CN103492406B - 嵌合抗原受体-修饰的t细胞治疗癌症的用途 - Google Patents
嵌合抗原受体-修饰的t细胞治疗癌症的用途 Download PDFInfo
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Abstract
本发明提供了治疗人癌症的组合物和方法。本发明包括涉及施用基因修饰的T细胞,以表达CAR,其中CAR包括抗原结合结构域、跨膜结构域、共刺激信号传导区和CD3ζ信号传导结构域。
Description
相关申请的交叉引用
本申请要求2010年12月9日提交的美国临时申请号61/421,470和2011年6 月29日提交的美国临时申请号61/502,649的优先权,其全部在此通过引用全文并入。
背景技术
大部分具有B-细胞恶性肿瘤——包括慢性淋巴细胞白血病(CLL)的患者,将死于他们的疾病。治疗这些患者的一个方法是基因修饰T细胞以通过嵌合抗原受体(CAR)的表达,靶向在肿瘤细胞上表达的抗原。CAR为设计来以人白细胞抗原-非依赖性的方式识别细胞表面抗原的抗原受体。利用表达CAR的基因修饰细胞治疗这些类型患者的尝试已经得到非常有限的成功。见例如,Brentjens等,2010, Molecular Therapy,18:4,666-668;Morgan等,2010,Molecular Therapy,2010 年2月23日在线公布,1-9页;和Till等,2008,Blood,112:2261-2271。
在多数癌症中,肿瘤-特异性抗原还没有被很好地定义,但在B细胞恶性肿瘤中,CD19是有吸引力的肿瘤标靶。CD19的表达限于正常和恶性B细胞(Uckun等, Blood,1988,71:13-29),所以CD19是安全测试CAR的广泛接受的标靶(target)。尽管CAR可以以类似于内源T-细胞受体的方式引发T-细胞活化,但至今对该技术的临床应用的主要阻碍已经限于CAR+T细胞的体内扩展、注入后细胞的快速消失和令人失望的临床活性(Jena等,Blood,2010,116:1035-1044;Uckun等, Blood,1988,71:13-29)。
因此,本领域迫切需要利用可体内扩展的CAR治疗癌症的组合物和方法。本发明解决了该需要。
发明内容
本发明提供了编码嵌合抗原受体(CAR)的分离的核酸序列,其中CAR包括抗原结合结构域、跨膜结构域、共刺激信号传导区和CD3ζ信号传导结构域,其中 CD3ζ信号传导结构域包括SEQ ID NO:24的氨基酸序列。
在一个实施方式中,核酸序列编码包括SEQ ID NO:12的氨基酸序列的CAR。
在一个实施方式中,编码CAR的核酸序列包括SEQ ID NO:8的核酸序列。
在一个实施方式中,CAR中的抗原结合结构域为抗体或其抗原-结合片段。优选地,抗原-结合片段为Fab或scFv。
在一个实施方式中,CAR中的抗原结合结构域结合肿瘤抗原。在一个实施方式中,肿瘤抗原与血液恶性肿瘤相关。在另一个实施方式中,肿瘤抗原与实体瘤相关。还在另一个实施方式中,肿瘤抗原选自CD19、CD20、CD22、RORl、间皮素(mesothelin)、CD33/IL3Ra、c-Met、PSMA、糖脂F77、EGFRvIII、GD-2、NY-ESO-1 TCR、MAGE A3TCR和其任何组合。
在一个实施方式中,CAR中的共刺激信号传导区包括共刺激分子的细胞内结构域,所述共刺激分子选自CD27、CD28、4-1BB、OX40、CD30、CD40、PD-1、 ICOS、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3、与CD83特异性结合的配体和其任何组合。
在一个实施方式中,CAR中的CD3ζ信号传导结构域由SEQ ID NO:18的核酸序列编码。
本发明也提供了分离的CAR,其包括抗原结合结构域、跨膜结构域、共刺激信号传导区和CD3ζ信号传导结构域,其中CD3ζ信号传导结构域包括SEQ ID NO: 24的氨基酸序列。
本发明也提供了包括编码CAR的核酸序列的细胞,其中CAR包括抗原结合结构域、跨膜结构域、共刺激信号传导区和包括SEQ ID NO:24的氨基酸序列的 CD3ζ信号传导结构域。
在一个实施方式中,包括CAR的细胞选自T细胞、自然杀伤(NK)细胞、细胞毒性T淋巴细胞(CTL)和调节T细胞。
在一个实施方式中,当CAR的抗原结合结构域结合它相应的抗原时,包括 CAR的细胞显示了抗肿瘤免疫。
本发明也提供了包括编码CAR的核酸序列的载体,其中CAR包括抗原结合结构域、共刺激信号传导区和CD3ζ信号传导结构域,其中CD3ζ信号传导结构域包括SEQ ID NO:24的氨基酸序列。
本发明也提供了刺激对哺乳动物中靶细胞群或组织的T细胞-介导的免疫应答的方法。在一个实施方式中,该方法包括施用给哺乳动物有效量的基因修饰以表达CAR的细胞,其中CAR包括抗原结合结构域、共刺激信号传导区和包括SEQ ID NO:24的氨基酸序列的CD3ζ信号传导结构域,其中选择抗原结合结构域以特异性识别靶细胞群或组织。
本发明也提供了提供哺乳动物中抗肿瘤免疫的方法。在一个实施方式中,该方法包括施用给哺乳动物有效量的基因修饰以表达CAR的细胞,其中CAR包括抗原结合结构域、共刺激信号传导区和包括SEQ ID NO:24的氨基酸序列的CD3ζ信号传导结构域,由此提供哺乳动物中的抗肿瘤免疫。
本发明也包括治疗具有与升高的肿瘤抗原表达相关的疾病、紊乱或病症的哺乳动物的方法。在一个实施方式中,该方法包括施用给哺乳动物有效量的基因修饰以表达CAR的细胞,其中CAR包括抗原结合结构域、共刺激信号传导区和包括SEQ ID NO:24的氨基酸序列的CD3ζ信号传导结构域,由此治疗哺乳动物。
在一个实施方式中,细胞为自体T细胞。
在一个实施方式中,肿瘤抗原选自CD19、CD20、CD22、RORl、间皮素、 CD33/IL3Ra、c-Met、PSMA、糖脂F77、EGFRvIII、GD-2、NY-ESO-1TCR、MAGE A3TCR和其任何组合。
本发明也提供了治疗具有慢性淋巴细胞白血病的人的方法。在一个实施方式中,该方法包括施用给人基因工程改造以表达CAR的T细胞,其中CAR包括抗原结合结构域、共刺激信号传导区和包括SEQ ID NO:24的氨基酸序列的CD3ζ信号传导结构域。
在一个实施方式中,人对至少一种化疗剂具有抗性。
在一个实施方式中,慢性淋巴细胞白血病为难治疗的CD19+白血病和淋巴瘤。
本发明也包括在诊断患有癌症的人中产生基因工程改造的T细胞的持续群的方法。在一个实施方式中,该方法包括施用给人基因工程改造的以表达CAR的T 细胞,其中CAR包括抗原结合结构域、共刺激信号传导区和包括SEQ ID NO:24 的氨基酸序列的CD3ζ信号传导结构域,其中基因工程改造的T细胞的持续群在施用后,在人中持续至少一个月。
在一个实施方式中,基因工程改造的T细胞的持续群包括至少一种选自以下的细胞:施用给人的T细胞、施用给人的T细胞的子代和其组合。
在一个实施方式中,基因工程改造的T细胞的持续群包括记忆T细胞。
在一个实施方式中,基因工程改造的T细胞的持续群在施用后,在人中持续至少三个月。在另一个实施方式中,基因工程改造的T细胞的持续群在施用后,在人中持续至少四个月、五个月、六个月、七个月、八个月、九个月、十个月、十一个月、十二个月、两年或三年。
在一个实施方式中,慢性淋巴细胞白血病被治疗。
本发明也提供了在诊断患有癌症的人中扩展基因工程改造的T细胞群的方法。在一个实施方式中,该方法包括施用给人基因工程改造的以表达CAR的T细胞,其中CAR包括抗原结合结构域、共刺激信号传导区和包括SEQ ID NO:24的氨基酸序列的CD3ζ信号传导结构域,其中施用的基因工程改造的T细胞在人中产生子代T细胞群。
在一个实施方式中,人中的子代T细胞包括记忆T细胞。
在一个实施方式中,T细胞为自体T细胞。
在另一个实施方式中,人对至少一种化疗剂具有抗性。
在一个实施方式中,癌症为慢性淋巴细胞白血病。在另一个实施方式中,慢性淋巴细胞白血病为难治疗的CD19+白血病和淋巴瘤。
在一个实施方式中,子代T细胞群在施用后在人中持续至少三个月。在另一个实施方式中,子代T细胞的群在施用后,在人中持续至少四个月、五个月、六个月、七个月、八个月、九个月、十个月、十一个月、十二个月、两年或三年。
在一个实施方式中,癌症被治疗。
附图说明
当与附图结合阅读时,将更好地理解本发明的优选实施方式的以下详细描述。为了说明本发明的目的,在附图中显示了目前优选的实施方式。然而,应当理解本发明不限于附图显示的实施方式的精确布置和手段。
图1,包括图1A至1C,为基因转移载体和转基因、基因修饰的T细胞制造和临床方案设计的示意图的一系列图像。图1A描绘了显示主要功能元件的慢病毒载体和转基因。产生指导源于FMC63鼠科单克隆抗体的抗-CD19scFv、人CD8α铰合和跨膜结构域、和人4-1BB和CD3ζ信号传导结构域的表达的水泡性口炎病毒G蛋白假型临床等级慢病毒载体(命名为pELPs19BBz)。通过包括EF-lα(延伸因子-lα启动子);LTR,长末端重复;RRE,rev应答元件(cPPT)和中央终止序列(CTS),指导转基因的组成型表达。图不是按比例的。图1B描绘了T细胞制造。自体细胞经单采血液成分术获得,和T细胞由单核细胞淘洗(elutriation)富集,冲洗,并且残余的白血病细胞通过添加抗-CD3/CD28包被的顺磁珠用于阳性选择和活化T细胞而被耗尽。慢病毒载体在细胞活化时被添加,并在培养开始3天后被冲洗。细胞在摇动平台装置(WAVEBioreactor System)上扩展8-12天。在培养的最后一天中,通过经过磁场移除珠,并且收获CART19T细胞并在可注入的(infusible)培养基中冷藏。图1C描绘了临床方案设计。给予患者如上所述的淋巴耗尽化疗,随后是在 15-20分钟的时间期间内通过静脉内重力流滴注(gravity flow drip)的CART19注入 #1。在完成化疗后1至5天开始,利用在3天期间的分次剂量方法(10%、30%、 60%)提供注入。在研究第4周进行终点测定。在主动监测结束后,按照FDA指南,实验对象被转移至目的地协议,以长期跟踪。
图2,包括图2A至2F,是显示CART19细胞的持续体内扩展以及血液和骨髓中持久性的一系列图像。如图2A至2C所描绘的从全血或如图2D至2F所描绘的从骨髓中分离的DNA,如图2A和2D所描绘的从UPN01、如图2B和2E所描绘的从UPN02和如图2C和2F所描绘的从UPN03获得的样本,利用合格测定 (qualified assay)成批经历Q-PCR分析,以检测和量化CART19序列。每个数据点代表对100-200ng基因组DNA三次测量值的平均,最大%CV小于1.56%。对于测定的通过/失败参数包括扩增的斜率和效率的预定范围,和参考样本的扩增。由标准曲线范围建立的测定的定量下限为2个拷贝转基因/微克的基因组DNA;在该数字以下的样本值被考虑为估计值并显示是否至少2/3复制产生了具有%CV为值 15%的Ct值。对于UPN01和UPN03,CART19细胞在第0、1和2天被注入,和对于UPN02,CART19细胞在第0、1、2和11天被注入。
图3,包括图3A至3D,是显示以下的一系列图像:在CAR T细胞注入前后血清和骨髓细胞因子;在CART1细胞注入后的指定天,如图3A所描绘的UPN01、如图3B所描绘的UPN02和如图3C所描绘的UPN03中血清细胞因子、趋化因子和细胞因子受体的改变的纵向测量值,和来自如图3D所描绘的UPN03的骨髓中相同分析物的系列评估。利用Luminex珠阵列技术和预组装并验证的多重试剂盒,使样本经历多重分析。具有≥3倍变化的分析物被指示,并标绘为如图3A至3C所描绘的与基线的相对变化,或标绘为如图3D所描绘的绝对值。在每个时间点上每种分析物的绝对值源于在3-倍8-点稀释系列上的基于重组蛋白的标准曲线,通过标准曲线的80-120%实测/期望的截断值确定定量的上限和下限(ULOQ、LLOQ)。每个样本一式两份进行评价,计算平均值,并且在多数情况下%CV小于10%。为了适应在绝对值的宽范围内容中的统一数据显示,对每种分析物,数据显示为相对于基线值的倍数-变化。在基线值是不可检测的情况下,最低标准曲线值的一半用作基线值。分析物的标准曲线范围和基线(第0天)值(对UPN01、02和03连续地在圆括号中列出)的单位都为pg/ml:IL1-Rα:35.5-29,318(689、301、287);IL-6: 2.7-4,572(7、10.1、8.7);IFN-γ:11.2-23,972(2.8、ND、4.2);CXCL10:2.1-5,319(481、 115、287);MIP-1β:3.3-7,233(99.7、371、174);MCP-1:4.8-3,600(403、560、828); CXCL9:48.2-3,700(1,412、126、177);IL2-Rα:13.4-34,210(4,319、9,477、610); IL-8:2.4-5,278(15.3、14.5、14.6);IL-10:6.7-13,874(8.5、5.4、0.7);MIP-1α:7.1-13,778 (57.6、57.3、48.1)。
图4,包括图4A至4D,是描绘了延长的表面CART19表达和体内功能记忆 CAR的建立的一系列图像。图4A描绘了CAR-表达CD3+淋巴细胞的检测和外围和骨髓中B细胞的不存在。在CART19细胞注入后的第169天,从UPN03获得的新鲜处理的外周血或骨髓单核细胞通过流式细胞术对CAR19的表面表达(顶部) 或B细胞的存在(底部)进行评价;作为对照,从健康捐赠者ND365获得的PBMC 被染色。CD3+和B细胞群的设门策略(gating strategy)显示在图9中。为了评价CD3+ 淋巴细胞中的CAR19表达,样本与CD14-PE-Cy7和CD16-PE-Cy7(泄放通道(dump channel))和CD3-FITC的抗体进行共染色,对CD3+阳性设门,并且通过与CD8α-PE 和与Alexa-647缀合的抗-CAR19个体基因型抗体的共染色评价CD8+和CD8-淋巴细胞区室中的CAR19表达。标绘图中的数据对泄放通道-阴性/CD3-阳性细胞群设门。为了评价B细胞的存在,样本与对CD14-APC和CD3-FITC(泄放通道)的抗体进行共染色,并通过与对CD20-PE和CD19-PE-Cy-7的抗体的共染色评价泄放通道-阴性部分中B细胞的存在。在所有情况中,阴性门象限被建立在非染色对照上,如图4B和4C所描绘的。显示了CD4+(图4B)和CD8+(图4C)T细胞亚型的T细胞免疫表型分析。在T细胞注入后第56和169天,通过单采血液成分术获得的来自 UPN03的冷冻外周血样本在没有添加因子的培养基中静置过夜,冲洗,并经历用于表达T细胞记忆、活化和消耗的标记的多参数免疫表型分析。如图8所描绘的设门策略包括对泄放通道(CD14、CD16、Live/Dead Aqua)-阴性和CD3-阳性细胞最初设门,随后对CD4+和CD8+细胞阳性设门。门和象限利用FMO对照(CAR、 CD45RA、PD-1、CD25、CD127、CCR7)或通过对阳性细胞群(CD3、CD4、CD8) 和清楚描绘的亚型(CD27、CD28、CD57)设门建立;在对事件(event)的客观可视化的双指数转化后,显示数据。图4D描绘了持续CAR细胞的功能性能力(functional competence)。在T细胞注入后第56和169天通过单采血液成分术获得的来自UPN 03的冷冻外周血样本在没有添加因子的培养基中静置过夜,冲洗,并利用CD107 脱粒测定直接离体评价识别CD19-表达靶细胞的能力。在抗-CD28、抗-CD49d和 CD107-FITC的存在下两个小时的温育后,细胞混合物被收获、冲洗和经历多参数流式细胞检测分析,以评价响应CD19-表达靶CART19细胞脱粒的能力。设门策略包括对泄放通道(CD14-PE-Cy7、CD16-PE-Cy7、Live/Dead Aqua)-阴性和CD3-PE- 阳性细胞的最初门,随后是对CD8-PE-TexasRed-阳性细胞设门;显示的数据是针对CD8+设门的群。在所有情况中,阴性门象限建立在非染色对照上。
图5,包括图5A至5C,是系列图像,其描绘了CART1细胞注入后评估临床应答的实验结果。图5A描绘了UPN02用两个周期的利妥昔单抗和苯达莫司汀以最小应答进行治疗(R/B,箭头)。CART19T细胞在仅苯达莫司汀(B,箭头)后4天开始注入。耐利妥昔单抗和苯达莫司汀的白血病快速从血液中清除,如在注入的 18天内,绝对淋巴细胞计数(ALC)从60,600/μl降低至200/μl所指示的。由于身体不适和非传染性发热综合征,皮质类固醇治疗在注入后的第18天开始。参考线(点线的)指示ALC的正常上限。图5B描绘了针对CD20将来自患者UPN01和03的连续的骨髓活组织检查或凝块标本染色的实施例实验的结果。用存在于两个患者中的白血病的预处理浸润在处理后标本上不存在,伴随细胞构成和三系造血作用的正常化。UPN01没有检测到任何CLL细胞,如由流式细胞术、细胞遗传学和荧光原位杂交评估的,也没有在骨髓或血液中由流式细胞术检测到正常B细胞。UPN 03在第+23天通过流式细胞术证实具有5%残余的正常CD5-阴性B细胞,其也显示它们为多克隆的;在第+176天未检测到正常B细胞。图5C描绘了利用连续CT 成像评估耐化疗的普遍性淋巴结病的快速消散(resolution)的实验结果。双侧腋窝肿块(axillary mass)在注入后的第83(UPN01)和31(UPN03)天消散,如箭头和圆圈指示的。
图6,包括图6A至6C,是一系列图像,其描绘了UPN01、02、03的循环中的绝对淋巴细胞计数和总CART19+细胞。利用来自CBC值的绝对淋巴细胞计数并假设5.0L体积的血液,对所有3个实验对象,绘制循环中淋巴细胞总数(总的正常细胞和CLL细胞)对总CART19+细胞的图。循环中的CART19细胞总数如下计算:通过利用串联CBC值与绝对淋巴细胞计数和Q-PCR标记值,如图2所描绘的,将拷贝数/ng DNA转化为平均%标记,如本文其他地方所述的。发现Q-PCR% 标记与注入产物的流式细胞术特性和来自其中伴随的流式细胞术数据可通过染色直接计数CART19细胞获得的样本数据紧密相关(<2倍变化)。
图7,包括图7A至7D,是一系列图像,其描绘了涉及T细胞注入后71天, UPN-01PBMC中CART19-阳性细胞的直接离体检测的实验。在注入后第71天,单采血液成分术后新鲜收集或在用于制造T细胞产物(基线)的单采血液成分术时冷冻并在染色前存活地解冻的UPN-01PBMC,经历流式细胞计数分析,以检测在表面上表达CAR19部分的CART19细胞的存在。为了评价CAR19在淋巴细胞中的表达,将样本与CD3-PE和缀合至Alexa-647的抗-CAR19个体基因型抗体共染色,或与仅CD3-PE(CAR19的FMO)共染色。图7A描绘了最初的淋巴细胞门基于前向和侧向散射(FSC对SSC),随后对CD3+细胞设门建立。图7B描绘了CD3+ 淋巴细胞门;图7C描绘了CAR个体基因型染色;图7D描绘了CAR个体基因型 FMO。CAR19-阳性门建立在CAR19FMO样本上。
图8,包括图8A至8C,是一系列图像,其描绘了在UPN03血液标本中通过使用多色流式细胞术鉴定CART19表达的设门策略。图8C的设门策略显示为针对 UPN03第56天的样本,并为在UPN03第169天样本上使用的策略的代表。图 8A描绘了初级门:Dump(CD14、CD16、LIVE/dead Aqua)阴性,CD3-阳性。图8B 描绘了次级门:CD4-阳性,CD8阳性。图8C描绘了三级门:CAR19-阳性和CAR19- 阴性,其建立在CAR FMO样本(最右图)上。
图9描绘了直接鉴定血液和骨髓标本中的CART19表达和B细胞的设门策略。图4A的设门策略,其显示外周和骨髓中的CAR-表达CD3+淋巴细胞的检测和B 细胞的缺失:左标绘图:细胞门;上图:CD3+细胞的阳性门;下图:B细胞的阴性门(CD14-阴性,CD3-阴性)。NC365:来自健康捐赠者的外周血对照细胞。
图10为概括患者人口统计学特征和应答的图像。
图11描绘了CART-19细胞的制造方法。
图12,包括图12A至12D,为描绘了患者临床应答的一系列图像。图12A显示用于感染该患者T细胞的慢病毒载体。产生水泡性口炎病毒G蛋白(pELPs 19-BB-z)的假型的、临床级慢病毒载体,其指导源于FMC63鼠科单克隆抗体的抗 -CD19scFv、人CD8α铰合和跨膜结构域、和人4-1BB和CD3ζ信号传导结构域的表达。在图12A底部的CAR19转基因的细节显示了主要的功能元件。该图不是按比例的。3'LTR指示3'长末端重复;5'LTR:5'长末端重复;Amp R:氨苄西林抗性基因;牛GH Poly A:具有多腺苷酸化尾的牛生长激素;cPPT/CTS:具有中心终止序列的中心聚嘌呤区;EF-lα:延伸因子1-α;env:包膜;gag:群特异性抗原; pol:编码聚合酶和逆转录酶的HIV基因;R:重复;RRE:rev应答元件;scFv:单链可变片段;TM:跨膜;和WPRE:土拨鼠肝炎病毒后转录调节元件。图12B 显示在首次CART19-细胞注入后从第1天至第28天的血清肌酸酐、尿酸和乳酸脱氢酶(LDH)水平。峰值水平与肿瘤溶解综合征的住院治疗同时发生。图12C显示在化疗后第3天(第-1天,在CART19-细胞注入前)和在CART19-细胞注入后第23天和第6个月获得的骨髓-活组织检查标本(苏木精和曙红)。基线标本显示了具有三系造血作用的细胞过多骨髓(60%),其由占总细胞构成40%的小的、成熟的淋巴细胞的占主导的间质聚集体浸润。第23天获得的标本显示对慢性淋巴白血病(CLL) 为阴性的残余淋巴聚集体(10%),和T细胞和CD5-阴性B细胞的混合物。注入后 6个月获得的标本显示三系造血作用,没有淋巴聚集体和CLL继续缺失。图12D 显示了在该患者被招入研究前和在首次注入后第31天和第104天获得的对比增强 (照影增强)的CT扫描。注入前(preinfusion)CT扫描显示l至3-cm双侧肿块。腋淋巴结病的衰退发生在注入后1个月内并为持续性的。箭头强调在治疗前多种扩大的淋巴结和在治疗后可比CT扫描上的淋巴结应答。
图13,包括图13A至13E,是一系列图像,其描绘了嵌合抗原受体T-细胞注入前后的血清和骨髓细胞因子。细胞因子干扰素-γ(图13A)、干扰素-γ-刺激的趋化因子C-X-C基序趋化因子10(CXCL10)(图13B)和C-X-C基序配体9(CXCL9)(图 13C)和白细胞介素-6(图13D)的一系列测量值在指示的时间点上进行测量。这些炎性细胞因子和趋化因子的增加与肿瘤溶解综合征的开始同时发生。低水平的白细胞介素-6在基线上检测到,而干扰素-γ、CXCL9和CXCL10在基线上的检测限以下。患者中的分析物标准曲线范围和基线值——提供在圆括号内——如下:干扰素-γ:11.2至23,972pg每毫升(1.4pg每毫升);CXCL10:2.1至5319pg每毫升(274 pg每毫升);CXCL9:48.2至3700pg每毫升(177pg每毫升);白细胞介素-6:2.7 至4572pg每毫升(8.3pg每毫升);肿瘤坏死因子α(TNF-α):1.9至4005pg每毫升 (不可检测);和可溶白细胞介素-2受体:13,4至34,210pg每毫升(644pg每毫升)。图13E显示骨髓中免疫应答的诱导。细胞因子TNF-α、白细胞介素-6、干扰素-γ、趋化因子CXCL9和可溶白细胞介素-2受体在CART19-细胞注入前后的指定天,在从骨髓吸取物中获得的上清液中进行测量。白细胞介素-6、干扰素-γ、CXCL9 和可溶白细胞介素-2受体的水平增加与肿瘤溶解综合征、峰值嵌合抗原受体T-细胞浸润和白血病浸润的根除同时发生。
图14,包括图14A至14C,是描绘了体内嵌合抗原受体T细胞的扩展和持久性的一系列图像。基因组DNA(gDNA)从在嵌合抗原受体T-细胞注入前后的一系列时间点上收集的该患者的全血(图14A)和骨髓吸取物(图14B)的样本中分离,并用于定量实时聚合酶链反应(PCR)分析。如在转基因DNA和表达CAR19的淋巴细胞百分数的基础上评估的,嵌合抗原受体T细胞扩展至的水平高于外周血和骨髓中最初移植物移入水平的1000倍。嵌合抗原受体T细胞的峰值水平与肿瘤溶解综合征时间地相关。在第0天获得的血液样本和在第1天获得的骨髓样本在基线上没有PCR信号。基线上骨髓吸取物的流式细胞计数分析(图14C)显示用克隆的CD19+CD5+细胞的占主导的浸润——如通过免疫球蛋白κ轻链染色评估的,具有极少量的T细胞。在注入后第31天,存在CD5+T细胞,并且没有检测到正常或恶性的B细胞。该数目指示每个象限中细胞的相对频率。x轴和y轴两者显示log10 比例范围。该设门策略包括左边方框中对CD19+和CD5+细胞的最初设门,和随后对CD19+CD5+亚型的免疫球蛋白κ和λ表达的鉴定(右边方框)。
发明详述
本发明涉及治疗癌症的组合物和方法,所述癌症包括但不限于血液学恶性肿瘤和实体瘤。本发明涉及被转导以表达嵌合抗原受体(CAR)的T细胞的过继细胞转移的策略。CAR是联合对期望抗原(例如,肿瘤抗原)的基于抗体的特异性和T细胞受体-活化细胞内结构域以产生显示特异性抗肿瘤细胞免疫活性的嵌合蛋白的分子。
本发明一般地涉及被基因修饰以稳定表达期望的CAR的T细胞的应用。表达 CAR的T细胞在本文中被称为CAR T细胞或CAR修饰T细胞。优选地,该细胞可被基因修饰,以在它表面上稳定表达抗体结合结构域,给予MHC非依赖性的新型抗原特异性。在一些例子中,T细胞被基因修饰,以稳定表达CAR,所述CAR 将特异性抗体的抗原识别结构域与CD3-ζ链或FcyRI蛋白的细胞内结构域联合成为单一嵌合蛋白。
在一个实施方式中,本发明的CAR包括具有抗原识别结构域、跨膜结构域和胞浆结构域的胞外结构域。在一个实施方式中,使用天然与CAR中的结构域之一相关联的跨膜结构域。在另一个实施方式中,可选择跨膜结构域,或可由氨基酸置换修饰,以避免这样的结构域结合至相同或不同的表面膜蛋白的跨膜结构域,以最小化与受体复合物的其他成员的相互作用。优选地,跨膜结构域为CD8铰合结构域。
相对于胞浆结构域,本发明的CAR可被设计以由其本身包括CD28和/或 4-1BB信号传导结构域,或与在本发明的CAR的内容下有用的任何其他期望的胞浆结构域(一个或多个)联合。在一个实施方式中,CAR的胞浆结构域可被设计以进一步包括CD3-ζ的信号传导结构域。例如,CAR的胞浆结构域可包括但不限于 CD3-ζ、4-1BB和CD28信号传导模块和其组合。因此,本发明提供了CAR T细胞和它们用于过继疗法的方法。
在一个实施方式中,本发明的CAR T细胞可通过将包括期望的CAR的慢病毒载体引入细胞而产生,所述期望的CAR是例如包括抗-CD19、CD8α铰合和跨膜结构域、和人4-1BB和CD3ζ信号传导结构域的CAR。本发明的CAR T细胞能够体内复制,产生可导致持续肿瘤控制的长期持久性。
在一个实施方式中,本发明涉及利用淋巴细胞注入施用表达CAR的基因修饰 T细胞,以治疗具有癌症或处于具有癌症风险下的患者。优选地,自体淋巴细胞注入用于治疗。自体PBMC从需要治疗的患者收集,和T细胞利用本文描述和本领域已知的方法进行活化和扩展,并且随后注入返回患者。
还在另一个实施方式中,本发明一般地涉及处于形成CLL的风险下的患者的治疗。本发明也包括治疗恶性肿瘤或自身免疫疾病,其中患者的化疗和/或免疫疗法产生患者的显著免疫抑制,由此增加患者形成CLL的风险。
本发明包括利用表达包括CD3-ζ和4-1BB共刺激结构域两者的抗-CD19CAR 的T细胞(也被称为CART19T细胞)。本发明的CART19T细胞可承受稳固的体内 T细胞扩展,并可建立CD19-特异性记忆细胞,其在血液和骨髓中以高水平持续延长的时间量。在一些例子中,本发明的注入患者的CART19T细胞可消除具有晚期耐化疗CLL的患者体内的白血病细胞。然而,本发明不限于CART19T细胞,更确切地,本发明包括与选自CD137(4-1BB)信号传导结构域、CD28信号传导结构域、CD3ζ信号传导结构域和其任何组合的一个或多个细胞内结构域融合的任何抗原结合部分。
定义
除非另有定义,本文使用的所有的技术和科学术语具有与本发明涉及领域的技术人员通常理解的相同的含义。尽管可在测试本发明的实践中使用类似于或等于本文描述的那些的任何方法和材料,但优选的材料和方法在本文中进行描述。在描述和要求保护本发明中,将使用以下术语。
也应理解本文使用的术语仅是为了描述具体实施方式的目的,并不意欲是限制性的。
本文使用冠词“一个(a)”和“一个(an)”,指的是该冠词语法对象的一个或多于一个(即,指的是至少一个)。以例子说明,“一个元件”表示一个元件或多于一个的元件。
如本文使用的“大约”,当指的是可测量的值诸如量、时间期间等时,表示包括从给定值±20%或±10%的变化,更优选±5%,甚至更优选±1%,和还要更优选±0.1%的变化,只要这种变化适于实施公开的方法。
“活化”,如本文所用的,指的是已经被充分刺激以诱导可检测的细胞增殖的T细胞的状态。活化也可与诱导的细胞因子产生和可检测的效应子功能相关。术语“活化的T细胞”等指的是经历细胞分裂的T细胞。
术语“抗体”,如本文所用的,指的是与抗原特异性结合的免疫球蛋白分子。抗体可为源于自然源或源于重组源的完整的免疫球蛋白,并可为完整免疫球蛋白的免疫反应部分。抗体通常为免疫球蛋白分子的四聚物。本发明中的抗体可以以多种形式存在,包括例如,多克隆抗体、单克隆抗体、Fv、Fab和F(ab)2,以及单链抗体和人源化抗体(Harlow等,1999,In:Using Antibodies:A Laboratory Manual, Cold Spring Harbor LaboratoryPress,NY;Harlow等,1989,In:Antibodies:A Laboratory Manual,Cold Spring Harbor,New York;Houston等,1988,Proc.Natl. Acad.Sci.USA85:5879-5883;Bird等,1988,Science242:423-426)。
术语“抗体片段”指的是完整抗体的一部分,并指的是完整抗体的抗原决定可变区。抗体片段的例子包括但不限于Fab、Fab'、F(ab')2和Fv片段,由抗体片段形成的线性抗体、scFv抗体和多特异性抗体。
“抗体重链”,如本文所用的,指的是以它们自然发生构象存在于所有抗体分子的两种类型的多肽链中较大的链。
“抗体轻链”,如本文所用的,指的是以它们自然发生构象存在于所有抗体分子的两种类型的多肽链中较小的链,κ和λ轻链指的是两种主要的抗体轻链同种型。
如本文所用的术语“合成抗体”,指利用重组DNA技术产生的抗体,诸如例如,由如本文所述的噬菌体表达的抗体。该术语也应当被解释为指已经由DNA分子的合成产生的抗体,所述DNA分子编码抗体并且该DNA分子表达抗体蛋白或规定抗体的氨基酸序列,其中DNA或氨基酸序列已经利用本领域可用和公知的合成DNA或氨基酸序列技术获得。
如本文所用的术语“抗原”或“Ag”被定义为激发免疫应答的分子,该免疫应答可涉及抗体产生,或特异性免疫活性细胞的活化,或两者。技术人员将理解任何大分子——实际上包括所有的蛋白质或肽,可用作抗原。此外,抗原可源自重组或基因组DNA。技术人员将理解任何DNA——其包括编码引起免疫应答的蛋白质的核苷酸序列或部分核苷酸序列,因此编码如本文使用的术语“抗原”。此外,本领域技术人员将理解抗原不必单独地由基因的全长核苷酸序列编码。容易显而易见的是本发明包括但不限于,多于一个的基因的部分核苷酸序列的用途,并且这些核苷酸序列以不同的组合进行布置,以引起期望的免疫应答。此外,技术人员将理解抗原根本不必由“基因”进行编码。容易显而易见的是抗原可被产生、合成或可源自生物学样本。这种生物学样本可包括但不限于组织样本、肿瘤样本、细胞或生物学流体。
如本文所用的术语“抗肿瘤效应”,指的是生物学效应,其可由肿瘤体积的减少、肿瘤细胞数的减少、转移数的减少、预期寿命的增加或与癌性病症相关的各种生理症状的改善清楚表示。“抗肿瘤效应”也可由本发明的肽、多核苷酸、细胞和抗体在预防肿瘤在第一位置发生的能力清楚表示。
根据本发明,术语“自体抗原”指由免疫系统错误识别为外源(foreign)的任何自身抗原。自体抗原包括但不限于细胞蛋白、磷蛋白、细胞表面蛋白、细胞脂质、核酸、糖蛋白,包括细胞表面受体。
如本文所用的术语“自身免疫疾病”被定义为由自身免疫应答产生的紊乱。自体免疫疾病是对自身抗原的不适当和过度应答的结果。自身免疫疾病的例子包括但不限于阿狄森氏疾病、斑秃、强直性脊柱炎、自身免疫肝炎、自身免疫腮腺炎、克罗恩氏疾病、糖尿病(1型)、营养不良性大疱性表皮松解症、附睾炎、肾小球性肾炎、格雷夫斯氏疾病、吉兰-巴雷综合征、桥本氏疾病、溶血性贫血、系统性红斑狼疮、多发性硬化症、重症肌无力、寻常型天疱疮、牛皮癣、风湿热、类风湿性关节炎、结节病、硬皮病、斯耶格伦氏综合征、脊椎关节病变、甲状腺炎、血管炎、白癜风、粘液性水肿、恶性贫血、溃疡性结肠炎等等。
如本文所用的,术语“自体”指关于源自相同个体的任何物质,它随后被再次引入该个体。
“同种异基因的(allogeneic)”指的是源自相同物种的不同动物的移植物。
“异种的(xenogeneic)”指的是源自不同物种的动物的移植物。
如本文所用的术语“癌症”被定义为以畸变细胞的快速和失控生长为特征的疾病。癌症细胞可局部蔓延或通过血流和淋巴系统蔓延至身体的其他部分。各种癌症的例子包括但不限于乳腺癌、前列腺癌、卵巢癌、子宫颈癌、皮肤癌、胰腺癌、结肠直肠癌、肾癌、肝癌、脑癌、淋巴瘤、白血病、肺癌等等。
如本文使用的术语“共刺激配体”包括特异性结合T细胞上的关联(cognate) 共刺激分子的抗原呈递细胞(例如,aAPC、树突细胞、B细胞等等)上的分子,由此除了通过例如将TCR/CD3复合物与用肽负载的MHC分子结合提供的初级信号之外,还提供介导T细胞应答的信号,所述T细胞应答包括但不限于增殖、活化、分化等等。共刺激配体可包括但不限于CD7、B7-1(CD80)、B7-2(CD86)、PD-L1、 PD-L2、4-1BBL、OX40L、可诱导的共刺激配体(ICOS-L)、细胞间粘附分子(ICAM)、 CD30L、CD40、CD70、CD83、HLA-G、MICA、MICB、HVEM、淋巴毒素β受体、3/TR6、ILT3、ILT4、HVEM、结合Toll配体受体的激动剂或抗体和与B7-H3 特异性结合的配体。共刺激配体也包括,特别是与存在于T细胞上的共刺激分子特异性结合的抗体,诸如但不限于CD27、CD28、4-1BB、OX40、CD30、CD40、 PD-1、ICOS、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、 B7-H3和与CD83特异性结合的配体。
“共刺激分子”指的是与共刺激配体特异性结合的T细胞上的关联结合伴侣,由此介导T细胞的共刺激应答,诸如但不限于增殖,共刺激分子包括但不限于MHC I类分子、BTLA和Toll配体受体。
如本文所用的,“共刺激信号”指的是与初级信号结合,诸如TCR/CD3连接作用,导致T细胞增殖和/或关键分子的上调或下调的信号。
“疾病”是动物的一种健康状态,其中动物不能保持稳态,和其中如果不改善该疾病,则动物的健康继续恶化。与之相比,动物中的“紊乱”是一种健康状态,其中动物能够保持稳态,但其中动物的健康状态与它没有处于该紊乱相比不太有利。保持不治疗,紊乱不必定引起动物健康状态的进一步降低。
如本文所用的“有效量”,指提供治疗性或预防性益处的量。
“编码”指的是多核苷酸诸如基因、cDNA或mRNA中核苷酸的特异性序列用作模板合成在生物学过程中的其他多聚体和大分子的固有性质,所述多聚体和大分子具有核苷酸(即,rRNA、tRNA和mRNA)的限定序列或氨基酸的限定序列中的任一个和由其产生的生物学性质。因此,如果相应于那个基因的mRNA的转录和翻译在细胞或其他生物学系统中产生蛋白质,则基因编码蛋白质。核苷酸序列等同mRNA序列并通常提供在序列表中的编码链,和用作转录基因或cDNA的模板的非编码链两者,都可被称为编码那个基因或cDNA的蛋白质或其他产物。
如本文所用的“内源的”指的是来自有机体、细胞、组织或系统的或在有机体、细胞、组织或系统内产生的任何物质。
如本文所用的,术语“外源的”指的是任何从有机体、细胞、组织或系统引入的或在有机体、细胞、组织或系统外产生的物质。
如本文所用的术语“表达”被定义为由它的启动子驱动的特定核苷酸序列的转录和/或翻译。
“表达载体”指的是包括重组多核苷酸的载体,所述重组多核苷酸包括可操作地连接至待表达的核苷酸序列的表达控制序列。表达载体包括足够的用于表达的顺式作用元件;用于表达的其他元件可由宿主细胞供应或在体外表达系统中供应。表达载体包括所有本领域已知的那些,诸如并入重组多核苷酸的粘粒、质粒(例如,裸露或包含在脂质体中)和病毒(例如,慢病毒、逆转录病毒、腺病毒和腺伴随病毒)。
“同源的”指的是两个多肽之间或两个核酸分子之间的序列相似性或序列同一性。当两个比较序列中的位置被相同的碱基或氨基酸单体亚单元占据时,例如,如果两个DNA分子的每一个中的位置被腺嘌呤占据,则所述分子在那个位置上是同源的。两个序列之间的同源性百分比为由两个序列共有的匹配或同源的位置数除以比较的位置数×100的函数。例如,如果两个序列中10个位置中的6个是匹配或同源的,则两个序列是60%同源的。以例子说明,DNA序列ATTGCC和TATGGC 享有50%的同源性。通常,当比对两个序列以给出最大同源性时,进行比较。
如本文所用的术语“免疫球蛋白”或“Ig”被定义为起到抗体作用的一类蛋白质。由B细胞表达的抗体有时被称为BCR(B细胞受体)或抗原受体。包括在该类蛋白质中的五个成员为IgA、IgG、IgM、IgD和IgE。IgA为存在于身体分泌物诸如唾液、泪液、母乳、胃肠分泌物和呼吸道和泌尿生殖道的粘液分泌物中的初级抗体。IgG是最常见的循环抗体。IgM是在多数对象的初级免疫应答中产生的主要免疫球蛋白。它在凝集反应、补体结合和其他抗体应答中是最有效的免疫球蛋白,并且在抵御细菌和病毒方面是很重要的。IgD是不具有已知抗体功能的免疫球蛋白,但可用作抗原受体。IgE是在暴露于过敏原后,通过引起从肥大细胞和嗜碱性粒细胞释放介体,介导速发过敏性的免疫球蛋白。
如本文所用的,“指导材料”包括出版物、记录、图表或任何其他可用于传达本发明组合物和方法的有用性的表达媒介。本发明的试剂盒的指导材料可例如被附加在包含本发明的核酸、肽和/或组合物的容器上,或与包含核酸、肽和/或组合物的容器一起运送。可选地,指导材料可与容器分开地运送,目的是指导材料和化合物由接受者配合使用。
“分离的”指从自然状态改变或移出。例如,天然存在于活动物中的核酸或肽不是“分离的”,但部分或完全与它的自然状态的共存物质分离的同一核酸或肽是“分离的”。分离的核酸或蛋白可以以基本上纯化的形式存在,或例如,可存在于非自然环境,诸如宿主细胞。
在本发明的内容中,对于通常发生的核酸碱基使用以下缩写。“A”指的是腺苷,“C”指的是胞嘧啶,“G”指的是鸟苷,“T”指的是胸苷,和“U”指的是尿苷。
除非另有规定,“编码氨基酸序列的核苷酸序列”包括为彼此简并版本并编码相同的氨基酸序列的所有的核苷酸序列。短语编码蛋白质或RNA的核苷酸序列也可包括内含子,其程度为编码该蛋白质的核苷酸序列可在某些版本中包含内含子(一个或多个)。
如本文所用的“慢病毒”指的是逆转录病毒科的属。在逆转录病毒中慢病毒是唯一能够感染非分裂细胞的;它们可传递显著量的遗传信息进入宿主细胞的 DNA,以便它们是基因传递载体的最有效的方法之一。HIV、S1V和FIV是所有慢病毒的例子。源自慢病毒的载体提供了完成显著水平基因体内转移的工具。
如本文所用的术语“调节”指与缺少治疗或化合物的对象中的应答水平相比,和/或与以其他方式相同但未治疗的对象中的应答水平相比,介导对象中应答水平的可检测的增加或减少。该术语包括扰乱和/或影响天然信号或应答,由此介导对象优选人的有益的治疗性应答。
除非另有规定,“编码氨基酸序列的核苷酸序列”包括为彼此简并版本并编码相同的氨基酸序列的所有核苷酸序列。编码蛋白质和RNA的核苷酸序列可包括内含子。
术语“可操作地连接”指的是调节序列和异源核酸序列之间的功能连接,其产生后者的表达。例如,当第一核酸序列位于与第二核酸序列的功能关系中时,第一核酸序列与第二核酸序列可操作地连接。例如,如果启动子影响编码序列的转录或表达,则启动子被可操作地连接至编码序列。通常地,可操作地连接的DNA 序列是邻近的,其中在相同的阅读框中必须连接两个蛋白编码区。
术语“过表达的”肿瘤抗原或肿瘤抗原的“过表达”意欲指示相对于来自组织或器官的正常细胞的表达水平,来自疾病区如患者的特定组织或器官内的实体瘤的细胞中肿瘤抗原表达的异常水平。具有以肿瘤抗原过表达为特征的实体瘤或血液学恶性肿瘤的患者可由本领域已知的标准测定确定。
免疫原性组合物的“肠胃外”施用包括例如皮下(s.c)、静脉内(i.v.)、肌肉内(i.m.) 或胸骨内注射,或注入技术。
术语“患者”、“对象”、“个体”等等在本文中可交换使用,并指的是服从本文描述方法的任何动物或其细胞,不论是体外或原位。在一些非限制性实施方式中,患者、对象或个体为人。
如本文所用的术语“多核苷酸”被定义为核苷酸链。此外,核酸为核苷酸的多聚体。因此,如本文所用的核酸和多核苷酸是可交换的。本领域技术人员具有核酸为可被水解成单体“核苷酸”的多核苷酸的一般常识。单体核苷酸可被水解成核苷。如本文所用的多核苷酸包括但不限于通过本领域可用的任何手段获得的所有的核酸序列,所述手段包括但不限于重组手段,即,从重组文库或细胞基因组,利用普通克隆技术和PCRTM等等克隆核酸序列,和合成手段。
如本文所用的,术语“肽”、“多肽”和“蛋白质”可交换使用,并指的是由肽键共价连接的氨基酸残基组成的化合物。蛋白或肽必须包含至少两个氨基酸,和对可包括蛋白质或肽的序列的最大数目的氨基酸没有限制。多肽包括任何肽或蛋白质,所述肽或蛋白质包括通过肽键相互连接的两个或多个氨基酸。如本文所用的,该术语指的是短链,其在本领域中也例如通常被称为肽、寡肽和寡聚体;和较长链,其在本领域中通常被称为蛋白质,其具有很多类型。“多肽”包括例如生物学活性片段、基本上同源的多肽、寡肽、同二聚体、异二聚体、多肽的变体、修饰多肽、衍生物、类似物、融合蛋白等等。多肽包括天然肽、重组肽、合成肽或其组合。
如本文所用的术语“启动子”被定义为开始多核苷酸序列的特异性转录需要的,由细胞的合成机器识别,或引导合成机器的DNA序列。
如本文所用的,术语“启动子/调节序列”指可操作地连接至启动子/调节序列的基因产物表达所需的核酸序列。在一些例子中,该序列可为核心启动子序列,并且在其他例子中,该序列也可包括基因产物表达所需的增强子序列和其他调节元件。启动子/调节序列可例如为以组织特异方式表达基因产物的序列。
“组成型”启动子为核苷酸序列,其当与编码或规定基因产物的多核苷酸可操作地连接时,使得在细胞的多数或所有生理学条件下在细胞中产生基因产物。
“诱导型”启动子为核苷酸序列,其当与编码或规定基因产物的多核苷酸可操作地连接时,使得在基本上仅当相应于启动子的诱导物存在于细胞中时,在细胞中产生基因产物。
“组织-特异性”启动子为核苷酸序列,其当与编码基因或由基因规定的多核苷酸可操作地连接时,使得基本上只要细胞为相应于启动子的组织类型的细胞,则在细胞中产生基因产物。
如本文所用的关于抗体的术语“特异性结合”指识别特异性抗原但基本上不识别或结合样本中的其他分子的抗体。例如,特异性结合来自一个物种的抗原的抗体也可结合来自一个或多个物种的抗原。但是,这种跨种反应性本身不改变抗体的类别成为特异性的。在另一个实例中,特异性结合抗原的抗体也可结合抗原的不同等位基因形式。然而,这种交叉反应性本身不改变抗体的类别成为特异性的。在一些例子中,术语“特异性的结合”或“特异性地结合”可关于抗体、蛋白质或肽与第二化学种类的相互作用使用,用于指该相互作用依赖化学种类上特定结构(例如,抗原决定簇或表位)的存在;例如,抗体通常识别和结合特异性蛋白结构而不是一般地识别和结合蛋白质。如果抗体对表位“A”是特异性的,则在包含标记的“A”和抗体的反应中存在包含表位A(或游离的、未标记的A)的分子,将降低结合至抗体的标记的A的量。
通过术语“刺激”指通过结合刺激分子(例如,TCR/CD3复合物)与它的关联配体,由此介导信号转导事件——诸如但不限于经TCR/CD3复合物的信号转导——诱导的初级应答。刺激可介导某些分子的改变的表达,诸如TGF-β的下调和/或细胞骨架结构的再组织等等。
“刺激分子”,作为本文使用的术语,指与存在于抗原呈递细胞上的关联刺激配体特异性结合的T细胞上的分子。
如本文所用的“刺激配体”指如此配体,其当存在于抗原呈递细胞(例如,aAPC、树突细胞、B-细胞等等)上时,可与T细胞上的关联结合伴侣(在本文中被称为“刺激分子”)特异性结合,由此介导T细胞的初级应答,其包括但不限于,活化、免疫应答的开始、增殖等等。刺激配体在本领域中是公知的,并包括,特别是利用肽、抗-CD3抗体、超激动剂抗-CD28抗体和超激动剂抗-CD2抗体负载的MHC I 类分子。
术语“对象”意欲包括在其内可引起免疫应答的活有机体(例如,哺乳动物)。对象的例子包括人、狗、猫、小鼠、大鼠和其转基因物种。
如本文所用的“基本上纯化的”细胞为基本上不含其他细胞类型的细胞。基本上纯化的细胞也指的是已经与在其天然发生状态中与其正常相关联的其他细胞类型分离的细胞。在一些例子中,基本上纯化的细胞群指的是均质细胞群。在其他例子中,该术语简单地指的是已经与在其天然状态中与其正常相关联的细胞分离的细胞。在一些实施方式中,体外培养细胞。在其他实施方式中,不在体外培养细胞细胞。
如本文所用的术语“治疗性的”表示治疗和/或预防。治疗性效应通过疾病状态的抑制、缓和或根除获得。
术语“治疗有效量”指的是将引起由研究者、兽医、医学医生或其他临床医生正在寻找的组织、系统或对象的生物学或医学应答的对象化合物的量。术语“治疗有效量”包括以下的化合物的量:当被施用时,其足以预防治疗的紊乱或疾病的迹象或症状中的一个或多个的发展,或以一定程度减轻治疗的紊乱或疾病的迹象或症状中的一个或多个。治疗有效量将根据化合物、疾病和其严重性、和待治疗的对象的年龄、重量等而变化。
“治疗”疾病,作为本文使用的术语,指降低对象经历的疾病或紊乱的至少一种迹象或症状的频率或严重性。
如本文所用的术语“转染的”或“转化的”或“转导的”指的是如此过程,通过该过程外源的核酸被转移或引入宿主细胞。“转染的”或“转化的”或“转导的”细胞是已经由外源核酸转染、转化或转导的细胞。该细胞包括原代对象细胞和它的子代。
如本文所用的短语“转录控制下”或“可操作地连接”指启动子处于与多核苷酸有关的正确的位置和朝向,以控制通过RNA聚合酶进行的转录的开始和多核苷酸的表达。
“载体”为物质组合物,其包括分离的核酸,并且其可用于传递分离的核酸至细胞内部。很多载体在本领域中是已知的,包括但不限于线性多核苷酸、与离子或两性分子化合物相关的多核苷酸、质粒和病毒。因此,术语“载体”包括自主复制的质粒或病毒。该术语也应被解释为包括便于将核酸转移入细胞的非质粒和非病毒化合物,诸如例如聚赖氨酸化合物、脂质体等等。病毒载体的例子包括但不限于,腺病毒载体、腺伴随病毒载体、逆转录病毒载体等等。
范围:在该公开中,本发明的多个方面可以以范围形式中示出。应当理解范围形式中的描述仅是为了方便和简洁,并不应被解释为对本发明范围不可动摇的限制。因此,范围的描述应被考虑为具有具体公开的所有可能的子范围以及处于那个范围内的单个数值。例如,范围诸如从1至6的描述应被考虑为具有具体公开的子范围诸如从1至3、从1至4、从1至5、从2至4、从2至6、从3至6等,以及那个范围内的单个数字,例如,1、2、2.7、3、4、5、5.3和6。不管范围的宽度如何,这一点是适用的。
说明
本发明提供了治疗癌症等疾病的组合物和方法。该癌症可为血液学恶性肿瘤、实体瘤、原发肿瘤或转移性肿瘤。优选地,该癌症为血液学恶性肿瘤,和更优选地,该癌症为慢性淋巴细胞白血病(CLL)。利用本发明的组合物和方法可治疗的其他疾病包括病毒、细菌和寄生虫感染以及自身免疫疾病。
在一个实施方式中,本发明提供了工程改造以表达CAR的细胞(例如,T细胞),其中CAR T细胞显示抗肿瘤性质。本发明的CAR可被工程改造以包括胞外结构域,所述胞外结构域具有融合至T细胞抗原受体复合物ζ链(例如,CD3ζ)的细胞内信号传导结构域的抗原结合结构域。本发明的CAR当在T细胞中表达时,能够基于抗原结合特异性改变(redirect)抗原识别。示例性抗原为CD19,因为该抗原在恶性B细胞上表达。然而,本发明不限于靶向CD19。相反地,本发明包括任何抗原结合部分,当其结合其关联抗原时,影响肿瘤细胞,以便肿瘤细胞不生长、被促使死亡或以其他方式被影响,以便患者的肿瘤负荷(tumor burden)缩小或消除。抗原结合部分优选与来自共刺激分子和ζ链中的一个或多个的细胞内结构域融合。优选地,抗原结合部分与选自CD137(4-1BB)信号传导结构域、CD28信号传导结构域、CD3ζ信号结构域和其任何组合的一个或多个细胞内结构域融合。
在一个实施方式中,本发明的CAR包括CD137(4-1BB)信号传导结构域。这是因为本发明部分地基于CAR-介导的T-细胞应答可利用共刺激结构域的添加而进一步提高的发现。例如,与没有被工程改造以表达CD137(4-1BB)的其他方式相同的CAR T细胞相比,包括CD137(4-1BB)信号传导结构域显著增加了抗肿瘤活性和CAR T细胞的体内持久性。
组合物
本发明提供了包括细胞外结构域和细胞内结构域的嵌合抗原受体(CAR)。胞外结构域包括靶-特异性结合元件,其另外被称为抗原结合部分。细胞内结构域或另外的胞浆结构域包括共刺激信号传导区和ζ链部分。共刺激信号传导区指的是包括共刺激分子的细胞内结构域的一部分CAR。共刺激分子为淋巴细胞对抗原的有效应答所需要的细胞表面分子,而不是抗原受体或它们的配体。
在CAR的胞外结构域和跨膜结构域之间,或在CAR的胞浆结构域和跨膜结构域之间,可并入间隔结构域。如本文所用的,术语“间隔结构域”通常指起到将跨膜结构域连接至多肽链的胞外结构域或胞浆结构域作用的任何寡肽或多肽。间隔结构域可包括上至300个氨基酸,优选地10至100个氨基酸和最优选地25 至50个氨基酸。
抗原结合部分
在一个实施方式中,本发明的CAR包括另外被称为抗原结合部分的靶-特异性结合元件。部分的选择取决于限定靶细胞表面的配体的类型和数目。例如,可选择抗原结合结构域,以识别用作与具体疾病状态相关的靶细胞上的细胞表面标记的配体。因此,可用作本发明的CAR的抗原部分结构域的配体的细胞表面标记的例子包括与病毒、细菌和寄生虫感染,自身免疫疾病和癌细胞相关的那些标记。
在一个实施方式中,本发明的CAR可经由工程改造特异性结合至肿瘤细胞上抗原的期望抗原结合部分被工程改造,以便靶向兴趣肿瘤抗原。在本发明的内容中,“肿瘤抗原”或“过度增生性紊乱(hyperproliferative disorder)抗原”或“与过度增生性紊乱相关的抗原”指的是对于特定过度增生性紊乱诸如癌症常见的抗原。本文讨论的抗原仅以实例的方式被包括。该列举不意欲是穷尽的,并且更多的实例对于本领域技术人员将是容易显而易见的。
肿瘤抗原是由引起免疫应答特别是T-细胞介导的免疫应答的肿瘤细胞产生的蛋白质。本发明的抗原结合部分的选择将取决于待治疗癌症的具体类型。肿瘤抗原在本领域中是公知的,并包括例如神经胶质瘤相关的抗原、癌胚抗原(CEA)、β- 人绒毛膜促性腺素、α-胎蛋白(AFP)、凝集素-反应的AFP、甲状腺球蛋白、RAGE-1、 MN-CA IX、人端粒酶反转录酶、RU1、RU2(AS)、肠羧酸酯酶、mut hsp70-2、 M-CSF、前列腺酶、前列腺-特异性抗原(PSA)、PAP、NY-ESO-1、LAGE-la、p53、 prostein、PSMA、Her2/neu、存活素和端粒酶、前列腺-癌肿瘤抗原-1(PCTA-1)、 MAGE、ELF2M、中性白细胞弹性蛋白酶、ephrinB2、CD22、胰岛素生长因子(IGF)-I、 IGF-II、IGF-I受体和间皮素。
在一个实施方式中,肿瘤抗原包括与恶性肿瘤相关的一个或多个抗原癌症表位。恶性肿瘤表达可用作免疫攻击的靶抗原的许多蛋白。这些分子包括但不限于组织-特异性抗原诸如MART-1、黑素瘤中的酪氨酸酶和GP100、和前列腺癌中的前列腺酸性磷酸酶(PAP)和前列腺-特异性抗原(PSA)。其他靶分子属于转化相关分子诸如致癌基因HER-2/Neu/ErbB-2的组。而另一组的靶抗原为胎性癌抗原诸如癌胚抗原(CEA)。在B-细胞淋巴瘤中,肿瘤-特异性个体基因型免疫球蛋白构成对个体肿瘤唯一的真正的肿瘤-特异性免疫球蛋白抗原。B-细胞分化抗原诸如CD19、 CD20和CD37是B-细胞淋巴瘤中靶抗原的其他候选物。这些抗原中的一些(CEA、 HER-2、CD19、CD20、个体基因型)已经有限成功地用作利用单克隆抗体的被动免疫疗法的标靶。
本发明中提及的该类型肿瘤抗原也可为肿瘤-特异性抗原(TSA)或肿瘤相关抗原(TAA)。TSA为对肿瘤细胞唯一的,并不发生在身体的其他细胞上。TAA相关的抗原不是对肿瘤细胞唯一的,并且相反,其在不能诱导对抗原的免疫耐受状态的病症下,也在正常细胞上进行表达。肿瘤上的抗原表达可在使免疫系统能够响应抗原的病症下发生。TAA可为在胚胎发育期间,当免疫系统不成熟并且不能响应时,在正常细胞上表达的抗原,或它们可为在正常细胞上以极低的水平正常存在的抗原,但其在肿瘤细胞上以高得多的水平进行表达。
TSA或TAA抗原的非限制性例子包括以下:分化抗原诸如 MART-l/MelanA(MART-1)、gp100(Pmel17)、酪氨酸酶、TRP-1、TRP-2和肿瘤- 特异性多谱系抗原诸如MAGE-1、MAGE-3、BAGE、GAGE-1、GAGE-2、p15;过表达的胚胎抗原诸如CEA;过表达的致癌基因和突变的肿瘤-抑制基因诸如p53、 Ras、HER-2/neu;由染色体易位产生的独特的肿瘤抗原诸如BCR-ABL、E2A-PRL、 H4-RET、1GH-IGK、MYL-RAR;和病毒抗原,诸如Epstein Barr病毒抗原EBVA和人乳头瘤病毒(HPV)抗原E6和E7。其他大的、基于蛋白的抗原包括TSP-180、 MAGE-4、MAGE-5、MAGE-6、RAGE、NY-ESO、p185erbB2、p180erbB-3、c-met、 nm-23H1、PSA、TAG-72、CA19-9、CA72-4、CAM17.1、NuMa、K-ras、β-联蛋白、CDK4、Mum-1、p15、p16、43-9F、5T4、791Tgp72、α-胎蛋白、β-HCG、BCA225、BTAA、CA125、CA15-3\CA27.29\BCAA、CA195、CA242、CA-50、 CAM43、CD68\P1、CO-029、FGF-5、G250、Ga733\EpCAM、HTgp-175、M344、 MA-50、MG7-Ag、MOV18、NB/70K、NY-CO-1、RCAS1、SDCCAG16、TA-90\Mac-2 结合蛋白\亲环蛋白C相关蛋白、TAAL6、TAG72、TLP和TPS。
在优选的实施方式中,CAR的抗原结合部分靶向如此抗原,所述抗原包括但不限于CD19、CD20、CD22、RORl、间皮素、CD33/IL3Ra、c-Met、PSMA、糖脂F77、EGFRvIII、GD-2、MY-ESO-1TCR、MAGE A3TCR等等。
取决于待靶向的期望抗原,本发明的CAR可被工程改造以包括对期望抗原靶特异性的适当的抗原结合部分。例如,如果CD19是待靶向的期望抗原,则CD19 的抗体可用作抗原结合部分,并入本发明的CAR。
在一个实施方式中,本发明的CAR的抗原结合部分靶向CD19。优选地,本发明的CAR中的抗原结合部分为抗-CD19scFV,其中抗-CD19scFV的核酸序列包括SEQ ID:14中提出的序列。在一个实施方式中,抗-CD19scFV包括编码SEQ ID NO:20的氨基酸序列的核酸序列。在另一个实施方式中,本发明的CAR的抗 -CD19scFV部分包括SEQ ID NO:20中提出的氨基酸序列。
跨膜结构域
对于跨膜结构域,CAR可被设计以包括融合至CAR的胞外结构域的跨膜结构域。在一个实施方式中,使用天然与CAR中的结构域之一相关联的跨膜结构域。在一些例子中,可选择跨膜结构域,或通过氨基酸置换进行修饰,以避免将这样的结构域结合至相同或不同的表面膜蛋白的跨膜结构域,从而最小化与受体复合物的其他成员的相互作用。
跨膜结构域可源于天然来源或合成来源。在天然来源中,该结构域可源于任何膜结合蛋白或跨膜蛋白。具体用于本发明的跨膜区可源于T-细胞受体的α、β或ζ链、CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、 CD64、CD80、CD86、CD134、CD137、CD154(即至少包括上述中的跨膜区(一个或多个))。可选地,跨膜结构域可为合成的,在该情况下,它将包括占主导的疏水残基诸如亮氨酸和缬氨酸。优选地,将在合成跨膜结构域的每一端上发现苯基丙氨酸、色氨酸和缬氨酸的三联体。任选地,短的寡肽或多肽连接体,优选长度在2 和10个氨基酸之间,可在CAR的跨膜结构域和胞浆信号传导结构域之间形成连接。甘氨酸-丝氨酸双联体提供了特别合适的连接体。
优选地,本发明的CAR中的跨膜结构域为CD8跨膜结构域。在一个实施方式中,CD8跨膜结构域包括SEQ ID NO:16的核酸序列。在一个实施方式中,CD8 跨膜结构域包括编码SEQ ID NO:22的氨基酸序列的核酸序列。在另一个实施方式中,CD8跨膜结构域包括SEQ IDNO:22的氨基酸序列。
在一些例子中,本发明的CAR的跨膜结构域包括CD8α铰合结构域。在一个实施方式中,CD8铰合结构域包括SEQ ID NO:15的核酸序列。在一个实施方式中,CD8铰合结构域包括编码SEQ ID NO:21的氨基酸序列的核酸序列。在另一个实施方式中,CD8铰合结构域包括SEQ ID NO:21的氨基酸序列。
胞浆结构域
本发明的CAR的胞浆结构域或另外的细胞内信号传导结构域是造成其中已放置CAR的免疫细胞的至少一种正常效应子功能的活化的原因。术语“效应子功能”指的是细胞的专有功能。例如,T细胞的效应子功能可为包括细胞因子分泌的细胞溶解活性或辅助活性。因此术语“细胞内信号传导结构域”指的是转导效应子功能信号并指导细胞实施专有功能的蛋白部分。尽管通常可使用整个细胞内信号传导结构域,但在很多例子中,不必使用整个链。就使用细胞内信号传导结构域的截短部分而言,这种截短部分可用于代替完整的链,只要它转导效应子功能信号。术语细胞内信号传导结构域因此指包括足以转导效应子功能信号的细胞内信号传导结构域的任何截短部分。
用于本发明的CAR的细胞内信号传导结构域的优选例子包括T细胞受体 (TCR)的胞浆序列和协同行动以在抗原受体结合后开始信号转导的共受体,以及这些序列的任何衍生物或变体和具有相同的功能能力的任何合成序列。
已知通过TCR单独产生的信号不足以完全活化T细胞,并且也需要次级或共刺激信号。因此,T细胞活化可被认为由两个不同类的胞浆信号传导序列介导:通过TCR(初级胞浆信号传导序列)开始抗原-依赖性初级活化的那些和以抗原-非依赖性方式起作用以提供次级或共刺激信号(次级胞浆信号传导序列)的那些。
初级胞浆信号传导序列以刺激方式或以抑制方式调节TCR复合物的初级活化。以刺激方式起作用的初级胞浆信号传导序列可包含信号传导基序,其已知为基于免疫受体酪氨酸的活化基序或ITAM。
包含在本发明中具有具体用途的初级胞浆信号传导序列的ITAM的例子包括源于TCRζ、FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD5、CD22、CD79a、CD79b 和CD66d的那些。特别优选地,本发明的CAR中的胞浆信号传导分子包括源于 CD3ζ的胞浆信号传导序列。
在优选的实施方式中,CAR的胞浆结构域可被设计以本身包括CD3-ζ信号传导结构域,或可与在本发明的CAR的内容中有用的任何其他期望的胞浆结构域(一个或多个)联合。例如,CAR的胞浆结构域可包括CD3ζ链部分和共刺激信号传导区。共刺激信号传导区指的是包括共刺激分子的细胞内结构域的一部分CAR。共刺激分子是淋巴细胞对抗原的有效应答所需的细胞表面分子,而不是抗原受体或它们的配体。这种分子的例子包括CD27、CD28、4-1BB(CD137)、OX40、CD30、CD40、PD-1、ICOS、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3和与CD83特异性结合的配体等等。因此,尽管本发明主要以4-1BB 作为共刺激信号传导元件的例子,但其他共刺激元件也位于本发明的范围内。
本发明的CAR的胞浆信号传导部分内的胞浆信号传导序列可以随机或以规定的顺序相互连接。任选地,短的寡肽或多肽连接体,优选长度在2和10个氨基酸,可形成该连接。甘氨酸-丝氨酸双联体提供了特别合适的连接体。
在一个实施方式中,胞浆结构域被设计以包括CD3-ζ的信号传导结构域和 CD28的信号传导结构域。在另一个实施方式中,胞浆结构域被设计以包括CD3-ζ的信号传导结构域和4-1BB的信号传导结构域。还在另一个实施方式中,胞浆结构域被设计以包括CD3-ζ的信号传导结构域和CD28和4-1BB的信号传导结构域。
在一个实施方式中,本发明的CAR中的胞浆结构域被设计以包括4-1BB的信号传导结构域和CD3-ζ的信号传导结构域,其中4-1BB的信号传导结构域包括SEQ TD NO:17中提出的核酸序列和CD3-ζ的信号传导结构域包括SEQ ID NO:18中提出的核酸序列。
在一个实施方式中,本发明的CAR中的胞浆结构域被设计以包括4-1BB的信号传导结构域和CD3-ζ的信号传导结构域,其中4-1BB的信号传导结构域包括编码SEQ ID NO:23的氨基酸序列的核酸序列,和CD3-ζ的信号传导结构域包括编码SEQ ID NO:24的氨基酸序列的核酸序列。
在一个实施方式中,本发明的CAR中的胞浆结构域被设计以包括4-1BB的信号传导结构域和CD3-ζ的信号传导结构域,其中4-1BB的信号传导结构域包括SEQ ID NO:23中提出的氨基酸序列,和CD3-ζ的信号传导结构域包括SEQ ID NO:24 中提出的氨基酸序列。
载体
本发明包括包含CAR序列的DNA构建体,其中该序列包括可操作地连接至细胞内结构域的核酸序列的抗原结合部分的核酸序列。可用于本发明的CAR的示例性细胞内结构域包括但不限于CD3-ζ、CD28、4-1BB等等的细胞内结构域。在一些例子中,CAR可包括CD3-ζ、CD28、4-1BB等等的任何组合。
在一个实施方式中,本发明的CAR包括抗-CD19scFv、人CD8铰合和跨膜结构域、和人4-1BB和CD3ζ信号传导结构域。在一个实施方式中,本发明的CAR 包括SEQ ID NO:8中提出的核酸序列。在另一个实施方式中,本发明的CAR包括编码SEQ ID NO:12的氨基酸序列的核酸序列。在另一个实施方式中,本发明的 CAR包括SEQ ID NO:12中提出的氨基酸序列。
编码期望分子的核酸序列可利用在本领域中已知的重组方法获得,诸如例如通过从表达基因的细胞中筛选文库,通过从已知包括该基因的载体中得到该基因,或通过利用标准的技术,从包含该基因的细胞和组织中直接分离。可选地,感兴趣的基因可被合成生产,而不被克隆。
本发明也提供了其中插入本发明的DNA的载体。源于逆转录病毒诸如慢病毒的载体是实现长期基因转移的合适工具,因为它们允许转基因长期、稳定的整合并且其在子细胞中增殖(propagation)。慢病毒载体具有超过源自致癌逆转录病毒诸如鼠科白血病病毒的载体的额外优点,因为它们可转导非增殖的细胞,诸如肝细胞。它们也具有低免疫原性的额外优点。
简单概括,通常通过可操作地连接编码CAR多肽或其部分的核酸至启动子,并将构建体并入表达载体,实现编码CAR的天然或合成核酸的表达。该载体对于复制和整合真核细胞可为合适的。典型的克隆载体包含可用于调节期望核酸序列表达的转录和翻译终止子、初始序列和启动子。
本发明的表达构建体也可利用标准的基因传递方案,用于核酸免疫和基因疗法。基因传递的方法在本领域中是已知的。见例如美国专利号5,399,346、5,580,859、 5,589,466,在此通过引用全文并入。在另一个实施方式中,本发明提供了基因疗法载体。
该核酸可被克隆入许多类型的载体。例如,该核酸可被克隆入如此载体,其包括但不限于质粒、噬菌粒、噬菌体衍生物、动物病毒和粘粒。特定的感兴趣载体包括表达载体、复制载体、探针产生载体和测序载体。
进一步地,表达载体可以以病毒载体形式提供给细胞。病毒载体技术在本领域中是公知的并在例如Sambrook等(2001,Molecular Cloning:A Laboratory Manual, ColdSpring Harbor Laboratory,New York)和其他病毒学和分子生物学手册中进行了描述。可用作载体的病毒包括但不限于逆转录病毒、腺病毒、腺伴随病毒、疱疹病毒和慢病毒。通常,合适的载体包含在至少一种有机体中起作用的复制起点、启动子序列、方便的限制酶位点和一个或多个可选择的标记(例如,WO01/96584; WO01/29058;和美国专利号6,326,193)。
已经开发许多基于病毒的系统,用于将基因转移入哺乳动物细胞。例如,逆转录病毒提供了用于基因传递系统的方便的平台。可利用在本领域中已知的技术将选择的基因插入载体并包装入逆转录病毒颗粒。该重组病毒可随后被分离和传递至体内或离体的对象细胞。许多逆转录病毒系统在本领域中是已知的。在一些实施方式中,使用腺病毒载体。许多腺病毒载体在本领域中是已知的。在一个实施方式中,使用慢病毒载体。
额外的启动子元件,例如增强子,调节转录开始的频率。通常地,这些位于起始位点上游的30-110bp区域中,尽管最近已经显示许多启动子也包含起始位点下游的功能元件。启动子元件之间的间隔经常是柔性的,以便当元件相对于另一个被倒置或移动时,保持启动子功能。在胸苷激酶(tk)启动子中,启动子元件之间的间隔可被增加隔开50bp,活性才开始下降。取决于启动子,表现出单个元件可合作或独立地起作用,以起动转录。
合适的启动子的一个例子为即时早期巨细胞病毒(CMV)启动子序列。该启动子序列为能够驱动可操作地连接至其上的任何多核苷酸序列高水平表达的强组成型启动子序列。合适的启动子的另一个例子为延伸生长因子-1α(EF-1α)。然而,也可使用其他组成型启动子序列,包括但不限于类人猿病毒40(SV40)早期启动子、小鼠乳癌病毒(MMTV)、人免疫缺陷病毒(HIV)长末端重复(LTR)启动子、MoMuLV 启动子、鸟类白血病病毒启动子、艾伯斯坦-巴尔(Epstein-Barr)病毒即时早期启动子、鲁斯氏肉瘤病毒启动子、以及人基因启动子,诸如但不限于肌动蛋白启动子、肌球蛋白启动子、血红素启动子和肌酸激酶启动子。进一步地,本发明不应被限于组成型启动子的应用。诱导型启动子也被考虑为本发明的一部分。诱导型启动子的使用提供了分子开关,其能够当这样的表达是期望的时,打开可操作地连接诱导型启动子的多核苷酸序列的表达,或当表达是不期望的时关闭表达。诱导型启动子的例子包括但不限于金属硫蛋白启动子、糖皮质激素启动子、孕酮启动子和四环素启动子。
为了评估CAR多肽或其部分的表达,被引入细胞的表达载体也可包含可选择的标记基因或报道基因中的任一个或两者,以便于从通过病毒载体寻求被转染或感染的细胞群中鉴定和选择表达细胞。在其他方面,可选择的标记可被携带在单独一段DNA上并用于共转染程序。可选择的标记和报道基因两者的侧翼都可具有适当的调节序列,以便能够在宿主细胞中表达。有用的可选择标记包括例如抗生素抗性基因,诸如neo等等。
报道基因用于鉴定潜在转染的细胞并用于评价调节序列的功能性。通常地,报道基因为以下基因:其不存在于受体有机体或组织或由受体有机体或组织进行表达,并且其编码多肽,该多肽的表达由一些可容易检测的性质例如酶活性清楚表示。在DNA已经被引入受体细胞后,报道基因的表达在合适的时间下进行测定。合适的报道基因可包括编码荧光素酶、β-半乳糖苷酶、氯霉素乙酰转移酶、分泌型碱性磷酸酶或绿色萤光蛋白基因的基因(例如,Ui-Tei等,2000FEBS Letters479: 79-82)。合适的表达系统是公知的并可利用已知技术制备或从商业上获得。通常,显示最高水平的报道基因表达的具有最少5个侧翼区的构建体被鉴定为启动子。这样的启动子区可被连接至报道基因并用于评价试剂调节启动子-驱动转录的能力。
将基因引入细胞和将基因表达入细胞的方法在本领域中是已知的。在表达载体的内容中,载体可通过在本领域中的任何方法容易地引入宿主细胞,例如,哺乳动物、细菌、酵母或昆虫细胞。例如,表达载体可通过物理、化学或生物学手段转移入宿主细胞。
将多核苷酸引入宿主细胞的物理方法包括磷酸钙沉淀、脂质转染法、粒子轰击、微注射、电穿孔等等。生产包括载体和/或外源核酸的细胞的方法在本领域中是公知的。见例如Sambrook等(2001,Molecular Cloning:A Laboratory Manual,Cold Spring HarborLaboratory,New York)。将多核苷酸引入宿主细胞的优选方法为磷酸钙转染。
将感兴趣的多核苷酸引入宿主细胞的生物学方法包括使用DNA和RNA载体。病毒载体,特别是逆转录病毒载体,已经成为最广泛使用的将基因插入哺乳动物例如人细胞的方法。其他病毒载体可源自慢病毒、痘病毒、单纯疱疹病毒I、腺病毒和腺伴随病毒等等。见例如美国专利号5,350,674和5,585,362。
将多核苷酸引入宿主细胞的化学手段包括胶体分散系统,诸如大分子复合物、纳米胶囊、微球、珠;和基于脂质的系统,包括水包油乳剂、胶束、混合胶束和脂质体。用作体外和体内传递工具(delivery vehicle)的示例性胶体系统为脂质体(例如,人造膜囊)。
在使用非病毒传递系统的情况下,示例性传递工具为脂质体。考虑使用脂质制剂,以将核酸引入宿主细胞(体外、离体(ex vivo)或体内)。在另一方面,该核酸可与脂质相关联。与脂质相关联的核酸可被封装入脂质体的水性内部中,散布在脂质体的脂双层内,经与脂质体和寡核苷酸两者都相关联的连接分子附接至脂质体,陷入脂质体,与脂质体复合,分散在包含脂质的溶液中,与脂质混合,与脂质联合,作为悬浮液包含在脂质中,包含在胶束中或与胶束复合,或以其他方式与脂质相关联。与组合物相关联的脂质、脂质/DNA或脂质/表达载体不限于溶液中的任何具体结构。例如,它们可存在于双分子层结构中,作为胶束或具有“坍缩的(collapsed)”结构。它们也可简单地被散布在溶液中,可能形成大小或形状不均一的聚集体。脂质为脂肪物质,其可为天然发生或合成的脂质。例如,脂质包括脂肪小滴,其天然发生在细胞质以及包含长链脂肪族烃和它们的衍生物诸如脂肪酸、醇类、胺类、氨基醇类和醛类的该类化合物中。
适于使用的脂质可从商业来源中获得。例如,二肉豆蔻酰磷脂酰胆碱(“DMPC”) 可从Sigma,St.Louis,MO中获得;磷酸二鲸蜡酯(“DCP”)可从K&K Laboratories (Plainview,NY)中获得;胆固醇(“Choi”)可从Calbiochem-Behring中获得;二肉豆蔻酰磷脂酰甘油(“DMPG”)和其他脂质可从Avanti Polar Lipids,Inc.(Birmingham, AL)中获得。氯仿或氯仿/甲醇中的脂质原液可被保存在大约-20℃下。氯仿用作唯一的溶剂,因为它比甲醇更容易蒸发。“脂质体”为通用术语,其包括通过产生封闭的脂双层或聚集体而形成的多种单一和多层脂质工具。脂质体可以以具有含有磷脂双层膜和内部水性介质的囊泡结构为特征。多层脂质体具有由水性介质分开的多个脂质层。当磷脂悬浮在过量的水性溶液中时,它们自发形成。在形成封闭的结构和使水和溶解的溶质陷入脂双层之间前,该脂质成分经历自身重排 (Ghosh等,191Glycobiology5;505-10)。然而,也包括与正常的囊泡结构相比具有溶液中的不同结构的组合物。例如,脂质可呈现胶束结构或仅作为脂质分子的非均一聚集体而存在。同样考虑的是脂质转染胺-核酸复合物。
不管用于将外源核酸引入宿主细胞的方法,或以其他方式将细胞暴露于本发明的抑制剂,以便证实在宿主细胞中存在重组DNA序列,可实施多种测定。这样的测定包括例如本领域技术人员公知的“分子生物学”测定,诸如DNA印迹法和 RNA印迹法、RT-PCR和PCR;“生物化学”测定,诸如例如通过免疫学手段(ELlSA 和蛋白质印迹)或通过本文描述的鉴定落入本发明范围内的试剂的测定,检测特定肽的存在或不存在。
T细胞的来源
在本发明的T细胞的扩展和遗传修饰前,从对象获得T细胞的来源。T细胞可从许多来源中获得,包括外周血单核细胞、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。在本发明的某些实施方式中,可使用在本领域中可用的任何数量的T细胞系。在本发明的某些实施方式中,T细胞可利用技术人员已知的任何数量的技术诸如FicollTM分离法从对象中收集的单位血液中获得。在一个优选实施方式中,来自个体循环血液中的细胞通过单采血液成分术获得。单采血液成分术产物通常包含淋巴细胞,其包括T 细胞、单核细胞、粒细胞、B细胞、其他成核的白细胞、红细胞和血小板。在一个实施方式中,可冲洗由单采血液成分术收集的细胞,以移除血浆部分并将细胞放置在适当的缓冲液或介质中,用于随后的处理步骤。在本发明的一个实施方式中,用磷酸盐缓冲盐水(PBS)冲洗细胞。在一个可选实施方式中,冲洗液缺少钙并可缺少镁,或可缺少很多——如果不是全部的话——的二价阳离子。此外,令人惊讶地,在缺少钙的情况下的初始活化步骤导致放大的活化。本领域技术人员将容易理解冲洗步骤可通过本领域中技术人员已知的方法完成,诸如根据制造商的使用说明通过使用半自动“最大限度(直流,flow-through)”沉降离心机(例如,Cobe2991 细胞处理器、Baxter CytoMate或Haemonetics细胞回收器5)。在冲洗后,细胞可重悬浮在生物相容的缓冲液中,诸如,例如,无Ca2+、无Mg2+PBS、PlasmaLyteA 或含有或不含有缓冲液的其他盐溶液。可选地,可移除单采血液成分术样本的不期望组分,并且将细胞直接重悬浮在培养基中。
在另一个实施方式中,T细胞通过溶解红细胞和耗尽单核细胞从外周血淋巴细胞中分离出来,例如,通过经过PERCOLLTM梯度的离心或通过逆流离心淘洗 (counterflowcentrifugal elutriation)。T细胞的特定亚群,诸如CD3+、CD28+、CD4+、 CD8+、CD45RA+和CD45RO+T细胞,可进一步通过阳性或阴性选择技术进行分离。例如,在一个实施方式中,T细胞通过与抗-CD3/抗-CD28(即,3×28)-缀合珠诸如M-450CD3/CD28T一起温育持续足以阳性选择期望T细胞的时间段,进行分离。在一个实施方式中,时间段为大约30分钟。在进一步的实施方式中,时间段范围为30分钟至36小时或更长,和其间的所有的整数值。在进一步的实施方式中,时间段为至少1、2、3、4、5或6个小时。还在另一个优选的实施方式中,时间段为10至24个小时。在一个优选实施方式中,温育时间段为24个小时。对于分离来自具有白血病的患者的T细胞,使用更长的温育时间诸如24个小时,可增加细胞产量。更长的温育时间可用于在与其他细胞类型相比具有更少T细胞的任何情况下分离T细胞,例如,在分离来自肿瘤组织或来自无免疫应答(immune-compromised)个体的肿瘤浸润淋巴细胞(TIL)中。进一步地,使用更长的温育时间可增加CD8+T细胞的捕获效率。因此,通过简单地缩短或延长时间,允许T细胞结合至CD3/CD28珠,和/或通过增加或减少珠与T细胞的比率(如本文中进一步描述的),在培养初始或在该过程的其他时间点上,可优先选择或排除T细胞的亚群。另外,通过增加或减少珠或其他表面上抗-CD3和/或抗-CD28 抗体的比率,在培养初始或在其他期望的时间点上,可优先选择或排除T细胞的亚群。技术人员将理解多轮选择也可用于本发明的内容中。在某些实施方式中,可期望实施选择程序并在活化和扩展过程中使用“未选择的”细胞。“未选择的”细胞也可经历更多轮的选择。
通过阴性选择的T细胞群的富集可利用涉及对阴性选择的细胞独特的表面标记的抗体的组合完成。一种方法为细胞分选和/或选择,其经阴性磁性免疫粘附或使用针对存在于阴性选择的细胞上的细胞表面标记的单克隆抗体的混合物的流式细胞术进行。例如,为了通过阴性选择富集CD4+细胞,单克隆抗体混合物通常包括对CD14、CD20、CD11b、CD16、HLA-DR和CD8的抗体。在某些实施方式中,可期望富集或阳性选择通常表达CD4+、CD25+、CD62Lhi、GITR+和FoxP3+的调节 T细胞。可选地,在某些实施方式中,T调节细胞通过抗-C25缀合珠或其他类似的选择方法耗尽。
对于通过阳性或阴性选择分离期望的细胞群,可改变细胞和表面(例如,颗粒诸如珠)的浓度。在某些实施方式中,可期望显著减少其中珠和细胞被混合在一起的体积(即,增加细胞浓度),以确保细胞和珠的最大接触。例如,在一个实施方式中,使用20亿细胞/ml的浓度。在一个实施方式中,使用10亿细胞/ml的浓度。在进一步的实施方式中,使用多于1亿细胞/ml。在进一步的实施方式中,使用10、 15、20、25、30、35、40、45或50×106细胞/ml的细胞浓度。还在另一个实施方式中,使用75、80、85、90、95或100×106细胞/ml的细胞浓度。在进一步的实施方式中,可使用125或150×106细胞/ml的浓度。使用高浓度可产生增加的细胞产量、细胞活化和细胞扩展。进一步地,使用高细胞浓度允许更有效捕获可微弱表达感兴趣的靶抗原的细胞,诸如CD28-阴性T细胞,或捕获来自有很多肿瘤细胞存在的样本(即白血病血液、肿瘤组织等)的细胞。这样的细胞群可具有治疗价值并将期望获得。例如,使用高浓度的细胞允许更有效选择正常具有更弱CD28表达的 CD8+T细胞。
在相关的实施方式中,可期望使用更低浓度的细胞。通过显著稀释T细胞和表面(例如,颗粒诸如珠)的混合物,颗粒和细胞之间的相互作用被最小化。这选择表达高数量的结合至颗粒的期望抗原的细胞。例如,在稀浓度,CD4+T细胞比CD8+ T细胞表达更高水平的CD28并更有效地被捕获。在一个实施方式中,使用的细胞浓度为5×106/ml。在其他实施方式中,使用的浓度可从大约1×105/ml至1× 106/ml,和之间的任何整数值。
在其他实施方式中,细胞可在旋转器上以变化的速度,在2-10℃或室温的任一个温度下温育变化的时间长度。
在冲洗步骤后,用于刺激的T细胞也可被冷冻。不希望被理论所束缚,通过去除细胞群中的粒细胞和以一定程度去除单核细胞,冷冻和随后的解冻步骤提供了更均一的产物。在去除血浆和血小板的冲洗步骤后,细胞可被悬浮在冷冻液中。尽管很多冷冻液和参数在本领域中是已知的,并将在该背景下是有用的,但一个方法包括使用包含20%DMSO和8%人血清白蛋白的PBS,或包含10%葡聚糖40 和5%右旋糖、20%人血清白蛋白和7.5%DMSO,或31.25%Plasmalyte-A、31.25% 右旋糖5%、0.45%NaCl、10%葡聚糖40和5%右旋糖、20%人血清白蛋白和7.5% DMSO的培养基,或包含例如Hespan和PlasmaLyte A的其他合适的细胞冷冻培养基,细胞随后被以1°每分钟的速率冷冻至-80℃,并保存在液氮储罐的蒸汽相中。可使用受控冷冻的其他方法以及在-20℃下或液氮中不受控的即刻冷冻。
在某些实施方式中,冷藏的细胞如本文所述的解冻和冲洗,并允许在使用本发明的方法活化前在室温下静止1个小时。
在本发明的内容下也考虑到的是在当可能需要如本文所述的扩展细胞前的时间段上,从对象收集血液样本或单采血液成分术产物。如此,待扩展的细胞的来源可在必要的任何时间点收集,并且期望的细胞,诸如T细胞,被分离和冷冻,以便以后在T细胞疗法中用于将受益于T细胞疗法的任何数量的疾病或病症,诸如本文所述的那些。在一个实施方式中,血液样本或单采血液成分术样本取自大体健康的对象。在某些实施方式中,血液样本或单采血液成分术样本取自处于患病风险下但还没有患病的大体健康的对象,和感兴趣的细胞被分离和冷冻以便以后使用。在某些实施方式中,T细胞可在以后的时间被扩展、冷冻和使用。在某些实施方式中,如本文所述的具体疾病的诊断后立刻但在任何治疗前,从患者收集样本。在进一步的实施方式中,在任何数量的有关治疗形式前,从来自对象的血液样本或单采血液成分术样本分离细胞,所述治疗形式包括但不限于用以下治疗:试剂,诸如那他珠单抗(natalizumab)、厄法珠单抗(efalizumab)、抗病毒剂、化疗、辐射(radiation)、免疫抑制剂,诸如环孢菌素、硫唑嘌呤、甲氨喋呤、麦考酚酯和 FK506,抗体或其他免疫烧蚀剂(immunoablative agent)诸如CAMPATH、抗-CD3 抗体、环磷酰胺(cytoxan)、氟达拉滨、环孢菌素、FK506、雷帕霉素、麦考酚酸、类固醇类、FR901228和照射(irradiation)。这些药物抑制钙依赖性磷酸酶——钙调磷酸酶(环孢菌素和FK506)或抑制对生长因子诱导的信号传导(雷帕霉素)重要的 p70S6激酶(Liu等,Cell66:807-815,1991;Henderson等,Immun.73:316-321,1991; Bterer等,Curr.Opin.Immun.5:763-773,1993)。在进一步的实施方式中,对患者分离细胞并冷冻以便以后与骨髓或干细胞移植、利用化疗剂诸如氟达拉滨、外部光束放射疗法(XRT)、环磷酰胺或抗体诸如OKT3或CAMPATH的T细胞烧蚀疗法结合(例如,之前、同时或之后)使用。在另一个实施方式中,细胞被分离,然后可被冷冻以便以后在B-细胞烧蚀疗法诸如与CD20反应的试剂例如Rituxan之后的治疗使用。
在本发明的进一步实施方式中,在治疗后直接从患者获得T细胞。在这点上,已经观察到在某些癌症治疗后,特别是用损坏免疫系统的药物的治疗后,在治疗后不久当患者将正常地从治疗中恢复期间,获得的T细胞的质量对于它们的离体扩展能力可为最佳或改善的。同样的,在利用本文描述的方法离体操纵后,这些细胞可处于提高的移植物移入和体内扩展的优选状态。因此,在本发明的内容内考虑在该恢复期期间收集血液细胞,包括T细胞、树突细胞或造血系的其他细胞。进一步地,在某些实施方式中,转移(例如,用GM-CSF转移)和调节方案可用于在对象中产生病症,其中具体细胞类型的再群体化(repopulation)、再循环、再生和/ 或扩展是有利的,特别是在疗法后限定的时间窗期间。说明性的细胞类型包括T 细胞、B细胞、树突细胞和免疫系统的其他细胞。
T细胞的活化和扩展
不论在T细胞遗传修饰以表达期望的CAR之前或之后,T细胞都可通常使用以下所述的方法活化和扩展:例如美国专利6,352,694;6,534,055;6,905,680; 6,692,964;5,858,358;6,887,466;6,905,681;7,144,575;7,067,318;7,172,869; 7,232,566;7,175,843;5,883,223;6,905,874;6,797,514;6,867,041;和美国专利申请公布号20060121005。
通常地,本发明的T细胞通过与表面的接触进行扩展,所述表面具有附着于其的刺激CD3/TCR复合物相关信号的试剂和刺激T细胞表面上的共刺激分子的配体。特别地,T细胞群可如本文所述的诸如通过与固定在表面上的抗-CD3抗体、或其抗原-结合片段或抗-CD2抗体接触,或通过和与钙离子载体组合的蛋白激酶C 激活剂(例如,苔藓抑制素)接触进行刺激。对于T细胞表面上的辅助分子的共刺激,使用结合辅助分子的配体。例如,T细胞群可在适于刺激T细胞增殖的条件下与抗-CD3抗体和抗-CD28抗体接触。为了刺激CD4+T细胞或CD8+T细胞的增殖,使用抗-CD3抗体和抗-CD28抗体。可与在本领域中公知的其他方法一样,可使用包括9.3、B-T3、XR-CD28(Diacione,Besancon,France)的抗-CD28抗体的例子(Berg等,Transplant Proc.30(8):3975-3977,1998;Haanen等,J.Exp.Med.190(9):13191328,1999;Garland等,J.Immunol Meth.227(1-2):53-63,1999)。
在某些实施方式中,T细胞的初级刺激信号和共刺激信号可通过不同的方案提供。例如,提供每个信号的试剂可在溶液中或连接至表面。当连接至表面时,试剂可被连接至同一表面(即,以“cis”形式)或分开的表面(即,以“trans”形式)。可选地,一种试剂可被连接至表面和另一种试剂处于溶液中。在一个实施方式中,提供共刺激信号的试剂被结合至细胞表面,并且提供初级活化信号的试剂在溶液中或被连接至表面。在一些实施方式中,两种试剂可都在溶液中。在另一个实施方式中,试剂可处于可溶形式,随后被交联至表面,诸如表达Fc受体或抗体的细胞或将结合该试剂的其他结合剂。在这点上,见例如用于人造抗原呈递细胞(aAPC) 的美国专利申请公布号20040101519和20060034810,其被考虑用于活化和扩展本发明的T细胞。
在一个实施方式中,两种试剂被固定在珠上,在同一珠即“cis”上或分开的珠即“trans”上。作为例子,提供初级活化信号的试剂为抗-CD3抗体或其抗原- 结合片段,和提供共刺激信号的试剂为抗-CD28抗体或其抗原-结合片段;并且两种试剂都以相等的分子数量被共固定至同一珠。在一个实施方式中,使用结合至用于CD4+T细胞扩展和T细胞生长的珠的1:1比率的每种抗体。在本发明的某些方面中,使用结合至珠的抗CD3:CD28抗体的比率,以便与利用1:1比率观察到的扩展相比,观察到T细胞扩展的增加。在一个具体的实施方式中,与利用1:1比率观察到的扩展相比,观察到从大约1至大约3倍的增加。在一个实施方式中,结合至珠的CD3:CD28抗体的比率处于100:1至1:100的范围中和其间的所有整数值。在本发明的一个方面中,比抗-CD3抗体更多的抗-CD28抗体被结合至颗粒,即 CD3:CD28的比率小于1。在本发明的某些实施方式中,结合至珠的抗CD28抗体与抗CD3抗体的比率大于2:1。在一个具体的实施方式中,使用结合至珠的抗体的 1:100的CD3:CD28比率。在另一个实施方式中,使用结合至珠的抗体的1:75的 CD3:CD28比率。在进一步的实施方式中,使用结合至珠的抗体的1:50的CD3:CD28 比率。在另一个实施方式中,使用结合至珠的抗体的1:30的CD3:CD28比率。在一个优选实施方式中,使用结合至珠的抗体的1:10的CD3:CD28比率。在另一个实施方式中,使用结合至珠的抗体的1:3的CD3:CD28比率。还在另一个实施方式中,使用结合至珠的抗体的3:1的CD3:CD28比率。
从1:500至500:1和其间任何整数值的颗粒与细胞的比率可用于刺激T细胞或其他靶细胞。因为在本领域技术人员可容易地领会到,颗粒与细胞的比率可取决于相对于靶细胞的颗粒大小。例如,小尺寸的珠仅可结合一些细胞,而较大的珠能结合很多。在某些实施方式中,细胞与颗粒的比率在从1:100至100:1的范围内和其间任何整数值,和在进一步的实施方式中,该比率包括1:9至9:1和其间任何整数值,也可用于刺激T细胞。抗-CD3-和抗-CD28-结合的颗粒与产生T细胞刺激的T细胞的比率可如以上记录的变化,然而某些优选的值包括1:100、1:50、1:40、 1:30、1:20、1:10、1:9、1:8、1:7、1:6、1:5、1:4、1:3、1:2、1:1、2:1、3:1、4:1、 5:1、6:1、7:1、8:1、9:1、10:1和15:1,一个优选的比率为至少1:1颗粒每T细胞。在一个实施方式中,使用1:1或更小的颗粒与细胞的比率。在一个具体的实施方式中,优选的颗粒:细胞比率为1:5。在进一步的实施方式中,颗粒与细胞的比率可根据刺激天数而改变。例如,在一个实施方式中,颗粒与细胞的比率在第一天为从 1:1至10:1,和额外的颗粒每天或此后每隔一天直至10天,以从1:1至1:10的最终比率(基于添加日的细胞计数)被添加至细胞。在一个具体的实施方式中,颗粒与细胞的比率在刺激的第一天为1:1并在刺激的第三和第五天被调节至1:5。在另一个实施方式中,颗粒在每天或每隔一天的基础上添加,以在第一天最终比率为1:1,并在刺激的第三和第五天最终比率为1:5。在另一个实施方式中,颗粒与细胞的比率在刺激的第一天为2:1并在刺激的第三和第五天被调节至1:10。在另一个实施方式中,颗粒在每天或每隔一天的基础上添加,以在第一天最终比率为1:1,和在刺激的第三和第五天最终比率为1:10。本领域技术人员将理解多种其他比率可适于用于本发明。特别地,比率将根据颗粒大小和细胞大小和类型而变化。
在本发明的进一步的实施方式中,细胞诸如T细胞,与包被试剂的珠组合,随后分离该珠和细胞,并且随后培养该细胞。在一个可选实施方式中,在培养前,不分离包被试剂的珠和细胞,而是在一起进行培养。在进一步的实施方式中,珠和细胞首先通过施加力诸如磁力被聚集,产生增加的细胞表面标记的连接作用,由此诱导细胞刺激。
作为例子,可通过允许附接抗-CD3和抗-CD28的顺磁珠(3×28珠)接触T细胞,来连接细胞表面蛋白。在一个实施方式中,细胞(例如,104至109个T细胞)和珠(例如,以1:1比率的M-450CD3/CD28T顺磁珠)在缓冲液优选PBS(没有二价阳离子诸如,钙和镁)中进行联组合。此外,本领域技术人员可容易理解可使用任何细胞浓度。例如,靶细胞可在样本中非常稀少并仅占0.01%的样本,或整个样本(即,100%)可包括感兴趣的靶细胞。因此,任何细胞数量都在本发明的内容内。在某些实施方式中,可期望显著降低其中颗粒和细胞混合在一起的体积(即,增加细胞浓度),以确保细胞和颗粒的最大接触。例如,在一个实施方式中,使用大约20亿细胞/ml的浓度,在另一个实施方式中,使用多于1亿细胞/ml。在进一步的实施方式中,使用细胞浓度10、15、20、25、30、35、40、45或50×106细胞 /ml。还在另一个实施方式中,使用细胞浓度75、80、85、90、95或100×106细胞 /ml,在进一步的实施方式中,可使用125或150×106细胞/ml的浓度。利用高浓度可产生增加的细胞产量、细胞活化和细胞扩展。进一步地,使用高细胞浓度允许更有效地捕获可微弱表达感兴趣的靶抗原的细胞,诸如CD28-阴性T细胞。这样的细胞群可具有治疗价值并将在某些实施方式中期望获得。例如,利用高浓度的细胞允许更有效选择正常具有更弱CD28表达的CD8+T细胞。
在本发明的一个实施方式中,混合物可被培养数个小时(大约3个小时)至大约 14天或其间任何个小时的整数值。在另一个实施方式中,混合物可被培养21天。在本发明的一个实施方式中,珠和T细胞在一起培养大约八天。在另一个实施方式中,珠和T细胞在一起培养2-3天。也可期望数个周期的刺激,以便T细胞的培养时间可为60天或更多天。适于T细胞培养的条件包括适当的培养基(例如,最小必需培养基或RPM1培养基1640或X-vivo15,(Lonza)),其可包含增殖和存活必须的因子,包括血清(例如,胎牛或人血清)、白细胞介素-2(IL-2)、胰岛素、IFN-γ、 IL-4、IL-7、GM-CSF、IL-10、IL-12、IL-15、TGFp和TNF-α或技术人员已知的用于细胞生长的任何其他添加剂。用于细胞生长的其他添加剂包括但不限于表面活性剂、人血浆蛋白粉(plasmanate)和还原剂诸如N-乙酰基-半胱氨酸和2-巯基乙醇。培养基可包括RPMI1640、AIM-V、DMEM、MEM、α-MEM、F-12、X-Vivo 15和X-Vivo20、优选的(Optimizer),具有添加的氨基酸、丙酮酸钠和维生素、无血清或补充适当量的血清(或血浆)或限定的激素组,和/或足够T细胞的生长和扩展量的细胞因子(一个或多个)。抗生素,例如青霉素和链霉素,仅被包括在实验培养物中,而不包括在注入对象的细胞培养物中。靶细胞被保持在支持生长必须的条件下,例如,适当的温度(例如,37℃)和气氛(例如,空气加5%CO2)。
已经暴露于变化刺激时间的T细胞可显示不同的特性。例如,典型的血液或单采的(apheresed)外周血单核细胞产物具有比细胞毒性或抑制T细胞群(Tc,CD8+) 更多的辅助T细胞群(TH,CD4+)。T细胞通过刺激CD3和CD28受体的离体扩展在大约8-9天前产生主要由TH细胞组成的T细胞群,而在大约8-9天后,T细胞群包括渐增的更多的Tc细胞群。因此,取决于治疗目的,用主要包括TH细胞的T 细胞群注入对象可为有利的。类似地,如果已经分离了Tc细胞的抗原-特异性亚型,则它可有益于以更大的程度扩展该亚型。
进一步地,除了CD4和CD8标记,其他表型标记在细胞扩展过程的进程期间,也显著地但以大部分可重复地变化。因此,这种重复性使针对具体目的调节活化的T细胞产物的能力能够实现。
治疗性应用
本发明包括用慢病毒载体(LV)转导的细胞(例如,T细胞)。例如,LV编码将特异性抗体的抗原识别结构域与CD3-ζ、CD28、4-1BB或任何其组合的细胞内结构域联合的CAR。因此,在一些例子中,转导的T细胞可引起CAR-介导的T-细胞应答。
本发明提供了CAR改变初级T细胞对肿瘤抗原的特异性的用途。因此,本发明也提供了刺激对哺乳动物的靶细胞群或组织的T细胞-介导的免疫应答的方法,其包括以下步骤:施用给哺乳动物表达CAR的T细胞,其中CAR包括特异性地与预定标靶相互作用的结合部分,包括例如人CD3ζ的细胞内结构域的ζ链部分,和共刺激信号传导区。
在一个实施方式中,本发明包括一类细胞疗法,其中T细胞被基因修饰以表达CAR,和CAR T细胞被注入需要其的接受者中。注入的细胞能够杀死接受者的肿瘤细胞。不像抗体疗法,CAR T细胞能够体内复制,产生可导致持续肿瘤控制的长期持久性。
在一个实施方式中,本发明的CAR T细胞可经历稳固的体内T细胞扩展并可持续延长的时间量。在另一个实施方式中,本发明的CAR T细胞发展成可被重新活化以抑制任何额外肿瘤形式或生长的特异性记忆T细胞。例如,不期望本发明的CART19细胞可经历稳固的体内T细胞扩展并在血液和骨髓中以高水平持续延长的时间量,并形成特异性记忆T细胞。不希望被任何具体的理论所束缚,在遇到并随后消除表达替代抗原的靶细胞后,CAR T细胞可体内分化成中心记忆样状态。
不希望被任何具体的理论所束缚,由CAR-修饰T细胞引起的抗肿瘤免疫应答可为主动或被动免疫应答。另外,CAR介导的免疫应答可为过继免疫疗法步骤的一部分,其中CAR-修饰T细胞诱导对CAR中的抗原结合部分特异性的免疫应答。例如,CART19细胞引起抗表达CD19的细胞的特异性免疫应答。
尽管本文公开的数据具体公开了包括源于FMC63鼠科单克隆抗体的抗-CD19scFv、人CD8α铰合和跨膜结构域、和人4-1BB和CD3ζ信号传导结构域的慢病毒载体,但本发明应被解释为包括对构建体组成部分中的每一个的任何数量的变化,如本文其他地方所述的。即,本发明包括CAR中任何抗原结合部分产生对抗原结合部分特异性的CAR-介导的T-细胞应答的用途。例如,本发明的CAR中的抗原结合部分可出于治疗癌症的目的靶向肿瘤抗原。
可治疗的癌症包括没有被血管化或基本上还没有被血管化的肿瘤,以及血管化的肿瘤。癌症可包括非实体瘤(诸如血液学肿瘤,例如白血病和淋巴瘤)或可包括实体瘤。用本发明的CAR治疗的癌症类型包括但不限于癌、胚细胞瘤和肉瘤,和某些白血病或淋巴恶性肿瘤、良性和恶性肿瘤、和恶性瘤,例如肉瘤、癌和黑素瘤。也包括成人肿瘤/癌症和儿童肿瘤/癌症。
血液学癌症为血液或骨髓的癌症。血液学(或血原性)癌症的例子包括白血病,包括急性白血病(诸如急性淋巴细胞白血病、急性髓细胞白血病、急性骨髓性白血病和成髓细胞性、前髓细胞性、粒-单核细胞型、单核细胞性和红白血病)、慢性白血病(诸如慢性髓细胞(粒细胞性)白血病、慢性骨髓性白血病和慢性淋巴细胞白血病)、真性红细胞增多症、淋巴瘤、霍奇金氏疾病、非霍奇金氏淋巴瘤(无痛和高等级形式)、多发性骨髓瘤、瓦尔登斯特伦氏巨球蛋白血症、重链疾病、骨髓增生异常综合征、多毛细胞白血病和脊髓发育不良。
实体瘤为通常不包含囊肿或液体区的组织的异常肿块。实体瘤可为良性或恶性的。不同类型的实体瘤以形成它们的细胞类型命名(诸如肉瘤、癌和淋巴瘤)。实体瘤诸如肉瘤和癌的例子包括纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤和其他肉瘤、滑膜瘤、间皮瘤、尤因氏肿瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、淋巴恶性肿瘤、胰腺癌、乳腺癌、肺癌、卵巢癌、前列腺癌、肝细胞癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、甲状腺髓样癌、乳头状甲状腺癌、嗜铬细胞瘤皮脂腺癌、乳头状癌、乳头状腺癌、髓样癌、支气管癌、肾细胞癌、肝细胞瘤、胆管癌、绒膜癌、维尔姆斯氏肿瘤、子宫颈癌、睾丸肿瘤、精原细胞瘤、膀胱癌、黑素瘤和CNS肿瘤(诸如神经胶质瘤(诸如脑干神经胶质瘤和混合神经胶质瘤)、成胶质细胞瘤(也已知为多形性成胶质细胞瘤)星形细胞瘤、CNS淋巴瘤、生殖细胞瘤、成神经管细胞瘤、神经鞘瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突神经胶质瘤、脑膜瘤、神经细胞瘤、视网膜母细胞瘤和脑转移)。
在一个实施方式中,本发明的CAR的抗原结合部分被设计以治疗具体的癌症。例如,被设计以靶向CD19的CAR可用于治疗癌症和紊乱,包括但不限于前-B ALL(儿童指征)、成人ALL、套细胞淋巴瘤、扩散大B-细胞淋巴瘤,同种骨髓移植后的补救等等。
在另一个实施方式中,CAR可被设计以靶向CD22,治疗扩散大B-细胞淋巴瘤。
在一个实施方式中,癌症和紊乱包括但不限于前-B ALL(儿童指征),成人ALL、套细胞淋巴瘤、扩散大B-细胞淋巴瘤、同种骨髓移植后的补救等等,其可利用靶向CD19、CD20、CD22和ROR1的CAR的组合进行治疗。
在一个实施方式中,CAR可被设计以靶向间皮素,来治疗间皮瘤、胰腺癌、卵巢癌等等。
在一个实施方式中,CAR可被设计以靶向CD33/IL3Ra,来治疗急性骨髓性白血病等等。
在一个实施方式中,CAR可被设计以靶向c-Met,来治疗三阴性乳腺癌、非小细胞肺癌等等。
在一个实施方式中,CAR可被设计以靶向PSMA,来治疗前列腺癌等等。
在一个实施方式中,CAR可被设计以靶向糖脂F77,来治疗前列腺癌等等。
在一个实施方式中,CAR可被设计以靶向EGFRvIII,来治疗成胶质细胞瘤等等。
在一个实施方式中,CAR可被设计以靶向GD-2,来治疗神经细胞瘤、黑素瘤等等。
在一个实施方式中,CAR可被设计以靶向NY-ESO-1TCR,来治疗骨髓瘤、肉瘤、黑素瘤等等。
在一个实施方式中,CAR可被设计以靶向MAGE A3TCR,来治疗骨髓瘤、肉瘤、黑素瘤等等。
然而,本发明不应被解释为仅限于本文公开的抗原标靶和疾病。相反地,本发明应被解释为包括任何与可使用CAR治疗的疾病相关的抗原标靶。
本发明的CAR-修饰T细胞也可用作对哺乳动物离体免疫和/或体内疗法的疫苗类型。优选地,哺乳动物为人。
对于离体免疫,以下中的至少一项在将细胞施用进入哺乳动物前在体外发生: i)扩展细胞,ii)将编码CAR的核酸引入细胞,和/或iii)冷冻保存细胞。
离体程序在本领域中是公知的,并在以下更完全地进行讨论。简单地说,细胞从哺乳动物(优选人)中分离并用表达本文公开的CAR的载体进行基因修饰(即,体外转导或转染)。CAR-修饰的细胞可被施用给哺乳动物接受者,以提供治疗益处。哺乳动物接受者可为人,和CAR-修饰的细胞可相对于接受者为自体的。可选地,细胞可相对于接受者为同种异基因的、同基因的(syngeneic)或异种的。
在此通过引用并入的在美国专利号5,199,942中描述的造血干细胞和祖细胞的离体扩展程序,可被应用至本发明的细胞。其他合适的方法在本领域中是已知的,因此本发明不限于细胞离体扩展的任何具体方法。简单地说,T细胞的离体培养和扩展包括:(1)从外周血收获物或骨髓外植体收集来自哺乳动物的CD34+造血干细胞和祖细胞;和(2)离体扩展这样的细胞。除了美国专利号5,199,942中描述的细胞生长因子,其他因子诸如flt3-L、IL-1、IL-3和c-kit配体,也可用于培养和扩展细胞。
除了就离体免疫而言使用基于细胞的疫苗之外,本发明也提供了体内免疫以引起针对患者中抗原的免疫应答的组合物和方法。
通常地,如本文所述活化和扩展的细胞可用于治疗和预防无免疫应答的个体中产生的疾病。特别地,本发明的CAR-修饰的T细胞用于治疗CCL。在某些实施方式中,本发明的细胞用于治疗处于形成CCL风险中的患者。因此,本发明提供了治疗或预防CCL的方法,其包括施用给需要其的对象治疗有效量的本发明的 CAR-修饰的T细胞。
本发明的CAR-修饰的T细胞可被单独施用或作为药物组合物与稀释剂和/或与其他组分诸如IL-2或其他细胞因子或细胞群结合施用。简单地说,本发明的药物组合物可包括如本文所述的靶细胞群,与一种或多种药学或生理学上可接受载体、稀释剂或赋形剂结合。这样的组合物可包括缓冲液诸如中性缓冲盐水、硫酸盐缓冲盐水等等;碳水化合物诸如葡萄糖、甘露糖、蔗糖或葡聚糖、甘露醇;蛋白质;多肽或氨基酸诸如甘氨酸;抗氧化剂;螯合剂诸如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内施用。
本发明的药物组合物可以以适于待治疗(或预防)的疾病的方式施用。施用的数量和频率将由这样的因素确定,如患者的病症、和患者疾病的类型和严重度——尽管适当的剂量可由临床试验确定。
当指出“免疫学上有效量”、“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由医师确定,其考虑患者(对象)的年龄、重量、肿瘤大小、感染或转移程度和病症的个体差异。可通常指出:包括本文描述的T细胞的药物组合物可以以104至109个细胞/kg体重的剂量,优选105至106个细胞/kg体重的剂量——包括那些范围内的所有整数值——施用。T细胞组合物也可以以这些剂量多次施用。细胞可通过使用免疫疗法中公知的注入技术 (见例如Rosenberg等,New Eng.J.of Med.319:1676,1988)施用。对于具体患者的最佳剂量和治疗方案可通过监测患者的疾病迹象并因此调节治疗由医学领域技术人员容易地确定。
在某些实施方式中,可期望向对象施用活化的T细胞,并随后重新抽取(redraw)血液(或实施单采血液成分术),根据本发明活化来自其中的T细胞,和用这些活化和扩展的T细胞再注入该患者。该过程可每几个周进行多次。在某些实施方式中, T细胞可从10cc至400cc的血液抽取中进行活化。在一些实施方式中,T细胞从 20cc、30cc、40cc、50cc、60cc、70cc、80cc、90cc或100cc的血液抽取中进行活化。不被理论所束缚,利用多份血液抽取/多个再输注方案可用于选出某些T细胞群。
对象组合物的施用可以以任何方便的方式进行,包括通过喷雾法、注射、吞咽、输液、植入或移植。本文描述的组合物可被皮下、皮内、瘤内、结内、脊髓内、肌肉内、通过静脉内(i.v.)注射或腹膜内施用给患者。在一个实施方式中,本发明的T细胞组合物通过皮内或皮下注射被施用给患者。在另一个实施方式中,本发明的T细胞组合物优选通过i.v.注射施用。T细胞的组合物可被直接注入肿瘤,淋巴结或感染位置。
在本发明的某些实施方式中,利用本文描述的方法或本领域已知的其他将T 细胞扩展至治疗性水平的方法活化和扩展的细胞,与任何数量的有关治疗形式结合(例如,之前、同时或之后)施用给患者,所述治疗形式包括但不限于用以下试剂进行治疗:所述试剂诸如抗病毒疗法、西多福韦和白细胞介素-2、阿糖胞苷(也已知为ARA-C)或对MS患者的那他珠单抗治疗或对牛皮癣患者的厄法珠单抗治疗或对PML患者的其他治疗。在进一步的实施方式中,本发明的T细胞可与以下结合使用:化疗、辐射、免疫抑制剂,诸如,环孢菌素、硫唑嘌呤、甲氨喋呤、麦考酚酯和FK506,抗体或其他免疫烧蚀剂诸如CAM PATH、抗-CD3抗体或其他抗体疗法、细胞毒素、氟达拉滨、环孢菌素、FK506、雷帕霉素、麦考酚酸、类固醇类、FR901228、细胞因子和照射。这些药物抑制钙依赖性磷酸酶——钙调磷酸酶(环孢菌素和FK506)或抑制对生长因子诱导的信号传导(雷帕霉素)重要的p70S6激酶(Liu 等,Cell66:807-815,1991;Henderson等,Immun.73:316-321,1991;Bierer等,Curr. Opin,Tmmun.5:763-773,1993)。在进一步的实施方式中,本发明的细胞组合物与骨髓移植、利用化疗剂诸如氟达拉滨、外部光束放射疗法(XRT)、环磷酰胺或抗体诸如OKT3或CAMPATH的T细胞烧蚀疗法结合(例如,之前、同时或之后)而施用给患者。在另一个实施方式中,本发明的细胞组合物在B-细胞烧蚀疗法诸如与 CD20反应的试剂例如Rituxan后进行施用。例如,在一个实施方式中,对象可经历高剂量化疗的标准治疗,之后进行外周血干细胞移植。在一些实施方式中,在移植后,对象接受本发明的扩展的免疫细胞的注入。在一个额外的实施方式中,扩展的细胞在外科手术前或外科手术后施用。
施用给患者的以上治疗的剂量将随着治疗病症的精确属性和治疗的接受者而变化。人施用的剂量比例可根据本领域接受的实践实施。例如,CAMPATH的剂量对于成人患者将通常在1至大约100mg的范围中,通常每天施用,持续1和30 天之间的时期。尽管在一些例子中可使用上至40mg每天的较大剂量(美国专利号 6,120,766中描述),但优选的日剂量为1至10mg每天。
实验实施例
本发明通过参考以下实验实施例进一步详细地进行描述。这些实施例仅出于说明性的目的提供,并不意欲为限制性的,除非另有规定。因此,本发明决不应被解释为限于以下实施例,而是应被解释为包括由于本文提供的教导变得显而易见的任何和全部的变化。
没有进一步的描述,相信利用先前的描述和以下的说明性实施例,本领域技术人员可制造和利用本发明的化合物,并实践请求保护的方法。以下工作实施例因此具体指出本发明的优选实施方式,并不解释为以任何方式限制本公开背景的剩余部分。
实施例1:表达嵌合受体的T细胞在具有晚期白血病的患者中建立记忆和有效的抗
肿瘤效应
被工程改造以表达嵌合抗原受体(CAR)的淋巴细胞在先前临床试验中已经证明了最小的体内扩展和抗肿瘤效应。本文显示的结果证明在注入治疗的具有晚期慢性淋巴细胞白血病(CLL)的三个患者中的三个后,包含CD137的CAR T细胞具有有效的非交叉抗性临床活性。被工程改造的T细胞体内扩展超过一千倍,运送至骨髓并继续以高水平表达功能性CAR至少6个月。平均起来,每个注入的CAR+ T细胞根除至少1000个CLL细胞。在血液和骨髓中证明CD19特异性免疫应答,伴随三个患者中的两个完全缓和。一部分细胞持续作为记忆CAR+T细胞,指示该非MHC限制性方法有效治疗B细胞恶性肿瘤的潜力。
现在描述在这些实验中使用的材料和方法。
材料和方法
一般的实验室说明
研究样本处理、冷冻和实验室分析在宾夕法尼亚大学的翻译和相关研究实验室(Translational and Correlative Studies Laboratory)中进行,该实验室在良好实验室实践(Good Laboratory Practice)的原则下以建立的用于样本接收、处理、冷冻和分析的SOP和/或协议运行。测定性能和数据报告符合MIATA指南(Janetzki等,2009, Immunity31:527-528)。
方案设计
临床试验(NCT01029366)如在图1中图解地进行。具有CD19阳性血液恶性肿瘤的如此患者适合该试验,所述患者在至少两个之前的治疗方案后具有持续的疾病,并且不适合同种异基因的干细胞移植。在肿瘤再分级(restaging)后,用于 CART19制造的外周血T细胞通过单采血液成分术收集,并且在注入前的一周期间提供给对象单一过程的化疗,如图10所规定的。CART19细胞以图10中指示的剂量,使用3天分次剂量方案(10%、30%和60%)通过静脉内注入施用,并且如果可行,在第10天施用第二剂量;仅患者UPN02具有足够的细胞用于第二次注入。以频繁的间隔评估对象的毒性和应答,持续至少6个月。该方案由美国食品药品管理局(US Food and Drug Administration)、重组DNA咨询委员会(AdvisoryCommittee)和宾夕法尼亚大学的机构审查委员会(Institutional Review Board)批准。注入的第一天设定为研究第0天。
对象:临床总结
临床总结在图10中概述,并且详细的历史在本文的其他位置提供。患者UPN 01在55岁时首次诊断为第ΙI阶段B细胞CLL。该患者无临床症状并被观察大约 1-1/2年,直到需要对进行性淋巴细胞增多、血小板减少、腺病和脾肿大治疗。在该时间过程内,该患者接受当前的疗法(prior lines of therapy)。最近的疗法为在 CART19细胞注入前2个月的2个周期的喷司他丁、环磷酰胺和利妥昔单抗,伴随最小应答。该患者随后接受一个周期的苯达莫司汀作为在CART-19细胞注入前的淋巴耗尽化疗。
患者UPN02在68岁,当该患者显示疲劳和白细胞增多时,首次诊断患有CLL。该患者相对稳定持续4年,此时该患者形成需要治疗的进行性白细胞增多 (195,000/μl)、贫血症和血小板减少。核型分析显示CLL细胞已经缺失染色体17p。因为进行性疾病,该患者用阿仑单抗治疗,有部分缓解,但在一年半内,该患者具有进行性疾病。该患者用阿仑单抗再治疗18个周,有部分缓解,并且1年无进展的间隔时间。该患者随后接受2个周期的苯达莫司汀和利妥昔单抗,没有显著应答(图5A)。该患者在CART-19细胞注入前,接受单一试剂苯达莫司汀作为淋巴耗尽化疗。
患者UPN03在50岁显示无症状第I阶段CLL,并随后观察数年。该患者具有需要治疗的进行性白细胞增多(白细胞计数92,000/μl)和进行性腺病。该患者接受 2个周期的利妥昔单抗和氟达拉滨,其导致血细胞计数正常化和显著的改善,尽管没有完全解决腺病。该患者具有大约3年的无进展的间隔时间。核型测试显示细胞包含染色体17p的缺失,FISH证明200个细胞中的170个中TP53缺失。在接下来的数年中,该患者需要针对进行性白细胞增多和腺病的3种不同线的疗法(图 10),最后在CART1细胞注入前接受阿仑单抗6个月,有部分缓解。在CART-19 细胞注入前,该患者接受喷司他丁和环磷酰胺作为淋巴耗尽化疗。
载体产生
CD19-BB-Z转基因(GeMCRIS0607-793)如所述进行设计和构造(Milone等, 2009,Mol Ther.17:1453-1464)。慢病毒载体如所述根据目前良好的制造实践,利用 Lentigen公司的三质粒生产方法进行生产(Zufferey等,1997,Nature biotechnol 15:871-875)。
CART19细胞产物的制备
已经描述了利用包被有抗-CD3和抗-CD28单克隆抗体的顺磁聚苯乙烯珠的T 细胞制备方法(Laport等,2003,Blood102:2004-2013)。慢病毒转导如所述进行 (Levine等,2006,Proc Natl Acad Sci U S A103:17372-17377)。
肿瘤负荷计算的方法
估计基线上的CLL负荷,如图10所示。如下述计算骨髓、血液和次级淋巴组织中的CLL细胞数量。
骨髓:在健康的成人中,骨髓占大约5%的总体重(Woodard等,1960,Phys MedBiol,5:57-59;Bigle等,1976,Health Phys31:213-218)。髂嵴样本中的骨髓具有随年龄增加的非活性(脂肪)骨髓百分比,从5岁的总骨髓的20%上升至35岁的大约50%,此时它保持稳定,直到65岁,并且随后到75岁上升至大约67%的非活性骨髓(Hartsock等,1965,Am J ClinPath43:326-331)。35岁男性的活性(红细胞) 和非活性(脂肪)骨髓的总骨骼重量的国际参考值目前分别设定为1170g和 2480g((Basic anatomical and physiological data foruse in radiological protection:The Skeleton in Annals of the ICRP(用于放射防护的基础解剖和生理学数据:ICRP年报中的骨骼),Vol.25(ed.Smith,H.)58-68(放射防护国际委员会的委员会2的任务组的报告,牛津,1995))。35岁至65岁之间的成年男性具有占总体重5.0%、由1.6% 的活性(红细胞)骨髓和3.4%的非活性(脂肪)骨髓组成的骨髓(Basicanatomical and physiological data for use in radiological protection:TheSkeleton in Annals of the ICRP,Vol.25(ed.Smith,H.)58-68(放射防护国际委员会的委员会2的任务组的报告,牛津,1995))。基于骨髓活组织检查和吸取物标本,计算基线上三个患者的 CLL细胞的重量,如表1所示。这些总CLL骨髓质量的估计值随后利用1Kg=1012个细胞转变成骨髓中的总CLL细胞数,并且所得数目显示在图10中。这些计算基于CLL在骨髓中具有均匀分布的假设。对于患者UPN01,显示对在苯达莫司汀化疗前获得的骨髓活组织检查,和在苯达莫司汀之后且CART19注入前获得的吸取物的计算。由于第-1天吸取物的技术限制,与第-14天活组织检查标本相比,第-1 天吸取物的数目不太精确。患者UPN02具有单一治疗前活组织检查标本,其显示骨髓由CLL完全取代。该患者在CART19后的第30天具有未改变的标本。患者 UPN03的骨髓负荷基于化疗后且CART19活组织检查前进行计算。
表1:骨髓质量
血液:仅患者UPN02在CART19注入前的血液中具有大量CLL肿瘤负荷。流式细胞术显示该细胞具有典型的表型作为具有弱(dim)表面κ限制的CD5+ CD10-CD19+CD20(弱)+CD23(可变的)+IgM-B细胞群的克隆群。大约35%的CLL 细胞共表达的CD38。CLL负荷没有通过3个周期的苯达莫司汀化疗清除,并且在 CART19注入时存在。在CART19注入时,血液中的CLL计数为55,000个细胞/μL。假设血液体积为5.0L,患者UPN02在第0天在血液中具有2.75×1011个CLL细胞。在患者UPN01和03中给出正常的全部WBC,没有计算这些患者中的循环疾病负荷,其将导致略微低估总身体负荷。
次级淋巴组织:淋巴腺病和脾肿大的体积利用FDA-批准软件在轴向CT扫描上进行定量。该体积仅针对胸部、腹部和骨盆。在所有患者中测量从T1椎体至股总动脉分叉的水平面的质量,和在一些患者中,也包括腹股沟区中的结(node)。头 /颈中的结和骨端被排除不进行分析并从基线CLL靶细胞数中排除,其也将导致略微低估总身体负荷。患者UPN01和03已经具有持续的完全缓和超过6个月,并且因此公式(基线体积-第3月体积)用于确定肿瘤负荷从基线的减小;患者UPN02 具有腺病中的稳定疾病,并且因此基线肿瘤质量通过从年龄匹配的健康男性减去参考脾体积进行估计(Harris等,2010,Eur J Radiol75:e97-el01)。基线肿瘤质量利用密度方法(1Kg/L密度,和1Kg=1012个细胞)或体积方法(CLL细胞为10μΜ直径或600fL,假设为球形)转变为CLL细胞,并且两个值显示在图10中。三个患者中次级淋巴组织中的肿瘤体积在以下显示在表2中,如从可用的CT扫描计算的。
表2:肿瘤体积
患者UPN01的基线CT扫描在2个周期的喷司他丁/环磷酰胺/利妥昔单抗后8 天实施,并显示与先前的CT扫描相比,对该化疗方案无应答。该患者在CART19 前具有一个周期的苯达莫司汀,并且因此,对于UPN01从第-37天至第+31天的肿瘤体积的改变不可排除苯达莫司汀以及CART19的潜在贡献。类似地,UPN03 的肿瘤体积的改变反映了1个周期的喷司他丁/环磷酰胺和CART19的联合效应。
估计患者中有效体内E:T比率的方法
注入的CAR T细胞与杀死的肿瘤细胞数的E:T比率利用在CAR T细胞注射时存在的肿瘤细胞数和注射的CAR T细胞数进行计算(Carpenito等,2009,Proc Natl Acad Sci U SA106:3360-3365)。对于本发明,使用如图10所示的注射的CART19+ T细胞数,因为不可能以足够的准确性或精确性确定体内存在的CART19+T细胞的绝对数。如图2和图6所描绘的,血液和骨髓中CART19扩展的可用数据是稳固的。然而,不可能确定CART19向其他位置诸如次级淋巴组织的运输,产生在最大肿瘤减小时体内获得的CART19细胞总数的大量不确定性。表3的计算值用于得到有效的E:T比率。
表3:计算的体内获得的CART19E:T比率
1=密度和体积方法的平均
2=患者UPN02在骨髓中不应答,并且具有由脾和淋巴结中的CT测量的腺病 (3.1E+11个细胞)中肿瘤质量的部分减小。对在血液中应答,参见图5A。
样本处理和冷冻
样本(外周血、骨髓)在淡紫色顶部(K2EDTA)或红色顶部(无添加剂)vacutainer管(Becton Dickinson)中收集,并在抽取的2个小时内传递至TCSL。样本根据建立的实验室SOP,在接收的30分钟内进行处理。外周血和骨髓单核细胞利用 Ficoll-Paque(GE Healthcare,17-1440-03)经Ficoll密度梯度离心法进行纯化,并利用5100Cryo1°冷冻容器在补充有4%人血清白蛋白(Gemini Bio-Products,800-120)、 2%Hetastarch(Novaplus,NDC0409-7248-49)和10%DMSO(Sigma,D2650)的RPM1 (Gibco11875-135)中进行冷冻;在-80℃下24-72小时后,将细胞转移至液氮以便长期保存。单采血液成分术样本通过宾夕法尼亚大学医院血库获得并在CVPF中通过Ficoll梯度纯化进行处理,和如上进行冷冻。当评估时,解冻后即刻的存活大于 85%。对于血清分离,允许样本在室温下凝固1.5-2个小时;血清由离心法进行分离,和单一使用100μl等分试样在-80℃下冷冻。
细胞系
K562(CML,CD19-阴性)从ATCC(CCL-243)获得。K562/CD19—Carmine Carpenito的慷慨礼物,并且为以100%频率进行慢病毒转导以表达CD19分子的 K562。NALM-6是CD19-阳性非T、非B ALL前体B细胞系(Hurwitz等,1979, Int J Cancer23:174-180)并证实表达CD19抗原,是Laurence Cooper的慷慨礼物。将以上细胞系保持在补充有10%胎牛血清(Hycione)和1%Pen-Strep(Gibco, 15140-122)的R10培养基(RPMI1640(Gibco,11875))中。来自健康捐赠者的外周单核细胞(ND365)由来自宾夕法尼亚大学的人免疫学核心的单采血液成分术获得,如上被处理并冷冻。
DNA分离和Q-PCR分析
全血或骨髓样本在淡紫色顶部(K3EDTA)BD vacutainer管(Becton Dickinson)中收集。基因组DNA利用QIAamp DNA血液中量提取试剂盒(Qiagen)和建立的实验室SOP直接从全血中分离,由分光光度计定量,并在-80℃下进行保存。对基因组DNA样本的Q-PCR分析利用123-200ng基因组DNA/时间点、ABI Taqman技术和确认的检测整合的CD19CAR转基因序列的测定成批实施。从资格研究和预建立的认可范围,计算通过/失败参数范围,包括标准曲线斜率和r2值,准确定量参考样本(1000个拷贝/质粒掺杂(spike))的能力和健康的捐赠者DNA样本中的无扩增。CD19CAR转基因的引物/探针如所述的(Milone等,2009,Mol Ther17:1453-1464)。为了确定拷贝数/单位DNA,产生8点标准曲线,其由被掺杂入100 ng非转导的对照基因组DNA的106-5拷贝慢病毒质粒组成。每个数据点(样本、标准曲线、参考样本)一式三份进行评估,报告平均值。对于患者UPN01,所有的报告值都源于3/3复制中的阳性Ct值,%CV小于0.46%。对于患者UPN02,除了第+177天样本(2/3复制阳性,高%CV),所有的报告值都源于3/3复制中的阳性Ct 值,%CV小于0.72%。对于患者UPN03,除了第+1天样本(2/3复制阳性,0.8%CV) 和第+3天样本(2/3复制阳性,0.67%CV),所有的报告值都源3/3复制中的阳性Ct 值,%CV小于1.56%。测定的定量下限(LLOQ)由标准曲线确定为2拷贝/微克 DNA(10个拷贝/200ng输入DNA);考虑LLOQ以下的平均值(即可报告但不可计量的)为近似的。控制询问的DNA(interrogated DNA)的量的平行扩增反应利用以下实施:12-20ng输入基因组DNA,对CDKN1A基因(GENEBANK:Z85996)上游的非转录基因组序列特异性的引物/探针组合(有义引物: GAAAGCTGACTGCCCCTATTTG;SEQ ID NO.25,反义引物:GAGAGGAAGTGCTGGGAACAAT;SEQ ID NO.26,探针:VIC-CTC CCC AGT CTC TTT;SEQ IDNO.27),和由稀释对照基因组DNA产生的8点标准曲线;这些扩增反应产生校正系数(CF)(ng检测的/ng输入的)。拷贝转基因/微克DNA根据下述公式进行计算:由CD19标准曲线计算的拷贝/输入DNA(ng)×CF×1000ng。该测定的准确度根据下述公式通过Q-PCR量化注入细胞产物的标记的能力确定:平均标记=检测的拷贝/输入的DNA×6.3pg DNA/男性体细胞×CF,与利用 CAR-特异性检测反应物,通过流式细胞术的转基因阳性率(positivity)相比较。这些盲确定(blinded determination)对UPN01注入产物产生了22.68%的标记(22.6%,通过流式细胞术),对UPN02注入产物产生了32.33%的标记(23%,通过流式细胞术),和对UPN03注入产物产生了4.3%的标记(4.7%标记,通过流式细胞术)。
细胞因子分析
可溶性细胞因子的量化利用从Life technologies(Invitrogen)购买的Luminex珠阵列技术和试剂盒实施。按照制造商协议,利用3倍系列稀释产生的8点标准曲线实施测定。每个标准点和样本以1:3稀释一式两份进行评价;对于两份测量,计算的%CV小于15%。数据利用5参数逻辑回归分析,在Bioplex200上获得并用 Bioplex Manager5.0版软件分析。标准曲线量化范围由80-120%(观察/期望值)范围确定。个体分析物量化范围在图说明中报告。
检测CAR功能的细胞测定
细胞在TCM中解冻和静置过夜后,通过测量响应靶细胞的CD107脱粒,来评价功能性。脱粒测定利用在48孔平板中最终体积500μl的1×106PBMC和 0.25×106靶细胞,在37℃下、在CD49d(Becton Dickinson)、抗-CD28、莫能星(e-Bioscience)和CD107a-FITC抗体(eBiosciences)存在下,基本如所述的,进行2 个小时(Betts等,2003,J ImmunolMethods281:6578)。
抗体反应物
这些研究使用以下抗体:MDA-CAR——缀合至Alexa647的鼠科抗CD19CAR 抗体,是Bipulendu Jena和Laurence Cooper博士(MD Anderson Cancer Center)的慷慨礼物。对于多参数免疫表型分析和功能测定:抗-CD3-A700、抗-CD8-PE-Cy7、抗-PD-l-FITC、抗-CD25-AF488、抗-CD28-PercP-Cy5.5、抗-CD57-eF450、抗 -CD27-APC-eF780、抗-CD17-APC-eF780、抗-CD45RA-eF605NC、CD107a-FITC(都来自e-Bioscience)、抗-CD4-PE-Texas Red和Live/Dead Aqua(来自Life Technologies) 和抗-CD14-V500、抗-CD16-V500(来自BectonDickinson)。对于通常的免疫表型分析:CD3-PE、CD14-APC、CD14-PE-Cy7、CD16-FITC、CD16PE-Cy7、CD19-PE-Cy7、 CD20-PE,所有都来自Becton Dickinson。
多参数流式细胞术
细胞通过流式细胞术进行评价,如果是新鲜的,在Ficoll-Paque处理后,或者如果是冷冻的,在静置过夜后,以密度2×106个细胞/ml的密度在补充有5%人AB 血清(GemCall,100-512)、1%Hepes(Gibco,15630-080)、1%Pen-Strep(Gibco, 15140-122)、1%Glutamax(Gibco,35050-061)和0.2%N-乙酰基半胱氨酸(American Regent,NDC0517-7610-03)的T细胞培养基(TCM)(X-vivo15(Lonza,04-418Q))中进行。多参数免疫表型分析利用如正文所述的FMO染色,对4×106个总细胞/条件进行。细胞利用由制造商推荐的抗体和反应物浓度,在冰上,在1×106个细胞/100 μl PBS的密度下染色30分钟,冲洗,重悬浮在0.5%低聚甲醛中,并利用用于以上抗体组合的检测和分离的装备有蓝色(488nm)、紫色(405nm)、绿色(532)和红色(633 nm)激光器和适当滤光器组的修改的LSRII(BDImmunocytometry系统)获得。每个染色获得最小100,000个CD3+细胞。为了功能测定,细胞被冲洗、对表面标记染色、重悬浮在0.5%低聚甲醛中并如上获得;对每个染色条件收集最小50,000个 CD3+事件(event)。补偿值利用单一抗体染色和BD补偿珠(Becton Dickinson)确定,并由仪器计算和自动应用。利用FlowJo软件(8.8.4版,Treestar)分析数据。对于通常的免疫表型分析,细胞利用装备有蓝色(488)和红色(633nm)激光器的Accuri C6 细胞计数器获得。补偿值利用单一抗体染色和BD补偿珠(Becton Dickinson)确定,并手动计算。利用C-Flow软件分析包(1.0,264.9版,Accuri细胞计数器)分析数据。
患者过去的病史和对疗法的应答
临床治疗总结在图10中概述。患者UPN01在55岁时首次诊断为第ΙI阶段B 细胞CLL。该患者无临床症状并被观察大约1-1/2年,直到需要对进行性淋巴细胞增多、血小板减少、腺病和脾肿大治疗。在4个周期的氟达拉滨后,该患者具有完全正常的血细胞计数和CT扫描的完全缓解。在5个月内记录到进展,具有无临床症状的淋巴细胞增多、血小板减少和增加的腺病。该患者被观察到没有症状持续大约3年,和后来需要用利妥昔单抗和氟达拉滨治疗进行性白细胞增多、贫血症和血小板减少。该患者用4个周期的利妥昔单抗和氟达拉滨进行治疗,血细胞计数部分改善。该患者再次在一年内有所进展,需要由白细胞增多(WBC150,000/μl) 和血小板减少(血小板30,000/μl)清楚表示的疗法,并用阿仑单抗进行治疗,血细胞计数正常。在13个月内记录到进展。该患者随后接受单一试剂利妥昔单抗,没有显著应答,并且随后是利妥昔单抗、环磷酰胺、长春新碱和泼尼松(R-CVP),持续 2个周期,具有最小应答,随后使用来那度胺。因为毒性,来那度胺停药。该患者接受2个周期的喷司他丁、环磷酰胺和利妥昔单抗,具有最小应答。
后来,患者在CART19细胞注入前4天接受苯达莫司汀作为淋巴耗尽化疗。在治疗前,WBC为14,200/μl,血红素11.4gm/dl,血小板计数78,000/μl和ALC 为8000/μl。CT扫描显示扩散的腺病,和骨髓大量被CLL(67%的细胞)浸润。患者接受了1.6×107个CART-19细胞/kg(1.13×109个总CART19细胞,如通过FACS评估的)。无注入毒性。该患者在苯达莫司汀后大约10天和在CART19细胞注入后6 天成为中性白细胞减少,并在首次CART19注入后10天开始,该患者患发热、寒战和短暂的低血压。同时,胸部X-射线和CT扫描证明用抗生素治疗的左上叶肺炎。发热持续大约2个周,并当嗜中性白细胞恢复时其得以解决。该患者已经不具有进一步的感染或全身症状。
该患者实现了如图5中所描绘的快速和完全缓解。在注入后1到6个月之间,在血液中通过流式细胞术没有检测到循环的CLL细胞。在CART-19细胞注入后1、 3和6个月的骨髓通过形态学和流式细胞术测试显示了持续不存在淋巴细胞浸润。在注入后1和3个月的CT扫描显示了异常腺病的完全解决。该患者已经具有持续的白细胞减少(WBC1000-3900/ul)和血小板减少(血小板,大约100,000/ul),和轻度低丙种球蛋白血症(IgG525mg/dL,正常650-2000mg/dL),但没有感染并发症。
患者UPN02在77岁用CART19细胞进行治疗。该患者具有相关的冠状动脉疾病史,并且在2000年68岁,当该患者出现疲劳和白细胞增多时,被首先诊断患有CLL。该患者相对稳定持续4年,此时该患者形成需要治疗的进行性白细胞增多(195,000/μl)、贫血症和血小板减少。那时的遗传测试显示CLL细胞具有染色体17p的缺失。因为进行性疾病,该患者用12周疗程的阿仑单抗治疗,有部分缓解并且血细胞计数改善。在1年半内,该患者具有进行性白细胞增多、贫血症、血小板减少和脾肿大。核型分析证实染色体17p的缺失,现在具有染色体13q的缺失。该患者再次用阿仑单抗治疗18周,具有白细胞增多的改善和贫血症和脾肿大的稳定。该患者一年内具有进行性白细胞增多、贫血症和血小板减少的迹象。治疗包括2个周期的苯达莫司汀和利妥昔单抗,导致病情稳定,但没有如图5A所示的显著改善。
该患者在CART-19细胞注入前仅接受苯达莫司汀作为淋巴耗尽化疗,以3个分次注入,该患者接受4.3×106个CART19细胞/kg(4.1×108个总细胞),该患者并发高至102度的短暂发热,持续24个小时。在首次注入后的第11天,该患者接受4.1×l08(4.3×l06/kg)个CART19细胞的增强,并且该注入并发需要24个小时住院治疗的发热、寒战和呼吸急促但无缺氧。没有心肌缺血的证据,并且症状被解决。在首次CART-19注入后的第15天,和在增强CART19细胞注入后的第4天,该患者因高热(高至104℉)、冷颤和寒战被许可住院。利用血液和尿培养物以及 CXR的大量测试不能鉴定感染源。该患者抱怨呼吸急促但没有缺氧。超声心动图显示了严重的运动功能减退。射血分数为20%。该患者接受泼尼松1mg每千克持续一天和0.3mg每千克持续大约一周。这导致发热和心功能不全快速解决。
与开始高热同时,该患者具有来自外周血的淋巴细胞的快速下降,如图5A所描绘的。尽管该患者具有正常化的白细胞计数,但该患者具有持久的循环CLL、稳定的中度贫血症和血小板减少。骨髓在治疗后一个月显示持久的大量的CLL浸润,尽管有显著的外周血细胞减少,和CT扫描显示腺病和脾肿大的部分减小。在 CART19细胞注入后五个月,该患者形成进行性淋巴细胞增多。在注入后九个月,该患者具有淋巴细胞增多(16,500/μl)和稳定的适度的贫血症和血小板减少,腺病稳定。该患者保持无临床症状并还没有进一步的疗法。
患者UPN03在50岁被诊断为无临床症状的第I阶段CLL,并且随后观察6 年。后来,该患者具有需要治疗的进行性白细胞增多(白细胞计数92,000/μl)和进行性腺病。该患者接受2个周期的利妥昔单抗和氟达拉滨,导致血细胞计数的正常化和显著改善,尽管没有完全解决腺病。该患者具有大约3年的无进展的间隔时间,随后在接下来6个月内是需要治疗的快速进行性白细胞增多(WBC165,000/μl) 和进行性腺病。该患者接受一个周期的氟达拉滨和3个周期的利妥昔单抗和氟达拉滨,具有正常化的血细胞计数并解决明显(palpable)的腺病。该患者具有大约20 个月无进展的间隔时间,直到该患者再次快速形成进展性白细胞增多和腺病。在这时,骨髓被CLL大量浸润,并且核型分析显示细胞包含染色体17p的缺失,在 170/200细胞中FISH证明TP53缺失。该患者接受一个周期的利妥昔单抗和苯达莫司汀,随后是4个周期的仅苯达莫司汀(由于对利妥昔单抗的严重变应性反应)。该患者具有最初正常化的血细胞计数,但在疗法中止之后不久具有进行性白细胞增多和腺病。
从患者UPN3用单采血液成分术收集自体T细胞并冷藏。该患者随后用阿仑单抗治疗11周,具有优异的血液学应答。腺病尽管没有完全解决但有改善。在接下来的6个月内,该患者病情活跃但稳定。后来,在CART19细胞注入前,该患者接受喷司他丁和环磷酰胺作为淋巴耗尽化疗。
在化疗后三天但在细胞注入前,骨髓是细胞过多的(60%),大约40%牵涉CLL。因为如表3和(Bonyhadi等,2005,J Immunol174:2366-2375)所述的,从CLL患者单采血液成分术收集固有的制造限制,该患者在3天中被注入总共1.46×105个 CART19+细胞每kg(1.42×107个总CART19+细胞)。没有注入毒性。在首次注入后十四天,该患者开始具有为治疗症状的冷颤、高至102℉的发热、寒战、恶心和腹泻。该患者没有呼吸或心脏症状。到注入后的第22天,肿瘤溶解综合征通过由升高的LDH、尿酸清楚表示而诊断,并发有肾功能不全。该患者被送院并用流体复苏和拉布立酶治疗,尿酸和肾功能快速正常化。利用CXR、血液、尿和粪便培养物进行详细的临床评价,并且全部是阴性或正常的。
在1个月的CART-19注入内,通过形态学、流式细胞术、细胞遗传学和FISH 分析,该患者从血液和骨髓中清除循环CIX,并且CT扫描显示解决了异常腺病(图 5C)。该患者的缓和从最初的CART19细胞注入起已经持续超过8个月。
现在描述实验结果。
临床方案
具有晚期、耐化疗CLL的三位患者被招收至试验性临床试验,如图1所描绘的。所有的患者都用多种化疗和生物学方案广泛地进行预治疗,如图10所示。患者中的两位具有p53缺陷CLL——一种预示对常规疗法弱应答并快速进展的缺失(Dohner等,1995,Blood,851580-1589)。患者中的每一个在准备性化疗之后都具有大的肿瘤负荷,包括大量骨髓浸润(40至95%)和淋巴腺病;患者UPN02也具有显著的外周淋巴细胞增多。CART19T细胞如图1B所描绘地制备,并且每个患者的细胞制造和产物特征的细节显示在表4中。所有患者在CART19T细胞注入前用淋巴耗尽化疗预治疗1-4天。因为试验测试并入4-1BB共刺激信号传导区的 CAR,所以使用分次剂量细胞注入安排,如图1A所绘的。
表4:单采血液成分术产物和CART19产物释放标准
1=剂量#2。
2=第12天的测定值在LOQ以下,并从扩展初期一直降低,与自载体产生的质粒DNA的遗留一致。作为信息修改提交给FDA。
3=基于FACS的表面染色的产物释放。
4=针对外部DSMC和IRB的释放标准准许的治疗例外。
CART19的体内扩展和持久性,以及运送至骨髓
相信利用CD3/CD28珠扩展的并表达4-1BB信号传导结构域的CAR+T细胞对缺少4-1BB的CAR是有改善的。开发Q-PCR测定,以便能够定量跟踪血液和骨髓中的CART19细胞。所有患者在血液中都具有CART19-细胞的扩展和持久性,持续至少6个月,如图2A和2C所绘的。特别地,患者UPN01和UPN03在注入后第一个月期间在血液中具有1,000至10,000倍扩展的CAR+T细胞。峰值扩展水平与患者UPN01(第15天)和患者UPN03(第23天)的注入后临床症状的开始同时。此外,在可用一阶动力学模拟的最初延迟在后,CART19T细胞水平在注入后,从天90至180,在所有3位患者中稳定。显著地,CART19T细胞也被运送至所有患者的骨髓,尽管低于血液中观察的水平5至10倍,如图2D至2F所描绘的。患者UPN01和03在骨髓中具有对数线性延迟,消失T1/2为大约35天。
CART19注入后血液和骨髓区室中特异性免疫应答的诱导
来自所有患者的血清样本被收集并成批分析,以定量确定细胞因子水平,评估一组细胞因子、趋化因子和其他可溶因子,以评估潜在毒性并提供CART19细胞功能的证据,如图3所描绘的。在三十种测试的分析物中,十一种具有从基线3 倍或更多的改变,包括4种细胞因子(IL-6、INF-γ、IL-8和IL-10),5种趋化因子 (ΜIΡ-1α、ΜIΡ-1β、MCP-1、CXCL9、CXCL10)和IL-1Rα和IL-2Rα的可溶受体。这些中,干扰素-γ具有从基线最大的相对改变。有趣地,UPN01和UPN03中细胞因子升高的峰值时间与先前描述的每个患者的临床症状和血液中CART19细胞的峰值水平时间地(temporally)相关。仅记录到患者UPN02中的适度改变,有可能是由于提供给该患者的皮质类固醇治疗的结果。可溶IL-2的升高没有在该患者的血清中检测到,即使用4-1BB信号传导结构域的形成CAR+T细胞的临床前基本原理之一是与CD28信号传导结构域相比降低的触发IL-2分泌的倾向(Milone等, 2009,Mol Ther.17:1453-1464)。这可与持续的临床活性有关,因为先前的研究已经显示CAR+T细胞有可能被调节T细胞抑制(Lee等,2011,Cancer Res 71:2871-2881),细胞可通过分泌大量IL-2的CAR或通过注入后提供外源IL-2而引起。最终,如图3D所描绘的,观察到在来自UPN03的骨髓吸取物的上清液中细胞因子分泌的稳固诱导,其也与肿瘤溶解综合征的发展和完全缓和同时。
血液中记忆CART19细胞群的延长表达和建立
CAR-介导的癌症免疫疗法的中心问题是最化的细胞制造和共刺激结构域是否提高了基因修饰T细胞的持久性并且允许在患者中建立CAR+记忆T细胞。先前的研究还没有证明注入后T细胞上CAR的稳固扩展、延长的持久性和/或表达 (Kershaw等,2006,ClinCancer Res12:6106-6115;Lamers等,2006,J Clin Oncol 24:e20-e22;Till等,2008,Blood,112,2261-2271;Savoldo等,2011,J Clin Invest doi:10.1172/JCI46110)。注入后第169天,来自血液和骨髓两者的样本的流式细胞检测分析显示在UPN03中存在CAR19表达细胞(图4A和4B),和不存在B细胞,如图4A所描绘的。值得注意地,通过Q-PCR测定,所有三个患者在4个月和更长都具有持久性的CAR+细胞,如图2和图6所描绘的。流式细胞术的CAR+细胞的体内频率密切匹配从对CART19转基因的PCR测定获得的值。重要地,在患者 UPN03中,仅CD3+细胞表达CAR19,因为CAR19+细胞在CD16或CD14-阳性亚型中是不可检测的,如图4A所描绘的。CAR表达也在注入后的第71天,在患者UPN01血液中4.2%的T细胞表面上检测到,如图7所描绘的。
接下来,利用抗-CAR个体基因型抗体(MDA-647)和图8所示的设门策略,多色流式细胞术用于实施更详细的研究,以进一步描述UPN03中CART19细胞的表达、表型和功能。基于CAR19表达观察到CD8+和CD4+细胞两者中记忆和活化标记的表达的明显差异。在第56天,CART19CD8+细胞首先显示与对抗原的延长和稳固的暴露一致的初级效应子记忆表型(CCR7-CD27-CD28-),如图4C所描绘的。相比之下,CAR-阴性CD8+细胞由效应子和中心记忆细胞的混合物组成,在细胞亚型中CCR7表达,和在CD27+/CD28-和CD27+/CD28+分数中大的数字。尽管 CART19和CAR-阴性细胞群两者都基本上表达CD57,但该分子与PD-1在 CART19细胞中一致地共表达,这是这些细胞的大量复制历史的可能反映。与CAR- 阴性细胞群相比,CART19CD8+群的整体缺少CD25和CD127两者的表达。到第 169天,尽管CAR-阴性细胞群的表型保持类似于第56天样本,但CART19群已经演变成包含少量具有中心记忆细胞特征的群,值得注意地,CCR7表达,更高水平的CD27和CD28,以及为PD-1-阴性、CD57-阴性和CD127-阳性的CAR+细胞。
在CD4+区室中,在第56天,CART19细胞的特征为在CD57+和-区室两者内分布的一致缺少CCR7和CD27+/CD28+/PD-1+细胞占主导,并且基本上不存在 CD25和CD127表达,如图4B所描绘的。相比之下,在该时间点上,CAR-阴性细胞在CCR7、CD27和PD-1表达方面是非均匀的(heterogeneous),表达CD127 并且也包含大量CD25+/CD127-(可能的调节T细胞)群。到第169天,尽管CD28 表达在所有CAR+CD4+细胞中保持一致地阳性,但一部分CART19CD4+细胞已经向具有CCR7表达的中心记忆表型、更高百分比的CD27-细胞、PD-l-阴性亚型的出现和CD127表达的获得演变。CAR-阴性细胞保持与它们第56天的相应物合理地一致,除了CD27表达的减少和CD25+/CD127-细胞百分比的降低。
在血液中,CART19细胞可在6个月后保持效应子功能
除了短的持久性和不充足的体内增殖之外,利用CAR+T细胞的先前试验的限制还为体内注入的T细胞功能活性的快速丧失。患者UPN01和03中高水平 CART19细胞持久性和CAR19分子的表面表达提供了直接测试从冷藏的外周血样本中恢复的细胞中的抗-CD19-特异性效应子功能的机会。来自患者UPN03的 PBMC与对CD19表达为阳性或阴性的靶细胞一起培养(图4D )。CART19T细胞的稳固CD19-特异性效应子功能通过对CD19-阳性而不是CD19-阴性靶细胞的特异性脱粒证明,如由表面CD107a表达评估的。值得注意地,CART19群对CD19- 阳性靶的暴露诱导表面CAR-19的快速内化——如图8所绘的,用于标准流式细胞术染色中相同效应子细胞中CAR19的表面表达。靶细胞上共刺激分子的存在不需要触发CART19细胞脱粒,因为NALM-6系不表达CD80或CD86(Brentjens等, 2007,Clin CancerRes1:5426-5435)。效应子功能在注入后第56天明显,并在169 天的时间点上保持。CAR+和CAR-T细胞的稳固效应子功能也可由药理学刺激证明。
CART19细胞的临床活性
任何患者中在注入后四天期间没有观察到显著的毒性,除了短暂的发热反应。然而,在首次注入后的7到21天之间,所有的患者随后发展显著的临床和实验室毒性。这些毒性是短期和可逆的。在治疗至今的三个患者中,根据标准准则,在 CART1注入后>6个月具有2CR和1PR(Hallek等,2008,Blood111:5446)。每个患者的过去病史和对疗法的应答的细节在图10中描绘。
简单地说,患者UPN01在注入后10天开始形成发热综合征,伴随寒战和短暂的低血压。发热持续大约2周并得以解决;该患者还没有进一步的全身症状。该患者得到快速和完全缓解,如图5所描绘。在注入后1到6个月之间,在血液中通过流式细胞术没有检测到循环CLL细胞。通过形态学和流式细胞检测分析在 CART19细胞注入后1、3和6个月的骨髓显示淋巴细胞浸润的持续不存在,如图5B所描绘的。注入后1和3个月的CT扫描显示腺病解决,如图5C所描绘的。在该报告时,完全缓和持续10+个月。
患者UPN02用2个周期的苯达莫司汀和利妥昔单抗进行治疗,导致稳定的病情,如图5A所描绘的。该患者在CART19T细胞注入前接受第三剂苯达莫司汀作为淋巴耗尽化疗。该患者在首次注入后的第11天和第二CART19细胞加强的当天形成发热至40℃、寒战和呼吸困难,需要24小时住院治疗。发热和全身症状持续并在第15天,该患者具有短暂的心功能不全;在第18天开始皮质类固醇疗法后,所有症状解决。在CART19注入后,同时高热开始,该患者从外周血中快速清除 p53-缺陷CLL细胞,如图5A所描绘的,和腺病部分减少,在治疗后一个月,骨髓显示持久性大量的CLL浸润,尽管有显著外周血细胞减少。该患者保持无临床症状。
患者UPN03在CART19细胞注入前接受喷司他丁和环磷酰胺作为淋巴耗尽化疗。在化疗后三天但在细胞注入前,骨髓是细胞过多的(60%),大约50%牵涉CLL。该患者接受低剂量的CART19细胞(1.5×105个CAR+T细胞/kg,分成3天)。此外,没有急性注入毒性。然而,在首次注入后14天,该患者开始具有寒战、发热、恶心和腹泻。到注入后的22天,诊断肿瘤溶解综合征,需要住院治疗。该患者已经解决全身症状,并在CART19注入1个月内,通过形态学、流式细胞术、细胞遗传学和FISH分析,该患者从血液和骨髓中已经清除循环CLL。CT扫描显示异常腺病解决,如图5B和5C所描绘的。从最初CART19细胞注入,完全缓和持续超过8个月。
体内CART19效应子与CLL靶细胞比率的考虑
临床前研究显示大肿瘤能够被切除,并且对于人源化小鼠中1:42的体内E:T 比率,注入2.2×107个CAR能根除由1×109个细胞组成的肿瘤(Carpenito等,2009, Proc NatlAcad Sci U S A106:3360-3365),尽管这些计算不考虑注射后T细胞的扩展。随时间的CLL肿瘤负荷的估计允许基于注入的CAR+T细胞数计算三个对象内得到的肿瘤减少和估计的CART19E:T比率。肿瘤负荷通过测量骨髓、血液和次级淋巴组织中的CLL负载进行计算。如图10所示的基线肿瘤负荷指示每个患者在 CART19注入前具有1012数量级的CLL细胞(即,1千克肿瘤负载)。患者UPN03 在第-1天(即化疗后和CART19注入前)在骨髓中具有8.8×1011个CLL细胞的估计的基线肿瘤负荷,和次级淋巴组织中3.3-5.5×1011个CLL细胞的测量的肿瘤质量,这取决于体积CT扫描分析的方法。考虑到UPN03仅被注入1.4×107个CART19 细胞,利用最初总肿瘤负荷(1.3×1012个CLL细胞)的估计,并且没有CLL细胞在治疗后是可检测到的,得到惊人的1:93,000E:T比率。通过类似的计算,对UPN01 和UPN02,计算有效的体内E:T比率为1:2200和1:1000,如表3所示)。最后,通过CART19T细胞的连续杀死的贡献,联合>1,000-倍的体内CART19扩展,可能有助于由CART19细胞介导的强大的抗-白血病效应。
T细胞表达嵌合受体在具有晚期白血病的患者中建立记忆和有效的抗肿瘤效应
CAR的有限的体内表达和效应子功能是测试第一代CAR的试验中的中心限制(Kershaw等,2006,Clin Cancer Res12:6106-6115;Lamers等,2006,J Clin Oncol 24:e20-e22;Till等,2008,Blood,112,2261-2271;Park等,2007,Mol Ther15:825833; Pule等,2008,Nat Med14:1264-1270)。基于证明包含4-1BB信号传导模块的CAR 提高的持久性的临床建模(Milone等,2009,Mol Ther.17:1453-1464;Carpenito等, 2009,Proc NatlAcad Sci U S A106:3360-3365),设计实验以形成用慢病毒载体技术工程改造的第二代CAR。发现该第二代CAR在慢性HIV感染环境中是安全的 (Levine等,2006,Proc Natl AcadSci U S A103:17372-17377)。本结果显示当该第二代CAR在T细胞中表达并在被设计以促进中心记忆T细胞的移入的条件下培养时(Rapoport等,2005,Nat Med11:1230-1237;Bondanza等,2006,Blood 107:1828-1836),观察到与先前报告相比注入后改善的CAR T细胞扩展。CART19 细胞建立了CD19-特异性细胞记忆,和以先前没有实现的体内E:T比率杀死肿瘤细胞。
CART19为并入4-1BB信号传导结构域的第一个CAR试验并第一次使用慢病毒载体技术。本结果证明有效跟踪CAR至肿瘤位点,实际上建立显示CD19特异性的“肿瘤浸润淋巴细胞”。显著的体内扩展允许首次证明从患者中直接回收的 CAR可保持体内效应子功能数月。先前的研究已经提示优选对初级T细胞,将第一代CAR引入病毒特异性T细胞(Pule等,2008,Nat Med14:1264-1270),然而第二代CAR引入最佳共刺激的初级T细胞的结果使该观念被质疑。不希望被任何具体的理论所束缚,提出警告注意:随着所有三位患者中千克大小的肿瘤负荷溶解,伴随患者中的两位中可能的危险的高水平细胞因子的延迟释放,临床效应是深远和前所未有的。没有观察到经典的细胞因子风暴(storm)效应。然而,本研究被设计以通过在三天时间中慎重注入CART19减轻该可能性。
发现非常低剂量的CAR可引起有效的临床应答。这是证明CART19载体设计的安全性的试验性研究。低于先前试验中测试的那些几个数量级的CART19细胞剂量可具有临床益处的观察可对未来在更宽规模上CAR疗法的执行和测试针对非 CD19的标靶的CAR的试验设计具有重要含意。
本研究进一步指出CART19在中心记忆和效应子T细胞两者中都表达,并且与先前的报告相比,这可能有助于它们的长期存活。不希望被任何具体的理论所束缚,CAR T细胞可在遇到和随后消除表达替代抗原的靶细胞(例如CLL肿瘤细胞或正常B细胞)后,体内分化成中心记忆样状态。确实地,已经报告4-1BB的信号传导在TCR信号传导的内容中促进记忆的发展(Sabbagh等,2007,Trends Immunol 28:333-339)。
CART19扩大的增殖和存活已经显示先前还没有报道的CAR T细胞的药学动力学的方面。观察到血清和骨髓中的细胞因子释放动力学与峰值CART19水平相关,所以可能当表达CD19的细胞标靶变得有限时,开始延迟。CART19的扩大存活的机制可能涉及上述4-1BB结构域的并入或通过天然TCR和/或CAR的信号传导。一个令人感兴趣的可能性是扩大的存活与已经在骨髓标本中识别的CART19 群相关,这提出了CD19CAR能通过遇到骨髓中的B细胞祖细胞(progenitor)保持的假说。涉及该问题的是什么促使体内CART19细胞的最初扩展?极少的例外 (Savoldo等,2011,J Clin Invest doi:10.1172/JCI46110;Pule等,2008,NatMed 14:1264-1270),本研究是唯一的省略1L-2注入的试验,以便CART19细胞有可能响应稳态细胞因子被扩展或更有可能地响应白血病标靶和/或正常B细胞上表达的 CD19而被扩展。在后一种情况下,这可为针对正常APC上的标靶,诸如CD19 和CD20,的CAR的有吸引力的特征,因为CART19的自我更新有可能发生在正常细胞上,这通过“自接种/加强”的手段提供了CAR记忆的机制,和因此长期肿瘤免疫监督。该CART19稳态的机制可需要进一步的研究,以阐明持久性的细胞内在和外在机制。在这些结果前,多数研究者已经将CAR疗法视为临时形式的免疫疗法,然而具有优化的信号传导结构域的CAR可起到缓和诱导和巩固两者的作用,以及用于长期免疫监督。
在所有三位患者——包括两位具有p53缺陷白血病的患者——中已经观察到有效的抗-白血病效应。先前利用CAR的研究有困难将抗肿瘤效应从淋巴耗尽化疗中分开。然而,同时发生的并且可能依赖于本研究中体内CAR扩展的与氟达拉滨 -难治疗的患者中肿瘤溶解动力学联合的延迟的细胞因子释放,指示CART19介导有效的抗肿瘤效应。本结果不排除化疗在增强CAR效应方面的作用。
可需要载体、转基因和细胞制造程序与来自其他中心的正在进行研究的结果的彻底比较,以得到获得体内CAR T细胞的持续功能需要的关键特征的完全理解。不像抗体疗法,CAR-修饰的T细胞具有体内复制的潜力,和长期持久性开导致持续的肿瘤控制。由非交叉抗性杀手T细胞组成的现成疗法的可利用性具有改善具有B细胞恶性肿瘤的患者的结果的潜力。例如,利用试剂诸如利妥昔单抗和贝伐单抗的抗体疗法的限制在于该疗法需要重复的抗体注入,那是不方便和昂贵的。具有在CART1细胞的单一注入后在T细胞上表达的抗-CD19scFv的延长抗体疗法的递送(delivery)(在该例子中,治疗至今的3位患者中的3位持续至少6个月)具有许多实践优点,包括方便性和成本节约。
实施例2:慢性淋巴白血病中的嵌合抗原受体-修饰的T细胞
设计慢病毒载体,其表达具有对B-细胞抗原CD19特异性、与CD137(T细胞中的共刺激受体[4-1BB])和CD3-ζ(T-细胞抗原受体的信号-转导部件)信号传导结构域结合的嵌合抗原受体。观察到再输注入具有难治疗的慢性淋巴细胞白血病(CLL) 的患者的低剂量(大约1.5×105个细胞每千克体重)的自体嵌合抗原受体-修饰的T细胞扩展至超过体内最初移入水平1000倍的水平。也观察到该患者显示肿瘤溶解综合征的延迟发展和完全缓和。
除了肿瘤溶解综合征,涉及嵌合抗原受体T细胞的仅其他等级3/4毒性的效应为淋巴细胞减少。被工程改造的细胞在血液和骨髓中持续高水平至少6个月,并继续表达嵌合抗原受体。特异性免疫应答在骨髓中检测出,伴随表达CD19的正常 B细胞和白血病细胞的损失。在治疗后缓和持续10个月。低丙种球蛋白血症是预料的慢性毒性效应。
现在描述用于这些实验的材料和方法。
材料和方法
研究程序
设计自身非活化慢病毒载体(GeMCRTS0607-793),其受到临床前安全性测试,如先前报告的(Milone等,2009,Mol Ther,17:1453-64)。先前也已经描述了T细胞制备的方法(Porter等,2006,Blood,107:1325-31)。进行定量聚合酶链反应(PCR) 分析,以检测血液和骨髓中的嵌合抗原受体T细胞。定量的下限根据标准曲线确定;低于定量下限的平均值(即,可报告但不可量化的)被考虑为近似的。测定的定量下限为25个拷贝每微克的基因组DNA。
使用被分成等分试样用于单次使用并保存在-80℃的来自全血和骨髓的血清,进行可溶因子分析。通过使用Luminex珠-阵列技术和反应物(Life Technologies)进行可溶细胞因子的量化。
单采血液成分术#1
在单采血液成分术中心进行12-15升单采血液成分术程序。在该程序期间,获得外周血单核细胞(PBC)用于生产CART-19T细胞。从单一白细胞提取法中收获至少50×109个白细胞,以制造CART-19T细胞。也获得和冷藏基线血液白细胞。
细胞减少性(cytoreductive)化疗
化疗在注入前大约5-10天开始,以便在化疗完成后1-2天,可给出CART-19 细胞。因此,化疗开始的时机取决于方案的长度。化疗的目的是诱导淋巴细胞减少,以便于CART-19细胞的移入和稳态扩展。也可选择化疗,以减少疾病肿瘤负荷。由社区肿瘤学家选择和施用细胞减少性化疗。化疗的选择取决于该患者潜在的疾病和之前的疗法。氟达拉滨(30mg/m2/天×3天)和环磷酰胺(300mg/m2/天×3 天)是选择的试剂,因为在促进过继免疫疗法中使用这些试剂具有最多的经验。利用FDA批准的药物的一些其他可接受方案是适当的,包括CHOP、HyperCVAD、 EPOCH、DHAP、ICE或其他方案。
再分级评估
在化疗完成时进行有限的再分级,以便提供基线肿瘤负荷测量值。这包括成像、身体检查和最小残余疾病(MRD)评估。对象经历以下,以进行注入前测试:身体检查、不利事件记录和血液抽取,用于血液学、化学和妊娠测试(如果是合适的话)。
CART-19T细胞的制备
自体T细胞被工程改造以表达对CD19具有特异性的细胞外单链抗体(scFv)。细胞外scFv可改变转导的T细胞对表达CD19的细胞的特异性,后者是一种在恶性细胞的表面上和正常B细胞上表达受限制的分子。除了CD19scFv之外,细胞还被转导以表达由TCRζ链或者由4-1BB和TCRζ信号传导模块组成的串联信号传导结构域中任一个组成的细胞内信号传导分子。scFv源自小鼠单克隆抗体,并因此包含小鼠序列,并且信号传导结构域完全是天然人序列的。CART-19T细胞通过由单采血液成分术分离T细胞并使用慢病毒载体技术制造(Dropulic等,2006, Human Gene Therapy,17:577-88;Naldini等,1996,Science,272:263-7;Dull等, 1998,J Virol,72:8463-71),以将scFv:TCRζ:4-1BB引入CD4和CD8T细胞。在一些患者中,将对照scFv:TCRζ:引入一部分细胞,用于竞争性再群体化实验。这些受体是“普遍的”,因为它们以MHC-非依赖性方式结合抗原,因此,一种受体构建体可用于治疗具有CD19抗原-阳性肿瘤的患者群体。
CAR构建体在宾夕法尼亚大学研发,和临床级载体在Lentigen公司制造。 CART-19细胞根据图11显示的方法在宾夕法尼亚大学的临床细胞和疫苗生产设备中制造。在细胞培养结束时,细胞被冷藏在可注入的冷冻培养基。以1个或2个袋,施用包括2.5×109至5×109个总细胞注入的单一剂的CART-19转导的T细胞。每个袋包含冷冻培养基的等分试样(体积决定于剂量),其以下可注入级的反应物 (%v/v):31.25plasmalyte-A、31.25右旋糖(5%)、0.45NaCl、上至7.50的DMSO、 1.00葡聚糖40、5.00人血清白蛋白,大约2.5-5×109个自体T细胞每袋。为了增加安全性,首次剂量在第0天、第1天和第2天以分次剂量给予,第0天为大约10% 的细胞,第1天为30%的细胞和第2天为60%的细胞。
储存
包含CART-19-转导的T细胞的袋(10至100ml容量)被储存在血库条件下受监测的-135℃冷冻室中。注入袋被储存在冷冻室中,直到需要。
细胞解冻
在记录研究性药房中的细胞后,冷冻的细胞在干冰中被运送至对象的床边。在使用保持在36℃至38℃的水浴时,细胞在床边解冻一袋。该袋被温和地按摩,直到细胞刚好解冻。不应有冷冻块留在容器内。如果CART-19细胞产物显示处于损坏或泄漏的袋,或以其他方式显示受损害,则它不应被注入。
术前用药法
T细胞注入后的副作用可包括短暂的发热、冷颤和/或恶心。推荐对象在注入CART-19细胞前,通过口服醋氨酚650mg和口服或IV盐酸苯海拉明25-50mg进行预用药。这些药物处理在需要时可每六个小时进行重复。如果该患者持续发热,没有由醋氨酚缓解,则可采用非甾类的抗炎性药物的疗程。推荐患者在任何时间都不接受全身性皮质类固醇类诸如氢化可的松、泼尼松、泼尼松龙(甲强龙制剂 (Solu-Medrol))或地塞米松(地卡特隆(Decadron)),除了在威胁生命的紧急情况下,因为这可对T细胞产生反作用。如果需要皮质类固醇类进行急性注入反应,则推荐100mg最初剂量的氢化可的松。
施用/注入
在完成化疗后1至2天开始注入。首次注入当天,患者具有有差异的CBC,和CD3、CD4和CD8计数的评估,因为给出的化疗部分上诱导淋巴细胞减少。不希望被任何具体的理论所束缚,相信2.5-5×109个CART-19细胞的最初i.v.剂量对于该方案是最优的。因为健康的成人具有大约1×1012个T细胞,所以建议的总剂量等于细胞总体质量的大约0.5%(Roederer,1995,Nat Med,1:621-7;Macallan 等,2003,Eur J Immunol,33:2316-26)。第一剂量利用第0天(10%)、第1天(30%) 和第2天(60%)的分次剂量施用。对象在隔离室中接受注入。细胞如本文其他地方描述的在该患者床边解冻。以能容忍地快速注入速度给予解冻的细胞,以便注入持续大约10-15分钟。转导的T细胞通过以大约10mL至20mL每分钟的流速通过具有三通旋塞的18-规格的不含乳胶的Y-型输血器的快速静脉内注入进行施用。注入持续大约15分钟。一袋或两袋CART-19修饰的细胞在冰上输送,和该细胞在还是冷的时被施用给对象。在接受CART-19细胞混合物的对象中,为了便于混合,利用Y-转接器(Y-adapter)同时施用细胞。对象如本文其他地方所述的进行注入和预用药。在给药前、注入结束时和此后每15分钟持续1个小时并且直到这些是稳定的和令人满意的,进行评估对象的生命体征和进行脉搏血氧测定。在注入前和在注入后20分钟获得确定基线CART-19水平的血液样本。从他们之前的细胞减少性化疗中经历毒性的患者,他们的注入安排延迟,直到解决这些毒性。许可T细胞注入延迟的具体毒性包括:1)肺部的:要求补充氧以保持多于95%的饱和或胸部x-射线上存在进行性的放射照相异常;2)心脏的:不受医学处理控制的新的心律失常;3)需要增压支持的低血压;4)主动感染:在T细胞注入48小时内细菌、真菌或病毒的阳性血液培养物。在首次注入前以及每个随后注入后两个小时收集钾和尿酸的血清样本。
注入后实验室,以评估移入和持久性
对象在最初CART-19细胞注入后第4天和第10天返回,以抽取血液,用于血清细胞因子水平,和CART-19PCR,以便评估CART-19细胞的存在。对象每周一次返回,持续三周,以经历以下:身体检查、不利事件的记录和血液抽取,用于血液学、化学、CART-19细胞的移入和持久性、和研究化验(research lab)。
第二注入
不希望被任何具体的理论所束缚,相信可在第11天给予患者第二剂CART-19 细胞,条件是它们显示对第一剂的充分耐受,和制造足够的CART-19细胞。该剂为2-5×109个总细胞。在注入后两个小时可收集钾和尿酸的血清样本。
第二单采血液成分术
在单采血液成分术中心,进行2升单采血液成分术程序。获得PBMC用于研究并冷藏。实验对象经历以下:身体检查、不利事件的记录和血液抽取,用于血液学、化学、CART-19细胞的移入和持久性、和研究化验。另外,进行再分级,以便提供了肿瘤负荷测量值。再分级测试由疾病类型确定,并包括成像、MRD评估、骨髓吸取和活组织检查和/或淋巴结活组织检查。
注入后2至6个月的每月评估
对象在CART-19细胞注入后,在2至6个月期间每月返回。在这些研究访问中,对象经历以下:伴随施药、身体检查、不利事件的记录和血液抽取,用于血液学、化学、CART-19细胞的移入和持久性、和研究化验。HIV DNA测定在 CART-19细胞注入后2-6个月进行,以排除可检测的RCL的存在。
在注入后每季评估直到2年
对象在注入后在每季进行评估,直到2年。在这些研究访问中,实验对象经历以下:伴随施药、身体检查、不利事件的记录和血液抽取,用于血液学、化学、 CART-19细胞的移入和持久性、和研究化验。HIV DNA测定在CART-19细胞注入后3个月和6个月进行,以排除可检测的RCL的存在。
现在描述实验结果。
患者病史
该患者在1996年接受第I阶段CLL的诊断。他在6年的观察后首次需要治疗进行性白细胞增多和腺病。在2002年,他用两个周期的利妥昔单抗加氟达拉滨进行治疗;该治疗导致血细胞计数的正常化和腺病的部分解决。在2006年,他因疾病进展接受四个周期的利妥昔单抗和氟达拉滨,再次血细胞计数正常化和腺病部分恢复(regression)。该应答后后是20个月无进展间隔时间和2年无治疗间隔时间。在2009年2月,他具有快速进行性白细胞增多和复发的腺病。他的骨髓被CLL 大量浸润。细胞遗传学分析显示15个细胞中的3个包含染色体17p的缺失,和荧光原位杂交(FISH)测试显示200个细胞中的170个具有包括染色体17p上TP53的缺失。他接受利妥昔单抗和苯达莫司汀一个周期和没有利妥昔单抗(因为严重的变应性反应)的苯达莫司汀的三个额外的周期。该治疗仅产生短暂的淋巴细胞增多的改善。进行性腺病在治疗后利用计算断层照相法(CT)进行记录。
自体T细胞利用白细胞提取法收集并冷藏。该患者随后接受阿仑单抗(抗 -CD52,成熟的淋巴细胞,细胞-表面抗原)11周,具有改善的造血作用并且腺病部分解决。在接下来的6个月内,他病情稳定,具有持续、大量的骨髓牵涉和具有多个1至3-cm淋巴结的扩散腺病。在2010年7月,该患者被招入嵌合抗原受体- 修饰的T细胞的第1阶段临床试验中。
细胞注入
来自该患者的自体T细胞被解冻并用慢病毒转导,以表达CD19-特异性嵌合抗原受体(图12A);在表5中描绘了针对慢病毒载体和有关序列的序列识别符。在细胞注入前四天,该患者接受设计用于耗尽淋巴细胞的化疗(4mg每平方米身体表面积剂量的喷司他丁和600mg每平方米剂量的环磷酰胺),而不使用利妥昔单抗 (Lamanna等,2006,J Clin Oncol,24:1575-81)。在化疗后三天但在细胞注入前,骨髓是细胞过多的,大约40%牵涉CLL。白血病细胞表达κ轻链和CD5、CD19、 CD20和CD23。细胞遗传学分析显示两种单独的克隆,两者都导致染色体17p和 TP53基因座的丧失 (46,XY,del(17)(p12)[5]/46,XY,der(17)t(l7;21)(q10;q10)[5]/46,XY[14])。在化疗后四天,该患者接受总共3×108个T细胞,其中的5%被转导,总共1.42×107个转导的细胞(1.46×105个细胞每千克)分成三个连续的每日静脉内注入(第1天为10%、第2 天为30%和第3天为60%)。没有施用注入后细胞因子。没有记录到注入的毒性效应。
表5:pELPS-CD19-BBz转移载体的序列标识符
SEQ ID NO:# | 身份 |
SEQ ID NO:1 | pELPS-CD19-BBZ转移载体(核酸序列) |
SEQ ID NO:2 | PSV’s U3(核酸序列) |
SEQ ID NO:3 | HIV R重复(核酸序列) |
SEQ ID NO:4 | HIV U5重复(核酸序列) |
SEQ ID NO:5 | 部分Gag/Pol(核酸序列) |
SEQ ID NO:6 | cPPT(核酸序列) |
SEQ ID NO:7 | EF1α启动子(核酸序列) |
SEQ ID NO:8 | CD19-BBζCAR(核酸序列) |
SEQ ID NO:9 | Hu Woodchuck PRE(核酸序列) |
SEQ ID NO:10 | R重复(核酸序列) |
SEQ ID NO:11 | U5重复(核酸序列) |
SEQ ID NO:12 | CD19-BBζCAR(氨基酸序列) |
SEQ ID NO:13 | CD8前导序列(核酸序列) |
SEQ ID NO:14 | 抗-CD19scFv(核酸序列) |
SEQ ID NO:15 | CD8铰合(核酸序列) |
SEQ ID NO:16 | CD8跨膜(核酸序列) |
SEQ ID NO:17 | 4-1BB(核酸序列) |
SEQ ID NO:18 | CD3ζ(核酸序列) |
SEQ ID NO:19 | CD8前导序列(氨基酸序列) |
SEQ ID NO:20 | 抗-CD19scFv(氨基酸序列) |
SEQ ID NO:21 | CD8铰合(氨基酸序列) |
SEQ ID NO:22 | CD8跨膜(氨基酸序列) |
SEQ ID NO:23 | 4-1BB(氨基酸序列) |
SEQ ID NO:24 | CD3ζ(氨基酸序列) |
临床应答和评估
在首次注入后十四天,该患者开始有冷颤和与2级疲劳相关的低等级的发热。在接下来的5天内,冷颤加重,并且他的温度升高至39.2℃(102.5℉),伴随寒战、发汗、厌食、恶心和腹泻。他没有呼吸或心脏症状。因为发热,进行胸部放射照相和血液、尿和粪便培养物,并且都是阴性或正常的。在注入后第天22,诊断肿瘤溶解综合征(图12B)。尿酸水平为10.6mg每分升(630.5μmol每升),磷水平为 4.7mg每分升(1.5mmol每升)(正常范围,2.4至4.7mg每分升[0.8至1.5mmol每升]),和乳酸脱氢酶水平为1130U每升(正常范围,98至192)。有急性肾损伤的证据,肌酸酐水平为2.60mg每分升(229.8μmοl每升)(基线水平,<1.0mg每分升 [<88,4μmοl每升])。该患者被送院并用流体复苏和拉布立酶进行治疗。尿酸水平在24个小时内返回至正常范围,和肌酸酐水平在3天内返回至正常范围;他在医院第4天获准离开。乳酸脱氢酶水平逐步降低,在随后的月份内变得正常。
到CART19-细胞注入后的第28天,腺病不再明显,并且在第23天,骨髓中没有CLL的证据(图12C)。核型现在在15个细胞中的15个(46,XY)中正常,和对于检查的200个细胞中的198个缺失TP53,FISH测试是阴性的;这考虑为处于阴性对照的正常限度内。流式细胞检测分析显示无残余的CLL,和B细胞是不可检测的(在CD5+CD10-CD19+CD23+淋巴细胞门内<1%的细胞)。注入后第31天进行的CT扫描显示腺病解决(图12D)。
在CART19-细胞注入后三个月和六个月,身体检查保持寻常,没有明显的腺病,和在CART19-细胞注入后3个月进行的CT扫描显示持续缓和(图12D)。利用形态学分析、核型分析(46,XY)或流式细胞检测分析,在3个月和6个月的骨髓研究也显示没有CLL的证据,也持续缺少正常B细胞。缓和已经持续至少10个月。
CART19细胞的毒性
细胞注入没有急性毒性效应。唯一记录的严重的(等级3或4)不利事件是上述的第3级肿瘤溶解综合征。该患者具有在基线上的1级淋巴细胞减少,和在治疗后第1天开始并继续至少10个月的第2或3级淋巴细胞减少。在天19记录4级淋巴细胞减少,其具有140个细胞每立方毫米的绝对淋巴细胞计数,但从第22天至至少10个月,绝对淋巴细胞计数处于390和780细胞每立方毫米(2或3级的淋巴细胞减少)之间的范围内。该患者从第19天至第26天具有短暂的1或2级血小板减少(血小板计数,98,000至131,000个每立方毫米)和从第17天至第33天具有 1或2级的中性白细胞减少症(绝对中性白细胞计数,1090至1630每立方毫米)。可能与研究治疗相关的其他迹象和症状包括1和2级的氨基转移酶和碱性磷酸酶水平升高,其在首次注入后17天形成并在第33天解决,1和2级的由发热、冷颤、发汗、肌痛、头疼和疲劳组成的全身症状。2级低丙种球蛋白血症用注入静脉内免疫球蛋白校正。
血清和骨髓细胞因子的分析
该患者的临床应答伴随炎性细胞因子水平的延迟增加(图13A至图13D),干扰素-γ水平、干扰素-γ-反应趋化因子CXCL9和CXCL10和白细胞介素-6是基线水平的160倍高。T细胞因子水平的短暂升高与临床症状对应,在首次CART19-细胞注入后17至23天达到峰值。
测量来自系列骨髓吸取物的上清液的细胞因子并显示免疫活化的证据(图13E)。记录了与在T-细胞注入前的日子的基线水平相比,干扰素-γ、CXCL9、白细胞介素-6和可溶白细胞介素-2受体的显著增加;该值在首次CART19-细胞注入后的第23天达到峰值。骨髓细胞因子增加与白血病细胞从骨髓中消失一致。血清和骨髓肿瘤坏死因子α保持不变。
嵌合抗原受体T细胞的扩展和持久性
在首次注入后的第1天开始,实时PCR检测编码抗-CD19嵌合抗原受体 (CAR19)的DNA(图14A)。到注入后的第21天,记录体内多于3-log扩展的细胞。在峰值水平上,血液中的CART19细胞占了多于20%的循环淋巴细胞;这些峰值水平与全身症状的发生、肿瘤溶解综合征(图12B)和血清细胞因子水平升高(图13A 至图13D)同时。CART19细胞在注入后6个月保持在高水平上可检测,尽管该值从峰值水平降低10倍。血液中嵌合抗原受体T细胞的加倍时间为大约1.2天,消除半衰期为31天。
骨髓中的嵌合抗原受体T细胞
CART19细胞在首次注入后23天开始在骨髓标本中识别到(图14B)和持续至少6个月,衰减半衰期为34天。骨髓中最高水平的CART19细胞在首次注入后23 天的首次评估中识别到并与免疫应答的诱导同时,如细胞因子-分泌分布图所指示的(图13E)。骨髓吸取物的流式细胞检测分析指示CD5+CD19+细胞的克隆扩展处于基线,其在注入后1个月和注入后3个月获得的样本中缺失(数据未显示)。正常 B细胞在治疗后没有检测到(图14C)。
利用自体基因修饰的CART19细胞的治疗
本文描述的是在通过用表达连接至CD3-ζ和CD137(4-1BB)信号传导结构域的抗-CD19的慢病毒载体转导,对自体T细胞基因修饰以靶向CD19的治疗后3周,肿瘤溶解综合征的延迟发展和完全缓解。基因修饰细胞在注入后以高水平存在在骨髓中,持续至少6个月。骨髓中CD19-特异性免疫应答的产生通过与嵌合抗原受体T细胞的峰值浸润同时的细胞因子的短暂释放和白血病细胞的去除证明。先前还没有报道在细胞免疫疗法后肿瘤溶解综合征的发展(Baeksgaard等,2003, Cancer Chemother Pharacol,51:187-92)。
自体T细胞对靶特异性肿瘤抗原的基因操纵是癌症疗法的有吸引力的策略(Sadelain等,2009,Curr Opin Immunol,21:215-23;Jena等,2010,Blood, 116:1035-44)。本文描述的方法的重要特征是嵌合抗原受体T细胞可以以HLA-不受限制的方式识别肿瘤标靶,以便“现成”嵌合抗原受体可对具有多种组织学特征的肿瘤构建。HIV-源的慢病毒载体用于癌症疗法,这是一种可能相比逆转录病毒载体的使用具有一些优点的方法(June等,2009,Nat Rev Immunol,9:704-16)。
在嵌合抗原受体T细胞的先前试验中,目标肿瘤应答是适度的,并且修饰细胞的体内增殖是不持久的(Kershaw等,2006,Clin Cancer Res,12:6106-15;Till 等,2008,Blood,112:2261-71;Pule等,2008,Nat Med,14:1264-70)。Brentjens 和同事们报告了连接至CD28信号传导结构域的靶向CD19的嵌合抗原受体的临床试验的初步结果,并发现具有晚期CLL的三个患者中的两个的短暂肿瘤应答 (Brentjens等,2010,Mol Ther,18:666-8);然而,嵌合抗原受体快速从循环中消失。
出乎意料地,注入的非常低剂量的嵌合抗原受体T细胞将产生临床明显的抗肿瘤应答。确实地,1.5×105个嵌合抗原受体T细胞每千克的注入剂量低于在修饰以表达嵌合抗原受体或转基因T-细胞受体的T细胞的先前研究中使用的剂量几个数量级(Kershaw等,2006,Clin Cancer Res,12:6106-15;Brentjens等,2010, Mol Ther,18:666-8;Morgan等,2010,Mol Ther,18:843-51;Johnson等,2009,Blood,114:535-46)。不被任何具体的理论所支持,推测该化疗可增强嵌合抗原受体的作用。
患者血液和骨髓中CART19细胞的延长持久性由于包括4-1BB信号传导结构域。因为不排斥表达包含鼠科序列的单链Fv抗体片段的CART19细胞,所以有可能CART19-细胞-介导的正常B细胞的消除促进诱导对嵌合抗原受体的免疫耐受,。考虑到在该患者中缺少可检测的CD19-阳性白血病细胞,并且不被任何具体的理论所支持,有可能至少部分从由早期B-细胞祖细胞传递的刺激,实现嵌合抗原受体T细胞的稳态——因为它们开始出现在骨髓中。本发明涉及可存在保持“记忆”嵌合抗原受体T细胞的新机制的发现。
尽管CD19是有吸引力的肿瘤标靶,但是表达限于正常和恶性B细胞,有对嵌合抗原受体T细胞的持久性可介导长期B-细胞缺乏的担忧。实际上,在该患者中,在注入后,B细胞不存在于血液和骨髓中至少6个月。该患者不具有复发感染。用利妥昔单抗通过CD20靶向B细胞对于具有B-细胞瘤的患者是有效和相对安全的策略,并且长期B-细胞淋巴细胞减少是易处理的(Molina,2008,Ann Rev Med, 59:237-50)。已经报道用利妥昔单抗治疗的患者在疗法中止后的数月内B细胞恢复。还不清楚这样的恢复是否在抗B-细胞T细胞在体内持续的患者中发生。
具有TP53缺失的CLL的患者在标准疗法后具有短期缓和(Dohner等,1995, Blood,85:1580-9)。同种异基因的骨髓移植是在具有晚期CLL的患者中诱导长期缓和的唯一方法(Gribben等,2011,Biol Blood Marrow Transplant, 17:Suppl:S63-S70)。然而,因为高频率的慢性移植-对-宿主疾病——其在通常受CLL 影响的年长患者中经常是特别严重的(Gribben等,2011,Biol Blood Marrow Transplant,17:Suppl:S63-S70;Sorror等,2008,Blood,111:446-52),所得的有效的移植-对-肿瘤效应与相当大的发病率相关。本文提供的数据提示基因修饰的自体 T细胞可避免该限制。
肿瘤溶解综合征和细胞因子分泌的延迟开始,联合有力的体内嵌合抗原受体 T-细胞扩展和显著的抗白血病活性,指出CART19细胞的大量和持续的效应子功能。本文描述的实验强调该疗法的效力并提供了通过连接至有效信号传导结构域的嵌合抗原受体的转导,对自体T细胞基因修饰以靶向CD19(和其他标靶)的详细研究的支持。不像抗体-介导的疗法,嵌合抗原受体-修饰T细胞具有体内复制的潜力,并且长期持久性能导致持续的肿瘤控制。另两位具有晚期CLL的患者也已经根据该方案接受CART19注入,并且所有三位都已经具有肿瘤应答。这些发现确保针对B-细胞瘤的CD19-改变的T细胞的继续研究。
本文引用的每一和每个专利、专利申请和出版物的公开内容在此都通过引用全文并入。尽管已经参考具体实施方式公开了本发明,但显而易见的是可由本领域技术人员设计本发明的其他实施方式和变形,而不脱离本发明的真实精神和范围。权利要求意欲被解释为包括所有这样的实施方式和等同变形。
Claims (22)
1.自体T细胞在用于制备治疗具有癌症的人的药物中的用途,其中所述癌症是白血病,其中所述T细胞被基因修饰以表达CAR,所述CAR由SEQ ID NO:20的抗-CD19 scFv、SEQ IDNO:21的CD8α铰合区、SEQ ID NO:22的CD8α跨膜区、SEQ ID NO:23的4-1BB结构域和SEQ IDNO:24的CD3ζ胞内结构域组成,并且其中所述人对于至少一种治疗剂具有抗性,并且在所述人中获得所述癌症的缓和。
2.权利要求1所述的用途,其中所述T细胞被基因修饰以表达SEQ ID NO:12的氨基酸序列。
3.权利要求1或2所述的用途,其中所述癌症是急性淋巴细胞白血病。
4.权利要求1或2所述的用途,其中所述癌症是慢性淋巴细胞白血病。
5.权利要求4所述的用途,其中所述慢性淋巴细胞白血病为难治疗的CD19+白血病。
6.自体T细胞在用于制备在诊断患有癌症的人中产生基因工程改造的T细胞的持续群的药物中的用途,其中所述癌症是白血病,其中所述T细胞被基因工程改造以表达CAR,所述CAR由SEQ ID NO:20的抗-CD19 scFv、SEQ ID NO:21的CD8α铰合区、SEQ ID NO:22的CD8α跨膜区、SEQ ID NO:23的4-1BB结构域和SEQ ID NO:24的CD3ζ胞内结构域组成,其中当所述T细胞被施用至具有所述癌症的所述人时,生成基因工程改造的T细胞的持续群,其在施用后,在所述人中持续至少八个月,并且其中所述人对于至少一种治疗剂具有抗性,并且在所述人中获得所述癌症的缓和。
7.权利要求6所述的用途,其中所述T细胞被基因修饰以表达SEQ ID NO:12的氨基酸序列。
8.权利要求6或7所述的用途,其中所述基因工程改造的T细胞的持续群包括至少一种选自以下的细胞:施用给所述人的T细胞、施用给所述人的T细胞的子代和其组合。
9.权利要求6或7所述的用途,其中所述基因工程改造的T细胞的持续群包括记忆T细胞。
10.权利要求6或7所述的用途,其中所述癌症为慢性淋巴细胞白血病或急性淋巴细胞白血病。
11.权利要求10所述的用途,其中所述慢性淋巴细胞白血病为难治疗的CD19+白血病和淋巴瘤。
12.权利要求6或7所述的用途,其中所述基因工程改造的T细胞的持续群在施用后,在所述人中持续至少九个月、十个月、十一个月、十二个月、两年或三年。
13.权利要求10所述的用途,其中所述慢性淋巴细胞白血病被治疗。
14.自体T细胞在用于制备在诊断患有癌症的人中扩展包括子代T细胞群在内的基因工程改造的T细胞群的药物中的用途,其中所述癌症是白血病,其中所述T细胞被基因工程改造以表达CAR,所述CAR由SEQ ID NO:20的抗-CD19scFv、SEQ ID NO:21的CD8α铰合区、SEQID NO:22的CD8α跨膜区、SEQ ID NO:23的4-1BB结构域和SEQ ID NO:24的CD3ζ胞内结构域组成,其中当所述T细胞被施用至具有癌症的所述人时,在所述人中生成基因工程改造的子代T细胞的群,并且其中所述人对于至少一种治疗剂具有抗性,并且在所述人中获得所述癌症的缓和。
15.权利要求14所述的用途,其中所述T细胞被基因修饰以表达SEQ ID NO:12的氨基酸序列。
16.权利要求14或15所述的用途,其中所述人中的所述子代T细胞包括记忆T细胞。
17.权利要求14或15所述的用途,其中所述癌症是急性淋巴细胞白血病。
18.权利要求14或15所述的用途,其中所述癌症为慢性淋巴细胞白血病。
19.权利要求18所述的用途,其中所述慢性淋巴细胞白血病为难治疗的CD19+白血病和淋巴瘤。
20.权利要求14或15所述的用途,其中所述子代T细胞群在施用后,在所述人中能够持续至少八个月。
21.权利要求14或15所述的用途,其中所述子代T细胞群在施用后,在所述人中能够持续至少九个月、十个月、十一个月、十二个月、两年或三年。
22.权利要求14或15所述的用途,其中所述基因工程改造的T细胞能够治疗癌症。
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