltenyi Biotec Ltd;Bergisch Gladbach,德国)(ZOL/IL- 2)的组合在CLINIMACS的CentriCult-Unit中扩增细胞。将培养物保持在1- 2×106个细胞/ml的密度并每隔一天补充IL-2 100U/mL,直到第13天收获细胞。定期持续监测该过程以确定培养扩增动力学和表型,与在烧瓶中的小规模培养进行比较。在培养9到14天后,对扩增的γδT细胞进行表型分析,并确定针对标准白血病细胞系和神经胶质瘤肿瘤细胞的细胞毒性。
实施例2-当暴露于PARP抑制剂(PARPi)和替莫唑胺(TMZ)的组合时,应激配体在神经胶质瘤细胞系上的表达
材料和方法
细胞收集/处理/培养条件的方法
形成治疗方案的总体策略概述如下。目标是产生治疗患者所需的γδT细胞总数,初始剂量作为新鲜制备的细胞群施用。
在患者增加后,在切除后和诱导化疗/放疗开始前立即进行一次2倍体积的单采。
在生物反应器中以2.0×106/ml的浓度启动MNC扩增培养,由经验证的程序确定,并保持于OpTimizer(Life Technologies)5%CO2、37℃+5μgM唑来膦酸(NovartisOncology;East Hanover,NJ)+50U/ml IL-2(Miltenyi;Duarte,CA)。培养物保持7天,在培养后第2天、第5天和第7天添加100U/mL IL-2,并在+9天、+11天和+13天增加至 400U/mL。添加完整培养基取决于pH值和细胞密度。
在扩增前和第2、5、7、9、11和14天获得用于分析的样品,以评估细胞数量和分类。进行FACS分析以确定细胞活力并计算相关细胞亚群,包括总CD3 T细胞、总γδT 细胞(包括Vδ2和Vδ1亚群)、总αβT细胞(包括CD4和CD8亚群),以及NK和B细胞。所有样本均在FACS或LSR Fortessa流式细胞仪上使用FACS软件进行分析。
在第+14天,±3天收获最终产品。对最终产品的样品进行计数,通过流式细胞术进行分析,并提交进行载体拷贝数(VCN)和所需的微生物测试。最终产品将按1:2稀释并在Plasma-Lyte A和10%HSA中洗涤,以去除所有剩余的制备试剂。洗涤和浓缩后,产品将重新悬浮在Plasma-Lyte A、5%HSA和10%DMSO中,并以1×107/mL的浓度冷冻保存在2mL冷冻瓶中直至需要。
离体修饰
当培养物达到对数扩增阶段时(通常>20%γδT细胞),用MGMT慢病毒(MiltenyiLentigen:Baltimore,MD)进行细胞转导。培养物通过接种以10×2的MOI进行转导。
产物从冷冻保存状态解冻并在缓冲盐水和5%Plasma-Lyte中洗涤。解冻后,最终产品将重新悬浮在相同的洗涤缓冲液中,以使浓度为1×107γδT细胞。
分析
为了测量GBM+替莫唑胺(TMZ)对PARPi的推定差异敏感性,将标准化的GBM细胞系LN229、U87MG和U251MG细胞(96孔板的每孔6000个细胞,一式三份)暴露于单独的奥拉帕尼(5或10mM)、奥拉帕尼(示例性PARP抑制剂)+200mg/mL TMZ、或单独的培养基(RPMI+10%FBS培养基)4小时。在开始时和处理后8、16、24和36小时,使用标准化的MTT活力测定和在悬浮流式细胞术测定中加入7-AAD的方法进行活力测定。
数据表示为掺入相对未处理的细胞溶解后MTT的百分比和悬浮液流式细胞术检测的7-AAD阴性细胞的百分比。NKG2D配体MIC A/B和ULBP 1-6的表达也通过流式细胞术在悬浮测定中对上述每种细胞系和状态进行了评估。数据表示为所有时间点的平均荧光强度(MFI)比对照(仅培养基)的对数。
结果
图1-3中的数据显示,PARP抑制剂和替莫唑胺(TMZ)的组合协同作用,上调三种高级神经胶质瘤细胞系上的选定自然杀伤组2D(NKG2D)配体。
在多种情况下,NKG2DL最大化增加是短暂的,并且在大约24小时后表达开始下调,也在单独使用TMZ建立的DRI治疗的最佳治疗窗口期间,正如在例如Lamb et al., PloSONE 8(1):e51805.doi:10.1371/journal.pone.0051805.中所描述的一样。
本文提及的专利和科学文献确立了本领域技术人员可用的知识。本文引用的所有美国专利和已公布或未公布的美国专利申请均通过引用并入。本文引用的所有已公开的国外专利和专利申请均通过引用并入本文。本文引用的所有其他已发表的参考文献、文件、手稿和科学文献均通过引用并入本文。
虽然已经参考本发明的优选实施例具体地示出和描述了本发明,但是本领域技术人员将理解,在不脱离所附权利要求所涵盖的本发明的范围的情况下,可以在形式和细节上进行各种改变。还应理解,本文所描述的实施例中没有一个是互斥的,并且可以在不脱离所附权利要求所涵盖的本发明的范围的情况下以各种方式组合。
Claims (45)
1.一种治疗有需要的患者的癌症的方法,包括:
i)向所述患者施用包含治疗上有效量的γδT细胞的组合物,所述γδT细胞为对至少一种化学治疗剂具有抗性的基因工程γδT细胞;
ii)向所述患者施用治疗上有效量的化学治疗剂;和
iii)向所述患者施用治疗上有效量的DDR抑制剂。
2.如权利要求1所述的方法,其特征在于,所述DDR抑制剂为PARP抑制剂。
3.如权利要求2所述的方法,其特征在于,在施用所述化学治疗剂之前和在施用包含所述基因工程γδT细胞的所述组合物之前施用所述PARP抑制剂。
4.如权利要求3所述的方法,其特征在于,在施用所述化学治疗剂之前约1天至约21天施用所述PARP抑制剂。
5.如权利要求4所述的方法,其特征在于,在施用所述化学治疗剂后约8小时至约72小时施用包含所述基因工程γδT细胞的所述组合物。
6.如权利要求4所述的方法,其特征在于,在施用所述化学治疗剂后约12小时至约36小时施用包含所述基因工程γδT细胞的所述组合物。
7.如权利要求4所述的方法,其特征在于,在施用所述化学治疗剂后约24小时施用包含所述基因工程γδT细胞的所述组合物。
8.如权利要求4所述的方法,其特征在于,在施用所述化学治疗剂后约8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35或36小时施用包含所述基因工程γδT细胞的所述组合物。
9.如权利要求1所述的方法,其特征在于,所述化学治疗剂为烷基化剂;代谢拮抗剂;DNA脱甲基剂;取代的核苷酸;取代的核苷;抗肿瘤抗生素;植物来源的抗肿瘤剂或亚硝基脲。
10.如权利要求1所述的方法,其特征在于,所述化学治疗剂选自顺铂;卡铂;依托泊苷;甲氨蝶呤(MTX);三甲氧苯甲酸酯(TMTX);替莫唑胺;达卡巴嗪(DTIC);雷替曲塞;S-(4-硝基苄基)-6-硫肌苷(NBMPR);6-苄胍(6-BG);亚硝基脲(rabinopyranosyl-N-甲基-N-亚硝基脲(Aranose)、卡莫司汀(BCNU,BiCNU)、氯唑霉素、乙基亚硝脲(ENU)、福特莫司汀、洛莫司汀(CCNU)、尼莫司汀、N-亚硝基-N-甲基脲(NMU)、雷莫司汀(MCNU)、司莫司汀、链脲霉素(链脲菌素));阿糖胞苷;喜树碱;以及其任一的治疗衍生物。
11.如权利要求1所述的方法,其特征在于,所述γδT细胞已被基因修饰为编码烷基鸟嘌呤转移酶(AGT)、P140KMGMT、O6甲基鸟嘌呤DNA甲基转移酶(MGMT)、L22Y-DHFR、胸苷酸合成酶、二氢叶酸还原酶或多药耐药蛋白1(MDR1)。
12.如权利要求1所述的方法,其特征在于,所述γδT细胞已被基因修饰为对至少两种化学治疗剂具有抗性,所述化学治疗剂选自:烷基化剂;代谢拮抗剂;DNA脱甲基剂;取代的核苷酸;取代的核苷;抗肿瘤抗生素;植物来源的抗肿瘤剂或亚硝基脲。
13.如权利要求1所述的方法,其特征在于,所述γδT细胞已被基因修饰为对至少两种化学治疗剂具有抗性,所述化学治疗剂选自顺铂;卡铂;依托泊苷;甲氨蝶呤(MTX);三甲氧苯甲酸酯(TMTX);替莫唑胺;达卡巴嗪(DTIC);雷替曲塞;S-(4-硝基苄基)-6-硫肌苷(NBMPR);6-苄胍(6-BG);亚硝基脲(rabinopyranosyl-N-甲基-N-亚硝基脲(Aranose)、卡莫司汀(BCNU,BiCNU)、氯唑霉素、乙基亚硝脲(ENU)、福特莫司汀、洛莫司汀(CCNU)、尼莫司汀、N-亚硝基-N-甲基脲(NMU)、雷莫司汀(MCNU)、司莫司汀、链脲霉素(链脲菌素));阿糖胞苷;喜树碱;以及其任一的治疗衍生物。
14.如权利要求1所述的方法,其特征在于,所述化学治疗剂为TMZ、甲氨蝶呤、DTIC、BCNU、CCNU、MCNU、NMU或ENU。
15.如权利要求1所述的方法,其进一步包含施用免疫检查点抑制剂(ICP)的步骤。
16.如权利要求15所述的方法,其特征在于,所述免疫检查点抑制剂靶向CTLA-4、PDL1、PDL2、PD1、B7-H3、B7-H4、BTLA、HVEM、TIM3、GAL9、LAG3、VISTA、KIR、2B4、CD160(也称为BY55)、CGEN-15049、CHK 1激酶、CHK2激酶、A2aR、OX40或B-7家族配体。
17.如权利要求16所述的方法,其特征在于,所述检查点抑制剂靶向PD-1、PDL1、PDL2或CTLA-4。
18.如权利要求1所述的方法,其特征在于,所述癌症选自:中枢神经系统(CNS)肿瘤、黑色素瘤、葡萄膜黑色素瘤、神经内分泌肿瘤、肾上腺肿瘤、非霍奇金淋巴瘤、软组织肉瘤、骨癌、子宫肉瘤、卵巢癌癌症、小细胞肺癌(SCLC)和佐林格-埃利森综合征。
19.如权利要求1所述的方法,其特征在于,包含所述基因工程γδT细胞的所述组合物包含大于约60%的γδT细胞,小于约5%的αβT细胞和小于约25%的自然杀伤(NK)细胞。
20.如权利要求1所述的方法,其特征在于,包含所述基因工程γδT细胞的所述组合物包含约5×108γδT细胞/kg或更少的患者体重,约1×107γδT细胞/kg或更少的患者体重,或约5×106γδT细胞/kg或更少的患者体重。
21.一种在有需要的患者中治疗癌症的方法,包括:
i)向所述患者施用包含治疗上有效量的γδT细胞的组合物,所述γδT细胞为对至少一种化学治疗剂具有抗性的基因工程γδT细胞;
ii)向所述患者施用治疗上有效量的化学治疗剂;和
iii)向所述患者施用治疗上有效量的DDR抑制剂;
其中所述DDR抑制剂为PARP抑制剂,并且在施用所述化学治疗剂之前约1天至约21天施用所述PARP抑制剂,其中,在施用所述化学治疗剂后约8小时至约36小时施用包含所述基因工程γδT细胞的所述组合物。
22.如权利要求21的方法,其特征在于,在施用所述化学治疗剂后约8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35或36小时施用包含所述基因工程γδT细胞的所述组合物。
23.如权利要求21所述的方法,其特征在于,所述化学治疗剂为烷基化剂;代谢拮抗剂;DNA脱甲基剂;取代的核苷酸;取代的核苷;抗肿瘤抗生素;植物来源的抗肿瘤剂或亚硝基脲。
24.如权利要求21所述的方法,其特征在于,所述化学治疗剂选顺铂;卡铂;依托泊苷;甲氨蝶呤(MTX);三甲氧苯甲酸酯(TMTX);替莫唑胺;达卡巴嗪(DTIC);雷替曲塞;S-(4-硝基苄基)-6-硫肌苷(NBMPR);6-苄胍(6-BG);亚硝基脲(rabinopyranosyl-N-甲基-N-亚硝基脲(Aranose)、卡莫司汀(BCNU,BiCNU)、氯唑霉素、乙基亚硝脲(ENU)、福特莫司汀、洛莫司汀(CCNU)、尼莫司汀、N-亚硝基-N-甲基脲(NMU)、雷莫司汀(MCNU)、司莫司汀、链脲霉素(链脲菌素));阿糖胞苷;喜树碱;以及其任一的治疗衍生物。
25.如权利要求21所述的方法,其特征在于,所述γδT细胞已被基因修饰为编码烷基鸟嘌呤转移酶(AGT)、P140KMGMT、O6甲基鸟嘌呤DNA甲基转移酶(MGMT)、L22Y-DHFR、胸苷酸合成酶、二氢叶酸还原酶或多药耐药蛋白1(MDR1)。
26.如权利要求21所述的方法,其特征在于,γδT细胞已被基因修饰为对至少两种化学治疗剂具有抗性,所述化学治疗剂选自:烷基化剂;代谢拮抗剂;DNA脱甲基剂;取代的核苷酸;取代的核苷;抗肿瘤抗生素;植物来源的抗肿瘤剂或亚硝基脲。
27.如权利要求21所述的方法,其特征在于,所述γδT细胞已被基因修饰为对至少两种化学治疗剂具有抗性,所述化学治疗剂选自顺铂;卡铂;依托泊苷;甲氨蝶呤(MTX);三甲氧苯甲酸酯(TMTX);替莫唑胺;达卡巴嗪(DTIC);雷替曲塞;S-(4-硝基苄基)-6-硫肌苷(NBMPR);6-苄胍(6-BG);亚硝基脲(rabinopyranosyl-N-甲基-N-亚硝基脲(Aranose)、卡莫司汀(BCNU,BiCNU)、氯唑霉素、乙基亚硝脲(ENU)、福特莫司汀、洛莫司汀(CCNU)、尼莫司汀、N-亚硝基-N-甲基脲(NMU)、雷莫司汀(MCNU)、司莫司汀、链脲霉素(链脲菌素));阿糖胞苷;喜树碱;以及其任一的治疗衍生物。
28.如权利要求21所述的方法,其特征在于,所述化学治疗剂为TMZ、甲氨蝶呤、DTIC、BCNU、CCNU、MCNU、NMU或ENU。
29.如权利要求21所述的方法,其进一步包含施用免疫检查点抑制剂(ICP)的步骤。
30.如权利要求29所述的方法,其特征在于,所述免疫检查点抑制剂靶向CTLA-4、PDL1、PDL2、PD1、B7-H3、B7-H4、BTLA、HVEM、TIM3、GAL9、LAG3、VISTA、KIR、2B4、CD160(也称为BY55)、CGEN-15049、CHK 1激酶、CHK2激酶、A2aR、OX40或B-7家族配体。
31.如权利要求30所述的方法,其特征在于,所述检查点抑制剂靶向PD-1、PDL1、PDL2或CTLA-4。
32.如权利要求21所述的方法,其特征在于,所述癌症选自:中枢神经系统(CNS)肿瘤、黑色素瘤、葡萄膜黑色素瘤、神经内分泌肿瘤、肾上腺肿瘤、非霍奇金淋巴瘤、软组织肉瘤、骨癌、子宫肉瘤、卵巢癌癌症、小细胞肺癌(SCLC)和佐林格-埃利森综合征。
33.如权利要求21所述的方法,其特征在于,包含所述基因工程γδT细胞的所述组合物包含大于约60%的γδT细胞,小于约5%的αβT细胞和小于约25%的自然杀伤(NK)细胞。
34.如权利要求21所述的方法,其特征在于,包含所述基因工程γδT细胞的所述组合物包含约5×108γδT细胞/kg或更小患者体重,约1×107γδT细胞/kg或更小患者体重,或约5×106γδT细胞/kg或更小患者体重。
35.一种在有需要的患者中治疗癌症的方法,包括:
i.获得包含任选富集和/或任选扩增的γδT细胞群的组合物;
ii.向所述患者施用包含任选富集和/或任选扩增的γδT细胞群的组合物;
iii.向所述患者施用有效量的至少一种DNA损伤修复(DDR)抑制剂;和
iv.向所述患者施用有效量的化学治疗剂。
36.如权利要求35所述的方法,其特征在于,所述DDR抑制剂为PARP抑制剂。
37.如权利要求35所述的方法,其特征在于,所述化学治疗剂为烷基化剂;代谢拮抗剂;DNA脱甲基剂;取代的核苷酸;取代的核苷;抗肿瘤抗生素;植物来源的抗肿瘤剂或亚硝基脲。
38.如权利要求35所述的方法,其特征在于,所述化学治疗剂选顺铂;卡铂;依托泊苷;甲氨蝶呤(MTX);三甲氧苯甲酸酯(TMTX);替莫唑胺;达卡巴嗪(DTIC);雷替曲塞;S-(4-硝基苄基)-6-硫肌苷(NBMPR);6-苄胍(6-BG);亚硝基脲(rabinopyranosyl-N-甲基-N-亚硝基脲(Aranose)、卡莫司汀(BCNU,BiCNU)、氯唑霉素、乙基亚硝脲(ENU)、福特莫司汀、洛莫司汀(CCNU)、尼莫司汀、N-亚硝基-N-甲基脲(NMU)、雷莫司汀(MCNU)、司莫司汀、链脲霉素(链脲菌素));阿糖胞苷;喜树碱;以及其任一的治疗衍生物。
39.如权利要求35所述的方法,其特征在于,所述化学治疗剂为TMZ、甲氨蝶呤、DTIC、BCNU、CCNU、MCNU、NMU或ENU。
40.如权利要求35所述的方法,其进一步包含施用免疫检查点抑制剂(ICP)的步骤。
41.如权利要求40所述的方法,其特征在于,所述免疫检查点抑制剂靶向CTLA-4、PDL1、PDL2、PD1、B7-H3、B7-H4、BTLA、HVEM、TIM3、GAL9、LAG3、VISTA、KIR、2B4、CD160(也称为BY55)、CGEN-15049、CHK 1激酶、CHK2激酶、A2aR、OX40或B-7家族配体。
42.如权利要求41所述的方法,其特征在于,所述检查点抑制剂靶向PD-1、PDL1、PDL2或CTLA-4。
43.如权利要求35所述的方法,其特征在于,所述癌症选自:中枢神经系统(CNS)肿瘤、黑色素瘤、葡萄膜黑色素瘤、神经内分泌肿瘤、肾上腺肿瘤、非霍奇金淋巴瘤、软组织肉瘤、骨癌、子宫肉瘤、卵巢癌癌症、小细胞肺癌(SCLC)和佐林格-埃利森综合征。
44.如权利要求35所述的方法,其特征在于,包含所述基因工程γδT细胞的所述组合物包含大于约60%的γδT细胞,小于约5%的αβT细胞和小于约25%的自然杀伤(NK)细胞。
45.如权利要求35所述的方法,其特征在于,包含所述基因工程γδT细胞的所述组合物包含约5×108γδT细胞/kg或更小患者体重,约1×107γδT细胞/kg或更小患者体重,或约5×106γδT细胞/kg或更小患者体重。
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