CN115175686A - 用于增强嵌合t细胞持久性的akt抑制剂 - Google Patents
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Abstract
CAR‑T细胞的过继性细胞转移的复发通常是CAR‑T细胞消失的结果。本文公开了一种用于增强受试者的CAR‑T细胞疗法的方法,所述方法包括向正在经受治疗性CAR‑T细胞的过继性细胞转移的受试者施用有效量的Akt抑制剂以增加所述CAR‑T细胞的持久性。因此,用CAR‑T细胞和Akt抑制剂的组合治疗的受试者不太可能复发。因此,本文还公开了一种用于治疗受试者的方法,所述方法包括:将有效量的包括CAR‑T细胞的组合物过继转移到所述受试者;以及向所述受试者施用有效量的Akt抑制剂以增加所述CAR‑T细胞的持久性。
Description
相关申请的交叉引用
本申请要求于2019年11月18日提交的美国临时申请第62/937,028号、于2019年11月19日提交的美国临时申请第62/937,359号、于2019年12月2日提交的美国临时申请第62/942,662号、于2019年12月5日提交的美国临时申请第62/944,295号和于2020年2月27日提交的美国临时申请第62/982,480号的权益,所述美国临时申请特此以全文引用的方式并入本文。
背景技术
嵌合抗原受体(CAR)T细胞的持久性和效应子功能不足一直是过继性T细胞疗法的具挑战性的问题。CAR-T细胞的过继性细胞转移的复发通常是CAR-T细胞消失的结果。
发明内容
本文公开了一种用于增强受试者的CAR-T细胞疗法的方法,所述方法包括向正在经受治疗性CAR-T细胞的过继性细胞转移的受试者施用有效量的Akt抑制剂以增加所述CAR-T细胞的持久性。因此,用CAR-T细胞和Akt抑制剂的组合治疗的受试者不太可能复发。因此,本文还公开了一种用于治疗受试者的方法,所述方法包括:将有效量的包括CAR-T细胞的组合物过继转移到所述受试者;以及向所述受试者施用有效量的Akt抑制剂以增加所述CAR-T细胞的持久性。
在一些实施例中,所述Akt抑制剂是靶向蛋白激酶B(Akt)的ATP结合袋的正构抑制剂。实例包含异喹啉-5-磺酰胺(例如,H-8、H-89、NL-71-101);氮杂环庚烷衍生物(例如,衍生自(-)-巴拉诺尔(balanol)的一系列结构);氨基呋喃(例如,GSK690693);杂环(例如7-氮杂吲哚、6-苯基嘌呤衍生物、吡咯并[2,3-d]嘧啶衍生物、CCT128930、3-氨基吡咯烷、苯胺基三唑衍生物、螺二氢吲哚衍生物、AZD5363、帕塔色替(ipatasertib)(GDC-0068、RG7440、A-674563、A-443654);苯基吡唑衍生物(例如,AT7867、AT13148);噻吩甲酰胺衍生物(例如,阿氟色替(Afuresertib)(GSK2110183)、2-嘧啶基-5-氨基噻吩衍生物(DC120)、优泼色替(uprosertib)(GSK2141795)。
在一些实施例中,所述Akt抑制剂是变构抑制剂,所述变构抑制剂可能优于正构抑制剂,从而提供更高的特异性、降低的副作用以及更小毒性。实例包含类似物(例如,MK-2206);烷基磷脂(例如,依地福新(Edelfosine)(1-O-十八烷基-2-O-甲基-rac-丙三基-3-磷酸胆碱,ET-18-OCH3)、伊莫福新(ilmofosine)(BM 41.440)、米替福新(miltefosine)(十六烷基磷酸胆碱,HePC)、哌立福新(perifosine)(D-21266)、芥酸磷酸胆碱(ErPC)、艾路福新(erufosine)(ErPC3和芥酸磷酸高胆碱);吲哚-3-甲醇类似物(例如,吲哚-3-甲醇、3-氯乙酰吲哚、二吲哚甲烷、6-甲氧基-5,7-二氢吲哚并[2,3-b]咔唑-2,10-二甲酸二乙酯(SR13668)和OSU-A9);磺酰胺衍生物(例如,PH-316、PHT-427);硫脲衍生物(例如,PIT-1、PIT-2、DM-PIT-1、N-[(1-甲基-1H-吡唑-4-基)羰基]-N'-(3-溴苯基)-硫脲);嘌呤衍生物(例如,曲西立滨(Triciribine)(TCN,NSC 154020)、曲西立宾单磷酸活性类似物(TCN-P)、4-氨基-吡啶并[2,3-d]嘧啶衍生物API-1、3-苯基-3H-咪唑[4,5-b]吡啶衍生物、ARQ 092);以及其它结构、衍生物(例如,BAY 1125976、3-甲基-黄嘌呤、喹啉-4-甲酰胺和2-[4-(环己-1,3-二烯-1-基)-1H-吡唑-3-基]苯酚、3-氧代-蒂鲁卡酸(3-oxo-tirucallic acid)、3α乙酰氧基蒂鲁卡酸(3αacetoxytirucallic acid)和3β乙酰氧基蒂鲁卡酸(3βacetoxytirucallic acid)以及乙酰氧基蒂鲁卡酸(acetoxytirucallic acid))。
在一些实施例中,所述Akt抑制剂是不可逆抑制剂,如天然产物、抗生素、乳醌霉素(Lactoquinomycin)、富伦菌素B(Frenolicin B)、卡拉芬净(kalafungin)、曼得尔霉素(medermycin)、Boc-Phe-乙烯基酮、4-羟基壬烯醛(4-HNE)、1,6-萘啶酮衍生物和咪唑-1,2-吡啶衍生物。
在特定实施例中,所述Akt抑制剂是嘌呤衍生物,如曲西立滨(TCN、NSC154020)。
在以下的附图和说明中阐述了本发明的一个或多个实施例的细节。根据说明书和附图并且根据权利要求,本发明的其它特征、目的和优点将显而易见。
附图说明
图1A到1G示出TCN增加了中央记忆CAR T细胞群。使用负选择从健康供体PBMC中分离T细胞。在第一旋转转导前第2天添加TCN。在第7天,细胞被染色以用于流式细胞术并在LSRII上运行。
图2A和2B示出了TCN抑制m1928z CAR T细胞中的p-Akt。使用负选择从C57BL6脾细胞中分离T细胞。在第一旋转转导前第2天添加TCN。在第5天,用3T3-mCD19靶标刺激CAR T细胞持续24小时。刺激后,细胞被裂解并通过蛋白质印迹运行。
图3A到3N示出了TCN减少h19BBz CAR杀伤和细胞因子分泌。使用负选择从健康供体PBMC中分离T细胞。在第一旋转转导前第2天添加TCN。为了测量实时细胞杀伤,使用xCelligence RTCA机器,用3T3-hCD19靶细胞刺激CAR T细胞。为了测量细胞因子分泌,用靶细胞刺激CAR T细胞持续24小时。然后收集上清液并使用Ella运行以测量细胞因子。
图4示出了TCN增加效应子记忆CAR T细胞群。使用负选择从健康供体PBMC中分离T细胞。在第一旋转转导前第2天添加TCN。在第7天,细胞被染色以用于流式细胞术并在LSRII上运行。
图5展示了m19dz、m19z、m19hBBZ和m1928z构建。
图6展示了h19BBZ和h1928z构建体。
具体实施方式
在更详细地描述本公开之前,应理解的是,本公开不限于所描述的具体实施例,并且因此当然可以变化。还应当理解,本文所使用的术语仅仅是出于描述具体实施例的目的,并且不旨在是限制性的,因为本公开的范围将仅由所附权利要求限定。
在提供了值范围的情况下,应当理解的是,介于所述范围的上限与下限之间的每个中间值(到下限的单位的十分之一,除非另外明确说明)以及所述范围中的任何其它所陈述或中间值均涵盖于本公开内。这些较小范围的上限和下限可以独立地包含在更小的范围中,并且也涵盖在本公开内,这受制于所陈述的范围中的任何明确排除的限值。在所陈述的范围包含限值中的一个或两个限值的情况下,排除被包含在内的限值中的任一个或两个限值的范围也包含在本公开内。
除非另外定义,否则本文所使用的所有技术术语和科学术语均具有与本公开所属领域的普通技术人员通常所理解的含义相同的含义。虽然与本文所描述的那些方法和材料类似或等同的任何方法和材料也可以用于本公开的实践和测试中,但是现在描述优选的方法和材料。
在本说明书中引用的所有出版物和专利均通过引用并入本文,就好像每个单独的出版物或专利被确切且单独地指示为通过引用并入一样,并且通过引用并入本文以结合所引用的出版物来公开和描述所述方法和/或材料。对任何出版物的引用是针对其在提交日之前的公开内容,并且不应被解释为承认本公开因先前的公开而无权先于此类出版物。进一步地,所提供的公开日期可能与实际的公开日期不同,实际的公开日期可能需要单独确认。
如对于本领域技术人员将显而易见的是,在阅读本公开时,本文描述和展示的单独实施例中的每一个均具有离散的组成部分和特征,所述组成部分和特征可以在不偏离本公开的范围或精神的情况下易于与任何其它一些实施例的特征分离或组合。任何所叙述的方法都可以按所叙述的事件顺序或逻辑上可能的任何其它顺序进行。
除非另外指示,否则本公开的实施例将采用在本领域技术范围内的化学、生物学等技术。
提出以下实例以便向本领域的普通技术人员提供如何进行本文公开和要求保护的方法和使用探针的完整公开内容和描述。已经做出努力来确保关于数字(例如,量、温度等)的准确性,但应考虑到一些误差和偏差。除非另外指明,否则份数为重量份,温度以℃为单位,并且压力为大气压或接近大气压。标准温度和压力被定义为20℃和1个大气压。
在详细描述本公开的实施例之前,应理解,除非另外指明,否则本公开不限于特定材料、试剂、反应材料、制造工艺等,因为这些可以改变。还应该理解,本文所使用的术语仅出于描述特定实施例的目的,并且不旨在是限制性的。在本公开中,在逻辑上可能的情况下,还可以以不同顺序执行步骤。
必须注意,如在说明书和所附权利要求中所使用,单数形式“一个/一种(a/an)”和“所述(the)”包含复数指示物,除非上下文另外清楚地指示。
术语“氨基酸序列”是指表示氨基酸残基的缩写、字母、字符或词语的列表。本文使用的氨基酸缩写是氨基酸的常规单字母代码并且表示如下: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,谷氨酸盐、谷氨酸;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,甲硫氨酸;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、其维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在很大程度上同源的结合结构域的蛋白质。这些蛋白质可以源自天然来源,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,包含任何人类别:IgG、IgM、IgA、IgD和IgE。在示例性实施例中,与本文所描述的方法和组合物一起使用的抗体是IgG类的衍生物。除了完整的免疫球蛋白分子之外,术语“抗体”中还包含那些免疫球蛋白分子的片段或聚合物以及选择性与靶抗原结合的人或人源化免疫球蛋白分子版本。
术语“抗体片段”或是指长度小于全长的抗体的任何衍生物。在示例性实施例中,抗体片段至少保留全长抗体特异性结合能力的重要部分。抗体片段的实例包含但不限于Fab、Fab'、F(ab')2、scFv、Fv、dsFv双功能抗体、Fc和Fd片段。抗体片段可以通过任何方式产生。例如,抗体片段可以通过完整抗体的片段化酶促地或化学地产生,抗体片段可以由编码部分抗体序列的基因重组地产生,或者抗体片段可以完全或部分合成产生。抗体片段可以任选地为单链抗体片段。可替代地,片段可以包括通过例如二硫键连接在一起的多条链。片段也可以任选地是多分子复合物。功能性抗体片段通常将包括至少约50个氨基酸,并且更通常将包括至少约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“适体”是指与特异性靶分子结合的寡核酸或肽分子。这些分子通常选自随机序列池。所选择的适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。“核酸适体”是DNA或RNA寡核酸,所述寡核酸通过其构象与靶分子结合,并且由此抑制(inhibit)或抑制(suppress)此类分子的功能。核酸适体可以由DNA、RNA或其组合构成。“肽适体”是一种组合蛋白分子,所述组合蛋白分子具有插入在恒定支架蛋白中的可变肽序列。肽适体的鉴定通常在严格的酵母双杂交条件下进行,这增强了所选择的肽适体在细胞内背景下稳定表达和正确折叠的可能性。
术语“载体”意指当与化合物或组合物组合时,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达到其预期用途或目的的化合物、组合物、物质或结构。例如,可以选择载体以使活性成分的任何降解最小化并且使受试者的任何不良副作用最小化。
术语“嵌合分子”是指通过连接以其天然状态分开存在的两个或更多个分子而产生的单个分子。单个嵌合分子具有其所有组成分子的期望的功能。一种类型的嵌合分子是融合蛋白。
术语“工程化的抗体”是指重组分子,所述重组分子至少包括抗体片段(所述抗体片段包括源自抗体的重链和/或轻链的可变结构域的抗原结合位点),并且可以任选地包括来自Ig类别(例如,IgA、IgD、IgE、IgG、IgM和IgY)中的任一种的抗体的可变结构域和/或恒定结构域的全部或一部分。
术语“表位”是指抗体优先并且特异性结合的抗原区。单克隆抗体优先与分子地定义的分子的单个特异性表位结合。在本发明中,可以由多特异性抗体识别多个表位。
术语“融合蛋白”是指通过将两个或更多个多肽通过在一个多肽的氨基端与另一个多肽的羧基端之间形成的肽键进行连接而形成的多肽。融合蛋白可以通过构成的多肽的化学偶联形成,或者可以从对单个连续融合蛋白进行编码的核酸序列表达为单个多肽。单链融合蛋白是具有单个连续多肽主链的融合蛋白。可以使用分子生物学中的常规技术来制备融合蛋白,以将使用相同读框的这两个基因连接成单个核酸,并且然后在产生融合蛋白的条件下在适合的宿主细胞中表达核酸。
术语“Fab片段”是指包括通过用木瓜蛋白酶切割抗体产生的抗原结合位点的抗体片段,所述木瓜蛋白酶在铰链区N-末端切割H链间二硫键并且从一个抗体分子产生两个Fab片段。
术语“F(ab')2片段”是指含有通过用胃蛋白酶切割抗体分子产生的两个抗原结合位点的抗体片段,所述胃蛋白酶在铰链区C-末端切割H链间二硫键。
术语“Fc片段”是指包括其重链的恒定结构域的抗体片段。
术语“Fv片段”是指包括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,如载体、质粒、病毒基因组等,所述核酸包含多肽的“编码序列”或以其它方式可转录为生物活性RNA(例如,反义、诱饵、核酶等),可以转染到细胞中,例如在某些实施例中转染到哺乳动物细胞中,并且可以使编码序列在用构建体转染的细胞中表达。基因构建体可以包含可操作地连接到编码序列以及内含子序列、聚腺苷酸化位点、复制起点、标记基因等的一个或多个调节性元件。
术语“同一性”是指两个核酸分子或多肽之间的序列同一性。可以通过比较可以出于比较目的比对的每个序列中的位置来确定同一性。当比较的序列中的位置被相同碱基占据时,那么这些分子在所述位置处是相同的。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享的位置处相同或匹配的核苷酸的数目的函数。可以使用不同比对算法和/或程序来计算两个序列之间的同一性,包含可用作GCG序列分析包(威斯康星州麦迪逊威斯康星大学(University of Wisconsin,Madison,Wis.))的一部分的FASTA或BLAST,并且可以与例如默认设置一起使用。例如,考虑了与本文所述的特异性多肽具有至少70%、85%、90%、95%、98%或99%同一性并且优选地表现出基本上相同的功能的多肽以及编码此类多肽的多核苷酸。除非另外指明,相似性评分将基于BLOSUM62的使用。当使用BLASTP时,相似性百分比基于BLASTP阳性评分,并且序列同一性百分比基于BLASTP同一性评分。BLASTP“同一性”示出了相同的高评分序列对中的总残基的数量和分数;并且BLASTP“阳性”示出了比对评分具有正值并且彼此相似的残基的数量和分数。本公开考虑并且涵盖了与本文公开的氨基酸序列具有这些程度的同一性或相似性或任何中间程度的同一性或相似性的氨基酸序列。使用遗传密码推导出相似多肽的多核苷酸序列,并且可以通过常规手段获得多核苷酸序列,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,并且是指连接两种化合物(如两个多肽)的分子或分子组。接头可以包含单个连接分子,或者可以包括连接分子和间隔子分子,所述间隔子分子旨在将连接分子和化合物分离特定距离。
术语“多价抗体”是指包括多于一个抗原识别位点的抗体或工程化的抗体。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”等是指多价抗体中存在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全部与相同表位结合。“双特异性”抗体具有与第一表位结合的至少一个抗原识别位点和与不同于第一表位的第二表位结合的至少一个抗原识别位点。“多价单特异性”抗体具有全部与相同表位结合的多个抗原识别位点。“多价双特异性”抗体具有多个抗原识别位点,其中的一些与第一表位结合并且其中的一些与不同于第一表位的第二表位结合。
术语“核酸”是指包括单个核苷酸或两个或更多个核苷酸的天然或合成分子,所述两个或更多个核苷酸通过在一个核苷酸的3'位置处的磷酸基团连接到另一个核苷酸的5'末端。核酸的长度并没有限制,并且因此核酸可以包含脱氧核糖核酸(DNA)或核糖核酸(RNA)。
术语“与……可操作地连接”是指核酸与另一个核酸序列的功能性关系。启动子、增强子、转录和翻译终止位点以及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与启动子之间的物理关系和功能性关系,使得通过特异性识别DNA、与DNA结合并且转录DNA的RNA聚合酶从启动子启动此类DNA的转录。
术语“肽”、“蛋白质”和“多肽”可互换使用以指代包括两个或更多个氨基酸的天然或合成的分子,所述两个或更多个氨基酸通过一个氨基酸的羧基基团与另一个氨基酸的α氨基基团连接。
术语“药学上可接受的”是指在合理医学判断范围内适合于与人和动物的组织接触使用而不会产生过多毒性、刺激、过敏反应或其它问题或并发症的、与合理的益处/风险比相称的那些化合物、材料、组合物和/或剂型。
当关于具体多肽使用时,术语“多肽片段”或“片段”是指与参考氨基酸自身相比,其中缺失氨基酸残基、但其中剩余氨基酸序列通常与参考多肽的氨基酸序列相同的多肽。此类缺失可以发生在参考多肽的氨基末端或羧基末端处,或可替代地发生在以上二者处。片段通常为至少约5个、6个、8个或10个氨基酸长、至少约14个氨基酸长、至少约20个、30个、40个或50个氨基酸长、至少约75个氨基酸长或至少约100个、150个、200个、300个、500个或更多个氨基酸长。片段可以保留参考多肽的一种或多种生物活性。在各个实施例中,片段可以包括参考多肽的酶活性和/或相互作用位点。在另一个实施例中,片段可以具有免疫原性特性。
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示出结构整体性的整个蛋白质;这一测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”是指其中连接重链结构域和轻链结构域的Fv片段。可以将一个或多个scFv片段连接到其它抗体片段(如重链或轻链的恒定结构域)以形成具有一个或多个抗原识别位点的抗体构建体。
如本文所使用的,“间隔子”是指连接包括融合蛋白的蛋白质的肽。通常,除连接蛋白质或保持其之间的一些最小距离或其它空间关系以外,间隔子不具有特定的生物活性。然而,可以选择间隔子的组成氨基酸以影响分子的一些特性,如分子的折叠、净电荷或疏水性。
如本文所使用的,当参考多肽(包含抗体)或受体时,术语“特异性结合”是指在蛋白质的异质群体和其它生物制剂中决定蛋白质或多肽或受体的存在的结合反应。因此,在指定条件(例如,在抗体的情况下,免疫测定条件)下,当特定的配体或抗体不以显著量与样品中存在的其它蛋白质结合或不与生物体中配体或抗体可以接触的其它蛋白质结合时,所述特定的配体或抗体与其特定“靶标”“特异性结合”(例如,抗体与内皮抗原特异性结合)。通常,与第二分子“特异性结合”的第一分子的亲和力常数(Ka)比第二分子的Ka大约105M-1(例如,106M-1、107M-1、108M-1、109M-1、1010M-1、1011M-1、和1012M-1或更大)。
如本文所使用的,术语“特异性递送”是指分子与携带特定靶分子或标志物的细胞或组织优先缔合,并且不与缺乏所述靶分子的细胞或组织缔合。当然,已经认识到某种程度的非特异性相互作用可以发生在分子与非靶细胞或组织之间。尽管如此,特异性递送可以如通过靶分子的特异性识别介导的进行区分。通常,特异性递送使所递送的分子与携带靶分子的细胞之间的缔合比所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的靶标的任何个体。受试者可以是脊椎动物,例如,哺乳动物。因此,受试者可以是人或兽医患者。术语“患者”是指在临床医生,例如医师的治疗下的受试者。
术语“治疗有效的”是指所使用的组合物的量是足以改善疾病或病症的一种或多种病因或症状的量。此类改善仅需要减少或改变,并不需要消除。
术语“转化”和“转染”意指将核酸(例如,表达载体)引入到接受者细胞中,包含将核酸引入到所述细胞的染色体DNA。
术语“治疗”是指患者的医疗管理,旨在治愈、改善、稳定或预防疾病、病理病状或病症。此术语包含积极治疗,即特异性针对疾病、病理学病状或病症的改善的治疗,并且还包含病因治疗,即针对相关疾病、病理学病状或病症的病因的去除的治疗。另外,此术语包含姑息治疗,即设计用于减轻症状而不是治愈疾病、病理学病状或病症的治疗;预防治疗,即治疗针对将相关疾病、病理病状或病症的发展最小化或部分地或完全抑制其发展;以及支持性治疗,即用于对针对相关疾病、病理学病状或病症的改善的另一种特定疗法进行补充的治疗。
术语“变体”是指具有保守氨基酸取代、非保守氨基酸取代(即简并变体)、每个编码氨基酸的密码子(即DNA和RNA)的摆动位置内的取代的氨基酸或肽序列、添加到肽的C末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。
术语“载体”是指能够将载体序列已经连接到其上的另一种核酸转运到细胞中的核酸序列。术语“表达载体”包含含有呈适于由细胞表达的形式(例如,与转录控制元件连接)的基因构建体的任何载体(例如,质粒、粘粒或噬菌体染色体)。
CAR T细胞扩增
记忆T细胞是抗感染和抗癌T细胞(也称为T淋巴细胞)的子集,所述细胞以前遇到过并对其同源抗原做出应答;因此,经常使用抗原经历T细胞这一术语。
历史上,记忆T细胞被认为属于效应子或中央记忆亚型,每个亚型都有自己独特的一组细胞表面标志物。随后,发现了许多另外的记忆T细胞群。所有记忆T细胞亚型的单个统一主题是其寿命长,并且在重新暴露于其同源抗原后可以快速扩增为大量效应子T细胞。通过此机制,它们为免疫系统提供了针对先前遇到的病原体的“记忆”。记忆T细胞可以是CD4+或CD8+,并且通常表达CD45RO而缺乏CD45RA。
效应子记忆T细胞(TEM细胞)表达CD45RO,但缺乏C-C趋化因子受体7型(CCR7)和L选择素(CD62L)的表达。它们还具有CD44的中等高表达。这些记忆T细胞缺乏淋巴结归巢受体,并且因此存在于外周循环和组织中。
中央记忆T细胞(TCM细胞)表达CD45RO、CCR7和L选择素(CD62L)。中央记忆T细胞也具有CD44的中等到高表达。此记忆亚群通常存在于淋巴结和外周循环中。
可以在TCM子集和TEM子集两者中找到针对病毒或其它微生物分子的抗原特异性记忆T细胞。尽管目前大多数信息基于对细胞毒性T细胞(CD8阳性)子集的观察,但辅助T细胞(CD4阳性)和细胞毒性T细胞两者似乎都存在相似的群体。记忆细胞的主要功能是在通过将相关病原体重新引入到体内重新激活这些细胞后增强免疫应答。重要的是应注意,此领域正在深入研究,并且一些信息可能尚不可用。
CAR多肽
所公开的方法可以用于产生含有CAR多肽的嵌合抗原受体(CAR)T细胞。CAR多肽通常由三个结构域构成:胞外结构域、跨膜结构域和胞内结构域。胞外结构域负责抗原识别。其还任选地含有信号肽(SP),使得CAR可以被糖基化并且被锚定在免疫效应子细胞的细胞膜中。如跨膜结构域的名字所提示,当由细胞表达时,跨膜结构域(TD)将胞外结构域连接到胞内结构域并且驻留于细胞膜内。胞内结构域是CAR的起作用的一端,其在抗原识别后将激活信号传输到免疫效应子细胞。例如,胞内结构域可以含有细胞内信号传导结构域(ISD)以及任选地共刺激信号传导区(CSR)。CAR多肽通常并入来自单克隆抗体(mAb)的单链可变片段(scFv)的抗原识别结构域与淋巴细胞激活中涉及的跨膜信号传导基序(Sadelain M等人《癌症自然评论(Nat Rev Cancer)》2003 3:35-45)。
“信号传导结构域(SD)”通常含有基于免疫受体酪氨酸的活化基序(ITAM),当ITAM被磷酸化时,所述ITAM激活信号传导级联。术语“共刺激信号传导区(CSR)”是指能够通过T细胞受体增强T细胞激活的来自如CD28、41BB和ICOS等共刺激蛋白受体的细胞内信号传导结构域。
例如在Fresnak AD等人“工程化的T细胞:癌症免疫疗法的前景和挑战(Engineered T cells:the promise and challenges of cancer immunotherapy)”.《癌症自然评论》.2016年8月23日;16(9):566-81中描述了另外的CAR构建体,其出于教导这些CAR模型的目的以全文引用的方式并入。
例如,CAR可以是TRUCK、通用CAR、自驱动CAR、装甲的CAR、自毁CAR、条件CAR、标记的CAR、TenCAR、双重CAR或sCAR。
被工程化以抵抗免疫抑制的CAR T细胞(装甲的CAR)可以被遗传修饰以不再以免疫检查点开关受体表达不同免疫检查点分子(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)),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设计自毁CAR以编码CAR。可替代地,可以基于基因修饰的淋巴细胞中的与胸苷激酶结合的更昔洛韦(ganciclovir)或最近描述的通过小分子二聚化因子激活人胱天蛋白酶9的系统来实现T细胞的诱导型细胞凋亡。
条件CAR T细胞是默认无应答性的或“关闭”,直到添加小分子来完成回路,从而实现信号1和信号2两者的完全转导,由此激活CAR T细胞。可替代地,可以将T细胞工程化以表达对于随后施用的针对靶抗原的次级抗体具有亲和力的衔接子特异性受体。
串联CAR(TanCAR)T细胞表达由具有与细胞内共刺激结构域和CD3ζ结构域融合的不同亲和力的两个连接的单链可变片段(scFv)组成的单个CAR。仅当靶细胞共表达这两个靶标时才能实现TanCAR T细胞激活。
双重CAR T细胞表达具有不同配体结合靶标的两个分离的CAR;一个CAR仅包含CD3ζ结构域,并且另一个CAR仅包含共刺激结构域。双重CAR T细胞激活需要这两个靶标的共表达。
安全CAR(sCAR)由与细胞内抑制结构域融合的细胞外scFv组成。仅当遇到具有标准CAR靶标但缺乏sCAR靶标的靶细胞时,共表达标准CAR的sCAR T细胞才被激活。
所公开的CAR的抗原识别结构域通常是scFv。然而,存在很多替代方案。已经描述了来自天然T细胞受体(TCR)α和β单链的抗原识别结构域,它具有简单胞外结构域(例如,用于识别HIV感染的细胞的CD4胞外结构域)和更外来的识别组分(如连接的细胞因子,其导致识别携带细胞因子受体的细胞)。实际上,以高亲和力结合给定靶标的几乎任何事物都可以用作抗原识别区。
胞内结构域是CAR的起作用的一端,其在抗原识别后将信号传输到免疫效应子细胞,从而激活免疫效应子细胞的正常效应子功能中的至少一种。例如,T细胞的效应子功能可以是溶细胞活性或辅助活性,包含细胞因子的分泌。因此,胞内结构域可以包括T细胞受体(TCR)和任选的辅助受体的“细胞内信号传导结构域”。尽管通常可以采用整个细胞内信号传导结构域,但是在很多情况下,没有必要使用整个链。在使用细胞内信号传导结构域的截短部分的程度上,可以使用此类截短部分代替完整链,只要其转导效应子功能信号即可。
调节以共刺激方式发挥作用的TCR复合物的主要激活的胞质信号传导序列可以含有信号传导基序,所述信号传导基序被称为基于免疫受体酪氨酸的活化基序(ITAM)。含有胞质信号传导序列的ITAM的实例包含源自以下的那些:CD8、CD3ζ、CD3δ、CD3γ、CD3ε、CD32(FcγRIIa)、DAP10、DAP12、CD79a、CD79b、FcγRIγ、FcγRIIIγ、FcεRIβ(FCERIB)和FcεRIγ(FCERIG)。
在特定实施例中,细胞内信号传导结构域源自CD3ζ(TCRζ,GenBank登录号BAG36664.1)。T细胞表面糖蛋白CD3ζ链(也称为T细胞受体T3ζ链或CD247(分化簇247))是人体中由CD247基因编码的蛋白质。
第一代CAR通常具有来自作为内源性TCR信号的主要递质的CD3ζ链的胞内结构域。第二代CAR将来自不同共刺激蛋白受体(例如,CD28、41BB、ICOS)的细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。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。移植有这些CAR的T细胞已显示出独立于共刺激受体/配体相互作用的经改善的扩增、激活、持久性和肿瘤根除效率(Imai C等人《白血病(Leukemia)》200418:676-84;Maher J等人《自然生物技术(Nat Biotechnol)》2002 20:70-5)。
例如,可以将CAR的胞内结构域设计为包括单独的或与在本发明的CAR的上下文中有用的任何其它所希望的胞质结构域组合的CD3ζ信号传导结构域。例如,CAR的胞质结构域可以包括CD3ζ链部分和共刺激信号传导区。共刺激信号传导区是指CAR的一部分,其包括共刺激分子的胞内结构域。共刺激分子是除抗原受体或其配体以外的细胞表面分子,所述细胞表面分子是淋巴细胞对抗原的有效应答所必需的。此类分子的实例包含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CD123、CD8、CD4、b2c、CD80、CD86、DAP10、DAP12、MyD88、BTNL3和NKG2D特异性结合的配体。因此,尽管例证CAR主要具有CD28作为共刺激信号传导元件,但是其它共刺激元件可以单独使用或与其它共刺激信号传导元件组合使用。
在一些实施例中,CAR包括铰链序列。铰链序列是促进抗体灵活性的短氨基酸序列(参见例如Woof等人,《免疫学自然评论(Nat.Rev.Immunol.)》,4(2):89-99(2004))。铰链序列可以定位于抗原识别部分(例如,scFv)与跨膜结构域之间。铰链序列可以是源自或获得自任何合适的分子的任何合适的序列。在一些实施例中,例如,铰链序列源自CD8a分子或CD28分子。
跨膜结构域可以源自天然的或合成的来源。在来源是天然的情况下,所述结构域可以源自任何膜结合的蛋白或跨膜蛋白。例如,跨膜区可以源自(即至少包括以下的跨膜区):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(Tactile)、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。可替代地,跨膜结构域可以是合成的,在这种情况下,其将主要包括疏水残基,如亮氨酸和缬氨酸。在一些情况下,将在合成的跨膜结构域的每一端发现苯丙氨酸、色氨酸和缬氨酸的三联体。短寡肽或多肽接头,如长度介于2个与10个氨基酸之间,可以形成CAR的跨膜结构域与内质结构域之间的连接。
在一些实施例中,CAR具有多于一个跨膜结构域,所述跨膜结构域可以是同一跨膜结构域的重复序列,或者可以是不同的跨膜结构域。
在一些实施例中,CAR是多链CAR,如在WO2015/039523中描述的,其出于教导的目的通过引用并入。多链CAR可以包括不同跨膜多肽中的分离的细胞外配体结合结构域和信号传导结构域。可以将信号传导结构域设计为在近膜位置组装,这形成更接近赋予最佳信号转导的天然受体的柔性架构。例如,多链CAR可以包括FCERIα链的一部分和FCERIβ链的一部分,使得FCERI链自发二聚在一起以形成CAR。
在一些实施例中,抗原识别结构域是单链可变片段(scFv)抗体。scFv的亲和力/特异性在很大程度上由重链(VH)和轻链(VL)中的互补决定区(CDR)内的特异性序列驱动。每个VH和VL序列将具有三个CDR(CDR1、CDR2、CDR3)。
在一些实施例中,抗原识别结构域源自天然抗体,如单克隆抗体。在一些情况下,抗体是人抗体。在一些情况下,抗体已经受改变,以使得所述抗体在施用于人类时具有更小的免疫原性。例如,改变包括选自由以下组成的组的一种或多种技术:框架氨基酸的嵌合化、人源化、CDR移植、脱免疫和突变,以对应于最近的人种系序列。
还公开了靶向两种抗原的双特异性CAR。还公开了设计为仅在与结合不同抗原的另一种CAR结合时起作用的CAR。例如,在这些实施例中,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。如果被激活,第二CAR(或内源性T细胞)则会提供丢失信号。例如,如果所公开的CAR含有SD但不含有CSR,则仅在含有CSR的另一种CAR(或T细胞)结合其相应抗原的情况下激活含有此CAR的免疫效应子细胞。同样,如果所公开的CAR含有CSR但不含有SD,则仅在含有SD的另一种CAR(或T细胞)结合其相应抗原的情况下激活含有此CAR的免疫效应子细胞。
免疫效应子细胞
还公开了被工程化以表达所公开的CAR的免疫效应子细胞(本文也称为“CAR-TEM细胞”)。优选地,这些细胞从待治疗的受试者获得(即,是自体的)。然而,在一些实施例中,使用免疫效应子细胞系或供体效应子细胞(同种异体的)。在仍其它实施例中,免疫效应细胞不是HLA匹配的。免疫效应子细胞可以从多种来源获得,包含外周血单核细胞、骨髓、淋巴结组织、脐带血、胸腺组织、来自感染部位的组织、腹水、胸腔积液、脾组织和肿瘤。可以使用技术人员已知的任何多种技术(如FicollTM分离)从采集自受试者的血液中获得免疫效应子细胞。例如,来自个体的循环血液的细胞可以通过单采血液成分术获得。在一些实施例中,通过裂解红细胞并耗尽单核细胞(例如,通过PERCOLLTM梯度离心或通过逆流离心淘析)从外周血淋巴细胞中分离免疫细胞。可以通过阳性或阴性选择技术进一步分离免疫效应子细胞的特定亚群。例如,可以使用针对阳性选择的细胞特有的表面标志物的抗体的组合,例如通过与抗体缀合的珠一起温育足以阳性选择所期望的免疫效应子细胞的时间段来分离免疫效应子细胞。可替代地,可以通过使用针对阴性选择的细胞特有的表面标志物的抗体的组合进行阴性选择来实现免疫效应子细胞群体的富集。
治疗方法
表达所公开的CAR的免疫效应子细胞可以引发针对表达TAA的癌细胞的抗肿瘤免疫应答。由所公开的CAR修饰的免疫效应子细胞引发的抗肿瘤免疫应答可以是主动或被动免疫应答。另外,CAR介导的免疫应答可以是过继性免疫疗法方法的一部分,其中CAR修饰的免疫效应子细胞诱导对TAA具有特异性的免疫应答。
表达嵌合抗原受体的免疫效应子细胞的过继性转移是一种有前途的抗癌治疗剂。在收集患者的免疫效应子细胞后,所述细胞可以通过基因工程化以表达所公开的CAR,然后输注回患者体内。
所公开的CAR修饰的免疫效应子细胞可以单独施用或作为药物组合物与稀释剂和/或与其它组分(如IL-2、IL-15、或其它细胞因子或细胞群体)组合施用。简而言之,药物组合物可以包括如本文所述的靶细胞群体与一种或多种药学上或生理学上可接受的载体、稀释剂或赋形剂的组合。此类组合物可以包括缓冲剂,如中性缓冲盐水、磷酸盐缓冲盐水等;碳水化合物,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,如甘氨酸;抗氧化剂;螯合剂,如EDTA或谷胱甘肽;佐剂(例如,氢氧化铝);以及防腐剂。在一些实施例中,调配在所公开的方法中使用的组合物以静脉内施用。可以按适合治疗MM的任何方式施用药物组合物。施用的数量和频率将由如患者的病状以及患者的疾病的严重程度等因素确定,但是适当的剂量可以通过临床试验确定。
当指示“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以由医师考虑年龄、体重、肿瘤大小、感染或转移程度方面的个体差异以及患者(受试者)的病状来确定。通常可以说,包括本文所述的T细胞的药物组合物可以以104到109个细胞/千克体重,如105到106个细胞/千克体重(包含那些范围内的所有整数值)的剂量施用。还可以按这些剂量多次施用T细胞组合物。细胞可以通过使用免疫疗法中已知的输注技术来施用(参见例如Rosenberg等人,《新英格兰医学杂志》319:1676,1988)。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体征并相应地调整治疗容易地确定。
在某些实施例中,可能希望向受试者施用激活的T细胞,并且随后重新抽血(或进行单采血液成分术),由此根据所公开的方法激活T细胞并且向患者重新输注这些激活和扩增的T细胞。可以每隔几周进行多次此过程。在某些实施例中,可以抽取10cc到400cc的血液来活化T细胞。在某些实施例中,通过抽取20cc、30cc、40cc、50cc、60cc、70cc、80cc、90cc或100cc的血液来活化T细胞。使用此多次抽血/多次重新输注方案可以用于选出某些T细胞群。
可以按任何方便的方式(包含通过注射、输血或植入)来施用所公开的组合物。本文所述的组合物可以通过静脉内(i.v.)注射或腹膜内向患者皮下、皮内、瘤内、结内、髓内、肌内施用。在一些实施例中,通过皮内或皮下注射,将所公开的组合物施用于患者。在一些实施例中,通过静脉内注射施用所公开的组合物。也可以将组合物直接注射到肿瘤、淋巴结或感染部位中。
在某些实施例中,与(例如在其之前、同时或之后)任何数量的相关治疗方式(包含但不限于沙利度胺(thalidomide)、地塞米松(dexamethasone)、硼替佐米(bortezomib)和来那度胺(lenalidomide))结合将所公开的CAR修饰的免疫效应子细胞施用于患者。在另外的实施例中,可以与化学疗法、放射、免疫抑制剂(如环孢菌素(cyclosporin))、硫唑嘌呤(azathioprine)、甲氨蝶呤(methotrexate)、麦考酚酯(mycophenolate)和FK506)、抗体、或其它免疫去除剂(如CAM PATH)、抗CD3抗体或其它抗体疗法、细胞毒素、氟达拉滨(fludaribine)、环孢菌素、FK506、雷帕霉素(rapamycin)、霉酚酸(mycophenolic acid)、类固醇、FR901228、细胞因子和辐射组合使用CAR修饰的免疫效应子细胞。在一些实施例中,与(例如在其之前、同时或之后)骨髓移植、使用化学治疗剂(如氟达拉滨)的T细胞消融疗法、外束放射疗法(XRT)、环磷酰胺或抗体(如OKT3或CAMPATH)结合向患者施用CAR修饰的免疫效应子细胞。在另一个实施例中,在B细胞消融疗法(如与CD20反应的药剂,例如美罗华(Rituxan)后,施用本发明的细胞组合物。例如,在一些实施例中,受试者可能经受标准治疗,其中高剂量化学疗法之后是外周血干细胞移植。在某些实施例中,在移植后,受试者接受本发明的经扩增的免疫细胞的输注。在另外的实施例中,在外科手术之前或之后施用经扩增的细胞。
所公开的方法的癌症可以是受试者中任何表达TAA的细胞,所述细胞经受不受调节的生长、侵袭或转移。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。可替代地,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肿瘤。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列表包含淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、蕈样真菌病、霍奇金氏病(Hodgkin's Disease)、骨髓性白血病、膀胱癌、脑癌、神经系统癌、头颈癌(head andneck cancer)、头颈部鳞状细胞癌、肾癌、如小细胞肺癌和非小细胞肺癌等肺癌、成神经细胞瘤/胶质母细胞瘤、卵巢癌、胰腺癌、前列腺癌、皮肤癌、肝癌、黑色素瘤、口腔、咽喉、喉部和肺的鳞状细胞癌、子宫内膜癌、宫颈癌(cervical cancer)、宫颈癌(cervicalcarcinoma)、乳腺癌、上皮癌、肾癌、泌尿生殖系统癌症、肺癌(pulmonary cancer)、食管癌、头颈癌(head and neck carcinoma)、大肠癌、造血系统癌症;睾丸癌;结肠癌和直肠癌、前列腺癌和胰腺癌。
所公开的CAR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。药物部分包含化学治疗剂,所述化学治疗剂可以用作微管蛋白抑制剂、有丝分裂抑制剂、拓扑异构酶抑制剂或DNA嵌入剂以及特别是用于癌症疗法的那些。
所公开的CAR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)受体进行信号传导。这些蛋白质是共信号传导分子CD28-B7家族的成员,所述成员在T细胞功能的所有阶段都发挥着重要作用。PD-1受体(也称为CD279)在激活的T细胞的表面上表达。其配体PD-L1(B7-H1;CD274)和PD-L2(B7-DC;CD273)在APC的表面上表达,如树突细胞或巨噬细胞。PD-L1是主导配体,而PD-L2的表达模式更加受限。当配体与PD-1结合时,抑制性信号会传递到T细胞中,这减少细胞因子产生并抑制T细胞增殖。检查点抑制剂包含但不限于阻断PD-1的抗体(纳武单抗(Nivolumab)(BMS-936558或MDX1106)、CT-011、MK-3475)、PD-L1(MDX-1105(BMS-936559)、MPDL3280A、MSB0010718C)、PD-L2(rHIgM12B7)、CTLA-4(易普利姆玛(Ipilimumab)(MDX-010)、曲美木单抗(Tremelimumab)(CP-675,206))、IDO、B7-H3(MGA271)、B7-H4、TIM3、LAG-3(BMS-986016)。
美国专利第8,008,449号中描述了针对程序性死亡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治疗癌症的方法,所述美国专利因这些抗体通过引用并入。在美国专利第8,552,154号中描述了抗PD-L1抗体以及其用途,所述美国专利因这些抗体通过引用并入。在美国专利第8,617,546中描述了包括抗PD-1抗体或抗PD-L1抗体的抗癌剂,所述美国专利因这些抗体通过引用并入。
在一些实施例中,PDL1抑制剂包括与PDL1特异性结合的抗体,如BMS-936559(百时美施贵宝公司(Bristol-Myers Squibb))或MPDL3280A(罗氏公司(Roche))。在一些实施例中,PD1抑制剂包括与PD1特异性结合的抗体,如兰博利珠单抗(lambrolizumab)(默克公司(Merck))、纳武单抗(百时美施贵宝公司)或MEDI4736(阿斯利康公司(AstraZeneca))。美国专利第8,008,449号中描述了针对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治疗癌症的方法,所述美国专利因这些抗体通过引用并入。在美国专利第8,552,154号中描述了抗PD-L1抗体以及其用途,所述美国专利因这些抗体通过引用并入。在美国专利第8,617,546中描述了包括抗PD-1抗体或抗PD-L1抗体的抗癌剂,所述美国专利因这些抗体通过引用并入。
所公开的CAR可以与其它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件来引导针对癌细胞的靶向细胞毒性活性,而不必在患者体内启动免疫应答,而主动免疫疗法则主动触发内源性免疫应答。被动策略包含响应于特异性抗原而使用由B细胞产生的单克隆抗体(mAb)。20世纪70年代杂交瘤技术的发展和肿瘤特异性抗原的鉴定使得mAb的药物开发成为可能,所述mAb可以特异性地靶向肿瘤细胞,从而使其被免疫系统破坏。迄今为止,mAb一直是免疫疗法的最大成功案例;2012年最畅销的三种抗癌药物是mAb。其中有利妥昔单抗(rituximab)(美罗华,遗传技术公司(Genentech)),其与在如非霍奇金氏淋巴瘤(NHL)等B细胞恶性肿瘤的表面高度表达的CD20蛋白结合。利妥昔单抗已被FDA批准用于与化学疗法组合治疗NHL和慢性淋巴细胞性白血病(CLL)。另一个重要的mAb是曲妥珠单抗(trastuzumab)(Herceptin;遗传技术公司),其通过靶向HER2的表达彻底改变了HER2(人表皮生长因子受体2)阳性乳腺癌的治疗。
产生最佳的“杀伤”CD8 T细胞应答还需要T细胞受体激活加共刺激,这可以通过连接肿瘤坏死因子受体家族成员(包含OX40(CD134)和4-1BB(CD137))提供。OX40特别令人感兴趣,因为通过激活(激动剂)抗OX40 mAb治疗可增强T细胞分化和细胞溶解功能,从而增强针对各种肿瘤的抗肿瘤免疫力。
在一些实施例中,此类另外的治疗剂可以选自抗代谢物,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、地卡巴肼(decarbazine)、羟基脲、天冬酰胺酶、吉西他滨(gemcitabine)或克拉屈滨(cladribine)。
在一些实施例中,此类另外的治疗剂可以选自烷化剂,如氮芥(mechlorethamine)、色替派(thioepa)、苯丁酸氮芥(chlorambucil)、美法仑(melphalan)、卡莫司汀(carmustine)(BSNU)、罗氮芥(lomustine)(CCNU)、环磷酰胺、白消安(busulfan)、二溴甘露醇、链脲霉素(streptozotocin)、达卡巴嗪(dacarbazine)(DTIC)、丙卡巴肼(procarbazine)、丝裂霉素C、顺铂(cisplatin)和其它铂衍生物,如卡铂(carboplatin)。
在一些实施例中,此类另外的治疗剂可以选自抗有丝分裂剂,如紫杉烷,例如多西他赛(docetaxel)和紫杉醇(paclitaxel),以及长春花生物碱,例如长春地辛(vindesine)、长春新碱(vincristine)、长春花碱(vinblastine)和长春瑞滨(vinorelbine)。
在一些实施例中,此类另外的治疗剂可以选自拓扑异构酶抑制剂,如拓扑替康(topotecan)或伊立替康(irinotecan),或细胞抑制药物,如依托泊苷(etoposide)和替尼泊苷(teniposide)。
在一些实施例中,此类另外的治疗剂可以选自生长因子抑制剂,如ErbBl抑制剂(EGFR)(如EGFR抗体,例如扎芦木单抗(zalutumumab)、西妥昔单抗(cetuximab)、帕尼单抗(panitumumab)或尼妥珠单抗(nimotuzumab)或其它EGFR抑制剂,如吉非替尼(gefitinib)或厄洛替尼(erlotinib))、另一种ErbB2抑制剂(HER2/neu)(如HER2抗体,例如曲妥珠单抗、曲妥珠单抗DM l或帕妥珠单抗(pertuzumab))或EGFR和HER2两者的抑制剂,如拉帕替尼(lapatinib))。
在一些实施例中,此类另外的治疗剂可以选自酪氨酸激酶抑制剂,如伊马替尼(imatinib)(Glivec,Gleevec STI571)或拉帕替尼。
因此,在一些实施例中,所公开的抗体与奥法木单抗(ofatumumab)、扎诺木单抗(zanolimumab)、达雷木单抗(daratumumab)、兰尼单抗(ranibizumab)、尼妥珠单抗、帕尼单抗、hu806、达利珠单抗(daclizumab)(赛尼哌(Zenapax))、巴司利昔单抗(basiliximab)(舒莱(Simulect))、英夫利昔单抗(infliximab)(类克(Remicade))、阿达木单抗(adalimumab)(修美乐(Humira))、那他珠单抗(natalizumab)(Tysabri)、奥马珠单抗(omalizumab)(索雷尔(Xolair))、依法利珠单抗(efalizumab)(瑞体肤(Raptiva))和/或利妥昔单抗组合使用。
在一些实施例中,与用于治疗如上文描述的病症的CAR组合使用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实例包含IFNy、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、IFNa(例如,INFa2b)、IFN、GM-CSF、CD40L、Flt3配体、干细胞因子、ancestim和TNFa。合适的趋化因子可以包含来自人CXC和C-C趋化因子家族的Glu-Leu-Arg(ELR)阴性趋化因子,如IP-10、MCP-3、MIG和SDF-la。合适的细胞因子包含细胞因子衍生物、细胞因子变体、细胞因子片段和细胞因子融合蛋白。
在一些实施例中,与CAR组合使用以治疗如上文描述的病症的治疗剂可以是细胞周期控制/细胞凋亡调节剂(或“调节剂”)。细胞周期控制/细胞凋亡调节剂可以包含靶向和调节细胞周期控制/细胞凋亡调节剂的分子,如(i)cdc-25(如NSC 663284),(ii)过度刺激细胞周期的细胞周期蛋白依赖性激酶(如夫拉平度(flavopiridol)(L868275,HMR1275)、7-羟基星形孢菌素(UCN-01,KW-2401)和劳斯考文汀(roscovitine)(R-劳斯考文汀,CYC202)),以及(iii)端粒酶调节剂(如BIBR1532、SOT-095、GRN163和例如在US 6,440,735和US 6,713,055中描述的组合物)。干扰细胞凋亡通路的分子的非限制性实例包含TNF相关的细胞凋亡诱导配体(TRAIL)/细胞凋亡2配体(Apo-2L)、激活TRAIL受体的抗体、IFN和反义Bcl-2。
在一些实施例中,与CAR组合使用以治疗如上文描述的病症的治疗剂可以是激素调节剂,如可用于抗雄激素和抗雌激素疗法的调节剂。此类激素调节剂的实例是三苯氧胺(tamoxifen)、艾多昔芬(idoxifene)、氟维司群(fulvestrant)、屈洛昔芬(droloxifene)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene)、己烯雌酚(diethylstilbestrol)、乙炔雌二醇(ethinyl estradiol/estinyl)、抗雄激素(如氟他胺(flutaminde/eulexin))、孕激素(如己酸羟孕酮(hydroxyprogesterone caproate)、甲羟孕酮(medroxy-progesterone/provera)、甲地孕酮(megestrol acepate)/美可治(megace))、肾上腺皮质激素(如氢化可的松(hydrocortisone)、强的松(prednisone))、促黄体激素释放激素(以及其类似物和其它LHRH激动剂,如布舍瑞林(buserelin)和戈舍瑞林(goserelin))、芳香酶抑制剂(如阿那曲唑(anastrazole/arimidex)、氨鲁米特(aminoglutethimide/cytraden)、依西美坦(exemestane))或激素抑制剂(如奥曲肽(octreotide)/善宁(sandostatin))。
在一些实施例中,与CAR组合使用以治疗如上文描述的病症的治疗剂可以是抗癌核酸或抗癌抑制性RNA分子。
如上文所描述的,组合施用可以是同时的、分离的或顺序的。对于同时施用,药剂可以作为一种组合物或作为单独的组合物施用,视情况而定。
在一些实施例中,所公开的CAR与放射疗法组合施用。放射疗法可以包括向患者提供放射或相关的放射性药物的施用。放射源可以在正在治疗的患者的外部或内部(例如,放射治疗可以呈外束放射疗法(EBRT)或近距放射疗法(BT)的形式)。可以用于实施此类方法的放射性元素包含例如镭、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。
在一些实施例中,所公开的CAR与外科手术组合施用。
CAR-T细胞可以以增强肿瘤细胞毒性和特异性、逃避肿瘤免疫抑制、避免宿主排斥并延长其治疗半衰期的若干种方式设计。例如,TRUCK(被重定向为通用细胞因子杀伤的T细胞)T细胞拥有CAR,但也被工程化为释放促进肿瘤杀伤的细胞因子,如IL-12。由于这些细胞被设计为在CAR定位于肿瘤环境后激活时释放分子有效载荷,因此这些CAR-T细胞有时也被称为“装甲的CAR”。正在临床前和临床研究若干种细胞因子作为癌症疗法,并且当类似地并入到CAR-T疗法的TRUCK形式中时,也可能证明所述细胞因子是有用的。其中包含IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-10、IL-12、IL-13、IL-15、IL-18、M-CSF、GM-CSF、IFN-α、IFN-γ、TNF-α、TRAIL、FLT3配体、淋巴细胞趋化因子和TGF-β(Dranoff 2004)。“自驱动”或“归巢”CAR-T细胞被工程化以表达除其CAR之外的趋化因子受体。由于某些趋化因子可以在肿瘤中上调,因此趋化因子受体的并入有助于肿瘤向过继性T细胞的转运和通过过继性T细胞浸润,由此增强CAR-T的特异性和功能两者(Moon 2011)。通用CAR-T细胞也具有CAR,但被工程化,使得它们不表达内源性TCR(T细胞受体)或MHC(主要组织相容性复合物)蛋白。从过继性T细胞疗法的信号传导库中去除这两种蛋白分别可以预防移植物抗宿主疾病和排斥。另外,装甲的CAR-T细胞也因其逃避肿瘤免疫抑制和肿瘤诱导的CAR-T功能减退的能力而得名。这些特定的CAR-T具有CAR,并且可以被工程化以不表达检查点抑制剂。可替代地,这些CAR-T可以与阻断检查点信号传导的单克隆抗体(mAb)共同施用。施用抗PDL1抗体显著恢复了CAR TIL(肿瘤浸润淋巴细胞)的杀伤能力。虽然已经研究了PD1-PDL1和CTLA-4-CD80/CD86信号传导通路,但可以靶向装甲的CAR-T的设计中的其它免疫检查点信号传导分子,包含LAG-3、Tim-3、IDO-1、2B4和KIR。TIL的其它细胞内抑制剂包含磷酸酶(SHP1)、泛素连接酶(即,cbl-b)和激酶(即,二酰基甘油激酶)。装甲的CAR-T也可以被工程化以表达蛋白质或受体,所述蛋白质或受体保护其免受或抵抗肿瘤分泌的细胞因子的影响。例如,用双阴性形式的TGF-β受体转导的CTL(细胞毒性T淋巴细胞)对淋巴瘤分泌的TGF-β的免疫抑制具有抗性。与经转导的细胞的对照对应物相比,这些经转导的细胞在体内示出显著增加的抗肿瘤活性。
串联和双重CAR-T细胞的独特之处在于其具有两个不同的抗原结合结构域。串联CAR含有两个连续的抗原结合结构域,所述抗原结合结构域面对与细胞内共刺激和刺激结构域相连的细胞外环境。对双重CAR进行工程化,使得一个细胞外抗原结合结构域连接到细胞内共刺激结构域,并且第二不同的细胞外抗原结合结构域连接到细胞内刺激结构域。因为刺激和共刺激结构域在两个独立的抗原结合结构域之间分开,所以双重CAR也称为“分开的CAR”。在串联和双重CAR设计两者中,两个抗原结合结构域的结合对于允许T细胞中的CAR回路的信号传导是必要的。由于这两种CAR设计对不同的不同抗原具有结合亲和力,因此它们也被称为“双特异性”CAR。
关于作为“活的治疗剂”的形式的CAR-T细胞的一个主要问题是,其在体内的可操纵性和其潜在的免疫刺激副作用。为了更好地控制CAR-T疗法并且预防不需要的副作用,已经将多种特征工程化,包含关闭开关、安全机制和条件控制机制。例如,将自毁以及标记的(marked/tagged)CAR-T细胞工程化以具有促进表达CAR的T细胞的清除的“关闭开关”。自毁CAR-T含有CAR,但是也被工程化以表达当施用外源分子时可诱导的促细胞凋亡自杀基因或“消除基因”。出于此目的,可以采用多种自杀基因,包含HSV-TK(单纯疱疹病毒胸苷激酶)、Fas、iCasp9(诱导型胱天蛋白酶9)、CD20、MYC标签和截短的EGFR(内皮生长因子受体)。例如,HSK将前药更昔洛韦(GCV)转化为GCV-三磷酸盐,所述GCV-三磷酸盐将自身并入到复制型DNA中,最终导致细胞死亡。iCasp9是含有FK506结合蛋白组分的嵌合蛋白,所述结合蛋白结合小分子AP1903,从而导致胱天蛋白酶9二聚化和细胞凋亡。然而,标记的(marked/tagged)CAR-T细胞是具有CAR但被工程化以表达选择标志物的细胞。施用针对此选择标志物的mAb将促进CAR-T细胞的清除。截短的EGFR是一种抗EGFR mAb可靶向的此类抗原,并且施用西妥昔单抗可促进CAR-T细胞的消除。所产生的具有这些特征的CAR也称为sCAR(针对“可切换的CAR”)和RCAR(针对“可调节的CAR”)。“安全性CAR”(也称为“抑制性CAR”(iCAR))被工程化以表达两个抗原结合结构域。这些细胞外结构域中的一个细胞外结构域针对肿瘤相关抗原并且与细胞内共刺激结构域和刺激结构域结合。然而,第二细胞外抗原结合结构域对正常组织具有特异性并且与细胞内检查点结构域(如CTLA4、PD1或CD45)结合。也可以将多个细胞内抑制性结构域并入到iCAR中。一些可以提供这些抑制性结构域的抑制性分子包含B7-H1、B7-1、CD160、PIH、2B4、CEACAM(CEACAM-1、CEACAM-3和/或CEACAM-5)、LAG-3、TIGIT、BTLA、LAIR1和TGFβ-R。在正常组织存在的情况下,此第二抗原结合结构域的刺激将起到抑制CAR的作用。应注意,由于此双重抗原特异性,因此iCAR还处于双特异性CAR-T细胞的形式。安全性CAR-T工程化增强了CAR-T细胞对肿瘤组织的特异性,并且在某些正常组织可以表达极低水平的肿瘤相关抗原的情况下是有利的,所述抗原将导致在标准CAR的情况下的脱靶效应(Morgan 2010)。条件CAR-T细胞表达与细胞内共刺激结构域和单独的细胞内共刺激因子连接的细胞外抗原结合结构域。将共刺激结构域序列和刺激结构域序列工程化,其工程化方式使得当施用外源分子时,所得蛋白质将在细胞内聚集在一起以完成CAR回路。以这种方式,可以调节CAR-T激活,并且甚至可能针对具体患者“微调”或个性化。类似于双重CAR设计,当在条件CAR中无活性时,将刺激结构域和共刺激结构域在物理上分离;出于此理由,这些也称为“分开的CAR”。
在一些实施例中,这些工程化特征中的两个或更多个工程化特征可以组合以产生增强的多功能CAR-T。例如,可以产生具有双重或条件CAR设计的CAR-T细胞,所述细胞还可以像TRUCK一样释放细胞因子。在一些实施例中,可以制备双条件CAR-T细胞,使得其表达具有针对两种不同癌症抗原的两个单独抗原结合结构域的两种CAR,每种都与其相应的共刺激结构域结合。共刺激结构域仅在施用激活分子后才能与刺激结构域一起发挥作用。为了使此CAR-T细胞有效,癌症必须表达两种癌症抗原,并且必须将激活分子施用于患者;此设计由此并入双重和条件CAR-T细胞两者的特征。
通常,使用α-βT细胞产生CAR-T细胞,然而也可以使用γ-δT细胞。在一些实施例中,用于产生CAR-T细胞的所描述的CAR构建体、结构域和工程化的特征可以类似地用于产生其它类型的表达CAR的免疫细胞,包含NK(自然杀伤)细胞、B细胞、肥大细胞、骨髓源性吞噬细胞和NKT细胞。可替代地,可以产生表达CAR的细胞以具有T细胞和NK细胞二者的特性。在另外的实施例中,用CAR转导可以是自体的或同种异体的。
可以使用若干种不同的CAR表达方法,包含逆转录病毒转导(包含γ-逆转录病毒)、慢病毒转导、转座子/转座酶(睡美人(Sleeping Beauty)和PiggyBac系统)以及信使RNA转移介导的基因表达。相对于将CAR-T细胞工程化的可能性,基因编辑(基因插入或基因缺失/破坏)也已经变得越来越重要。CRISPR-Cas9、ZFN(锌指核酸酶)和TALEN(转录激活子样效应子核酸酶)系统是三种可能的方法,通过所述方法可以产生CAR-T细胞。
已经描述了本发明的许多实施例。然而,应当理解,在不背离本发明的精神和范围的情况下,可以做出各种修改。因此,其它实施例处于以下权利要求的范围内。
实例
实例1:
图1A到1G示出TCN增加了中央记忆CAR T细胞群。使用负选择从健康供体PBMC中分离T细胞。在第一旋转转导前第2天添加TCN。在第7天,细胞被染色以用于流式细胞术并在LSRII上运行。
对于抗人CD19构建体,SFG主链被修饰以包含FMC63 ScFv,其具有CD8α跨膜和铰链结构域,随后是CD28或4-1BB和CD3ζ。所有SFG构建体都被磷酸钙转染到H29细胞中。采集经转染的H29的逆转录病毒上清液并用于转导Phoenix E或RD114细胞。采集生产细胞的逆转录病毒上清液,过滤0.45μm,并用于如所描述的转导T细胞。通过台盼蓝染色测量活力并在自动化细胞计数器(Bio-Rad)上枚举。转导效率通过流式细胞术估计为蛋白质L+活细胞的百分比。对于下游实验,CAR T细胞剂量基于CAR基因转移进行归一化,但未分类以排除CAR阴性T细胞。结果,总T细胞剂量发生变化。
图2A和2B示出了TCN抑制m1928z CAR T细胞中的p-Akt。使用负选择从C57BL6脾细胞中分离T细胞。在第一旋转转导前第2天添加TCN。在第5天,用3T3-mCD19靶标刺激CAR T细胞持续24小时。刺激后,细胞被裂解并通过蛋白质印迹运行。
图3A到3N示出了TCN减少h19BBz CAR杀伤和细胞因子分泌。使用负选择从健康供体PBMC中分离T细胞。在第一旋转转导前第2天添加TCN。为了测量实时细胞杀伤,使用xCelligence RTCA机器,用3T3-hCD19靶细胞刺激CAR T细胞。为了测量细胞因子分泌,用靶细胞刺激CAR T细胞持续24小时。然后收集上清液并使用Ella运行以测量细胞因子。
图4示出了TCN增加效应子记忆CAR T细胞群。使用负选择从健康供体PBMC中分离T细胞。在第一旋转转导前第2天添加TCN。在第7天,细胞被染色以用于流式细胞术并在LSRII上运行。
实例2:评估在CAR T细胞生产期间给予TCN的影响。
先前的研究表明,在CAR T细胞生产期间给予的药物可能影响其功能。为了确定TCN的影响,在CAR转导之前,用TCN处理人健康供体T细胞。使用10μM的TCN,因为其是对T细胞而言最高的无毒剂量。在培养中进行转导和增殖后,进行体外测定以确定CAR T细胞功能。这些包含细胞毒性、细胞因子分泌、RNA-seq、多功能强度指数和CAR T细胞表型。接下来评估在体内生产期间给予TCN的CAR T细胞的功能。在第7天,总共60只NSG小鼠被给予含有荧光素酶的人B细胞肿瘤细胞系NALM6。在第0天,每组10只小鼠将被给予在有或没有TCN的情况下产生的未转导的h1928z或h19BBz CAR T细胞。使用生物发光成像确定肿瘤负荷并测量整体存活率。
实例3:评估CAR T细胞输注后给予TCN的影响。
为了确定TCN对体内已经存在的CAR T细胞的影响,在第0天对总共60只NSG小鼠给予NALM6。在第0天,20只小鼠被给予未转导的h1928z或h19BBz CAR T细胞。在实验期间,每组中一半的小鼠每周腹膜内注射一次TCN。生物发光成像用于确定肿瘤负荷并测量整体存活率,以将给予TCN和CAR的小鼠与仅给予CAR的小鼠进行比较。然后使用不同的人B细胞肿瘤系Raji重复此实验一次,所述肿瘤系也并入荧光素酶。这表明结果在不同的B细胞肿瘤之间是一致的。
除非另外定义,否则本文所使用的所有技术术语和科学术语均具有与所公开的本发明所属领域的普通技术人员通常所理解的含义相同的含义。本文所引用的出版物以及其所引用的材料通过引用具体并入。
仅使用常规实验,本领域的技术人员将认识到或者能够确定本文所述的本发明的具体实施例的许多等效物。此类等效物旨在被以下权利要求所涵盖。
Claims (19)
1.一种用于治疗受试者的方法,所述方法包括:
(a)将有效量的包括CAR-T细胞的组合物过继转移到所述受试者;以及
(b)向所述受试者施用有效量的Akt抑制剂以增加所述CAR-T细胞的持久性。
2.根据权利要求1所述的方法,其中所述Akt抑制剂是曲西立滨(Triciribine,TCN)。
3.根据权利要求1或2所述的方法,其中所述CAR-T细胞包括免疫效应子细胞,所述免疫效应子细胞包括嵌合抗原受体(CAR)多肽,所述CAR多肽包括肿瘤相关抗原(TAA)结合结构域、跨膜结构域、细胞内信号传导结构域和共刺激信号传导区。
4.根据权利要求3所述的方法,其中所述免疫效应子细胞选自由以下组成的组:αβT细胞、γδT细胞、自然杀伤细胞(NK)、自然杀伤T细胞(NKT)、B细胞、先天淋巴样细胞(ILC)、细胞因子诱导的杀伤细胞(CIK)、细胞毒性T淋巴细胞(CTL)、淋巴因子活化的杀伤细胞(LAK)、调节性T细胞或其任何组合。
5.一种用于增强受试者的CAR-T细胞疗法的方法,所述方法包括向正在经受治疗性CAR-T细胞的过继性细胞转移的受试者施用有效量的Akt抑制剂以增加所述CAR-T细胞的持久性。
6.根据权利要求5所述的方法,其中所述Akt抑制剂是曲西立滨(TCN)。
7.根据权利要求5或6所述的方法,其中所述CAR-T细胞包括免疫效应子细胞,所述免疫效应子细胞包括嵌合抗原受体(CAR)多肽,所述CAR多肽包括肿瘤相关抗原(TAA)结合结构域、跨膜结构域、细胞内信号传导结构域和共刺激信号传导区。
8.根据权利要求7所述的方法,其中所述免疫效应子细胞选自由以下组成的组:αβT细胞、γδT细胞、自然杀伤细胞(NK)、自然杀伤T细胞(NKT)、B细胞、先天淋巴样细胞(ILC)、细胞因子诱导的杀伤细胞(CIK)、细胞毒性T淋巴细胞(CTL)、淋巴因子活化的杀伤细胞(LAK)、调节性T细胞或其任何组合。
9.一种用于过继性细胞疗法的嵌合抗原受体效应子记忆T(CAR-TEM)细胞,所述CAR-TEM细胞包括被工程化以表达嵌合抗原受体(CAR)多肽的CD45RO+/CCR7-/CD62L-T细胞的纯化的群体。
10.根据权利要求9所述的CAR-TEM细胞,其中所述CAR多肽不包括CD28共刺激结构域。
11.根据权利要求9或10所述的CAR-TEM细胞,其中所述CAR多肽包括41BB共刺激结构域。
12.一种用于产生根据权利要求9到11中任一项所述的CAR-TEM细胞的方法,所述方法包括:
(a)从供体中分离PBMC,从所述PBMC中分离T细胞;
(b)用CD3/CD28珠粒刺激所述T细胞;
(c)用编码CAR多肽的病毒载体转导经活化的T细胞;
(d)使所述CAR-T细胞在含有有效量的Akt抑制剂的培养基中扩增以增加效应子记忆T细胞的比例;以及
(e)对所述CAR-T细胞进行分选以分离CD45RO+/CCR7-/CD62L-CAR-TEM细胞。
13.根据权利要求12所述的方法,其中所述CAR-TEM细胞是CD8+/CD4-T细胞。
14.根据权利要求12或13所述的方法,其中所述Akt抑制剂是曲西立滨(TCN)。
15.根据权利要求12到14中任一项所述的方法,其进一步包括:
(e)对所述CAR-T细胞进行分选以分离CD45RO+/CCR7-/CD62L-CAR-TEM细胞。
16.根据权利要求12到15中任一项所述的方法,其中所述培养基含有1到10μM的所述Akt抑制剂。
17.根据权利要求15所述的方法,其中所述培养基含有3μM的所述Akt抑制剂。
18.根据权利要求12到17中任一项所述的方法,其中所述CAR多肽不包括CD28共刺激结构域。
19.根据权利要求12到18中任一项所述的方法,其中所述CAR多肽包括41BB共刺激结构域。
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