CN118043450A - 用于增强癌症免疫疗法的表达il-10的细胞 - Google Patents
用于增强癌症免疫疗法的表达il-10的细胞 Download PDFInfo
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Abstract
本发明总体涉及抗癌疗法领域,特别是过继性T细胞转移疗法治疗癌症尤其是实体肿瘤的用途。更具体地,本发明涉及包含一种或多种重组构建体的免疫细胞,其中至少一种重组构建体编码白细胞介素‑10、其片段或变体。
Description
技术领域
本发明总体涉及抗癌疗法领域,特别是过继性T细胞转移疗法治疗癌症尤其是实体肿瘤的用途。更具体地,本发明涉及包含一种或多种重组构建体的免疫细胞,其中至少一种重组构建体编码白细胞介素-10、其片段或变体。
背景技术
嵌合抗原受体(CAR)T细胞和T细胞受体(TCR)转基因T细胞(均称为“过继性T细胞转移”疗法)是基于基因工程化T细胞的过继性转移免疫疗法。例如,CAR T细胞在临床上显示出有希望的结果,特别是在血液系统恶性肿瘤中,但在实体肿瘤中进展有限(Lim,W.A.&June,C.H.The Principles of Engineering Immune cells to Treat Cancer.Cell 168,724-740(2017))。
据报道,肿瘤微环境(TME)中的CAR T细胞表现出效应功能和增殖能力的丧失,被定义为T细胞“耗竭”,这可能是由实体肿瘤中持续的抗原刺激和其他代谢应激引起的(Schietinger,A.et al.Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis.Immunity45,389–401(2016);Vodnala,S.K.et al.T cell stemness and dysfunction in tumorsare triggered by a common mechanism.Science 363,(2019))。
据报道,耗竭的T细胞表现出线粒体呼吸抑制,这种较差代谢适能(metabolicfitness)可能会加剧T细胞耗竭并且损害其抗肿瘤免疫反应。在过继性转移的CAR T细胞扩增阶段中进行代谢干预显示可调节体内分化并提高抗肿瘤反应(Alizadeh,D.et al.IL15Enhances CAR T Cell Antitumor Activity by Reducing mTORC1 Activity andPreserving Their Stem Cell Memory Phenotype.Cancer Immunol.Res.7,759–772(2019))。
然而,这种类型的干预导致的抗肿瘤效果并不是最优的,这可能是由于所应用的细胞因子不是持续提供的,或者它们的代谢重编程能力有限,无法完全挽救耗竭的T细胞。
因此,仍然迫切需要开发支持免疫细胞在TME内的代谢适能、扩增和存活的工程方法、以及具有增强抗肿瘤活性的有效免疫细胞。
发明内容
本发明提供了一种表达白细胞介素-10、其片段或变体的免疫细胞,所述免疫细胞包含一种或多种重组构建体,其中至少一种重组构建体编码白细胞介素-10、其片段或变体。
还提供了编码本发明的一种或多种重组构建体的核酸序列。
还提供了包含本发明的核酸序列的质粒或载体。
还提供了一种药物组合物,其包含i)本发明的免疫细胞、ii)本发明的核酸、和/或iii)本发明的质粒或载体,以及至少一种药学上可接受的载体或稀释剂。
还提供了一种治疗和/或预防癌症的方法,其包括向有其需要的受试者施用本发明的药物组合物。
还提供了一种治疗和/或预防受试者癌症的方法,其包括(i)从所述受试者中移除且分离免疫细胞,优选初始T细胞,或提供免疫细胞,优选初始T细胞;(ii)用至少一种编码白细胞介素-10、其片段或变体的重组构建体和编码嵌合抗原受体(CAR)、T细胞受体(TCR)或任何其他合成的肿瘤靶向基序或抗原的第二重组构建体对所述T细胞进行基因工程化;(iii)离体扩增成更大的工程化T细胞群;和(iv)重引入患者或受试者中。
还提供了一种增强受试者抗肿瘤活性的方法,其包括(i)从所述受试者中移除且分离免疫细胞,优选初始T细胞,或提供免疫细胞,优选初始T细胞;(ii)用至少一种编码白细胞介素-10、其片段或变体的重组构建体和编码嵌合抗原受体(CAR)、T细胞受体(TCR)或任何其他合成的肿瘤靶向基序或抗原的第二重组构建体对所述T细胞进行基因工程化;(iii)离体扩增成更大的工程化T细胞群;和(iv)重引入患者或受试者中。
附图说明
图1-共表达IL-10的HER2特异性CAR T细胞(IL-10HER2 CAR T)在抗原刺激后增强CAR T细胞的OXPHOS,并且促进CAR T细胞增殖。(a)针对HER2的第二代CAR(HER2 CAR)和经修饰以在2A元件后表达鼠IL-10的针对HER2的第二代CAR(HER2 CAR-IL-10)的示意图。(b)通过逆转录病毒载体进行HER2 CAR或HER2 CAR-IL-10构建体的转导。通过流式细胞术分析CAR的表达水平。直方图中的数字表示HER2 CAR阳性染色细胞的百分比。从10个独立实验中获得了相似的结果。(c)CAR T细胞与经丝裂霉素C处理的MC38-HER2(表达HER2的MC38结肠癌细胞)共培养3天。通过酶联免疫吸附试验(ELISA)检测培养上清中的IL-10浓度。(d、e)CAR T细胞用细胞示踪剂CFSE标记,并与经丝裂霉素C处理的MC38-HER2细胞以1:1的效应细胞:靶细胞(E:T)比共培养指定时间。(d)不同天数存活的HER2 CAR T或IL-10HER2 CAR T的绝对数量。(e)在磷酸盐缓冲盐溶液(PBS)、同型对照抗体或抗IL-10mAb的存在下,HER2 CART或IL-10HER2 CAR T细胞分裂的百分比。(f)CAR T细胞在5:1的E:T比的MC38-HER2刺激下24h的代表性耗氧率(OCR)轨迹。(g)如(f)处理的细胞的代表性细胞外酸化率(ECAR)轨迹。(h)对(f)的基础OCR的统计分析。(i)对(g)的基础ECAR的统计分析。(j)(f)和(g)的OCR/ECAR比。数据表示平均值±SEM。从至少3次独立实验中获得了相似的结果。
图2-IL-10HER2 CAR T细胞通过丙酮酸盐依赖方式增强CAR T细胞的抗肿瘤活性。(a)以MC38-HER2细胞为靶细胞的细胞毒性试验。将靶细胞与HER2 CAR T细胞或IL-10HER2CAR T细胞以指定的E/T比混合。(b、c、d)未转导的对照T细胞(Ctrl T)、在0ng/mL和145ng/mL的小鼠重组IL-10(mIL-10)的存在下的HER2 CAR T细胞或IL-10HER2 CAR T细胞与MC38-HER2细胞以0.5:1的E:T比共培养48h。(b)通过流式细胞术分析MC38-HER2肿瘤细胞杀伤百分比。(c)通过流式细胞术分析存活的CAR T细胞计数。(d)通过细胞内细胞因子染色评估共培养期或静止期中的多功能CAR T细胞的比率。
图3-IL-10HER2 CAR T疗法根除了建立的小鼠MC38-HER2结肠腺癌。C57BL/6小鼠皮下接种MC38-HER2细胞(3×105),并且在第6天分别通过静脉注射(i.v.)接受过继性细胞转移:HER2 CAR T细胞(3×106)、IL-10HER2 CAR T细胞(3×106)、或HER2 CAR T细胞(3×106)且随后静脉施用mIL-10(1μg)。所示为各治疗组的平均肿瘤生长曲线(a)和生存曲线(b)。图中所示为组内小鼠总数中长期存活小鼠的数量。(c)IL-10HER2 CAR T单药治疗组的存活小鼠在首次接种后第90天皮下注射MC38-HER2(1×106)细胞进行再攻击。未经处理的WT小鼠(n=5)接种相同数量的肿瘤细胞作为对照。图中所示为长期存活小鼠在再攻击下的生存曲线和数量。数据表示平均值±SEM。
图4-TRP-1 IL-10CAR T疗法延长了小鼠B16F10黑色素瘤模型的存活时间。(a)针对TRP-1的第二代CAR(TRP-1 CAR)和经修饰以在2A元件后表达鼠IL-10的针对TRP-1的第二代CAR(IL-10TRP-1 CAR)的示意图。(b)通过逆转录病毒载体进行TRP-1 CAR或IL-10TRP-1CAR构建体的转导。通过流式细胞术分析CAR的表达水平。直方图中的数字表示c-Myc标记阳性染色细胞的百分比。从10次独立实验获得了相似的结果。(c、d)在0和145ng/mL小鼠重组IL-10(mIL-10)的存在下的TRP-1 CAR T、或IL-10TRP-1 CAR T细胞与B16F10细胞以0.5:1的E:T比共培养48h。(c)通过流式细胞术分析B16F10肿瘤细胞杀伤百分比。(d)通过流式细胞术分析存活的CAR T细胞计数。(e、f)C57BL/6小鼠皮下接种B16F10黑色素瘤细胞(3×105),并在第6天分别通过静脉注射接受TRP-1 CAR T细胞(3×106)或IL-10TRP-1 CAR T细胞(3×106)的过继性细胞转移。图中所示为各治疗组的平均肿瘤生长曲线(e)和生存曲线(f)。数据表示平均值±SEM。
图5-通过IL-10EGFRvIII CAR T细胞治疗,预先建立的小鼠4T1-Luc-EGFRvIII转移性乳腺癌模型完全消退。(a)针对EGFRvIII的第二代CAR(EGFRvIIICAR)和经修饰以在2A元件后表达鼠IL-10、的针对EGFRvIII的第二代CAR(IL-10EGFRvIIICAR)的示意图。(b)通过流式细胞术分析CAR的表达水平。直方图中的数字表示c-Myc标记阳性染色细胞的百分比。从10次独立实验获得了相似的结果。(c)CAR T细胞与经丝裂霉素C处理的4T1-Luc-EGFRvIII共培养3天。通过ELISA检测培养上清中的IL-10浓度。(d、e)Ctrl T、在0ng/mL和145ng/mL mIL-10存在下的EGFRvIIICAR T、或IL-10EGFRvIIICAR T细胞与4T1-Luc-EGFRvIII细胞以0.5:1的E:T比共培养48h。(d)通过流式细胞术分析4T1-Luc-EGFRvIII肿瘤细胞杀伤百分比。(e)通过流式细胞术分析存活的CAR T细胞计数。(f-h)BALB/c小鼠静脉注射4T1-Luc-EGFRvIII细胞(5×104),并且在第6天分别通过静脉注射接受过继性细胞转移:EGFRvIIICAR T细胞(3×106)、IL-10EGFRvIIICAR T细胞(3×106)、或EGFRvIIICAR T细胞(3×106)随后静脉施用mIL-10(1μg)。(f)各组小鼠在不同时间点的个体平均辐射(p/s/cm2/sr)。(g)图中所示为各治疗组的生存曲线和组内小鼠总数中长期存活小鼠的数量。(h)通过流式细胞术定量第15天血液中CAR T细胞的数量。数据表示平均值±SEM。
图6-IL-10Pmel TCR T疗法延长了小鼠B16F10黑色素瘤模型的存活时间。(a)通过逆转录病毒载体用IL-10构建体进行转导。通过ELISA分析IL-10的表达水平。(b-f)C57BL/6小鼠皮下接种B16F10黑色素瘤细胞(3×105),并且在第6天分别通过静脉注射接受Pmel T细胞(10×106)或IL-10Pmel T细胞(10×106)的过继性细胞转移。(b-d)PBS对照组(b)、PmelT细胞疗法(c)和IL-10Pmel T细胞疗法(d)的个体肿瘤生长曲线。(e、f)所示为各治疗组的平均肿瘤生长曲线(e)和生存曲线(f)。数据表示平均值±SEM。
图7-IL-10CD19人类CAR T的体外表征。(a)针对CD19的第二代CAR(CD19 CAR)和经修饰表达人类IL-10的针对CD19的第二代CAR(IL-10CD19 CAR)的示意图。(b)通过流式细胞术分析CAR的表达水平。从10次独立实验获得了相似的结果。(c)通过ELISA检测分泌的IL-10的浓度。(d)Ctrl T、CD19 CAR T或IL-10CD19 CAR T细胞以1:32的E:T比与靶肿瘤细胞共培养,通过LDH试验分析肿瘤细胞杀伤百分比。(e)平均肿瘤生长曲线。NSG小鼠皮下(s.c.)接种PANC1-CD19人类上皮样癌细胞(2×106),并且在第8天通过静脉注射接受CD19 hCAR T细胞(1×106)或IL-10CD19 hCAR T细胞(1×106)的过继性细胞转移(每组n=9)。数据表示平均值±SEM。
图8-IL-10表达维持了CAR-T细胞的线粒体适能(mitochondrial fitness)。C57BL/6小鼠接种MC38-HER2肿瘤细胞(1×106,s.c.),在第5天通过辐照进行非致死地淋巴细胞清除,并在第6天通过静脉注射接受过继性转移:IL-10HER2 CAR-T细胞(3×106)、或在静脉施用或不施用IL-10(1μg)的情况下的HER2 CAR-T细胞(3×106)(每组n=5)。在第14天处死小鼠,并处理指定组织。CAR-T细胞通过流式细胞术进行线粒体表型分析或分选用于电子显微镜分析。分别用MitoTracker Green(MG)和MitoTracker Deep Red(MDR)染色检测CAR-T细胞的线粒体质量和膜电位。a,线粒体功能失调的HER2 CAR-T细胞的频率。b,指定治疗组的肿瘤浸润HER2 CAR-T细胞中的MDR/MG比。c,指定治疗组的分选肿瘤内HER2 CAR-T细胞的代表性电子显微镜图像。d-f,(c)中所示的分选的肿瘤内HER2 CAR-T细胞中每个细胞的线粒体数量(d)、每个线粒体的嵴数量(e)和每个线粒体面积的总嵴长度(f)的定量。所有数据表示为平均值±s.e.m.,并通过未配对的学生t检验(d、e、f)或单因素ANOVA与Tukey多重比较检验(a、b)进行分析。
图9-图5所述的IL-10HER2 CAR-T或IL-10TRP-1 CAR-T细胞治疗后的存活小鼠存活在首次肿瘤接种后第90天分别通过皮下注射MC38-HER2(1×106)和B16F10(1×105)细胞进行再攻击。未经处理的WT小鼠(每组n=5)接种相同数量的肿瘤细胞作为对照。a,实验时间线。b、c,图中所示为MC38-HER2肿瘤模型(b)和B16F10肿瘤模型(c)中的长期存活小鼠承受第二次肿瘤攻击的生存曲线和数量。
图10-IL-10 CAR-T细胞治疗的小鼠诱导了干细胞样记忆。C57BL/6小鼠接种MC38-HER2细胞(1×106,s.c.),在第5天通过辐照进行非致死地淋巴细胞清除,并在第6天通过静脉注射接受过继性转移:IL-10HER2 CAR-T细胞(3×106)、或在静脉施用或不施用IL-10(1μg)的情况下的HER2 CAR-T细胞(3×106)(每组n=5)。在第18天处死小鼠,通过流式细胞术分析脾脏和外周血中的CAR-T细胞的表型。a、b,脾脏中总CAR-T细胞中CD62L+CD44-的平均频率(a)和CD62L+CD44-CAR-T细胞中Sca-1+CD122+的平均频率(b)。c,脾脏CAR-T细胞中Sca-1表达的代表性流式细胞术图和平均MFI。d,脾脏和血液(e)中表示CAR-T细胞表型的代表性流式细胞术图。脾脏(d)和血液(e)中总CAR-T细胞中的IL-7Rα+KLRG-1-的频率。所有数据表示为平均值±s.e.m.,并通过单因素ANOVA与Tukey多重比较检验进行分析(a-e)。
具体实施方式
虽然与本文所述的方法和材料相似或等效的方法和材料可用于本发明的实践或测试中,但下文介绍了合适的方法和材料。本文提及的所有出版物、专利申请、专利和其他参考文献的全部内容均通过引用纳入本文。本文讨论的出版物和申请仅由于其公开早于本申请的提交日期而提供。本文中的任何内容都不应被解释为承认本发明无权凭借在先发明而早于此类公布。此外,材料、方法和实施例仅是说明性的,而非限制性的。
如有冲突,以本说明书(包括定义)为准。除非另有定义,否则本文使用的所有技术术语和科学术语具有与本文主题所属领域的技术人员通常理解的相同含义。如本文所用,提供以下定义以便于理解本发明。
术语“包含(comprise/comprising)”通常以包括(include/including)的含义使用,也就是说允许一个或多个特征或组分的存在。术语“包含(comprise(s)和comprising)”也分别包括更限制性的包含“由……组成(consist(s)、consisting)”以及“基本由……组成(consist/consisting essentially of)”。
如在说明书和权利要求中所使用的,单数形式“a”、“an”和“所述”包括复数形式,除非上下文另有明确规定。
如本文所用,“至少一种”表示“一种或多种”、“两种或多种”、“三种或多种”等。例如,至少一种表示一种或多种构建体,指一种构建体、两种构建体、三种构建体等……
如本文所用,术语“受试者”/“有其需要的受试者”、或“患者”/“有其需要的患者”在本领域中是公知的,且在本文中可互换地用于指哺乳动物,包括狗、猫、大鼠、小鼠、猴子、牛、马、山羊、绵羊、猪、骆驼,以及最优选地指人类。在一些情况下,所述受试者是有治疗需要的受试者或患有疾病或障碍的受试者。然而,在其他方面,所述受试者可以是正常的受试者。该术语不表示特定的年龄或性别。因此,成人和新生儿受试者,无论是男性还是女性,都应被包括在内。优选地,所述受试者是人类,最优选地,所述受试者是可能有患癌症风险的人类。
根据本发明,所述癌症是实体癌症或液体癌症。在一个方面,所述癌症是实体癌症。优选地,所述实体癌症选自包括以下的非限制性组:肺癌、乳腺癌、卵巢癌、宫颈癌、子宫癌、头颈癌、胶质母细胞瘤、肝细胞癌、结肠癌、直肠癌、结直肠癌、肾癌、前列腺癌、胃癌、支气管癌、胰腺癌、膀胱癌、肝癌、脑癌和皮肤癌、特别是黑色素瘤、或它们的一种或多种的组合。
术语“核酸”、“多核苷酸”和“寡核苷酸”可互换地使用,指线性或环状构象的、单链或双链形式的、任何种类的脱氧核糖核苷酸(例如DNA、cDNA……)聚合物或核糖核苷酸(例如RNA、mRNA……)聚合物或脱氧核糖核苷酸聚合物和核糖核苷酸(例如DNA/RNA)聚合物的组合。这些术语不应被解释为对聚合物长度的限制,并且可以包括已知的天然核苷酸类似物,以及碱基、糖和/或磷酸盐部分(例如硫代磷酸酯骨架)经修饰的核苷酸。通常,特定核苷酸的类似物具有相同的碱基配对特异性,即A的类似物将与T碱基配对。
如本文所用,术语“载体”指病毒载体或核酸(DNA或RNA)分子,例如质粒或其他媒介物,其包含本发明的一种或多种异源核酸序列,并且优选地,所述载体设计用于在不同宿主细胞之间进行转移和/或用于扩增目的。
术语“表达载体”、“基因递送载体”和“基因治疗载体”指优选地在启动子的调控下,有效地结合入细胞并表达本发明的一种或多种核酸的任何载体。除启动子外,克隆载体或表达载体可以包含另外的元件,例如调控元件和/或转录后调控元件。
如本文所用,白细胞介素-10(IL-10)指IL-10家族细胞因子的一员。因为IL-10能减少由不受控制的炎性反应引起的组织损伤,所以其通常被认为具有免疫抑制作用。“IL-10、其片段或变体”包括包含优选天然人类IL-10以及其片段及变体的序列(例如Mumm etal.,2011,Cancer Cell,20,781-796;Guo et al.,2012,Protein Expr.Purif.,83,152-156(2012);Zheng et al.,1997,J.Immunol.,158,4507-13;Qiao et al.,2019,CancerCell 35,901-915;Guo et al.,2021,Nat Immunol 22,746–756中所述的,其内容通过引用整体纳入本文)。在一个方面,所述IL-10序列是如SEQ ID No:1所示的人IL-10氨基酸序列。
当指IL-10时,术语“变体”表示IL-10的一种或多种生物活性衍生物,优选本发明的人IL-10序列。通常,术语“变体”指相对于天然分子具有一个或多个添加、替换(本质上通常是保守的)和/或缺失的天然序列的分子,只要这些修饰不破坏其生物活性,所述变体与参考分子“基本同源”(Gorby et al.,Sci.Signal.13,eabc0653,2020;Saxton et al.,Science 371,eabc8433,2021)。通常,这类变体的序列与参考序列具有高度的序列同源性或同一性,例如,当比对两个序列时,序列同源性或同一性大于25%、通常大于50%至70%、甚至更特别地为80%、或85%或更高,例如至少90%、或95%或更高。Spencer,Juliet V等人报道,尽管IL-10的剪接形式与hIL-10仅具有27%的序列同一性,但保留了生物活性或特性(Spencer,Juliet V et al.“Stimulation of B lymphocytes by cmvIL-10but notLAcmvIL-10.”Virology vol.374,1(2008):164-9.doi:10.1016/j.virol.2007.11.031,其内容通过引用整体纳入本文)。
如本文所用,本发明的IL-10(优选人IL-10)的“片段”指包含在长度上少于相应的多肽序列或核酸序列的核苷酸的序列。优选地,该序列或片段包含在长度上比相应的多肽序列或核酸序列少于90%、优选少于60%、尤其是少于30%的核苷酸。
当致力于开发用CAR工程化T细胞治疗肿瘤的新颖且有效的方法时,发明人惊奇地发现,代谢工程化的表达IL-10的CAR T将CAR T细胞的命运从耗竭转向类似记忆的状态,从而从大多数接受治疗的小鼠中根除已确立的实体肿瘤并实现持久治愈。这些有希望的结果证明了表达IL-10的CAR T或任何其他工程化免疫细胞提高临床过继性细胞疗法效果方面具有巨大潜力。
在一个方面,本发明提供了表达白细胞介素-10、其片段或变体的免疫细胞或免疫细胞群。在一个方面,所述免疫细胞是分离的免疫细胞。
如本文所用,术语“免疫细胞”包括分类为淋巴细胞、中性粒细胞和单核细胞/巨噬细胞的任何类型的免疫细胞,无论是否为重组的(工程化的)。在一个优选的方面,所述免疫细胞选自包括以下的非限制性组:T细胞、嵌合抗原受体(CAR)-T细胞、T细胞受体(TCR)-转基因T细胞、肿瘤浸润淋巴细胞(TIL)、NK细胞、NK-T细胞、CAR-NK细胞、CAR-NKT细胞、TCR-转基因NK细胞、TCR-转基因NK-T细胞、树突状细胞、巨噬细胞、CAR-巨噬细胞或任何合成的肿瘤特异性免疫细胞。免疫细胞的免疫细胞群可以是
-自体的,即使用患者自身的免疫细胞,
-同种异体的,即从捐赠者血液、脐带血或多能干细胞(例如可以进行基因工程的iPSC)中获得,或
-异源的。
在后两种情况下,也应考虑减少异体排斥的策略,并且该策略是技术人员已知的。
优选地,所述免疫细胞包含一种或多种重组构建体,其中至少一种重组构建体编码白细胞介素-10、其片段或变体。
在一个方面,所述编码白细胞介素-10、其片段或变体的构建体包含SEQ ID No.1的氨基酸序列或其片段或变体,或编码SEQ ID No.1的氨基酸序列、或其片段或变体。
在一个方面,所述编码白细胞介素-10、其片段或变体的重组构建体与所述编码CAR、TCR或任何其他合成的肿瘤靶向基序的第二重组构建体相连接。
还优选地,所述第二重组构建体编码嵌合抗原受体(CAR)、T细胞受体(TCR)或任何其他合成的肿瘤靶向基序。合成的肿瘤靶向基序的非限制性实例包括,例如,Liu R,Li X,Xiao W,Lam KS(Tumor-targeting peptides from combinatorial libraries)[修正于2018年3月9日发表在Adv Drug Deliv Rev.]的表2和表3中列举的肿瘤靶向肽,其全部内容通过引用纳入本文。
本领域技术人员知道肿瘤靶向基序(例如肿瘤靶向肽)可以通过体外、体内或离体选择方法的筛选方法,从例如噬菌体展示文库中检测到(参见例如Liu R,Li X,Xiao W,LamKS的图1)。癌症相关蛋白、特定癌细胞系、患者组织和肿瘤异种移植小鼠模型可用作筛选探针。
优选地,所述连接是通过编码自剪切肽(例如2A肽,参见例如Takahashi,K.&Yamanaka,S.Induction of pluripotent stem cells from mouse embryonic and adultfibroblast cultures by defined factors.Cell 126,663–676,其全部内容通过引用纳入本文,或内部核糖体进入位点(IRES)序列)的序列。例如,一旦所述自剪切肽被切割,IL-10、其片段或变体优选在肿瘤微环境中由所述免疫细胞分泌、或膜结合在所述免疫细胞上。
在一个方面,所述重组构建体包含编码所述CAR的核酸,其编码单链可变区片段(scFv)的胞外抗原识别结构域、跨膜区的多肽、胞内T细胞活化结构域和/或胞内区域。
所述单链可变区片段(scFv)的胞外抗原识别结构域优选源自抗体或配体或受体。在一些情况下,所述胞外结构域包含铰链部分。根据本发明可以采用多种铰链,例如CD8铰链。
通常,所述源自抗体的单链可变区片段(scFv)的胞外抗原识别结构域识别选自包括以下的非限制性组的抗原:c-MET、TRP-1、CD19、CD20、BCMA、CD133、CD171、CD70、CEA、EGFR、EGFR-vIII、EpCAM、EphA2、FAP、GD2、GPC3、HER2、HER3、IL-13Ra2、间皮素、MUC1、紧密连接蛋白18.2、PSCA、PSMA、ROR1和VEGFR2或它们的一种或多种的组合。在一个优选的方面,本发明的CAR中的胞外抗原识别结构域是例如连接到铰链的识别HER2的CD8或CD28跨膜结构域scFv(SEQ ID NO:2)、识别TRP-1的CD8或CD28跨膜结构域scFv(SEQ ID NO:3)、识别EGFR-vIII的CD8或CD28跨膜结构域scFv(SEQ ID NO:4)、或识别CD19的CD8或CD28跨膜结构域scFv(SEQ ID NO:5)。
跨膜区和铰链通常融合到所述CAR的胞外结构域。同样地,其也可以融合到所述CAR的胞内结构域。在一些情况下,可以通过氨基酸取代来选择或修饰所述跨膜结构域,以避免此类结构域与相同或不同的表面膜蛋白的跨膜结构域结合,以最小化与受体复合物的其他成员的相互作用。所述跨膜结构域可以源自天然来源或合成来源。如果所述是天然来源,所述结构域可以源自任何膜结合蛋白或跨膜蛋白。本发明中的特定用途的跨膜区可以源自(包含或对应于)CD28、CD28T、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程序性死亡-1(PD-1)、可诱导T细胞共刺激分子(ICOS)、淋巴细胞功能相关抗原-1(LFA-1、CDl-la/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7-H3)、LIGHT、(TNFSF14)、NKG2C、Igα(CD79a)、DAP-10、Fcγ受体、MHC 1类分子、TNF受体蛋白、免疫球蛋白蛋白质、细胞因子受体、整合素、信号淋巴细胞活化分子(SLAM蛋白)、活化NK细胞受体、BTLA、Toll配体受体、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2Rβ、IL-2Rγ、IL-7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CDl ld、ITGAE、CD103、ITGAL、CDl la、LFA-1、ITGAM、CDl lb、ITGAX、CDl lc、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRTAM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB-A、Lyl08)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、特异性结合CD83的配体、或它们的任何组合。
任选地,短连接物可以在CAR的任何或一些胞外结构域、跨膜结构域和胞内结构域之间形成连接。
在一个优选的方面,本发明的CAR中的跨膜结构域和铰链是CD8跨膜结构域和铰链。在一个方面,所述CD8跨膜结构域和铰链包含SEQ ID NO:6、其片段或变体的氨基酸序列的跨膜部分和铰链。
所述胞内T细胞活化结构域能够在抗原结合分子与其靶点结合后活化T细胞。应当理解的是,所述胞内结构域通常还包含本文所述的一种或多种共刺激分子。
在进一步方面,所述T细胞活化结构域包含CD3,优选CD3ζ,更优选SEQ ID NO:7、其片段或变体的氨基酸序列的CD3ζ。
本文所用的“共刺激分子”指提供介导T细胞反应的信号的分子,所述T细胞反应包括但不限于增殖、活化、分化等。共刺激分子可以提供除由本文所述的活化分子提供的主要信号外的信号。
本发明的工程化T细胞的胞内(胞质)区可以活化免疫细胞的至少一种正常效应功能。例如,T细胞的效应功能可以指细胞溶解活性或辅助活性。
应理解的是,合适的胞内区包括(即包含)但不限于源自(或对应于)以下的信号结构域:CD28、CD28T、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程序性死亡-1(PD-1)、可诱导T细胞共刺激分子(ICOS)、淋巴细胞功能相关抗原-1(LFA-1、CDl-la/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7-H3)、LIGHT、(TNFSF14)、NKG2C、Igα(CD79a)、DAP-10、Fcγ受体、MHC 1类分子、TNF受体蛋白、免疫球蛋白蛋白质、细胞因子受体、整合素、信号淋巴细胞活化分子(SLAM蛋白)、活化NK细胞受体、BTLA、Toll配体受体、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2Rβ、IL-2Rγ、IL-7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CDl ld、ITGAE、CD103、ITGAL、CDl la、LFA-1、ITGAM、CDl lb、ITGAX、CDl lc、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRT AM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB-A、Lyl08)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、特异性结合CD83的配体、或它们的任何组合。
组合的一个实例包含4-1BB胞内区和CD28胞内区。
在一个优选的方面,所述CAR的胞内结构域包含4-1BB胞内区。
根据本发明的示例性CAR构建体如图1a、图4a和图7a所示。
在所述第二重组构建体编码转基因TCR的情况下,所述TCR优选识别选自包括以下的非限制性组的抗原:gp100、NY-ESO-1、MAGE-A3和TRP-1、或它们的一种或多种的组合。
在一个方面,所述编码白细胞介素-10、其片段或变体的构建体包含在编码Fc、人类血清白蛋白(HSA)或抗体融合蛋白的序列中。
在本发明的一个方面中,本文所述的免疫细胞或免疫细胞群用于预防和/或治疗癌症。所述癌症可以是实体癌症或液体癌症。
优选地,所述癌症选自以下的非限制性组的实体癌症:肺癌、乳腺癌、卵巢癌、宫颈癌、子宫癌、头颈癌、胶质母细胞瘤、肝细胞癌、结肠癌、直肠癌、结直肠癌、肾癌、前列腺癌、胃癌、支气管癌、胰腺癌、膀胱癌、肝癌、脑癌、淋巴瘤和皮肤癌、尤其是黑色素瘤、或它们的一种或多种的组合。更优选地,所述实体癌症选自淋巴瘤、乳腺癌、胃癌和黑色素瘤。
本发明还提供了编码本文所述的一种或多种重组构建体的核酸序列,包括本文公开的SEQ ID。
本发明还提供了一种质粒或载体,其包含编码本文所述的一种或多种重组构建体的核酸序列,包括本文公开的SEQ ID。
本领域已知的任何载体均可适用于本发明。在一些方面,所述载体是病毒载体。在一些方面,所述载体是逆转录病毒载体(例如pMSGV)、DNA载体、鼠白血病病毒载体、SFG载体、RNA载体、腺病毒载体、杆状病毒载体、Epstein Barr病毒载体、乳多泡病毒(papovaviral)载体、牛痘病毒载体、单纯疱疹病毒载体、腺病毒相关载体(AAV)、慢病毒载体(例如pGAR)或它们的任何组合。
本发明还考虑了组合物以及药物组合物。
在本发明的一个方面,本发明的药物组合物包含治疗有效量的i)本文所述的免疫细胞或免疫细胞群、ii)本文所述的核酸、和/或iii)本文所述的质粒或载体,以及至少一种药学上可接受的载体和/或稀释剂。
本文所用的术语“治疗有效量”表示在合理的医学判断范围内的免疫细胞、核酸、质粒或载体的量,该量高至足以显著积极地改变待治疗的症状和/或病症,但又低至足以避免严重的副作用(以合理的风险/收益比)。
本文所述的免疫细胞、核酸、质粒或载体的治疗有效量是根据多种因素进行选择的,所述因素包括患者或受试者的类型、物种、年龄、体重、性别和医疗病症;待治疗的病症或疾病(例如癌症)的严重程度;施用途径;患者或受试者的肝肾功能。本领域的普通医生可以容易地确定并采用预防、对抗或阻止疾病例如癌症的进展所需的免疫细胞、核酸、质粒或载体的有效量。
“药学上可接受的载体或稀释剂”是指用于制备通常是安全的、无毒的和所需的药物组合物的载体或稀释剂,并且包括可用于人类药物用途的载体或稀释剂。
本发明的免疫细胞或免疫细胞群可以单独施用、或作为药物组合物施用。本发明的药物组合物可包含本文所述的免疫细胞或细胞群(例如T细胞),与一种或多种药学上或生理学上可接受的载体或稀释剂组合。这种组合物可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、蔗糖或葡萄聚糖、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;佐剂(例如氢氧化铝);和防腐剂。本发明的组合物优选配制用于静脉施用。
所述药物组合物(溶液、悬浮液等)可包括以下一种或多种:无菌稀释剂,例如注射用水、盐水溶液(优选生理盐水)、林格氏溶液、等渗氯化钠、固定油(例如可以作为溶剂或悬浮介质的合成单甘油酯或二甘油酯)、聚乙二醇、甘油、丙二醇或其他溶剂;抗菌剂,例如苯甲醇或对羟基苯甲酸甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;螯合剂,例如乙二胺四乙酸;缓冲液,例如乙酸盐、柠檬酸盐或磷酸盐;以及调节张力的剂,例如氯化钠或葡萄糖(dextrose)。肠胃外制剂可以封装在由玻璃或塑料制成的安瓿瓶、一次性注射器或多剂量小瓶中。可注射的药物组合物优选是无菌的。
本发明的药物组合物还可以包含至少一种另外的治疗剂或治疗。多种其它另外的治疗剂可以与本文所述的组合物联合使用。
在一个方面,所述至少一种另外的治疗剂或治疗是用于治疗癌症优选实体癌症的抗癌剂或抗癌治疗。优选地,所述一种或多种抗癌治疗将选自:放射治疗、化学治疗、免疫检查点抑制剂、免疫治疗和激素治疗或它们的一种或多种的组合。
优选地,所述免疫检查点抑制剂选自:PD-1抑制剂、PD-L1抑制剂和CTLA-4抑制剂、或它们的一种或多种的组合。
例如,潜在有用的另外的治疗剂包括PD-1抑制剂,例如纳武利尤单抗派姆单抗/>派姆单抗(pembrolizumab)、帕利珠单抗(pidilizumab)和阿特珠单抗(atezolizumab)。
例如,潜在有用的另外的治疗剂包括PD-L1抑制剂,例如阿特珠单抗、阿维鲁单抗(avelumab)、AMP-224、MEDI-0680、RG-7446、GX-P2、德瓦鲁单抗(durvalumab)、KY-1003、KD-033、MSB-0010718C、TSR-042、ALN-PDL、STI-A1014、CX-072和BMS-936559。
CTLA-4抑制剂的非限制性实例包括易普利姆玛(ipilimumab,Yervoy)(也称为BMS-734016、MDX-010、MDX-101)和曲美木单抗(tremelimumab,以前的ticilimumab,CP-675,206)。
本发明的化学治疗可涉及损伤DNA和/或阻止细胞增殖的剂,例如基因毒素。
基因毒素可以选自:烷化剂、抗代谢物、DNA切割剂、DNA结合剂、拓扑异构酶毒物和纺锤体毒物。烷化剂的实例是洛莫司汀、卡莫司汀、链脲菌素、氮芥、美法仑(melphalan)、尿嘧啶氮芥、苯丁酸氮芥、环磷酰胺、异环磷酰胺、顺铂、卡铂、丝裂霉素、噻替派、达卡巴嗪、甲基苄肼、六甲基三聚氰胺、三乙烯三聚氰胺、白消安、哌泊溴烷(pipobroman)、米托坦(mitotane)和其他铂类衍生物。
DNA切割剂的一个实例是博来霉素。
拓扑异构酶毒物可选自包括拓扑替康、伊立替康、喜树碱钠盐、柔红霉素(daorubicin)、多柔比星(doxorubicin)、伊达比星(idarubicin)、米托蒽醌替尼泊苷(mitoxantrone teniposide)、阿霉素(adriamycin)和依托泊苷的组。
DNA结合剂的实例是放线菌素D和光神霉素(mithramycin),而纺锤体毒物可以选自:长春花碱、长春花新碱、异长春花碱(navelbin)、紫杉醇和多西他赛。
本发明的化学治疗可以涉及选自以下化合物的抗代谢物:甲氨蝶呤、三甲曲沙(trimetrexate)、喷司他丁(pentostatin)、阿糖胞苷、ara-CMP、磷酸氟达拉滨、羟基脲、氟尿嘧啶、氟尿苷、氯脱氧腺苷、吉西他滨、硫鸟嘌呤和6-巯基嘌呤。
放射治疗指使用高能辐射来缩小肿瘤并杀死癌细胞。放射治疗的实例包括但不限于体外放射治疗和体内放射治疗(也称为近距离放射治疗)。
体外放射治疗是最常见的,通常包括将一束直接或间接的电离辐射指向肿瘤或癌症位点。虽然辐射光束、光子治疗、钴治疗或粒子治疗聚焦于肿瘤或癌症位点,但几乎不可能避免正常健康组织的暴露。体外放射治疗的能量源选自直接或间接的电离辐射(例如:X射线、γ射线和粒子束或它们的组合)。
体内放射治疗包括在体内、在肿瘤位点或肿瘤位点附近植入辐射发射源,例如珠、丝、小球、胶囊等。用于体内放射治疗的能量源选自放射性同位素,包括:碘(碘125或碘131)、锶89、磷的放射性同位素、钯、铯、铟、磷酸盐或钴、及它们的组合。此类植入物可以在治疗后去除,或留在体内处于非活性状态。体内放射治疗的类型包括但不限于间质近距离放射治疗和腔内近距离放射治疗(高剂量率、低剂量率、脉冲剂量率)。
目前不太常见的体内放射治疗形式涉及放射性同位素的生物载体,例如放射免疫治疗,其中向患者或受试者施用与放射性物质结合的肿瘤特异性抗体。所述抗体结合肿瘤抗原,从而有效地向相关组织施加一定剂量的辐射。
实施放射治疗的方法是本领域技术人员所熟知的。
多种其它另外的治疗剂可与本文所述的组合物联合使用。
适合与本发明联合使用的另外的治疗剂包括但不限于:依鲁替尼(ibrutinib,)、奥法木单抗(ofatumumab,/>)、利妥昔单抗(rituximab,)、贝伐单抗(bevacizumab,/>)、曲妥珠单抗(trastuzumab,)、恩美曲妥珠单抗(trastuzumab emtansine,/>)、伊马替尼(imatinib,/>)、西妥昔单抗(cetuximab,/>)、帕尼单抗(panitumumab,)、卡妥索单抗(catumaxomab)、替伊莫单抗(ibritumomab)、奥法木单抗(ofatumumab)、托西图单抗(tositumomab)、布伦图昔单抗(brentuximab)、阿仑单抗(alemtuzumab)、吉姆图珠单抗(gemtuzumab)、埃罗替尼(erlotinib)、吉非替尼(gefitinib)、万德他尼(vandetanib)、阿法替尼(afatinib)、拉帕替尼(lapatinib)、来那替尼(neratinib)、阿西替尼(axitinib)、马赛替尼(masitinib)、帕唑帕尼(pazopanib)、舒尼替尼(sunitinib)、索拉非尼(sorafenib)、托西尼布(toceranib)、来他替尼(lestaurtinib)、阿西替尼(axitinib)、西地尼布(cediranib)、乐伐替尼(lenvatinib)、尼达尼布(nintedanib)、帕唑帕尼(pazopanib)、瑞格非尼(regorafenib)、司马沙尼(semaxanib)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、替沃扎尼(tivozanib)、托西尼布(toceranib)、万德他尼(vandetanib)、恩曲替尼(entrectinib)、卡博替尼(cabozantinib)、伊马替尼(imatinib)、达沙替尼(dasatinib)、尼罗替尼(nilotinib)、帕纳替尼(ponatinib)、拉多替尼(radotinib)、博舒替尼(bosutinib)、来他替尼(lestaurtinib)、鲁索替尼(ruxolitinib)、帕克替尼(pacritinib)、考比替尼(cobimetinib)、司美替尼(selumetinib)、曲美替尼(trametinib)、贝美替尼(binimetinib)、阿来替尼(alectinib)、塞瑞替尼(ceritinib)、克唑替尼(crizotinib)、阿柏西普(aflibercept)、阻抑素靶向肽1(adipotide)、地尼白介素(denileukin diftitox)、mTOR抑制剂例如依维莫司和替西罗莫司、hedgehog抑制剂例如索尼德吉(sonidegib)和维莫德吉(vismodegib)、CDK抑制剂例如CDK抑制剂(帕博西尼(palbociclib))。
在另外的方面,所述另外的治疗剂可以是抗炎剂。抗炎剂或药物包括但不限于类固醇和糖皮质激素(包括倍他米松、布地奈德、地塞米松、醋酸氢化可的松、氢化可的松、氢化可的松、甲基强的松龙、泼尼松龙、强的松、去炎松);非甾体抗炎药(NSAID),包括阿司匹林、布洛芬、萘普生、甲氨蝶呤、柳氮磺胺吡啶、来氟米特;抗TNF药物,环磷酰胺和麦考酚酯。示例性的NSAID包括布洛芬、萘普生、萘普生钠、Cox-2抑制剂和唾液酸盐(sialylate)。示例性的镇痛药包括对乙酰氨基酚、氧可酮、曲马多或盐酸丙氧芬。示例性的糖皮质激素包括可的松、地塞米松、氢化可的松、甲基强的松龙、泼尼松龙或强的松。示例性的生物反应调节剂包括针对细胞表面标志物(例如,CD4、CD5等)的分子、细胞因子抑制剂例如TNF拮抗剂(例如,依那西普阿达木单抗/>和英夫利昔单抗)、趋化因子抑制剂和粘附分子抑制剂。所述生物反应调节剂包括单克隆抗体以及重组形式的分子。示例性的DMARD包括咪唑硫嘌呤、环磷酰胺、环孢霉素、甲氨蝶呤、青霉胺、来氟米特、柳氮磺胺吡啶、羟氯喹、Gold(口服(金诺芬)和肌肉内)和米诺环素。
本发明还考虑了治疗和/或预防癌症的方法。
术语“治疗(treatment)”或“治疗(treating)”是指为了以下目的向受试者施用本公开的组合物、药物组合物、治疗剂、化合物等:
(i)抑制疾病,即阻止临床症状的发展;和/或
(ii)缓解疾病,即使临床症状消退。
如本文所用,术语“预防(prevention)”或“预防(preventing)”是指为预防疾病(即使疾病的临床症状不发展)的目的而向受试者施用本公开的组合物、药物组合物、治疗剂、化合物等。
在本发明的上下文中,所述疾病是癌症,优选是本文公开的实体肿瘤。
在一个方面,所述治疗和/或预防患者或受试者的癌症的方法包括(i)从所述患者或受试者中移除且分离免疫细胞,优选初始T细胞;(ii)用一种编码白细胞介素-10、其片段或变体的重组构建体和编码嵌合抗原受体(CAR)、T细胞受体(TCR)或任何其他合成的肿瘤靶向基序或抗原的第二重组构建体对所述T细胞进行基因工程化;(iii)离体扩增成更大的工程化T细胞群;和(iv)将所述工程T细胞重引入所述患者或受试者中。所述工程T细胞被重引入所述患者或受试者中后,它们会介导针对表达本文所述的肿瘤靶向基序或抗原的细胞的免疫反应。这种免疫反应包括T细胞分泌IL-10、其片段或变体以及其他细胞因子、识别所述肿瘤靶向基序或抗原的T细胞的克隆扩增、以及T细胞介导的对靶点阳性细胞的特异性杀伤。
在一个方面,所述治疗和/或预防癌症的方法包括(i)从患者或受试者中移除且分离免疫细胞,优选初始T细胞,或提供免疫细胞,优选初始T细胞;(ii)用至少一种编码白细胞介素-10、其片段或变体的重组构建体和编码嵌合抗原受体(CAR)、T细胞受体(TCR)或任何其他合成的肿瘤靶向基序或抗原的第二重组构建体对所述T细胞进行基因工程化;(iii)离体扩增成更大的工程化T细胞群;和(iv)重引入所述患者或受试者中。
在一个方面,所述治疗和/或预防受试者癌症的方法包括向有其需要的受试者施用本发明的药物组合物。
在一个方面,上文所述的治疗和/或预防的方法还可以包括施用至少一种另外的治疗剂或治疗,优选抗癌剂或抗癌治疗,更优选治疗有效量或治疗有效剂量的抗癌剂或抗癌治疗。如上文所述,所述一种或多种抗癌剂或治疗将选自包括放射治疗、化学治疗、免疫检查点抑制剂、免疫治疗和激素治疗、或其一种或多种的组合的非限制性组。
可使用多种已知技术制备根据本发明的多核苷酸、多肽、载体、抗原结合分子、免疫细胞、组合物等。
在对本文所述的免疫细胞进行体外操作或遗传修饰之前,可以从受试者获得并分离所述细胞。在一些方面,所述免疫细胞包括T细胞。T细胞可以从多种来源获得,包括外周血单核细胞(PBMC)、骨髓、淋巴结组织、脐带血、胸腺组织、感染部位组织、腹水、胸腔积液、脾脏组织和肿瘤。在某些方面,可以使用技术人员已知的多种技术(例如FICOLLTM分离)从所述受试者收集的单位血液中获得T细胞。优选地,可以通过血液成分单采术从个体的循环血液中获得细胞。血液成分单采术产物通常包含淋巴细胞,包括T细胞、单核细胞、粒细胞、B细胞、其他有核白血细胞、红血细胞和血小板。在某些实施方案中,通过血液成分单采术收集的细胞可以通过洗涤以去除血浆部分,并放置在合适的缓冲液或培养基中用于后续处理。可用PBS洗涤细胞。应当理解,可以使用洗涤步骤。洗涤后,可将所述细胞重悬在多种生物相容的缓冲液或其他含或不含缓冲液的盐水溶液中。在某些方面,可以去除血液成分单采样品的不需要的成分。
在某些方面,通过裂解红血细胞并且清除单核细胞以从PBMC中分离T细胞,例如通过PERCOLLTM梯度使用离心分离。特定的T细胞亚群,例如CD28+T细胞、CD4+T细胞、CD8+T细胞、CD45RA+T细胞和CD45RO+T细胞,可通过本领域已知的正选择或负选择技术进一步分离。例如,通过负选择富集T细胞群可用针对负选择细胞独特的表面标志物的抗体组合来完成。本文使用的一种方法是通过负磁免疫粘附或流式细胞术使用针对负选择的细胞上存在的细胞表面标志物的单克隆抗体混合物进行细胞分选和/或细胞选择。例如,为了通过负选择富集CD4+细胞,单克隆抗体混合物通常包括针对CD14、CD20、CD11b、CD16、HLA-DR和CD8的抗体。流式细胞术和细胞分选也可以用于分离用于本发明的感兴趣的细胞群。
使用本文所述的方法,可将PBMC直接用于免疫细胞的遗传修饰(例如CAR或TCR)。在某些方面,在分离PBMC后,可进一步分离T淋巴细胞,并在遗传修饰和/或扩增之前或之后将细胞毒性T淋巴细胞和辅助T淋巴细胞分选为初始T细胞亚群、记忆T细胞亚群和效应T细胞亚群。
在一些方面,通过识别与每种类型的CD8+细胞相关的细胞表面抗原,将CD8+细胞进一步分选为初始细胞、中央记忆型细胞和效应细胞。
本文所述的免疫细胞可在使用已知方法分离后进行遗传修饰,或所述免疫细胞可在进行遗传修饰之前离体活化并扩增(例如TIL细胞),或分化(在祖细胞的情况下)。在另一个实施方案中,用本文所述的嵌合抗原受体对所述免疫细胞例如T细胞进行遗传修饰(例如,用包含编码CAR的一种或多种核苷酸序列的病毒载体进行转导),然后所述免疫细胞离体活化和/或扩增。活化和扩增T细胞的方法是本领域已知的,例如美国专利第6,905,874号、美国专利第6,867,041号、美国专利第6,797,514号和PCT WO2012/079000中所述的,其内容通过引用整体纳入本文。通常,这类方法包括在含有合适细胞因子(例如IL-2)的培养基中,使PBMC或分离的T细胞与通常附着在珠子或其他表面的刺激分子和共刺激分子(例如抗CD3抗体和抗CD28抗体)接触。在其他方面,可以使用例如美国专利第6,040,177号、美国专利第5,827,642号和WO2012129514(其内容通过引用整体纳入本文)中所述的方法,用饲养细胞和合适的抗体和细胞因子活化T细胞并刺激T细胞增殖。
制备本发明的构建体和工程化免疫细胞的某些方法被描述在例如PCT申请PCT/US2015/14520中,其内容通过引用整体纳入本文。
应当理解,PBMC还可以包括其他细胞毒性淋巴细胞,例如NK细胞或NKT细胞。携带本文所公开的本发明的重组构建体的表达载体可被导入人类供体T细胞、NK细胞或NKT细胞的群中。可使用流式细胞术对成功转导的携带表达载体的T细胞进行分选,以分离CD3阳性T细胞,然后除了使用抗CD3抗体和IL-2或本文其他地方所述的本领域已知的其他方法活化细胞外,进一步增值所述T细胞以增加这些表达CAR的T细胞的数量。使用标准程序对表达CAR的T细胞进行低温保藏,以保存和/或准备用于人类受试者的制。在一个方面,T细胞的体外转导、培养和/或扩增是在没有非人类动物衍生产品(例如胎小牛血清和胎牛血清)的情况下进行的。
为克隆本发明的多核苷酸,可以将所述载体引入宿主细胞(自体的、同种异体的或异源的)以使所述载体本身复制,从而扩增其中包含的多核苷酸的拷贝。本发明的克隆载体可包含序列组件,所述序列组件通常包括但不限于复制起点、启动子序列、转录起始序列、增强子序列和可选的标志物。本领域普通技术人员可适当选择这些元件。例如,可以选择复制起点以促进载体在宿主细胞中的自主复制。
术语“自体的”指源自同一个体的任何材料,该材料随后被重引入该个体。
术语“同种异体的”指源自一个个体的任何材料,该材料随后被引入至同一物种的另一个个体,例如同种异体的T细胞移植。
在某些方面,本公开提供了包含本文提供的载体的分离的宿主细胞。包含所述载体的宿主细胞可用于所述载体中包含的多核苷酸的表达或克隆。合适的宿主细胞可包括但不限于溶瘤病毒、原核细胞、真菌细胞、酵母细胞或高等真核细胞例如哺乳动物细胞。用于该目的的合适的原核细胞包括但不限于真细菌例如革兰氏阴性生物或革兰氏阳性生物,例如肠杆菌科(Enterobactehaceae),例如埃希氏杆菌属(Escherichia)(如大肠杆菌(E.coli))、肠杆菌(Enterobacter)、欧文氏菌(Erwinia)、克雷伯氏杆菌属(Klebsiella)、变形杆菌属(Proteus)、沙门氏菌(Salmonella)(如鼠伤寒沙门氏菌(Salmonellatyphimurium))、沙雷氏菌属(Serratia)(如粘质沙雷氏菌(Serratia marcescans)和志贺氏杆菌(Shigella)),以及杆菌(Bacilli),例如枯草芽孢杆菌(B.subtilis)和地衣芽孢杆菌(B.licheniformis),假单胞菌属(Pseudomonas)例如铜绿假单胞菌(P.aeruginosa),和链霉菌属(Streptomyces)。
可以使用本领域已知的任何合适的方法将所述载体引入所述宿主细胞,所述方法包括但不限于DEAE-葡萄聚糖介导的递送、磷酸钙沉淀法、阳离子脂质介导的递送、脂质体介导的转染、电穿孔、微弹轰击法、受体介导的基因递送、由聚赖氨酸、组蛋白、壳聚糖和肽介导的递送。转染和转化细胞以表达感兴趣载体的标准方法在本领域是众所周知的。
还考虑了一种增强受试者抗肿瘤活性的方法,其包括(i)从所述受试者中移除且分离免疫细胞,优选初始T细胞,或提供免疫细胞,优选初始T细胞;(ii)用至少一种编码白细胞介素-10、其片段或变体的重组构建体和编码嵌合抗原受体(CAR)、T细胞受体(TCR)或任何其他合成的肿瘤靶向基序或抗原的第二重组构建体对所述T细胞进行基因工程化;(iii)离体扩增成更大的工程化T细胞群;和(iv)重引入患者或受试者中。
还考虑了用于实施根据本发明的一种或多种方法的试剂盒。
进一步考虑了一种试剂盒,该试剂盒包含在一个或多个容器中的本发明的组合物或药物组合物的试剂。组合物可以是液体形式或冷冻的。适用于所述组合物的容器包括例如瓶、小瓶、注射器和试管。容器可由多种材料制成,包括玻璃或塑料。所述试剂盒还可包含说明书,所述说明书可包括处方的信息或说明、药物量、成分等。
本领域技术人员将理解,本文所述的发明不限于使用表达IL-10的免疫细胞(例如CAR T或TCR T)转移疗法来治疗癌症。由于表达IL-10的CAR T细胞可被认为是肿瘤靶向递送IL-10以增强抗肿瘤免疫的一个示例性策略,我们可以预期通过以下其他策略的肿瘤靶向递送IL-10:例如干细胞(Liu,L.,et al.,Mechanoresponsive stem cells to targetcancer metastases through biophysical cues.Sci.Transl.Med.9,eaan2966(2017))、血小板(Wang,C.et al.,In situ activation of platelets with checkpointinhibitors for post-surgical cancer immunotherapy.Nat.Biomed.Eng.1,(2017))、溶瘤病毒(Rivadeneira,D.B.et al.,Oncolytic Viruses Engineered to Enforce LeptinExpression Reprogram Tumor-Infiltrating T Cell Metabolism and Promote TumorClearance.Immunity 51,548-560.e4(2019))、mRNA(癌症疫苗,参见例如Sahin,U.,etal.,Personalized RNA mutanome vaccines mobilize poly-specific therapeuticimmunity against cancer.Nature 547,222–226(2017))或纳米技术(Tang,L.et al.,Enhancing T cell therapy through TCR-signaling-responsive nanoparticledrugdelivery.Nat.Biotechnol.36,707–716(2018))),上述内容也包含在本文所述的增强抗肿瘤免疫中。
除了具体描述的内容外,文中所述的本发明可进行变化和修改。应当理解,本发明包括所有不背离其精神或基本特征的此类变化和修改。本发明还包括在本说明书中单独或共同提及或指出的所有步骤、特征、组合物和化合物,以及所述步骤或特征的任何和所有组合或任何两个或更多个所述步骤或特征。因此,在所有方面,本公开应被认为是说明性的而非限制性的,本发明的范围由所附权利要求书指明,并且在等效的含义和范围内的所有变化均旨在包含在其中。在本说明书中引用了多篇参考文献,其中每篇参考文献均通过引用整体纳入本文。参考以下实施例将更充分地理解前述描述。
实施例
靶向HER2的IL-10CAR T细胞
我们首先研究了异位IL-10表达的CAR T是否调节代谢适能并提高其抗肿瘤活性。通过将HER2 CAR和有2A自剪切肽的IL-10基因片段融合到逆转录病毒载体pMSGV中,生成IL-10HER2 CAR构建体(图1a)。IL-10HER2 CAR T中的HER2 CAR的细胞表面表达与传统HER2CAR T细胞中的细胞表面表达几乎相当(图1b)。通过ELISA测量IL-10HER2 CAR产生的IL-10水平(图1c)。由于已知IL-10在抗原刺激下促进CD8 T细胞的增殖(Guo,Y.et al.Metabolicreprogramming of terminally exhausted CD8+T cells by IL-10enhances anti-tumorimmunity.Nat.Immunol.22,746–756(2021)),我们研究了CAR T细胞在接受抗原刺激时的绝对计数和细胞分裂数。当与丝裂霉素处理的MC38-HER2小鼠结肠癌细胞共培养时,IL-10HER2 CAR T细胞的计数和细胞分裂显著高于HER2 CAR T细胞(图1d、图e)。抗IL-10抗体充分减弱了IL-10HER2 CAR T细胞的增强分裂(图1e),表明IL-10对IL-10HER2 CAR T细胞增殖改善至关重要。在MC38-HER2细胞共培养系统中,与HER2 CAR T细胞相比,IL-10HER2CAR T细胞的基础耗氧率(OCR)升高,而细胞外酸化率(ECAR)保持不变(图1f-图1i)。另一方面,IL-10HER2 CAR T细胞在mIL-10的存在下显示出与HER2 CAR T相当的基础OCR。在mIL-10的存在下的HER2 CAR T和IL-10HER2 CAR T的OCR与EACR之比均显著增加(图1j),表面IL-10信号传导积极促进CAR T细胞的氧化磷酸化(OXPHOS)。由于代谢重编程,IL-10HER2CAR T的肿瘤消除潜能极大增强(图2a),同时,在模拟体内情况的共培养环境(E:T比为0.5:1,共培养48h)中,IL-10HER2 CAR T组的CAR T细胞的抗原特异性增殖能力、杀伤效率和多功能性极大增强(图2b-图2d)。
这些数据证实本发明的IL-10CAR T能够通过增加OXPHOS对CAR T细胞代谢进行重编程以促进细胞增殖,这表明本发明的IL-10CAR T也可以通过代谢干预促进肿瘤浸润CART细胞在TME中的增殖。
通过多种试剂增强CD8+T细胞中的OXPHOS或抑制CD8+T细胞中的糖酵解代谢促进TME中CD8+T细胞增殖、记忆发育和抗肿瘤功能(Sukumar,M.et al.Inhibiting glycolyticmetabolism enhances CD8+T cell memory and antitumorfunction.J.Clin.Invest.123,4479–4488(2013))。基于观察到IL-10HER2 CAR T细胞代谢调控功能,我们接下来研究了是否可以实现对CAR T细胞的体内代谢干预以增强针对实体肿瘤的疗效。
在预先建立的MC38-HER2肿瘤的治疗环境中,IL-10HER2 CAR T细胞(3×106)的过继性转移单药治疗与淋巴细胞清除预处理(4Gy)在80%的接受治疗的小鼠中持续诱导肿瘤完全消退以及持久治愈(图3a-图3b)。相比之下,HER2 CAR T单药治疗对肿瘤生长抑制作用极小。HER2 CAR T过继性转移与静脉施用mIL-10仅能短暂控制肿瘤生长,但不能诱导肿瘤消退。此外,所有接受IL-10HER2 CAR T细胞治疗的长期存活者在停止治疗后2个月都抵抗住了MC38-HER2细胞的再攻击,这表明诱导了抗肿瘤免疫记忆(图3c)。
靶向TRP-1的IL-10CAR T细胞
为了测试IL-10CAR T细胞疗法的稳健性,我们接下来评估了免疫原性差且侵袭性高的小鼠B16F10黑色素瘤模型是否也可被控制。我们接下来生成了靶向TRP-1的IL-10CART细胞,并通过流式细胞术证实了CAR的表达(图4a、图4b)。IL-10TRP-1 CAR T细胞的体外细胞增殖和抗肿瘤活性优于传统TRP-1 CAR T细胞(图4c、图4d)。携带B16F10小鼠黑色素瘤的小鼠在进行CAR T细胞转移前通过辐照(4Gy)清除淋巴细胞。在大多数荷瘤小鼠中,IL-10TRP-1 CAR T导致了显著的肿瘤消退并最终消除,而TRP-1 CAR T仅显示短暂的肿瘤生长抑制,没有持久的治疗效果(图4e)。此外,60%接受IL-10TRP-1 CAR T治疗的小鼠长期存活(图4f)。
靶向EGFRvIII的IL-10CAR T细胞
接下来,我们进一步将IL-10CAR T干预扩展到高侵袭性和转移性的4T1-Luc-EGFRvIII(用EGFRvIII和荧光素酶(Luc)稳定转染)小鼠乳腺癌模型。我们制备了靶向EGFRvIII的IL-10CAR T细胞。通过流式细胞术和ELISA分别证实了CAR的表达和IL-10的产生(图5a-图5c)。与EGFRvIIICAR T细胞相比,IL-10EGFRvIIICAR T细胞的体外细胞扩增和抗肿瘤活性显著提高(图5d、图5e)。给BALB/c小鼠静脉注射4T1-Luc-EGFRvIII肿瘤细胞(5×104)以发展肺转移。向小鼠转移EGFRvIIICAR T细胞(3×106)并且施用mIL-10或不施用mIL-10可导致短暂的肿瘤抑制(图5f)。值得注意的是,IL-10EGFRvIII CAR T细胞完全根除了肿瘤,并在100%接受治疗小鼠中导致持久治愈(图5g)。与强大的抗肿瘤疗效一致,IL-10EGFRvIII CAR T细胞在循环中诱导了显著高密度的CAR T细胞(图5h)。
这些结果表明IL-10HER2 CAR T表现出体内扩增提高、功能增强,最终促成了表达IL-10的CAR T细胞的更优疗效。
IL-10TCR T(Pmel)细胞
为了进一步将表达IL-10的T细胞策略扩展到针对高侵袭性的B16F10小鼠黑色素瘤模型的肿瘤特异性T细胞受体(TCR)转基因T细胞(TCR T),我们制备了与前文描述相似的表达IL-10的Pmel T细胞(IL-10Pmel T),并通过ELISA证实了IL-10的表达(图6a)。携带B16F10小鼠黑色素瘤的小鼠接受PBS对照、Pmel T或IL-10Pmel T细胞的过继性转移。IL-10Pmel T细胞在大多数荷瘤小鼠中导致显著的肿瘤消退,而Pmel T细胞仅表现出适度的肿瘤生长抑制(图6b-图6e)。此外,与用Pmel T细胞治疗的小鼠相比,用表达IL-10的Pmel T细胞治疗的小鼠的存活率提高(图6f)。相似地,该表达IL-10的TCR T细胞策略也可以用于增强TIL过继性转移疗法对实体肿瘤的疗效。
靶向CD19的人IL-10CAR T细胞
最后,我们将该表达IL-10的CAR T策略扩展到人CAR T。通过将CD19 CAR和有2A自剪切肽的人IL-10基因片段融合到慢病毒载体中,生成IL-10CD19 CAR构建体(图7a)。IL-10CD19 CAR T中CD19 CAR的细胞表面表达略高于传统CD19 CAR T细胞(图7b)。通过ELISA检测IL-10CD19 CAR产生的IL-10水平(图7c)。相应地,IL-10CD19 CAR T的肿瘤消除潜能也得到增强(图7d),这与我们在小鼠CAR T中观察到的结果一致。此外,在携带已建立的PANC1-CD19人胰腺肿瘤的免疫缺陷NSG小鼠中,所有用表达IL-10的CD19 hCAR T细胞治疗的小鼠均表现出完全缓解,且无复发(图7e),这表明表达IL-10的人CAR T细胞在异种移植模型中对实体肿瘤具有更强的抗肿瘤能力。
表达IL-10的CAR-T细胞可维持线粒体适能
线粒体适能受损已被证明会加剧T细胞耗竭。有趣的是,我们发现IL-10表达维持了肿瘤浸润CAR-T细胞中的线粒体适能,与单独的HER2 CAR-T细胞(27.4%)或HER2 CAR-T细胞结合外源性IL-10(21.7%)相比,IL-10HER2 CAR-T细胞中功能失调的线粒体的频率大幅降低(4.8%)(图8a)。IL-10表达也增加了IL-10HER2 CAR-T细胞中的MDR与MG的比(图8b)。线粒体超微结构的EM成像分析提供了另外的证据:与传统HER2 CAR-T细胞相比,肿瘤浸润的IL-10HER2CAR-T细胞中具有丰富的管状线粒体、每个线粒体中嵴结构良好、嵴数量增加、嵴长度增加(图8c-图8f)。
CAR-T细胞中的IL-10表达诱导持久的抗肿瘤免疫并促进干性
为了研究表达IL-10的CAR-T细胞是否产生了抗肿瘤免疫记忆,我们在过继性CAR-T细胞转移后3个月对存活小鼠进行再攻击。令人印象深刻的是,100%接受IL-10HER2 CAR-T或IL-10TRP-1CAR-T细胞治疗的长期存活小鼠都抵抗住了原肿瘤细胞的第二次攻击(图9a-图9c)。强大的免疫记忆反应促使我们检测淋巴组织和循环中表达IL-10的CAR-T细胞的记忆表型。治疗后12天CAR-T细胞(最初转移的CAR-T细胞均为CD44hi)的流式细胞术分析显示,IL-10HER2 CAR T细胞在脾脏和外周血中富集的群体具有Tscm表型(由CD62LhiCD44lo和干细胞抗原-1(Sca-1)+CD122+定义)(图10a和图10b)。与单独HER2 CAR-T细胞相比,脾脏中的IL-10HER2 CAR-T细胞的CD62LhiCD44loT细胞频率为约3.2倍,其中大多数(约71.2%)是Sca-1+CD122+Tscm(图10a和图10b)。此外,与单独HER2 CAR-T细胞或加入外源性IL-10的HER2 CAR-T细胞相比,IL-10HER2 CAR-T细胞的Sca-1表达大幅增加(图10c)。通过观察到脾脏和血液中的IL-10HER2 CAR T细胞的IL-7Rα+KLRG1-长寿命记忆前体T细胞的比例分别为HER2 CAR-T细胞的约3.7倍和约2.6倍,进一步证实了该发现(图10d和图10e)。此外,我们观察到与CD19 hCAR-T细胞相比,IL-10CD19hCAR-T细胞的治疗出现了Tscm富集。总之,这些结果表明IL-10信号可诱导小鼠Tscm CAR-T细胞和人Tscm CAR-T细胞的形成,从而有助于长期抗肿瘤免疫。
序列
SEQ ID NO:1–人IL-10
氨基酸序列
SEQ ID NO:2-HER2 scFv
氨基酸序列
SEQ
ID
NO:3–TRP-1
scFv
氨基酸序列
SEQ
ID
NO:4-EGFRvIII
scFv
氨基酸序列
SEQ ID NO:5-CD19 scFv
氨基酸序列
SEQ
ID
NO:6-CD8跨膜结构域和铰链
氨基酸序列
SEQ ID NO:7-CD3ζ
氨基酸序列
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Claims (31)
1.一种表达白细胞介素-10、其片段或变体的免疫细胞,所述免疫细胞包含一种或多种重组构建体,其中至少一种重组构建体编码白细胞介素-10、其片段或变体。
2.权利要求1的免疫细胞,其中第二重组构建体编码嵌合抗原受体(CAR)、T细胞受体(TCR)或任何其他合成的肿瘤靶向基序。
3.权利要求1或2的免疫细胞,其中所述免疫细胞是T细胞、嵌合抗原受体(CAR)-T细胞、T细胞受体(TCR)-转基因T
细胞、肿瘤浸润淋巴细胞(TIL)、NK细胞、NK-T细胞、CAR-NK细胞、CAR-NKT细胞、TCR-转基因NK细胞、TCR-转基因NK-T细胞、树突状细胞、巨噬细胞、CAR-巨噬细胞或任何合成的肿瘤特异性免疫细胞。
4.前述权利要求中任一项的免疫细胞,其中所述编码白细胞介素-10、其片段或变体的构建体包含SEQ ID No.1、或其片段或变体的序列,或编码SEQ ID No.1、或其片段或变体的序列。
5.前述权利要求中任一项的免疫细胞,其中所述编码白细胞介素-10、其片段或变体的重组构建体与所述编码CAR、TCR或任何其他合成的肿瘤靶向基序的第二重组构建体相连接。
6.权利要求5的免疫细胞,其中所述编码白细胞介素-10、其片段或变体的重组构建体通过编码自剪切肽(例如2A肽)的序列与所述编码CAR、TCR或任何其他合成的肿瘤靶向基序的第二重组构建体相连接。
7.权利要求5或6的免疫细胞,其中所述编码CAR的第二重组构建体包含源自抗体的单链可变区片段(scFv)的胞外抗原识别结构域。
8.权利要求5至7中任一项的免疫细胞,其中所述编码CAR的第二重组构建体包含编码跨膜区的多肽的核酸。
9.权利要求5至8中任一项的免疫细胞,其中所述编码CAR的第二重组构建体包含编码CD3ζ胞内T细胞活化结构域的多肽的核酸。
10.权利要求5至9中任一项的免疫细胞,其中所述编码CAR的第二重组构建体包含4-1BB胞内区或CD28胞内区或4-1BB胞内区和CD28胞内区的组合。
11.权利要求5至10中任一项的免疫细胞,其中
i)所述源自抗体的单链可变区片段(scFv)的胞外抗原识别结构域识别选自以下的抗原:c-MET、CD7、CD19、CD20、CD22、CD38、CD123、CD133、CD171、CD70、BCMA、CEA、EGFR-VIII、EpCAM、EphA2、FAP、GD2、GPC3、HER2、IL-13Ra2、间皮素、MUC1、PSCA、PSMA、ROR1、VEGFR2、紧密连接蛋白18.2,或
ii)所述TCR识别选自以下的抗原:gp100、NY-ESO-1、
MAGE-A3和TRP-1、或它们的一种或多种的组合。
12.前述权利要求中任一项的免疫细胞,其中所述白细胞介素-10、其片段或变体优选在肿瘤微环境中由所述免疫细胞分泌或膜结合。
13.权利要求中任一项的免疫细胞,其中所述编码白细胞介素-10、其片段或变体的构建体包含在编码Fc、HSA或抗体融合蛋白的序列内;或不包含在编码Fc、HSA或抗体融合蛋白的序列内。
14.前述权利要求中任一项的免疫细胞,其用于预防和/或治疗癌症,其中所述癌症是实体癌症或液体癌症。
15.权利要求14的免疫细胞,其中所述实体癌症选自:肺癌、乳腺癌、卵巢癌、宫颈癌、子宫癌、头颈癌、胶质母细胞瘤、肝细胞癌、结肠癌、直肠癌、结直肠癌、肾癌、前列腺癌、胃癌、支气管癌、胰腺癌、膀胱癌、肝癌、脑癌和皮肤癌、特别是黑色素瘤、或它们的一种或多种的组合。
16.前述权利要求中任一项的免疫细胞,其中所述免疫细胞是自体的、同种异体的或异源的。
17.权利要求7或11的免疫细胞,其中所述源自抗体的单链可变区片段(scFv)的胞外抗原识别结构域识别选自HER2、TRP-1、EGFRvIII和CD19的抗原。
18.权利要求17的免疫细胞,其中所述识别HER2的scFv的氨基酸序列如SEQ ID NO:2、其片段或变体所示。
19.权利要求17的免疫细胞,其中所述识别TRP-1的scFv的氨基酸序列如SEQ ID NO:3、其片段或变体所示。
20.权利要求17的免疫细胞,其中所述识别EGFRvIII的scFv的氨基酸序列如SEQ IDNO:4、其片段或变体所示。
21.权利要求17的免疫细胞,其中所述识别CD19的scFv的氨基酸序列如SEQ ID NO:5、其片段或变体所示。
22.权利要求8至21中任一项的免疫细胞,其中CD8跨膜结构域和铰链的多肽的氨基酸序列如SEQ ID NO:6、其片段或变体所示。
23.权利要求9至22中任一项的免疫细胞,其中所述CD3ζ胞内T细胞活化结构域的多肽的氨基酸序列如SEQ ID NO:7、其片段或变体所示。
24.一种药物组合物,其包含治疗有效量的i)权利要求1至23所述的免疫细胞、ii)编码权利要求1至23中任一项所述的一种或多种重组构建体的核酸和/或iii)包含编码权利要求1至23中任一项所述的一种或多种重组构建体的核酸序列的质粒或载体;以及至少一种药学上可接受的载体和/或稀释剂。
25.权利要求24的药物组合物,其还包含至少一种另外的治疗剂或治疗。
26.权利要求25的药物组合物,其中所述至少一种另外的治疗剂或治疗是用于治疗癌症优选实体癌症的抗癌剂或抗癌治疗、和/或抗炎剂。
27.权利要求26的药物组合物,其中所述抗癌治疗选自:放射治疗、化学治疗、免疫检查点抑制剂、免疫治疗和激素治疗、或它们的一种或多种的组合。
28.权利要求27的药物组合物,其中所述免疫检查点抑制剂选自:PD-1抑制剂、PD-L1抑制剂和CTLA-4抑制剂或它们的一种或多种的组合。
29.一种治疗和/或预防受试者癌症的方法,其包括施用权利要求24至28中任一项所述的药物组合物。
30.一种治疗和/或预防受试者癌症的方法,其包括(i)从所述受试者中移除且分离免疫细胞,优选初始T细胞,或提供免疫细胞,优选初始T细胞;(ii)用至少一种编码白细胞介素-10、其片段或变体的重组构建体和编码嵌合抗原受体(CAR)、T细胞受体(TCR)或任何其他合成的肿瘤靶向基序或抗原的第二重组构建体对所述T细胞进行基因工程化;(iii)离体扩增成更大的工程化T细胞群;和(iv)重引入患者或受试者中。
31.一种增强受试者抗肿瘤活性的方法,其包括(i)从所述受试者中移除且分离免疫细胞,优选初始T细胞,或提供免疫细胞,优选初始T细胞;(ii)用至少一种编码白细胞介素-10、其片段或变体的重组构建体和编码嵌合抗原受体(CAR)、T细胞受体(TCR)或任何其他合成的肿瘤靶向基序或抗原的第二重组构建体对所述T细胞进行基因工程化;(iii)离体扩增成更大的工程化T细胞群;和(iv)重引入患者或受试者中。
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US5827642A (en) | 1994-08-31 | 1998-10-27 | Fred Hutchinson Cancer Research Center | Rapid expansion method ("REM") for in vitro propagation of T lymphocytes |
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US6867041B2 (en) | 2000-02-24 | 2005-03-15 | Xcyte Therapies, Inc. | Simultaneous stimulation and concentration of cells |
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