CN107074957B - 在Fc间隔物区中具有突变的嵌合抗原受体(CAR)及其使用方法 - Google Patents
在Fc间隔物区中具有突变的嵌合抗原受体(CAR)及其使用方法 Download PDFInfo
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Abstract
使用经由表达嵌合抗原受体(CAR)遗传重定向的T细胞的过继免疫疗法是一种用于癌症治疗的有希望的方法。然而,此免疫疗法部分依赖于CAR的最佳分子设计,其牵涉通过间隔物和/或跨膜序列与胞内信号传导域连接的胞外配体结合域。
Description
优先权要求
本申请要求2014年1月13日提交的美国临时专利申请号61/926,881的优先权,通过提及以其全文(包括附图)并入本文。
政府利益的声明
本发明在国家健康研究所(NIH)授予的拨款号P50CA107399和P01CA030206下得到政府支持而完成。政府具有本发明的某些权利。
发明背景
使用表达嵌合抗原受体(CAR)的T细胞的过继免疫疗法是一种有希望的癌症治疗,因为这些细胞能以不依赖于人白细胞抗原(HLA)的方式直接识别并杀死表达抗原的肿瘤细胞。然而,除了靶肿瘤关联抗原的仔细选择外,此治疗方法高度依赖于CAR的最佳分子设计。
虽然已经在各种系统中显示了含有TAA特异性scFv的CAR,其经由与CD3-zeta融合的胞质共刺激(例如CD28或4-1BB)域产生胞内信号,展现出显著的抗肿瘤效力(Brentjenset al.2013;Brentjens et al.2011;Grupp et al.2013;Kalos et al.2011;Kochenderfer et al.2012),但是被宿主免疫学排斥和清除仍然是有效癌症治疗的挑战。
已经使用CAR设计中的某些修饰来防止FcR介导的对治疗细胞的清除。例如,可以使用不源自Ig Fc域的铰链/间隔物序列,诸如那些来自CD8α或CD28的(Brentjens etal.2007;Kalos et al.2011;Imai et al.2004;Kochenderfer et al.2009)。虽然这些间隔物序列可以减轻FcR结合,但是当靶向某些抗原时,其长度不能赋予CAR T细胞最佳的效力。例如,当使用CAR T细胞靶向5T4、NCAM和MUC1时,最佳的效力需要较长的接头区(即长于那些源自CD8α或CD28的接头)(Wilkie et al.2008;Guest et al.2005)。如此,会期望设计解决这些挑战,同时维持其在杀死癌细胞中的效力的CAR。
发明概述
根据一些实施方案,提供了对Fc受体(FcR)具有受损的结合的重组嵌合抗原受体(CAR)。此类CAR可以包括但不限于抗原识别域,源自经修饰的免疫球蛋白Fc区的间隔物域,和胞内信号传导域,所述经修饰的免疫球蛋白Fc区在其CH2区中具有导致受损的对FcR的结合的一个或多个突变。
在另一个实施方案中,提供了由病毒载体转导的人免疫细胞群体,所述病毒载体包含包括CAR基因的表达盒。在一些方面中,CAR基因包含核苷酸序列,所述核苷酸序列编码抗原识别域,源自经修饰的免疫球蛋白Fc区的间隔物域,和胞内信号传导域,所述经修饰的免疫球蛋白Fc区在其CH2区中具有导致受损的对FcR的结合的一个或多个突变,其中所述人免疫细胞群体表达所述CAR基因。
在另一个实施方案中,提供了治疗受试者中的癌症的方法。此类方法包括对所述受试者施用用CAR基因转导的人免疫细胞群体。在一些方面中,CAR基因包含核苷酸序列,所述核苷酸序列编码靶向对所述癌症特异性的癌症关联抗原的抗原识别域、源自经修饰的免疫球蛋白Fc区的间隔物域,和胞内信号传导域,所述经修饰的免疫球蛋白Fc区在其CH2区中具有导致受损的对FcR的结合的一个或多个突变。
设计具有降低或受损的对FcR的结合的间隔物域(诸如本文中描述的那些)的CAR帮助防止表达FcR的细胞在体内识别并破坏,或者无意地活化表达CAR的免疫治疗细胞。因此,此类CAR帮助防止免疫排斥和细胞的清除,意图对患者提供治疗益处。
附图简述
图1显示了根据一个实施方案,表达CD19特异性CAR的T细胞没有有效植入NSG小鼠中。图1a显示了用于基因修饰T细胞以进行植入研究的CD19R/EGFRt(顶部)和EGFRt(底部)表达构建体的示意图。标示了CD19特异性CD28-共刺激CAR(CD19R)、可自身切割T2A、huEGFRt、和药物抗性DHFRFS和IMPDH2IY基因的序列部分,以及延长因子1启动子序列(EF-1p)、GM-CSF受体alpha链信号序列(GMCSFRss)、和3个核苷酸终止密码子。图1b是对NSG小鼠施用以进行植入研究的T细胞的流式细胞术分析。将TCM衍生的细胞保持未转导(非-Txd),或者用含有(A)中描述的CD19R/EGFRt(CD19R)或EGFRt/DHFRFS/IMPDH2IY(EGFRt)构建体的慢病毒载体转导,并且在EGFRt表达方面进行免疫磁性选择。然后,在体外扩增细胞19天,并且分析表面表型。使用基于阴性对照染色创建的象限,在每个直方图中标示用对CD4(顶部)或CD8(底部)相对于对EGFRt特异性的抗体的细胞染色的百分比。在图1c中,在经照射的NS0-IL15支持物的情况下对NSG小鼠i.v.施用如(B)中描述的107个TCM衍生的细胞。使用缀合有FITC的抗人CD45,和生物素化的西妥昔单抗(cetuximab),接着用缀合有PE的链霉亲合素染色从每组(n=3-5只小鼠)收获的第7天和第14天外周血白细胞。使用基于阴性对照染色创建的象限,在每个直方图中标示淋巴细胞门控的huCD45+和huCD45+EGFRt+细胞的百分比。数据代表用来自多个供体的TCM衍生的细胞进行的4次不同实验。
图2显示了根据一个实施方案,CD19特异性表达CAR的T细胞结合可溶性FcγR1。用指定体积滴度的生物素化的可溶性人Fc gamma受体1,接着用缀合有PE的链霉亲合素(SA-PE,灰色直方图)染色图1中描述的相同T细胞。对于表达CD19R的细胞,免疫反应性细胞的百分比在每个直方图中标示,并且基于设置为检测仅用SA-PE染色的细胞(黑线)的<1%的M1门控。
图3显示了根据一个实施方案,突变IgG4间隔物不影响表达CAR的T细胞的CD19特异性效应功能。图3a显示了亲本CD19特异性CAR(CD19R)、在IgG4间隔物的CH2部分中含有2个点突变L235E和N297Q的CD19特异性CAR(CD19R(EQ))、和含有除去整个CH2域的截短的IgG4间隔物的CD19特异性CAR(CD19Rch2Δ)的示意图。还描绘了源自FMC63mAb的配体结合scFv域、源自huCD28的跨膜和胞质信号传导域、和huCD3ζ的胞质信号传导域。在图3b中,对TCM衍生的、EGFRt富集的且扩增的细胞分析转基因表达,所述细胞表达亲本CD19R、单独的EGFRt标志物、在氨基酸235(CD19R(L235E))或氨基酸297(CD19R(N297Q))处具有单一IgG4点突变的CD19R、双突变CD19R(EQ)或CH2缺失CD19Rch2Δ。用对含有Fc的CAR(顶部)或EGFRt(底部)特异性的抗体的细胞染色的百分比在每个直方图中标示,并且基于设置为检测仅用SA-PE染色的细胞(黑线)的<1%的M1门控。在图3c中,图3b中使用的相同细胞在针对经51Cr标记的CD19+LCL或SupB15靶物的4小时铬释放测定法中用作效应细胞。分别使用表达CD3激动剂OKT3的LCL(LCL-OKT3)和CD19阴性K562细胞作为阳性和阴性对照靶物。描述了在指定的E:T比率的一式三份孔的均值百分比铬释放+S.D.。
图4显示了根据一个实施方案,具有突变IgG4间隔物的CAR展现出抑制的FcγR结合。用以下生物素化的试剂染色表达单独的EGFRt标志物、亲本CD19R、单点突变CD19R(L235E)或CD19R(N297Q)、双点突变CD19R(EQ)、或CH2缺失CD19Rch2Δ的TCM衍生的、EGFRt富集的、扩增的细胞系:抗Fc抗体(以检测CAR)、西妥昔单抗(以检测EGFRt)或指定的人(Hu)或鼠(Mu)可溶性Fc受体(FcγR1、R2a、或R2b);接着用缀合有PE的链霉亲合素(SA-PE,灰色直方图)染色。免疫反应性细胞的百分比在每个直方图中标示,并且基于设置为检测仅用SA-PE染色的细胞(黑线)的<1%的M1门控。
图5显示了根据一个实施方案,表达具有突变IgG4间隔物的CAR的T细胞展现出增强的体内植入。使用经照射的NS0-IL15支持物,在第0天将107个表达亲本CD19R、单独的EGFRt标志物、单点突变CD19R(L235E)或CD19R(N297Q)、双点突变CD19R(EQ)、或CH2缺失CD19Rch2Δ(参见表型图3b)的TCM衍生的、EGFRt富集的细胞i.v.输注入NSG小鼠中。使用缀合有PerCP的抗人CD45,和生物素化的西妥昔单抗,接着用缀合有PE的链霉亲合素染色从每组(n=5只小鼠)收获的第7天和第14天外周血白细胞。在图5a中,标示活淋巴细胞门控群体中的CD45+EGFRt+细胞的均值百分比+S.E.M.。当使用未配对Student t检验与给予表达CD19R的细胞的小鼠相比时,*,p<0.034。图5b显示了代表性直方图(即5只小鼠的每组的中间3只),其用基于对照染色创建的象限描绘。在每个直方图中标示了huCD45+EGFRt+细胞的百分比。
图6显示了根据一些实施方案,表达具有突变IgG4间隔物的CAR的TCM衍生的细胞展现出增强的治疗效力。在第0天将1.5x 106个ffLuc+LCL细胞i.v.施用到NSG小鼠中,然后在第3天将5x 106个表达单独的EGFRt标志物、亲本CD19R、双点突变CD19R(EQ)、或CH2缺失CD19Rch2Δ的CAR+TCM衍生的细胞(总共107个细胞)i.v.输注到NSG小鼠中。然后,通过Xenogen成像监测LCL肿瘤生长。图6a显示了流式细胞术分析,其描绘了输入TCM衍生的细胞(在珠刺激和慢转导(lentitransduction)后第23天使用)的CAR概况。免疫反应性细胞的百分比在每个直方图中标示,并且基于设置为检测仅用SA-PE染色的细胞(黑线)的<1%的M1门控。图6b显示了对每组(n=6)描绘萤光素酶活性的均值通量水平(mean flux level)(+S.E.M.)。图6c显示了对每组描述第21天的NSG小鼠的代表性生物发光图像。图6d显示了标示第21天的外周血的活淋巴细胞门控群体中的CD45+EGFRt+细胞的均值百分比(+S.E.M.)。当使用未配对Student t检验与给予表达CD19R的细胞的小鼠相比时,*,p<0.035。图6e显示了每组的Kaplan Meier存活分析。使用时序(Mantel-COX)检验进行组间的统计学存活分析;当与接受表达亲本CD19R的T细胞的小鼠相比时,*,p=0.0009。
图7显示了根据一个实施方案,大量表达CD19R(EQ)的T细胞展现出增强的治疗效力。在第0天,将1.5x 106个ffLuc+LCL细胞i.v.施用到NSG小鼠中,然后,在第2天将5x 106个表达亲本CD19R或双点突变CD19R(EQ)的CAR+T细胞i.v.输注到NSG小鼠中。然后,通过Xenogen成像监测LCL肿瘤生长。图7a显示了输入T细胞(在珠刺激和慢转导后第21天使用)的CAR(顶部)、EGFRt对CD3(中间)和CD4对CD8(底部)概况的流式细胞术分析。每个直方图中描绘了如通过直方图扣除(顶部)测定,或者基于根据假(mock)转导细胞染色和同种型对照染色(中间,底部)画出的象限的免疫反应性细胞的百分比。图7b显示了对每组描绘了第2天、第11天和第23天的NSG小鼠的代表性生物发光图。图7c显示了对每组(n=3)描绘萤光素酶活性的均值通量水平(+S.E.)。图7d显示了每组的Kaplan Meier存活分析。使用时序(Mantel-COX)检验进行组间的统计学存活分析;当与接受表达亲本CD19R的T细胞的小鼠相比时,*,p=0.0295。
图8显示了根据一些实施方案,表达具有突变IgG4间隔物的CAR的非富集的TCM衍生的细胞展现出增强的体内植入。使用经照射的NS0-IL15支持物,在第0天将107个表达单独的EGFRt标志物、亲本CD19R、或双点突变CD19R(EQ)的TCM衍生的细胞i.v.输注到NSG小鼠中。使用缀合有PerCP的抗人CD45,和生物素化的西妥昔单抗,接着用缀合有PE的链霉亲合素染色从每组(n=4-6只小鼠)收获的第7天和第14天外周血白细胞。图8A显示了描绘输入TCM衍生的细胞(在珠刺激和慢转导后第26天使用)的CAR概况的流式细胞术分析。在每个直方图中标示用对含有Fc的CAR(顶部)或EGFRt(底部)特异性的抗体的细胞染色的百分比,并且基于设置为检测仅用SA-PE染色的细胞(黑线)的<1%的M1门控。图8B显示了标示活淋巴细胞门控群体中的CD45+EGFRt+细胞的均值百分比±S.E.M.。当使用未配对Student t检验比较输注有表达亲本CD19R对CD19R(EQ)的TCM衍生的细胞的小鼠时,*,p=0.004和**,p=0.057。图8C显示了描绘了代表性的直方图(即4-6只小鼠的每组的中间2只),基于对照染色创建象限。在每个象限中标示huCD45+EGFRt+细胞的百分比。
发明详述
以下实施例意图例示本发明的各个实施方案。因此,讨论的具体实施方案不应解释为对本发明的范围的限制。对于本领域技术人员会明显的是,可以在不偏离本发明的范围的前提下进行各种等同方案、变化和修改,并且应当理解此类等同实施方案被包括在本文中。此外,在此通过提及完整并入公开内容中引用的所有参考文献,就像在本文中完全列出一样。
嵌合抗原受体
根据本文中描述的实施方案,提供了靶向癌症相关抗原的重组嵌合抗原受体(CAR)及其使用方法。如下文实施方案描述,CAR可以包含一系列蛋白质或肽域,包括但不限于下列一项或多项:抗原结合域、间隔物域、跨膜域、胞内信号传导域和胞内共刺激域。
在一些实施方案中,提供了编码CAR的基因,其中基因包含核苷酸或核酸序列,其包括一系列编码与本文中描述的CAR的蛋白质或肽域对应的氨基酸序列的区域。由于遗传密码的简并性是已知的,本文中公开的任何氨基酸序列还指示与所述序列中的每个氨基酸对应的所有简并核酸密码子。因此,应当理解,描述CAR及其域的实施方案可以以包含核酸序列的基因及由所述基因编码的氨基酸序列提供。
在一个实施方案中,CAR可以包含但不限于抗原结合域、间隔物域、任选地至少一个胞内信号传导域和任选地至少一个胞内共刺激域。
在其它实施方案中,CAR可以包含但不限于抗原结合域、间隔物域和至少一个胞内信号传导域。
在其它实施方案中,CAR可以包含但不限于抗原结合域、间隔物域、至少一个胞内信号传导域和至少一个胞内共刺激域。
抗原结合域
CAR抗原结合域可以包含核苷酸序列,其在表达为肽或多肽时结合癌症相关抗原的表位。在一些实施方案中,癌症相关抗原可以是由癌细胞(例如肿瘤细胞、新生性细胞、恶性细胞、或任何其它癌性细胞)表达或过表达的任何抗原,并且可以是蛋白质、肽、碳水化合物、糖蛋白、神经节苷脂、蛋白聚糖、或其任何组合或复合物。在一些方面中,癌症相关抗原是可以仅在癌细胞或肿瘤细胞上表达的肿瘤特异性抗原(TSA),而在其它方面中,癌症相关抗原是可以在肿瘤细胞和正常细胞两者上表达的肿瘤关联抗原(TAA)。在其它方面中,癌症相关抗原可以是突变癌基因或肿瘤抑制基因的产物,或者另一种突变基因的产物(例如过表达或异常表达的细胞蛋白质、由致癌病毒生成的肿瘤抗原、癌胚抗原、改变的细胞表面糖脂或糖蛋白、或细胞类型特异性分化抗原)。
根据本文中描述的实施方案,可以通过本文中描述的CAR抗原结合域靶向的癌症相关抗原包括但不限于5T4、8H9、αvβ6整联蛋白、甲胎蛋白(AFP)、B7-H6、CA-125碳酸酐酶9(CA9)、CD19、CD20、CD22、CD30、CD33、CD38、CD44、CD44v6、CD44v7/8、CD52、CD123、CD171、癌胚抗原(CEA)、EGFrvIII、上皮糖蛋白-2(EGP-2)、上皮糖蛋白-40(EGP-40)、ErbB1/EGFR、ErbB2/HER2/neu/EGFR2、ErbB3、ErbB4、上皮肿瘤抗原(ETA)、FBP、胎儿乙酰胆碱受体(AchR)、叶酸受体-α、G250/CAIX、神经节苷脂2(GD2)、神经节苷脂3(GD3)、HLA-A1、HLA-A2、高分子量黑素瘤关联抗原(HMW-MAA)、IL-13受体α2、KDR、k-轻链、Lewis Y(LeY)、L1细胞粘附分子、黑素瘤关联抗原(MAGE-A1)、间皮素、鼠CMV感染的细胞、粘蛋白-1(MUC1).粘蛋白-16(MUC16)、天然杀伤组2成员D(NKG2D)配体、神经细胞粘附分子(NCAM)、NY-ESO-1、癌胚抗原(h5T4)、前列腺干细胞抗原(PSCA)、前列腺特异性膜抗原(PSMA)、受体酪氨酸激酶样孤儿受体1(ROR1)、由mAb IgE靶向的TAA、肿瘤关联糖蛋白-72(TAG-72)、酪氨酸酶、和血管内皮生长因子(VEGF)受体。在一些实施方案中,作为本文中描述的CAR的一部分的抗原结合域靶向CD19或CD123。
抗原结合域可以是靶向与癌症有关的抗原的任何靶向部分(moiety)。在一些实施方案中,抗原结合域是抗体或抗体的功能性片段。抗体指特异性结合抗原或表位,或与抗原或表位免疫性反应的免疫球蛋白分子,并且包括多克隆和单克隆抗体两者,以及功能性抗体片段,包括但不限于片段抗原结合(Fab)片段、F(ab')2片段、Fab’片段、Fv片段、重组IgG(rIgG)片段、单链可变片段(scFv)和单域抗体(例如,sdAb、sdFv、纳米抗体(nanobody))片段。术语“抗体或其功能片段”还包括免疫球蛋白的经遗传工程化或以其它方式修饰的形式,诸如内抗体(intrabodies)、肽抗体(peptibodies)、嵌合抗体、完全人抗体、人源化抗体、和异缀合物抗体(例如双特异性抗体、双抗体、三抗体(triabodies)、四抗体(tetrabodies)、串联二-scFv、串联三-scFv)。除非另有叙述,术语“抗体”应当理解为涵盖其功能性抗体片段。在一个实施方案中,抗原结合域是具有重链(VH)和轻链(VL)的scFv。在其它实施方案中,抗原结合域是靶向CD19或CD123的scFv。在此类实施方案中,靶向CD19的scFv可以具有以下的氨基酸序列:
CD19R VL DIQMTQTTSS LSASLGDRVT ISCRASQDIS KYLNWYQQKP DGTVKLLIYHTSRLHSGVPS RFSGSGSGTD YSLTISNLEQ EDIATYFCQQ GNTLPYTFGG GTKLEIT(SEQ ID NO:1)
CD19R VH EVKLQESGPG LVAPSQSLSV TCTVSGVSLP DYGVSWIRQP PRKGLEWLGVIWGSETTYYN SALKSRLTII KDNSKSQVFL KMNSLQTDDT AIYYCAKHYY YGGSYAMDYW GQGTSVTVSS(SEQ ID NO:2)
并且,靶向CD123的scFv可以具有以下氨基酸序列之一:
CD123VH1 QIQLVQSGPE LKKPGETVKI SCKASGYIFT NYGMNWVKQA PGKSFKWMGWINTYTGESTY SADFKGRFAF SLETSASTAY LHINDLKNED TATYFCARSG GYDPMDYWGQ GTSVTVSS(SEQ ID NO:3)
CD123VH2 QVQLQQPGAE LVRPGASVKL SCKASGYTFT SYWMNWVKQR PDQGLEWIGRIDPYDSETHY NQKFKDKAIL TVDKSSSTAY MQLSSLTSED SAVYYCARGN WDDYWGQGTT LTVSS (SEQID NO:4)
CD123VL1 DIVLTQSPAS LAVSLGQRAT ISCRASESVD NYGNTFMHWY QQKPGQPPKLLIYRASNLES GIPARFSGSG SRTDFTLTIN PVEADDVATY YCQQSNEDPP TFGAGTKLEL K(SEQ IDNO:5)
CD123VL2 DVQITQSPSY LAASPGETIT INCRASKSIS KDLAWYQEKP GKTNKLLIYSGSTLQSGIPS RFSGSGSGTD FTLTISSLEP EDFAMYYCQQ HNKYPYTFGG GTKLEIK(SEQ ID NO:6)
间隔物域
间隔物域(又称为“铰链区”或“间隔物/铰链区”)可以源自或包含免疫球蛋白Fc区,例如IgG1Fc区、IgG2Fc区、IgG3Fc区、IgG4Fc区、IgE Fc区、IgM Fc区、或IgA Fc区的至少一部分。在某些实施方案中,间隔物域包含IgG1、IgG2、IgG3、IgG4、IgE、IgM或IgA免疫球蛋白Fc区中落入其CH2和CH3域内的至少一部分。在一些实施方案中,间隔物域还可以包含相应的免疫球蛋白铰链区的至少一部分。在一些实施方案中,间隔物域源自或包含经修饰的免疫球蛋白Fc区,例如经修饰的IgG1Fc区、经修饰的IgG2Fc区、经修饰的IgG3Fc区、经修饰的IgG4Fc区、经修饰的IgE Fc区、经修饰的IgM Fc区、或经修饰的IgA Fc区的至少一部分。经修饰的免疫球蛋白Fc区可以具有一个或多个突变(例如点突变、插入、缺失、复制),导致一个或多个氨基酸取代、修饰、或缺失,其引起间隔物域对Fc受体(FcR)的受损的结合。在一些方面中,经修饰的免疫球蛋白Fc区可以设计为具有一个或多个突变,其导致一个或多个氨基酸取代、修饰、或缺失,其引起间隔物域对一种或多种FcR的受损的结合,所述FcR包括但不限于FcγRI、FcγR2A、FcγR2B1、FcγR2B2、FcγR3A、FcγR3B、FcεRI、FcεR2、FcαRI、Fcα/μR或FcRn。
Fc CH2域内的一些氨基酸序列已经被鉴定为在抗体-FcR相互作用中具有参与(Strohl,2009)。FcR,诸如FcγRI是位于免疫细胞,包括天然杀伤(NK)细胞和巨噬细胞上的整合膜蛋白质,其然后使用此Fc靶向能力实施各种免疫功能,诸如抗体依赖性细胞介导的细胞毒性(ADCC)和吞噬。
通过间隔物域损害对FcR的结合防止表达FcR的细胞识别并破坏,或无意地活化体内的表达CAR的免疫治疗细胞,从而帮助防止免疫学排斥和对细胞的清楚以意图对患者提供治疗益处。本文中描述的突变也促成降低CAR的脱靶效应,从而增加其特异性和效力。
如本文中使用,“氨基酸修饰”或“氨基酸取代”或“取代”指蛋白质或肽序列中的氨基酸取代、插入、和/或缺失。如本文中使用,“氨基酸取代”或“取代”意指将亲本肽或蛋白质序列中的特定位置处的氨基酸替换为另一种氨基酸。例如,取代S228P指其中228位的丝氨酸替换为脯氨酸的变体蛋白质或肽。
可以通过突变进行氨基酸取代,使得编码蛋白质或肽的核酸序列中的特定密码子改变为编码不同氨基酸的密码子。一般通过使可能的最少核苷酸变化做出此类突变。可以做出此种类的取代突变,从而以非保守的方式(即,通过将密码子从属于具有特定大小或特征的氨基酸分组的氨基酸改变为属于另一分组的氨基酸)或者以保守的方式(即通过将密码子从属于具有特定大小或特征的氨基酸分组的氨基酸改变为属于同一分组的氨基酸)改变所得的蛋白质中的氨基酸。此类保守变化一般导致所得的蛋白质的结构和功能的较小变化。
以下是氨基酸的各种分组的例子:
具有非极性R基团的氨基酸:丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、色氨酸、甲硫氨酸。
具有不带电荷的极性R基团的氨基酸:甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺。
具有电荷的极性R基团的氨基酸(在Ph 6.0带负电荷):天冬氨酸、谷氨酸。
碱性氨基酸(在pH 6.0带正电荷):赖氨酸、精氨酸、组氨酸(在pH 6.0)。
另一种分组可以是那些具有苯基基团的氨基酸:苯丙氨酸、色氨酸、酪氨酸。
另一个分组可以根据分子量(即R基团的大小),如下文显示:
在某些实施方案中,间隔物域源自经修饰的IgG1、IgG2、IgG3或IgG4Fc区,其包含用与存在于未修饰的铰链中的氨基酸残基不同的氨基酸残基取代的一个或多个氨基酸残基。一个或多个取代的氨基酸残基选自但不限于220,226,228,229,230,233,234,235,234,237,238,239,243,247,267,268,280,290,292,297,298,299,300,305,309,218,326,330,331,332,333,334,336,339位的一个或多个氨基酸残基,或其组合。
在一些实施方案中,间隔物域源自经修饰的IgG1、IgG2、IgG3或IgG4Fc区,其包含但不限于下列氨基酸残基取代中的一个或多个:C220S,C226S,S228P,C229S,P230S,E233P,V234A,L234V,L234F,L234A,L235A,L235E,G236A,G237A,P238S,S239D,F243L,P247I,S267E,H268Q,S280H,K290S,K290E,K290N,R292P,N297A,N297Q,S298A,S298G,S298D,S298V,T299A,Y300L,V305I,V309L,E318A,K326A,K326W,K326E,L328F,A330L,A330S,A331S,P331S,I332E,E333A,E333S,E333S,K334A,A339D,A339Q,P396L,或其组合。
在一些实施方案中,间隔物域源自IgG Fc区,其具有对其CH2-CH3区做出的一个或多个修饰,其中未修饰的IgG CH2-CH3区对应于以下氨基酸序列之一:
在一些实施方案中,间隔物域源自IgG Fc区,其具有对其铰链区做出的一个或多个修饰,其中未修饰的IgG铰链区对应于以下氨基酸序列之一:
在一些实施方案中,间隔物域源自具有以下氨基酸序列的IgG4Fc区:
在某些实施方案中,间隔物域源自经修饰的IgG4Fc,其包含用与存在于未修饰的IgG4Fc区中的氨基酸残基不同的氨基酸残基取代的一个或多个氨基酸残基。一个或多个取代的氨基酸残基选自但不限于220,226,228,229,230,233,234,235,234,237,238,239,243,247,267,268,280,290,292,297,298,299,300,305,309,218,326,330,331,332,333,334,336,339,396位的一个或多个氨基酸残基,或其组合。
在一些实施方案中,间隔物域源自经修饰的IgG4Fc区,其包含但不限于以下氨基酸残基取代中的一个或多个:220S,226S,228P,229S,230S,233P,234A,234V,234F,234A,235A,235E,236A,237A,238S,239D,243L,247I,267E,268Q,280H,290S,290E,290N,292P,297A,297Q,298A,298G,298D,298V,299A,300L,305I,309L,318A,326A,326W,326E,328F,330L,330S,331S,331S,332E,333A,333S,333S,334A,339D,339Q,396L,或其组合,其中未修饰的IgG4Fc区中的氨基酸取代为指定位置处的上文鉴定的氨基酸。
在一些实施方案中,间隔物域源自经修饰的IgG4Fc区,其包含但不限于下列氨基酸残基取代的两个或更多个(即“双重突变”)、三个或更多个(即“三重突变”)、四个或更多个、五个或更多个、或超过五个:220S,226S,228P,229S,230S,233P,234A,234V,234F,234A,235A,235E,236A,237A,238S,239D,243L,247I,267E,268Q,280H,290S,290E,290N,292P,297A,297Q,298A,298G,298D,298V,299A,300L,305I,309L,318A,326A,326W,326E,328F,330L,330S,331S,331S,332E,333A,333S,333S,334A,339D,339Q,396L,或其组合,其中未修饰的IgG4Fc区中的氨基酸被替换为指定位置处的上文鉴定的氨基酸。
在一些实施方案中,间隔物域源自经修饰的IgG4Fc区,其包含但不限于228位脯氨酸(P)替换丝氨酸(S)的取代(S228P)、235位亮氨酸(L)替换谷氨酸(E)的取代(L235E)、297位天冬酰胺(N)替换谷氨酰胺(Q)的取代(N297Q)、或其组合。在某些实施方案中,经修饰的IgG4Fc区具有单突变,如在以下氨基酸序列中指示(突变为粗体并且加下划线):
在其它实施方案中,间隔物域源自经修饰的IgG4Fc区,其被双重突变以包含L235E取代和N297Q取代(“EQ”)。在另一个实施方案中,经修饰的IgG4Fc区被三重突变以包含S228P取代、L235E取代、和N297Q取代(“S228P+L235E+N297Q”)。在某些实施方案中,经修饰的IgG4Fc和/或铰链区可以包含核苷酸序列,所述核苷酸序列编码选自下组的氨基酸序列(突变为粗体并且加下划线):
在某些实施方案中,间隔物域源自经修饰的免疫球蛋白Fc区,所述经修饰的免疫球蛋白Fc区包含其CH2域的全部或部分的一个或多个缺失(one or more deletions ofall of a part of its CH2domain)。在一个实施方案中,间隔物域源自经修饰的IgG4Fc区,所述经修饰的IgG4Fc区包含其CH2域的全部或部分的一个或多个缺失(“ch2Δ”)。在此类实施方案的一个方面中,间隔物域可以包含编码以下氨基酸序列的核苷酸序列:
ESKYGPPCPP CPGGGSSGGG SGGQPREPQV YTLPPSQEEM TKNQVSLTCL VKGFYPSDIAVEWESNGQPE NNYKTTPPVL DSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLGK(ch2Δ突变/缺失;SEQ ID NO:20)。
在一些实施方案中,间隔物域可以修饰为用免疫球蛋白Fc区取代没有结合FcR的能力的间隔物,诸如CD8a的铰链区。或者,可以缺失铰链的Fc间隔物区。此类取代会降低或消除Fc结合。
如本文中使用,术语“位置”指蛋白质的序列中的位置。位置可以序贯或根据建立的形式编号,例如Kabat位置或EU位置或如Kabat中的EU索引。对于本文中讨论的所有位置,编号根据EU索引或EU编号方案(Kabat等,1991,Sequences of Proteins ofImmunological Interest,5th Ed.,United States Public Health Service,NationalInstitutes of Health,Bethesda,在此通过提及完整并入)。EU索引或Kabat中的EU索引或EU编号方案指EU抗体的编号(Edelman等,1969,Proc Natl Acad Sci USA 63:78-85,其在此通过提及完整并入)。虽然Kabat位置也是本领域中公知的,但是对于给定的位置,它可以与EU位置存在变化。例如,上文描述的S228P和L235E取代指EU位置。然而,这些取代也可以对应于Kabat位置241(S241P)和248(L248E)。
跨膜和信号传导域
胞内信号传导域可以包含任何合适的T细胞受体(TCR)复合物信号传导域,或其部分。在一些实施方案中,胞内信号传导域源自CD3复合物。在一些实施方案中,胞内信号传导域是TCR zeta链(ζ链)信号传导域。在某些实施方案中,ζ-链信号传导域可以包含编码以下氨基酸序列的核苷酸序列:
RVKFSRSADA PAYQQGQNQL YNELNLGRRE EYDVLDKRRG RDPEMGGKPR RKNPQEGLYNELQKDKMAEA YSEIGMKGER RRGKGHDGLY QGLSTATKDT YDALHMQALP PR(SEQ ID NO:21)。
胞内信号传导域可以与任何合适的共刺激域,包括但不限于4-1BB共刺激域、OX-40共刺激域、CD27共刺激域、CD28共刺激域、DAP10共刺激域、诱导型共刺激(ICOS)域、或2B4共刺激域结合。根据本文中描述的实施方案,CAR可以包含至少一个共刺激信号传导域。在一个方面中,CAR具有单一共刺激信号传导域,或者它可以包含两个或更多个共刺激信号传导域,诸如上文描述的那些。在另一个方面中,共刺激域可以由单一共刺激域,诸如上文描述的那些共刺激域构成,或者备选可以由两个或更多个共刺激域的两个或更多个部分构成。或者,在一些实施方案中,CAR不包含共刺激信号传导域。在一个实施方案中,CAR包含共刺激信号传导域,其为CD28共刺激域。在此实施方案中,此类经修饰的CD28共刺激域可以具有一个或多个氨基酸取代或修饰,包括但不限于亮氨酸-亮氨酸(LL)至甘氨酸-甘氨酸(GG)的取代。在某些实施方案中,经修饰的共刺激信号传导域区可以包含编码选自以下的氨基酸序列的核苷酸序列:
RSKRSRGGHS DYMNMTPRRP GPTRKHYQPY APPRDFAAYR S(SEQ ID NO:22)
一个或多个信号传导域可以包含选自下组的跨膜域:CD28跨膜域、CD3跨膜域、或本领域中已知的任何其它合适的跨膜域。在一些实施方案中,跨膜域是CD28跨膜域。在某些实施方案中,经修饰的共刺激信号传导域区可以包含编码选自以下的氨基酸序列的核苷酸序列:
MFWVLVVVGG VLACYSLLVT VAFIIFWV(SEQ ID NO:23)
CAR基因的表达和T细胞的转导
在一些实施方案中,CAR基因是表达盒的一部分。在一些实施方案中,在CAR基因外,表达盒还可以包含附加基因(accessory gene)。当由T细胞表达时,附加基因可以充当经转导的T细胞的选择标志物、体外追踪标志物、或用于经转导的T细胞的自杀基因。
在一些实施方案中,附加基因是截短的EGFR基因(EGFRt)。EGFRt可以用作非免疫原性选择工具(例如与抗生物素微珠组合使用生物素化的西妥昔单抗进行的免疫磁性选择以富集已经用含有EGFRt的构建体以慢病毒转导的T细胞)、追踪标志物(例如流式细胞术分析以追踪T细胞植入)、和自杀基因(例如经由西妥昔单抗/介导的抗体依赖性细胞毒性(ADCC)途径)。可以根据本文中描述的实施方案使用的截短的EGFR(EGFRt)基因的例子记载于国际申请No.PCT/US2010/055329,其主题在此通过提及并入,就像在本文中完全列出一样。在其它实施方案中,附加基因是截短的CD19基因(CD19t)。
在另一个实施方案中,附加基因是诱导型自杀基因。自杀基因是会引起表达该基因的细胞在期望的时间经历程序性细胞死亡或抗体介导的清除的重组基因。在一个实施方案中,可以用作附加基因的诱导型自杀基因是诱导型胱天蛋白酶9基因(参见Straathof等(2005).An inducible caspase 9safety switch for T-cell therapy.Blood.June 1;105(11):4247–4254,其主题在此通过提及并入,就像在本文中完全列出一样)。
在一些实施方案中,可以将包含上文描述的CAR基因的表达盒插入载体中以经由转导或转染递送靶细胞。可以使用任何合适的载体,例如细菌载体、病毒载体、或质粒。在一些实施方案中,载体是病毒载体,所述病毒载体选自逆转录病毒载体、慢病毒载体、痘病毒载体、腺病毒载体、或腺相关病毒载体。在一些实施方案中,载体可以转导健康免疫细胞群体,例如T细胞。成功转导或转染的靶细胞表达作为表达盒的一部分的一种或多种基因。
因此,可以用CAR基因,诸如上文描述的CAR基因转导一种或多种免疫细胞群体,诸如T细胞。经转导的T细胞可以来自供体,或者可以来自具有癌症并且需要癌症治疗的受试者。在一些实施方案中,在过继免疫疗法治疗中使用转导的T细胞以治疗癌症(粗体/下划线中的残基标示取代)。在一些实施方案中,经转导的T细胞表达CAR基因,其编码选自SEQ IDNO:24-27的氨基酸序列:
CD19R(L235E)28Z(SEQ ID NO:24):
CD19R(N297Q)28Z(SEQ ID NO:25):
CD19R(EQ)28Z(SEQ ID NO:26):
CD19RCH2ΔCD28Z(SEQ ID NO:27):
此外,一个或多个T细胞群体可以是用于递送的药学可接受组合物的一部分,用于对受试者施用。在CAR转导的T细胞外,药学有效的组合物可以包含一种或多种药学有效的载体。如本文中使用,“药学可接受载体”指参与将感兴趣的治疗从身体的一个组织、器官或部分携带或转运到身体的另一个组织、器官或部分的药学可接受材料、组合物或媒介物。此类载体可以包含例如液体、固体、或半固体填充剂、溶剂、表面活性剂、稀释剂、赋形剂、佐剂、粘合剂、缓冲剂、溶解助剂、溶剂、包封材料、螯合剂、分散剂、防腐剂、润滑剂、崩解剂、增稠剂、乳化剂、抗微生物剂、抗氧化剂、稳定剂、着色剂、或一些其组合。
载体的每种组分是“药学可接受的”,因为它必须与组合物的其它成分相容,并且必须适合于接触身体中它可以遇到的任何组织、器官或部分,这意味着它必须不携带毒性、刺激、变应性反应、免疫原性、或过度超过其治疗益处的任何其它并发症的风险。
可以充当药学可接受载体的材料的一些例子包括:(1)糖,如乳糖,葡萄糖和蔗糖;(2)淀粉,如玉米淀粉和马铃薯淀粉;(3)纤维素,及其衍生物,诸如羧甲基纤维素钠,乙基纤维素和醋酸纤维素;(4)粉末状黄蓍胶;(5)麦芽;(6)天然的聚合物,如明胶,胶原蛋白,纤维蛋白,纤维蛋白原,层粘连蛋白,核心蛋白聚糖,透明质酸,藻酸盐和壳聚糖;(7)滑石;(8)赋形剂,如可可脂和栓剂蜡;(9)油,如花生油,棉籽油,红花油,芝麻油,橄榄油,玉米油和大豆油;(10)二醇,如丙二醇;(11)多元醇,如甘油,山梨醇,甘露醇和聚乙二醇;(12)酯,如三亚甲基碳酸酯(trimethylene carbonate),油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,如氢氧化镁和氢氧化铝;(15)藻酸(或藻酸盐);(16)无热原水;(17)等张盐水;(18)林格氏溶液;(19)醇,如乙醇和丙烷醇;(20)磷酸盐缓冲溶液;(21)热塑性塑料,如聚乳酸,聚乙醇酸,(22)聚酯,如聚己内酯;(23)自组装肽;和(24)在药物配制剂中采用的其它非毒性相容物质,如丙酮。
药物组合物可以含有为了接近生理学条件需要的药学可接受辅助物质,诸如pH调节和缓冲剂、毒性调节剂等,例如乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。
在一个实施方案中,药学可接受载体是水性载体,例如缓冲盐水等。在某些实施方案中,药学可接受载体是极性溶剂,例如丙酮和醇。
这些配制剂中的CAR转导的T细胞的浓度可以广泛变化,并且将根据选择的具体施用模式和生物系统的需要,主要基于流体体积、粘度、器官大小、体重等选择。
在某些实施方案中,可以在细胞培养物中培养用CAR基因转导的T细胞群体(即CAR转导的T细胞),如本文中描述的那些在用于靶向和杀死癌细胞或肿瘤细胞的方法中使用的细胞。在此实施方案的某些方面中,可以在体外或研究背景中使用方法以调查特定癌症相关抗原在癌症病因学中的作用,或者评估新的CAR构建体的靶向能力。
用CAR转导的T细胞治疗癌症
根据一些实施方案,可以在用于治疗受试者中的癌症的方法中使用CAR基因和用CAR基因转导的T细胞群体,如上文描述的那些。此类方法可以包括以下步骤:对受试者施用治疗有效量的用至少一个CAR基因转导的至少一个T细胞群体。在这些实施方案中,CAR转导的T细胞群体表达一种或多种CAR基因,如上文描述的那些CAR基因。在某些实施方案中,T细胞转导有并且表达单一突变体基因构建体,诸如如本文中描述的CD19R(L235E)或CD19R(N297Q)构建体,如本文中描述的具有L235E和N297Q突变两者(例如CD19R(EQ))的双重突变体基因构建体,或如本文中描述的缺失基因构建体(例如CD19Rch2Δ)。当经由过继免疫疗法治疗施用此类细胞时,经转导的T细胞特异性在体内靶向并且裂解表达癌症相关抗原的细胞(即癌细胞),从而递送其消除癌细胞的治疗效果。
可以使用经转导的T细胞群体治疗的癌症可以包括但不限于急性成淋巴细胞性白血病(ALL)、急性髓样白血病(AML)、肾上腺皮质、癌、AIDS相关癌症、肛门癌(Anal Cancer)、阑尾癌(Appendix Cancer)、星形细胞瘤、非典型畸胎样瘤/杆状瘤、中枢神经系统、基底细胞癌、胆管癌、膀胱癌、骨癌、骨肉瘤和恶性纤维组织细胞瘤、脑干胶质瘤、脑肿瘤、乳腺癌、支气管肿瘤、伯基特淋巴瘤、类癌瘤、中枢神经系统癌、宫颈癌、脊索瘤、慢性淋巴细胞性白血病(CLL)、慢性髓性白血病(CML)、慢性骨髓增殖性疾病、结肠癌、结肠直肠癌、颅咽管瘤、皮肤T细胞淋巴瘤、胚胎性肿瘤、中枢神经系统、子宫内膜癌、室管膜母细胞瘤、室管膜瘤、食道癌、鼻腔神经胶质瘤、尤因肉瘤肿瘤家族颅外胚细胞瘤(Ewing Sarcoma Family ofTumors Extracranial Germ Cell Tumor)、性腺外胚细胞瘤肝外胆管癌(ExtragonadalGerm Cell Tumor Extrahepatic Bile Duct Cancer)、眼癌骨纤维组织细胞瘤(EyeCancer Fibrous Histiocytoma of Bone)、恶性、和骨肉瘤、胆囊癌、胃癌、胃肠类癌肿瘤、胃肠间质瘤(GIST)-见软组织肉瘤、胚细胞瘤、妊娠滋养细胞肿瘤、神经胶质瘤、毛细胞白血病、头颈癌、心脏癌症、肝细胞(肝)癌、组织细胞增多症、霍奇金淋巴瘤、下咽癌、眼内黑素瘤、胰岛细胞瘤(内分泌胰腺)、卡波西(Kaposi)肉瘤、肾癌、朗格汉斯(Langerhans)细胞组织细胞增多症、喉癌、白血病、唇和口腔癌、肝癌(原发性)、原位小叶癌(LCIS)、肺癌、淋巴瘤、巨球蛋白血症、男性乳腺癌、恶性骨纤维组织细胞瘤和骨肉瘤、髓母细胞瘤、髓上皮瘤、黑色瘤、Merkel细胞癌、间皮瘤、转移性鳞状颈癌伴有牵涉NUT基因的隐性原发性中线束癌(Metastatic Squamous Neck Cancer with Occult Primary Midline Tract CarcinomaInvolving NUT Gene)、口腔癌、多发性内分泌新生物综合征、多发性骨髓瘤/浆细胞新生物、蕈样肉芽肿病、骨髓增生异常综合征、骨髓增生异常/骨髓增殖性新生物、骨髓性白血病、慢性(CML)、骨样白血病、急性(AML)、骨髓瘤、多发性、骨髓增殖性疾病、鼻腔及鼻窦癌、鼻咽癌、神经母细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌、口癌、口腔癌、口咽癌、骨肉瘤和恶性骨纤维组织细胞瘤、卵巢癌、胰腺癌、乳头状瘤病、副神经节瘤、鼻窦和鼻腔恶性癌、甲状旁腺癌、阴茎癌、咽癌、嗜铬细胞瘤、中间分化的松果体实质肿瘤(Pineal ParenchymalTumors of Intermediate Differentiation)、成松果体细胞瘤(Pineoblastoma)和幕上原始神经外胚层肿瘤(Supratentorial Primitive Neuroectodermal Tumor)、垂体瘤、浆细胞新生物/多发性骨髓瘤、胸膜肺母细胞瘤、妊娠和乳腺癌、原发性中枢神经系统(CNS)淋巴瘤、前列腺癌、直肠癌、肾细胞(肾)癌、肾盂和输尿管、移行细胞癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、肉瘤、塞扎里(Sézary)综合征、小细胞肺癌、小肠癌、软组织肉瘤、鳞状细胞癌、鳞状颈癌、胃癌、幕上原始神经外胚层肿瘤、T细胞淋巴瘤、皮肤、睾丸癌、咽喉癌、胸腺瘤和胸腺癌、甲状腺癌、肾盂和输尿管移行细胞癌、滋养细胞肿瘤、输尿管和肾盂癌、尿道癌、子宫癌、子宫肉瘤、阴道癌、外阴癌、沃尔登斯特伦巨球蛋白血症和Wilms瘤。
可以根据本文中描述的方法使用的用一种或多种CAR基因转导的一种或多种T细胞群体,可以通过任何合适的施用路径单独或作为药物组合物的一部分施用。施用路径可以指本领域中已知的任何施用途径,包括但不限于颅内、胃肠外、或经皮。“胃肠外”指一般与注射关联的施用路径,包括眶下,输注,动脉内,囊内,心内,皮内,肌内,腹膜内,肺内,脊柱内,胸骨内,鞘内,肿瘤内,子宫内,静脉内,蛛网膜下,囊下,皮下,经粘膜,或经气管。在某些实施方案中,静脉内或鞘内施用经转导的T细胞。
如本文中使用,术语“有效量”指产生期望的效果的药剂、化合物、治疗或疗法的量。例如,可以使细胞群体与有效量的药剂、化合物、治疗或疗法接触以研究其体外效果(例如细胞培养)或产生期望的离体或体外治疗效果。可以使用有效量的药剂、化合物、治疗或疗法以在受试者中产生治疗效果,诸如预防或治疗靶标状况,减轻与状况有关的症状,或者产生期望的生理学效果。在此类情况中,化合物的有效量是“治疗有效量”、“治疗有效浓度”或“治疗有效剂量”。精确的有效量或治疗有效量是在给定受试者或细胞群体中就治疗效力而言产生最有效的结果的组合物量。此量会随多种因素而变化,包括但不限于化合物的特征(包括活性、药代动力学、药效学、和生物利用度)、受试者的生理学状况(包括年龄、性别、疾病类型和阶段、一般身体状况、对给定剂量的响应性、和药物的类型)或细胞的生理学状况、配制剂中的一种或多种药学可接受载体的性质、和施用路径。此外,有效量或治疗有效量可以随单独还是与另一种化合物、药物、疗法或其它治疗方法或形式组合施用化合物而变化。临床和药理学领域的技术人员将能够经由常规实验,即通过监测细胞或受试者对化合物施用的响应并且相应调节剂量来确定有效量或治疗有效量。关于更多指导,参见Remington:The Science and Practice of Pharmacy,21st Edition,Univ.of Sciencesin Philadelphia(USIP),Lippincott Williams&Wilkins,Philadelphia,PA,2005,在此通过提及并入,就像在本文中完全列出一样。可以根据本文中描述的实施方案以有效量或治疗有效量使用以产生期望的效果的药剂、化合物、治疗或疗法可以包括但不限于CAR基因、包含CAR基因的表达盒、将包含CAR基因的表达盒递送到靶细胞如T细胞的载体、和用CAR基因转导的T细胞群体。
术语状况的“治疗/处理”可以指预防状况、减缓状况的发作或形成速率、降低形成状况的风险、防止或延迟与状况有关的症状的形成、降低或结束与状况有关的症状、产生状况的完全或部分消退、或其一些组合。治疗/处理也可以意味着状况的防范性或预防性治疗/处理。
如本文中使用,术语“受试者”指人或动物,包括所有哺乳动物,诸如灵长类(特别是高等灵长类)、绵羊、犬、啮齿类(例如小鼠或大鼠)、豚鼠、山羊、猪、猫、兔和牛。在一些实施方案中,受试者是人。
在某些实施方案中,用于治疗癌症的方法可以包括以下步骤:与治疗有效量的用第二CAR基因转导的T细胞的第二群体组合施用治疗有效量的用第一CAR基因转导的T细胞的第一群体。
在其它实施方案中,可以与一种或多种另外的抗癌疗法组合施用经CAR转导的T细胞。如本文中使用,“组合”或“与…组合”意指在治疗同一受试者中的同一癌症的过程中,以任何次序使用两种或更多种药剂、药物、治疗剂、规程、治疗方案、治疗形式或其组合。这包括同时施用,以及以相隔多达几天的时间间隔次序。此类联合治疗也可以包括药剂、药物、治疗剂、规程、治疗方案和治疗形式中的任何一种或多种的超过单次施用。此外,可以通过相同或不同施用路径施用两种或更多种药剂、药物、治疗剂、规程、治疗方案、治疗形式或其组合。
可以根据本文中描述的方法使用的另外的抗癌疗法可以包括一种或多种抗癌规程、治疗形式、抗癌治疗剂或其组合。在一些实施方案中,可以与一种或多种抗癌规程或治疗形式,包括但不限于干细胞移植(例如使用同种干细胞,自体干细胞的骨髓移植物或外周血干细胞移植物;或非清髓性移植物(non-myeloablative transplant))、放射疗法或手术切除联合施用经CAR转导的T细胞。在其它实施方案中,可以与一种或多种可以用于治疗癌症的抗癌治疗剂或药物,包括但不限于化学治疗剂和其它抗癌药物、免疫治疗剂、靶向治疗剂或其组合联合施用经CAR转导的T细胞。
可以根据本文中描述的实施方案与经CAR转导的T细胞联合施用的化学治疗剂和其它抗癌药物包括但不限于,全反式视黄酸(ATRA)、三氧化二砷、蒽环类抗生素和其药学可接受盐(例如盐酸多柔比星、盐酸柔红霉素、伊达比星、米托蒽醌)、烷化剂(例如环磷酰胺、laromustine)、抗代谢物类似物(阿糖胞苷、6-硫鸟嘌呤、6-巯嘌呤、甲氨蝶呤)、去甲基化剂(例如地西他滨、5-氮胞苷)、核酸合成抑制剂(例如羟基脲)、拓扑异构酶抑制剂(例如依托泊苷)、长春花生物碱(例如硫酸长春新碱)、或其组合(例如“ADE”,其是包含阿糖胞苷(Ara-C)、盐酸柔红霉素和依托泊苷的组合的联合治疗)。
可以根据本文中描述的实施方案与经CAR转导的T细胞联合施用的免疫治疗剂包括但不限于免疫调节剂(例如STAT3抑制剂、来那度胺(Lenalidomide))和治疗性单克隆抗体。治疗性单克隆抗体可以设计为靶向一种或多种另外的癌症相关抗原。
可以根据本文中描述的实施方案与经CAR转导的T细胞联合施用的靶向治疗剂包括但不限于酪氨酸激酶抑制剂(伊马替尼(imatinib)、达沙替尼(dasatinib)、尼洛替尼(nilotinib)、舒尼替尼(sunitinib))、法尼基转移酶抑制剂(例如tipifarnib)、FLT抑制剂、和c-Kit(或CD117)抑制剂(伊马替尼、达沙替尼、尼洛替尼)。
以下实施例意图例示本发明的各个实施方案。因此,讨论的具体实施方案不应解释为限制本发明的范围。例如,虽然下文的实施例涉及靶向CD19的CAR的实施方案,但是应当领会可以产生CAR靶向任何抗原。对于本领域技术人员会明显的是,可以在不背离本发明的范围的前提下做出各种等同方案、变化和修改,并且应当理解此类等同实施方案包含在本文中。此外,公开内容中提及的所有参考文献通过提及完整并入,就像本文中完全列出一样。
实施例
实施例1:在IgG4Fc间隔物区中掺入突变的嵌合抗原受体(CAR)避免Fc受体介导的CAR T细胞的识别和清除,从而导致改善的T细胞持久性和抗肿瘤效力。
为了测定细胞FcR介导的相互作用是否在过继性转移的表达CAR的T细胞的免疫学排斥和清除,或甚至无意活化中发挥作用,已经在CD19特异性CAR的IgG4Fc间隔物的CH2区内的一个或两个位点(L235E和/或N297Q)进行了突变–本文中称为CD19R(L235E)、CD19R(N297Q)或CD19R(EQ)–以及在其IgG4Fc间隔物中具有CH2缺失的CD19特异性CAR–本文中称为CD19Rch2Δ。然后对于体外FcγR结合和CAR介导的细胞溶解活性,以及体内植入和治疗效力,比较表达这些突变CAR的T细胞与表达非突变CAR(CD19R)或仅表达作为追踪标志物的截短的EGFR分子(EGFRt)的T细胞(Wang等2011)。结果提供了下述证据,即细胞FcγR相互作用的消除改善过继性转移的表达CAR的T细胞的持久性和抗肿瘤响应。
材料和方法
DNA构建体和慢病毒载体。CD19R28Z-T2A-EGFRt_epHIV7慢病毒构建体含有a)嵌合抗原受体(CAR)序列,其由CD19特异性FMC63mAb的VH和VL基因区段、含有增强嵌合受体表达和功能的gg突变的共刺激分子CD28的跨膜和胞质信号传导域(Nguyen等,2003)、和CD3ζ链的胞质域(Kowolik等2006)组成;b)核糖体跳跃T2A序列(Szymczak等,2004)和c)截短的EGFR序列(W ang等2011a)。如先前描述(Jonnalagadda等,2013)生成EGFRt-T2A-DHFRFS-T2A-IMPDH2IY_epHIV7慢病毒载体。通过使用QuikChange II XL试剂盒(Ag ilentTechnologies,Santa Clara,CA)对已经由Geneart合成的经密码子优化的CD19R28Z_pGA质粒进行定点诱变生成CD19R(L235E)28Z-T2A-EGFRt_e pHIV7、CD19R(N297Q)28Z-T2A-EGFRt_epHIV7和CD19R(EQ)28Z-T2A-EG FRt_epHIV7载体,用NheI/RsrII消化,并且与类似消化的CD19R28Z-T2A-EG FRt_epHIV7连接。从已经由Geneart合成的经密码子优化的CD19R-HL-CH3(CO)_pMK-RQ质粒生成CD19Rch2Δ28Z-T2A-EGFRt_epHIV7载体,用NheI/RsrII消化,并且与类似消化的CD19R28Z-T2A-EGFRt_epHIV7连接。
细胞系和维持。如描述(Wang,2011b),从肝素化外周血分离人外周血单核细胞(PBMC),所述肝素化外周血获自含有在希望之城国家医学中心(City of Hope NationalMedical Center,COHNMC)进行成分输血(apheresis)的健康供体的残留血液成分的弃去的试剂盒。由于这是去标识的(de-identified)弃去血液材料,知情同意在COHNMC内部审查委员会(IRB方案#09025),和CO HNMC人受试者保护局(Office of Human SubjectsProtection)批准下是放弃的。然后,完成TCM分离(使用CD14和CD45RA耗竭(depletion),接着是CD62L选择)、抗CD3/CD28珠刺激和慢病毒介导的转导,如先前描述(Wang等,2012)。在一些情况中,经转导的T细胞对于EGFRt表达进行免疫磁性富集,如先前描述(Wang等,2011a)。
在补充有10%热灭活的胎牛血清(FCS,Hyclone,Logan,UT),2mM L-谷氨酰胺(Irvine Scientific)和25mM HEPES(Irvine Scientific)的RPMI 1640(IrvineScientific,Santa Ana,CA)中培养经EBV转化的类淋巴母细胞细胞系(LCL)和表达OKT3的LCL(LCL-OKT3)(Wang等2011b)或ffLuc+LCL细胞。通过在500uL培养基中存在5μg/mL聚凝胺的情况下以20的MOI用慢病毒载体eGFP-ffluc_epHIV7转导,和随后通过分选GFP+细胞纯化产生ffLuc+LCL。
生成分泌人稳态IL-15细胞因子的小鼠骨髓瘤细胞(NSO-IL15),如先前描述(Wang等2011b)。
在相应的ATCC推荐培养基中培养SupB15和K562白血病细胞系(ATCC)。
抗体和流式细胞术。缀合有荧光染料的同种型对照、抗CD3、抗CD4、抗CD8、抗CD45和链霉亲合素获自BD Biosciences(San Jose,CA)。生物素化的抗-Fc购自JacksonImmunoResearch Laboratories,Inc.(West Grove,PA)。先前描述了生物素化的西妥昔单抗的生成(Wang等2011a)。生物素化的huFcγR1、muFcγR1、huFcγR2a、huFcγR2b和muFcγR2b获自Sino Biological,Inc.(Beijing,P.R.China)。通过FACScalibur系统(BDBiosciences)分析免疫荧光细胞的百分比,并且使用FCS Express V3(De Novo Software,CA,USA)计算分析区域中的细胞百分比。
体内T细胞植入和疗法。所有小鼠实验得到COHNMC机构动物护理和使用委员会批准。对于植入研究,在第0天6-10周龄NOD/Scid IL-2RγC null(NSG)小鼠静脉内(i.v.)注射107个指定的TCM衍生的细胞,并且一周三次腹膜内(i.p.)注射2x107个经照射的NS0-IL15以在体内提供人IL-15的系统性供应。从眶后出血收获外周血,裂解红细胞,并且通过流式细胞术分析细胞悬浮液。对于治疗研究,在第0天将1.5x 106个ffLuc+LCL细胞i.v.施用到6-8周龄NSG小鼠中,然后在第3天i.v.施用5x 106个指定的CAR+TCM衍生的细胞。通过Xenogen成像测量萤光素酶活性,如先前描述(Kahlon等2004)。
铬释放测定法。使用指定的效应器/靶细胞比率实施4小时51Cr-释放测定法,如先前描述(Stastny等2007)。
结果
CD19R+T细胞不能植入NSG小鼠中。已经将作为T细胞亚群的中枢记忆T细胞(TCM)表征为具有卓越的植入潜力,并且如此在过继性转移后具有治疗效力(Wang等2011b)。进一步的证据已经显示了TCM-衍生的细胞上的CAR表达似乎与使用NSG小鼠的体内异种移植物模型中的降低的体内持久性相关联。如本文中描述的研究指示,在实验中显示了持久性的此类降低,所述实验比较非转导的TCM衍生的细胞与(i)以慢病毒转导以表达CD19特异性CAR(CD19R)和作为追踪标志物的截短的EGFR(EGFRt)两者的TCM衍生的细胞,和(ii)以慢病毒转导以在细胞表面上仅表达EGFRt追踪标志物的TCM衍生的细胞的植入(图1)。查看将细胞i.v.施用到小鼠中后7和14天收集的外周血,用抗人CD45mAb染色允许检测非转导的TCM衍生的细胞(图1c)。然而,在EGFRt追踪标志物方面共染色以检测基因修饰的细胞后,明显的是,尽管输入细胞的类似水平的转导和/或EGFRt表达(图1b,78-79%阳性),与那些接受EGFRt+TCM的小鼠相比,接受CD19R/EGFRt+TCM的小鼠的外周血中有显著更少的细胞植入(图1c,p<0.0001,使用未配对Student t检验,比较第7天或第14天在每组中的CD45/EGFRt+细胞的百分比)。虽然对经CD19R/EGFRt+TCM处理的小鼠检出低水平的T细胞,但是在第7天和第14天的所有持续的T细胞为CAR阴性。此受损的体内持久性与T细胞的慢病毒转导无关,因为它对经转导而表达CAR转基因而非EGFRt转基因的细胞是特异性的。此外,这些NSG小鼠中的CD19抗原的缺乏,以及已经看到了与表达不同抗原特异性的CAR的T细胞相似的现象的实情(数据未显示)提示了外周血中的植入/持久性的缺乏是不依赖于抗原的。
HuFcγR结合CD19R+T细胞。CD19R构建体包含源自小鼠单克隆抗体FMC63的CD19特异性scFv、人IgG4Fc接头、人CD28跨膜域和胞质域、和人CD3-zeta胞质域。由于CAR构建体包含人IgG4Fc区的一部分,调查了FcR-介导的先天性免疫应答选择性清除CD19R/EGFRt+细胞,而非EGFRt+细胞的倾向。实际上,使用可溶性人FcγR1的结合测定法揭示了与未转导或仅表达EGFRt的TCM衍生的细胞形成对比,那些表达CD19R的细胞展现出可以以更高的稀释度(滴度降低)的FcγR1分子结合(图2)。值得注意地,虽然NSG小鼠是免疫缺陷的,但是已知它们仍具有表达FcR的嗜中性粒细胞和单核细胞(Ishikawa等2005;Ito等2002),如此为先前植入研究中观察到的CAR+T细胞持久性的缺乏提供潜在的基本原理。
CD19R突变体的生成。为了进一步测试对表达CAR的TCM群体的潜在的FcR介导的效应的意义,在IgG4CH2域内可以参与FcR结合的氨基酸处(L235E和/或N297Q)突变CD19特异性CAR(图3a)。还生成了具有IgG4CH2域缺失(即含有残基235和297的域缺失)的CD19特异性CAR(图3a)。将所得的单一突变体CD19R(L235E)和CD19R(N297Q)、双重突变体CD19R(EQ)(具有L235E和N297Q突变两者)、和缺失CD19Rch2Δ序列掺入不同的慢病毒构建体中,其中在与对非突变CD19R在图1a中描述的设计相似的设计中使用T2A核糖体跳跃序列,它们各自与EGFRt从单一转录物协调表达。在慢病毒转导、表达EGFRt的细胞的免疫磁性富集、和单轮快速扩增后,每个TCM衍生的品系在预期的转基因方面呈92-99%阳性(图3b),证明了突变没有不利影响CAR表达。此外,在4小时51Cr释放测定法中,这些突变无一改变这些TCM衍生的细胞的CD19特异性细胞溶解潜力(图3c).
huFcγR对具有突变IgG4间隔物的CAR的结合受损。为了测定CAR中的不同突变/缺失影响FcR结合的效力,使用各种人和鼠生物素化的可溶性FcγR,和PE-链霉亲合素(SA-PE)实施流式细胞术分析以检测FcγR对不同细胞群体的结合。表达非突变CD19R的T细胞被人FcγR1、FcγR2a和FcγR2b,以及鼠FcγR1和FcγR2b结合(图4)。比较而言,仅表达EGFRt的T细胞不被这些FcγR结合,并且表达CD19R(N297Q)、CD19R(L235E)或CD19R(EQ)突变体或CD19Rch2Δ缺失的T细胞都展示显著降低的对这些FcγR的结合。
具有CD19R突变体的T细胞展现出改善的体内植入和持久性。为了测定帮助防止FcγR结合的CD19R突变或缺失是否会转化为过继转移后增加的体内持久性,将107个表达亲本CD19R、单独的EGFRt标志物、CD19R(L235E)、CD19R(N297Q)、CD19R(EQ)、或CD19Rch2Δ的T细胞i.v.输注到NSG小鼠中。1和2周后,对外周血测定CD45+EGFRt+细胞植入(图5)。当T细胞表达单突变的CD19R(L235E)或CD19R(N297Q)时可以检出植入的EGFRt+细胞。此外,双点突变的CD19R(EQ)或CH2缺失的CD19Rch2Δ的表达挽救(rescued)T细胞植入,因为在这些组的小鼠中观察到的CD45/EGFRt+细胞水平类似于表达单独的EGFRt时看到的水平。使用在过继转移前不进行EGFRt富集的TCM衍生的细胞也观察到经基因修饰的细胞的此种挽救的植入和持久性(图8)。
具有CD19R突变体的T细胞展现出改善的治疗效力。基于植入发现,比较CD19R(EQ)或CD19Rch2Δ对TCM衍生的细胞的抗肿瘤效力的影响。LCL是一种表达CD19的肿瘤细胞系,其被转导以表达萤火虫萤光素酶(ffLuc),从而允许体内肿瘤生长的生物发光监测。对NSG小鼠i.v.施用ffLuc+LCL3天后,用PBS作为对照或5x 106个表达非突变CD19R、单独的EGFRt标志物、双点突变CD19R(EQ)、或CH2缺失的CD19Rch2Δ的T细胞i.v.治疗小鼠。TCM衍生的细胞上的CD19R(EQ)或CD19Rch2Δ表达导致肿瘤生长的显著控制(图6)。此效力与第21天时外周血中的经基因修饰的细胞的存在/持久性相关(图6d)。实际上,虽然PBS、CD19R和EGFRt对照组都必须在第21天时实施安乐死,CD19R(EQ)和CD19Rch2Δ组中的所有小鼠在100天后幸存(图6e)。虽然这些植入和效力研究聚焦于T细胞的TCM亚组,但是这些发现提示了IgG4突变对于消除FcR相互作用的积极益处不依赖于工程化改造的T细胞群体。实际上,大量PBMC衍生的T细胞,而不是TCM衍生的品系中的CD19R(EQ)表达也导致改善的抗肿瘤效力和延长的存活(p=0.0295)(图7)。
讨论
在临床上,过继性T细胞策略的体内治疗效力与过继性转移后的植入和持久性直接相关联(Heslop等2003;Brenner&Heslop 2010)。已经提出了各种方法来改善转移的T细胞持久性,包括细胞转移前的宿主淋巴耗竭(Gattinoni等2005)、细胞转移后的细胞因子支持(新近综述于(Overwijk&Schluns2009)、和使用最佳的T细胞群体进行转移(Berger等2008;Hinrichs等2011;Yang等2013;Gattinoni等2011;Cieri等2013)。上文描述的研究提供了进一步的证据,即嵌合抗原受体(CAR)设计在指导治疗细胞的植入和持久性中发挥重大的作用。先前,已经利用CAR设计通过在第二和第三代CAR中包含共刺激信号传导域来使植入和治疗细胞的持久性受益(参见Cartellieri等2010)。然而,如上文的数据还提示,用于连接CAR的配体结合域与信号传导域的序列(称为间隔物、铰链和/或接头)对于恶性疾病的鼠模型中的体内治疗结果有先前未领会的重要性。具体地,发现了Ig Fc间隔物的使用可以以与FcγR结合关联的方式潜在抑制NSG小鼠模型中表达CAR的细胞的植入和/或持久性。然后,通过CAR Fc域内的相关序列的点突变或缺失防止FcγR结合可以将过继转移细胞的体内持久性恢复到不表达CAR的细胞的体内持久性。然后,通过间隔物优化的CAR介导的增加的体内持久性转化为体内小鼠模型中的显著改善的CAR指导的抗肿瘤疗法。
过继转移的T细胞的免疫学清除不是新的问题。例如,已经显示了针对HyTK和NeoR选择基因的细胞免疫排斥响应与CAR协调表达(Berger等2006;Jensen等2010)。然而,上文描述的研究突出显示了FcR介导的针对表达CAR的T细胞的响应对于体内T细胞持久性和抗肿瘤效力的重要性。因此,研究还显示了避免此种免疫原性形式有“困境”,即在CAR设计中掺入突变以防止FcγR识别。
基于这些结果,可以将本文中描述的突变外推到人,并且因此应当提升表达含有IgG-间隔物的CAR的T细胞在人中的持久性和治疗效力。CAR T细胞植入和体内抗肿瘤效力中的任何差异可能受到鼠NSG模型系统的性质影响。已经显示了人IgG4有效结合鼠FcR以介导有力的抗体依赖性细胞介导的细胞毒性(Isaacs等Steplewski等1988)。与此相反,人FcR具有对IgG1和IgG3的最强的亲和力和降低的对IgG4的亲和力(Schroeder&Cavacini 2010;Nirula等2011)。另外,鉴于NSG小鼠缺乏血清抗体,由其先天性免疫细胞表达的FcR是未结合(unoccupied)的,并且如此具有更大的结合CAR内的IgG-Fc间隔物的潜力。除了低球蛋白血症病例外,有免疫能力的人具有约10mg/mL的高血清IgG水平(Stoop等,.1969),其可以潜在竞争含有IgG的CAR的识别。实际上,几个小组已经对人施用携带IgG-Fc的CAR T细胞,并且一些情况中在施用后通过定量PCR可检出低水平的CAR T细胞长达6周(Savoldo等2011)和甚至1年(Till等2012)。本文中描述的突变的掺入可能会进一步改善此CAR T细胞在人中的持久性。
总体上,本文报告的研究提供了下述证据,即含有Ig Fc间隔物组分的CAR应当掺入在体内防止FcR介导的细胞识别的修饰。此类修饰可以牵涉改变氨基酸序列或者序列缺失的点突变,诸如用本文中描述的CD19R(EQ)和CD19Rch2Δ构建体看到的。此类修饰不仅会在体内防止FcR表达细胞识别CAR表达免疫治疗细胞产品的能力,而且它们也可以防止转移的T细胞的无意活化和/或宿主免疫应答(Hombach等2010),所述转移的T细胞的无意活化和/或宿主免疫应答可以促成此免疫治疗策略的各种不想要的副作用。
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Claims (9)
1.对Fc受体(FcR)具有受损的结合的重组嵌合抗原受体(CAR),其包含:
抗原识别域;
包含以下氨基酸序列的间隔物域:ESKYGPPCPPCPGGGSSGGGSGGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK;
跨膜域;
胞内信号传导域,其中所述胞内信号传导域是T细胞受体zeta链信号传导域;和
一个或多个源自CD28、诱导型共刺激、OX40、CD27、DAP10、4-1BB、p56lck或2B4的共刺激胞内信号传导域。
2.权利要求1的重组CAR,其中所述抗原识别域是scFv。
3.权利要求1或2的重组CAR,其中所述抗原识别域靶向癌症关联抗原,所述癌症关联抗原选自:5T4、8H9、αvβ6整联蛋白、甲胎蛋白、B7-H6、CA-125、碳酸酐酶9、CD19、CD20、CD22、CD30、CD33、CD38、CD44、CD44v6、CD44v7/8、CD52、CD123、CD171、癌胚抗原、EGFRvIII、上皮糖蛋白-2、上皮糖蛋白-40、ErbB1/EGFR、ErbB2/HER2/neu/EGFR2、ErbB3、ErbB4、上皮肿瘤抗原、FBP、胎儿乙酰胆碱受体、叶酸盐受体-α、G250/CAIX、神经节苷脂2、神经节苷脂3、HLA-A1、HLA-A2、高分子量黑素瘤关联抗原、IL-13受体α2、KDR、k-轻链、Lewis Y、L1细胞粘附分子、黑素瘤关联抗原、间皮素、鼠CMV感染细胞、粘蛋白-1、粘蛋白-16、天然杀伤细胞2组成员D配体、神经细胞粘附分子、NY-ESO-1、癌胚抗原、前列腺干细胞抗原、前列腺特异性膜抗原、受体酪氨酸激酶样孤独受体1、由mAb IgE靶向的TAA、肿瘤关联糖蛋白-72、酪氨酸酶、和血管内皮生长因子受体。
4.权利要求1或2的重组CAR,其中所述CAR由病毒载体中插入的核酸序列编码。
5.权利要求3的重组CAR,其中所述CAR由病毒载体中插入的核酸序列编码。
6.由病毒载体转导的分离的人免疫细胞群体,所述病毒载体包含包括CAR基因的表达盒,所述基因包含编码权利要求1至3中任一项的重组嵌合抗原受体(CAR)的核苷酸序列,
其中所述人免疫细胞群体表达所述CAR基因。
7.用CAR基因转导的分离的人免疫细胞群体,其用于治疗受试者中的癌症的方法中,其中所述CAR基因包含编码以下项的核苷酸序列:
抗原识别域,其靶向对所述癌症特异性的癌症关联抗原;
包含以下氨基酸序列的间隔物域:ESKYGPPCPPCPGGGSSGGGSGGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK;
胞内信号传导域,其中所述胞内信号传导域是T细胞受体zeta链信号传导域;和
一个或多个源自CD28、诱导型共刺激、OX40、CD27、DAP10、4-1BB、p56lck或2B4的共刺激胞内信号传导域。
8.权利要求7的治疗受试者中的癌症的方法中使用的分离的人免疫细胞群体,其中与包含编码源自未修饰的免疫球蛋白Fc区的间隔物域的核苷酸序列的CAR基因转导的人免疫细胞相比,对FcR的受损的结合导致所述人免疫细胞的改善的持续性。
9.权利要求7或8的治疗受试者中的癌症的方法中使用的分离的人免疫细胞群体,所述方法进一步包括与一种或多种抗癌疗法联合施用所述CAR基因转导的人免疫细胞群体,所述抗癌疗法选自干细胞移植、放射疗法、手术切除、化学治疗剂、免疫治疗剂、靶向治疗剂或其组合。
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US20160333108A1 (en) | 2016-11-17 |
AU2023203097A1 (en) | 2023-06-08 |
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AU2020204351A1 (en) | 2020-07-16 |
EP3094653A4 (en) | 2017-08-30 |
EP3094653B1 (en) | 2019-10-23 |
CN113307880A (zh) | 2021-08-27 |
ES2767423T3 (es) | 2020-06-17 |
US20200040096A1 (en) | 2020-02-06 |
JP2017507919A (ja) | 2017-03-23 |
WO2015105522A1 (en) | 2015-07-16 |
EP3094653A1 (en) | 2016-11-23 |
JP6560235B2 (ja) | 2019-08-14 |
CA2936501A1 (en) | 2015-07-16 |
CN107074957A (zh) | 2017-08-18 |
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