CN107164330A - 使用嵌合细胞因子受体逆转肿瘤微环境的影响 - Google Patents
使用嵌合细胞因子受体逆转肿瘤微环境的影响 Download PDFInfo
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Abstract
本申请公开了组合物和方法,其与使得无效Th1 T细胞抵抗癌症微环境中存在的抑制性细胞因子环境的方案相关。肿瘤特异性T细胞经修饰以利用结合抑制性/阻抑性细胞因子并且使得它们的胞内结果转换成Th1免疫刺激性/活化信号的嵌合受体。所述T细胞利用嵌合抗原受体,所述嵌合抗原受体具有与IL2和/或IL7的信号转导胞内结构域融合的IL10、IL13和/或IL4的胞外结构域。
Description
本申请是申请日为2012年4月5日、申请号为201280024856.1、发明名称为“使用嵌合细胞因子受体逆转肿瘤微环境的影响”的发明专利申请的分案申请。
本申请要求2011年4月8日提交的美国临时专利申请系列号 61/473,457的优先权,所述文献通过引用的方式完整并入本文。
技术领域
本发明的领域至少总体上包括免疫学、细胞生物学、分子生物学和药学领域。
背景技术
常规化疗和放疗法经常产生不充分的益处,这强调对新治疗药的需要。体外扩充的肿瘤相关抗原(TAA)特异性细胞毒T淋巴细胞(CTL) 的过继转移可以有效地***,例如包括霍奇金淋巴瘤、鼻咽癌、神经母细胞瘤和黑色素瘤。尽管输注靶向癌表达的TAA的CTL在治疗上有用,但是至少一些肿瘤利用多种免疫逃避机制,包括下调抗原表达,和释放有利于形成Th2而非细胞毒性Th1型免疫反应的可溶性免疫调节细胞因子,如IL13和IL4。本发明提供为本领域中促进克服这类肿瘤逃避手段的需要解决方案。
发明简述
进行性肿瘤生长可能与免疫反应的抑制相关。许多不同的机制可以有助于免疫逃避,然而许多类型的癌症已经利用细胞因子的调节作用来下调以摧毁癌细胞为目标的适宜免疫反应。它们通过分泌免疫阻抑性细胞因子做到这点,其中所述免疫阻抑性细胞因子起到招募调节性免疫细胞至肿瘤并直接抑制细胞毒性Th1T细胞和/或使细胞毒性 Th1T细胞再极化成无效的Th2表型的作用。由癌细胞或周围肿瘤基质分泌的免疫阻抑性细胞因子至少包括白介素(IL)13、IL4、(转化生长因子β)TGF-β、IL6、IL8和IL-10。
本发明的实施方案提供一项新方案以使肿瘤反应性T细胞抵抗肿瘤微环境存在的免疫阻抑性/抑制性细胞因子。本发明的某些实施方案涉及使用转基因嵌合细胞因子受体改善肿瘤特异性CTL的扩充和抗肿瘤活性。
本发明的实施方案提供一项新方案以使效应Th1T细胞抵抗肿瘤微环境存在的抑制性细胞因子环境。这类实施方案包括具有嵌合受体的天然或基因修饰的肿瘤特异性T细胞,所述嵌合受体结合抑制性/ 阻抑性细胞因子并且使得它们的胞内结果转换成Th1免疫刺激性/活化信号,因此改善肿瘤特异性T细胞的功效。
例如,本发明包括载体,如示例性双顺反子逆转录病毒载体,所述载体编码与IL2和/或IL7细胞因子受体的信号转导胞内结构域融合的IL4和/或IL13细胞因子受体的胞外结构域。类似地,本发明包括载体,如逆转录病毒载体,所述载体编码与IL2和/或IL1细胞因子受体的信号转导胞内结构域融合的IL10细胞因子受体的胞外结构域。
在特定的实施方案中,其中IL13、IL4和/或IL10(或其他)的一种或多种存在微环境中的癌包括基本上全部实体瘤。具体的示例性癌包括至少:胰腺癌、霍奇金和非霍奇金淋巴瘤、黑色素瘤、乳腺癌、肺癌、***癌、胶质母细胞瘤、肝细胞癌、卵巢癌等。
本发明的实施方案可用来调节例如原代T细胞、天然存在的肿瘤抗原特异性细胞毒T淋巴细胞和NK细胞。利用本发明修饰的T/NK 细胞可以在自体或同种异型环境下使用。
在本发明的一些实施方案中,存在可以使负向免疫调节信号转化成正向信号的嵌合分子。仅以举例方式,这种方案涉及使IL-4和/或 IL-13的胞外结构域与IL-2和/或IL-7受体的信号转导胞内结构域融合。这种方案可以用来使得效应Th1细胞抵抗肿瘤微环境中经常存在的负向细胞因子信号。
在一些实施方案中,本发明提供了使用嵌合细胞因子受体,与 IL-2和/或IL-7受体的胞内结构域融合的IL-4和/或IL-13的胞外结构域,逆转肿瘤微环境的影响。
在特定的实施方案中,本发明允许使用嵌合细胞因子受体,例如与IL-2和IL-7受体的胞内结构域融合的IL-4和IL-13的胞外结构域,逆转肿瘤微环境的影响。
在本发明的一些实施方案中,存在防止对细胞毒性Th1T细胞的抑制或其再极化成具有Th2表型的细胞的方法,所述方法包括步骤:修饰肿瘤特异性T细胞以包含结合抑制性或阻抑性细胞因子的嵌合受体,其中经抑制性或阻抑性细胞因子与嵌合受体结合,从而防止对细胞毒性Th1T细胞的抑制或使其再极化,因而防止细胞毒性Th1T细胞的抑制或再极化。在特定的实施方案中,嵌合受体包含IL10、IL4 和/或IL13细胞因子受体的胞外结构域并且包含IL2和/或IL7细胞因子受体的信号转导胞内结构域。在某些实施方案中,嵌合受体包含免疫阻抑性细胞因子的胞外结构域和传递Th1信号的细胞因子的胞内结构域。
在某些实施方案中,存在一种载体,其包含嵌合受体,所述嵌合受体包含免疫阻抑性细胞因子受体的胞外结构域和传递Th1信号的细胞因子受体的胞内结构域。在一些实施方案中,免疫阻抑性细胞因子的胞外结构域是IL10、IL4和/或IL13细胞因子受体的胞外结构域。在某些实施方案中,传递Th1信号的细胞因子受体的胞内结构域是 IL2和/或IL7细胞因子的细胞因子受体的胞内结构域。载体可以是任何种类的载体,包括逆转录病毒载体、腺病毒载体、质粒或腺相关病毒病毒载体。在特定的实施方案中,嵌合受体包含IL4的胞外结构域和IL7的胞内结构域。
前文已经相当广泛地概述本发明的特征和技术优点,目的在于可以更好理解随之而来的本发明的详细描述。将在下文描述本发明的额外特征和优点,这形成本发明权利要求的主题。本领域技术人员应当理解,可以容易地使用所公开的构思和具体实施方案作为修改或设计用于实施本发明相同目的其他结构的基础。本领域技术人员也应当认识到,这类等同结构不脱离如所附权利要求书中所述的本发明精神和范围。联系附图考虑时,将从以下描述中更好地理解就其组织和操作方法而言据信是本发明特征的新特性,连同其他目的和优点。然而,将明确地理解,每张图仅出于说明和描述目的而提供并且是不意在作为限制本发明的定义。
附图简述
为了更完整地理解本发明,现在参考结合附图所取得的以下描述,其中:
图1.IL4和IL13信号传导的示意图。
图2.A)示例性构建体#1和#2的载体图。B)通过GFP(#1)和 mOrange(#2)表达评价转导效率;C)在10分钟细胞因子暴露后的磷酸化Stat5;D)在IL2、4或13存在下培养的转导和对照CTL。
图3示例性构建体#3.3B转基因细胞中IL4和IL13信号传导的示意图。
图4IL4Rα/IL7Rα(“4/7R”)和报道基因的示例性融合物
图5显示IL4R和mOrange在转导细胞上的稳定表达。
图6显示在施用IL-4后转基因细胞上的pSTAT5。
图7表明4/7R表达并未不利地影响CTL功能。
图8显示表达4/7R的转基因T细胞在IL-4的存在下体外增殖。
图9显示表达4/7R的CTL可以耗尽来自上清液的IL4。
图10表明表达4/7R的CTL抵抗其他免疫阻抑性细胞因子。
图11显示将免疫阻抑性细胞因子的信号传导改变成T细胞生长因子。
图12-14表明4/7R CTL控制肿瘤生长。
图15显示在某些实施方案中,可以调节患者衍生的CAR-PSCA 修饰的T细胞以例如共表达4/7R。
图16显示经修饰以共表达4/7R的CAR-PSCA T细胞保留它们杀伤肿瘤靶的能力。
本发明的具体实施方式
I.定义
如本说明书中在此所用,“一个”或“一种”可以意指一个(种)或多个(种)。如权利要求中在此所用,结合词语“包含”,词语“一个”或“一种”可以意指一个(种)或多于一个(种)。如本文所用,“另一个”可以意指事项的至少第二个或更多个。
如本文所用的术语“嵌合细胞因子受体”指来自一种受体的细胞因子结合部分的工程化受体,所述细胞因子结合部分与来自不同受体的胞内信号传导部分连接。
如本文所用的术语“细胞因子结合性胞外结构域”指细胞表面上与细胞因子结合的细胞因子受体的部分。
如本文所用的术语“信号转导胞内结构域”指细胞内部负责在细胞因子结合时传递信号的细胞因子受体的部分。
II.本发明的一般实施方案
为了克服本领域中的障碍并且开发对抗癌症的有效免疫治疗策略,本发明的实施方案包括CTL系(具有天然肿瘤特异性的T细胞系) 或靶向恶性细胞上表达的抗原的嵌合抗原受体(CAR)修饰的T细胞,和工程化这些细胞以表达嵌合受体,所述嵌合受体含有与传递Th1信号的IL2Rγ和IL7Rα的胞内结构域连接的IL13α受体(IL13Rα1)和 IL4Rα的细胞因子结合性胞外结构域。在特定的实施方案中,这些操作使得CTL抵抗极化Th2的肿瘤微环境并且反而维持Th1信号传导至靶向TAA的CTL。可以检验癌症患者样品并记录TAA表达模式和产生的Th2细胞因子的水平和模式。随后可以确定是否可以扩充针对来自患者PBMC的已表达抗原的CTL并且表征修饰这些CTL的作用,从而它们仍保持极化成Th1活性,甚至在诱导Th2的肿瘤微环境下也是如此。在特定的实施方案中,针对反应性胰腺癌相关抗原的T 细胞(仅举例)可以从患者的PBMC产生并且受到修饰以保留Th1功能,甚至在肿瘤的Th2细胞因子环境下也是如此。可以如下检查这类实施方案:1)记录TAA表达模式和评估初次活组织检查样品的细胞因子谱;2)产生对多种胰腺癌靶抗原特异的肿瘤反应性CTL并且体外评价它们的特异性和功能;和3)通过强制性表达嵌合细胞因子受体,保护CTL免受Th2细胞因子的信号传导的抑制作用。此后,可以评价TAA-CTL在患有癌症(包括胰腺癌)的个体中的安全性和抗肿瘤功效。
肿瘤特异性CTL的存活和扩充是对T细胞疗法的最佳体内功效重要的。虽然施用IL2可以产生这些效果,但是它与限制益处的抑制性T细胞群体的毒性和扩充相关。IL7受体的转基因表达可以改善 CTL存活和扩充,但是仅在重复外源性施用IL7细胞因子时才有益处,所述IL7细胞因子昂贵、依赖于临床级产物的可获得性并且可能在肿瘤部位处于不充足的浓度。本发明的实施方案提供针对IL4的受操作的T细胞反应,所述IL4是一种在几种肿瘤的微环境下内源性大量存在并且还与促肿瘤发生作用相关的细胞因子,所述促肿瘤发生作用包括癌细胞增殖、保护肿瘤细胞免于凋亡和使细胞毒性肿瘤特异性 T细胞再极化成阻抑性Th2表型。为逆转IL4对肿瘤特异性CTL的抑制性影响并相反使它们可能利用IL4作为生长因子,发明人将逆转录病毒载体工程化,所述逆转录病毒载体编码了与IL7R的胞内结构域(信号传导结构域)融合并与允许转基因检测的mOrange连接的 IL4Rα胞外结构域(细胞因子结合部分)。为确定嵌合IL4/7R的转基因表达是否改善CTL存活和扩充,发明人使用EBV-特异性CTL杀伤 Epstein Barr病毒+(EBV+)肿瘤。在转导后,通过流式细胞术(双阳性mOrange,IL4R)在13-76%的EBV-CTL中可检测到IL4/7R CTL。转基因分子是有功能的,因为IL4的添加仅在EBV-CTL/IL4/7R+中以与施用IL2后所实现的水平类似的水平磷酸化STAT5。转基因 CTL和对照CTL均应答于IL2而扩充(从1x106个细胞分别增加至 3.5x107个细胞和5.3x107个细胞),但是EBV-CTL/IL4/7R+仅在IL4 存在下(1000Ul/ml)在1周内扩充(从1x106个CTL分别增至2.9x107个CTL与3.2x106个CTL)。如预期那样,与IL2存在下培养的CTL 相比,EBV-CTL的转基因亚群在IL4存在下受到正向选择(在1周内从13%增至80%)。在采用IL4扩充后,转基因CTL仍是多克隆的,具有效应子记忆谱,并且保留由IFNγ释放、EBV五聚物结合和自体 EBV-LCL的MHC限制型杀伤所度量的抗原特异性。重要地,CTL 扩充严格地保持抗原和细胞因子依赖性,当任一种刺激撤除,则扩充终止。这些体外特征在异体移植物小鼠模型中体内复制,在所述小鼠模型中EBV-CTL/IL4/7R应答于IL2或IL4而扩充并且维持它们的抗EBV-肿瘤活性。最后,在从产生IL-4的肿瘤收获的上清液存在下培养CTL。仅转基因CTL耗尽来自培养基的细胞因子。因此,在本发明的实施方案中,IL4/7R CTL能够利用肿瘤衍生的IL4作为生长因子并且充当耗尽来自肿瘤微环境的细胞因子的接收器,因此使得恶性肿瘤缺乏否则将有益于肿瘤生长和存活的蛋白质。
III.肿瘤相关抗原
在其中采用多种TAA特异性CTL治疗和/或预防癌症的实施方案中,可以靶向多种TAA。肿瘤抗原是肿瘤细胞中产生的在宿主中触发免疫反应的物质。
示例性肿瘤抗原至少包括以下:肠癌的癌胚抗原(CEA);卵巢癌的CA-125;乳腺的MUC-1或上皮肿瘤抗原(ETA)或CA15-3癌;恶性黑色素瘤的酪氨酸酶或黑色素瘤相关抗原(MAGE);和多种类型肿瘤的ras、p53的异常产物;肝瘤、卵巢癌或睾丸癌的α胎蛋白;患有睾丸癌的男性的hCG的β亚基;***特异性抗原的***癌;多种骨髓瘤和在一些淋巴瘤中的β2微球蛋白;结直肠癌、胆管癌和胰腺癌的CA19-9;肺癌和***癌的嗜铬粒蛋白A;黑色素瘤、软组织肉瘤和乳腺癌、结肠癌及肺癌的TA90、GP100和 MelanA/MART1。肿瘤抗原的例子是本领域已知的,例如在Cheever 等人,2009中,所述文献通过引用的方式完整并入本文。
肿瘤抗原的具体例子至少包括CEA、MHC、CTLA-4、gp100、间皮素、PD-L1、TRP1、CD40、EGFP、Her2、TCRα、trp2、 TCR、MUC1、cdr2、ras、4-1BB、CT26、GITR、OX40、 TGF-α。例如WT1、MUC1、LMP2、HPVE6E7、EGFRvIII、 HER-2/neu、MAGEA3、p53非突变体、NY-ESO-1、PSMA、GD2、MelanA/MART1、Ras突变体、gp100、p53突变体、蛋白酶 3(PR1)、bcr-abl、酪氨酸酶、存活素、PSA、hTERT、EphA2、 PAP、ML-IAP、AFP、EpCAM、ERG(TMPRSS2ETS融合基因)、 NA17、PAX3、ALK、雄激素受体、细胞周期蛋白B1、聚唾液酸、 MYCN、RhoC、TRP-2、GD3、岩藻糖基GM1、间皮素、PSCA、 MAGEA1、sLe(a)、CYP1B1、PLAC1、GM3、BORIS、Tn、 GloboH、ETV6-AML、NY-BR-1、RGS5、SART3、STn、碳酸酐酶 IX、PAX5、OY-TES1、***蛋白17、LCK、HMWMAA、 AKAP-4、SSX2、XAGE1、B7H3、豆荚蛋白、Tie 2、Page4、 VEGFR2、MAD-CT-1、FAP、PDGFR-β、MAD-CT-2和Fos-相关抗原1。
IV.核酸
本发明的核酸可以编码嵌合细胞因子受体。核酸可以源自基因组 DNA、互补性DNA(cDNA)或合成性DNA。
如本文所用的“核酸”包括单链和双链分子,以及DNA、RNA、化学修饰的核酸及核酸类似物。构思本发明范围内的核酸可以具有几乎任何尺寸,部分地由编码的蛋白质或肽的长度决定。
构思了嵌合细胞因子受体可以由编码适宜氨基酸序列的任何核酸序列编码。使用标准化密码子表,编码所需氨基酸序列的核酸的设计和产生是本领域技术人员熟知的。在优选的实施方案中,可以修饰经选择用于编码每种氨基酸的密码子以优化核酸在目的宿主细胞中的表达。
V.定向递送基因治疗载体
在本发明的具体实施方案中,使用允许整合而非瞬时表达的载体,如逆转录病毒、慢病毒和转座子。
存在可以借以向细胞中引入基因治疗载体的许多方式。在本发明的某些实施方案中,基因治疗载体包括病毒。某些病毒借助受体介导的内吞作用进入细胞、整合至宿主细胞基因组中或以附加体方式维持和稳定且高效表达病毒基因的能力已经使它们成为诱人的转移外来基因至哺乳动物细胞中的候选者(Ridgeway,1988;Nicolas和Rubinstein,1988.;Baichwal和Sugden,1986;Temin,1986)。优选的基因治疗载体通常是病毒载体。用作基因治疗载体的DNA病毒包括乳多空病毒(例如,猴病毒40,牛***瘤病毒和多瘤病毒)(Ridgeway,1988;Baichwal和Sugden,1986)和腺病毒(Ridgeway,1988; Baichwal和Sugden,1986)。
其他基因转移载体可以从逆转录病毒构建。(Coffin,1990)为了构建体逆转录病毒载体,将编码目的蛋白的核酸***病毒基因组中替代某些病毒序列以产生复制缺陷的病毒。为了产生病毒粒,构建含有 gag、pol和env基因但没有LTR和包装组件的包装细胞系(Mann等人,1983)。将含有cDNA连同逆转录病毒LTR和包装序列的重组质粒导入这种细胞系(例如通过磷酸钙沉淀法)时,包装序列允许重组质粒的RNA转录物包装至病毒颗粒中,后者随后分泌至培养基中(Nicolas 和Rubenstein,1988;Temin,1986;Mann等人,1983)。随后将含有重组逆转录病毒的培养基收集,任选地浓缩,并用于基因转移。逆转录病毒载体能够感染广泛种类的细胞类型。然而,整合和稳定表达需要宿主细胞***(Paskind等人,1975)。
其他病毒载体可以用作定向基因治疗载体。可以使用源自病毒如痘苗病毒(Ridgeway,1988;Baichwal和Sugden,1986;Coupar等人, 1988)、腺联病毒(AAV)(Ridgeway,1988;Baichwal和Sugden,1986; Hermonat和Muzycska,1984)和疱疹病毒的载体。
在本发明的又一个实施方案中,基因治疗构建体可以包埋于脂质体中。脂质体介导的核酸递送和外来DNA体外表达已经非常成功的。Wong等人(1980)在培养的鸡胚、HeLa和肝瘤细胞中展示脂质体介导的外来DNA递送和表达的可行性。Nicolau等人(1987)实现静脉内注射后在大鼠中成功的脂质体介导的基因转移。
本发明的基因治疗载体可以包含各种转基因,它们一般由表达载体的DNA或RNA编码。基因治疗可以用于表达治疗性基因、表达 APA以增强新生血管化或用于抑制APA表达以治疗与新生血管化相关的疾病状态。DNA可以处于以下形式:cDNA、体外聚合的 DNA、质粒DNA、质粒DNA的部分、源自病毒的遗传物质、线性 DNA、载体(P1、PAC、BAC、YAC、人工染色体)、表达盒、嵌合序列、重组DNA、染色体DNA、寡核苷酸、反义DNA、或这些群组的衍生物。RNA可以处于以下形式:寡核苷酸RNA、tRNA(转移 RNA)、snRNA(小的核RNA)、rRNA(核糖体的RNA)、mRNA(信使 RNA)、体外聚合的RNA、重组RNA、嵌合序列、反义RNA、 siRNA(小干扰性RNA)、核酶或这些群组的衍生物。反义多核苷酸是干扰DNA和/或RNA功能的多核苷酸。反义多核苷酸包括但不限于:吗啉代、2'-O-甲基多核苷酸、DNA、RNA等。SiRNA包含双链结构,所述双链结构一般含有15-50碱基对和优选地21-25碱基对并且具有与细胞内部表达的靶基因或RNA相同或几乎相同的核苷酸序列。干扰可以导致表达的抑制。多核苷酸也可以其在细胞中的存在或表达改变细胞基因或RNA(例如,APA)的表达或功能的序列。此外, DNA和RNA可以是单链、双链、三链或四链的。
VI.药物组合物
本发明的药物组合物包含有效量的一种或多种组合物,所述组合物包含溶解或分散于可药用载体中的载体或携带载体的细胞,其中所述载体编码如本文所述的本发明嵌合细胞因子受体。短语“可药用或药理学可接受的”指当施用至动物(如果适宜,例如人)时不产生不良、变应性或其他不利反应的分子实体和组合物。根据本公开,制备含有至少一种本发明组合物或额外有效成分的药物组合物将是本领域技术人员已知的,如Remington'sPharmaceutical Sciences,第18版, Mack Printing Company,1990所例举,所述文献通过引用方式并入本文。另外,对于动物(例如,人类)施用,应当理解制品应当满足如 FDA生物学标准办公室所要求的无菌性、致热原性、总体安全性和纯度标准。
如本文所用,“可药用载体”包括任何和全部溶剂、分散介质、包衣、表面活性剂、抗氧化剂、防腐剂(例如,抗菌药、抗真菌药)、等渗剂、吸收延迟剂、盐、防腐剂、药物、药物稳定剂、凝胶、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、矫味剂、染料、这类相似材料和其组合,如本领域普通技术人员将已知(见例如,Remington's Pharmaceutical Sciences,第18版,Mack Printing Company,1990,第 1289-1329页,所述文献通过引用方式并入本文)。除了任何常规载体与有效成分不相容的情况下之外,构思了所述载体在治疗组合物或药物组合物中的用途。
本发明的治疗组合物和诊断组合物可以包含不同类型的载体,这取决于是否将以固态、液态或气溶胶形式施用它和对于这类施用途径是否需要它是无菌的。可以将本发明按静脉内、皮内、动脉内、腹膜内、病灶内、颅内、关节内、胸膜内、气管内、肿瘤内、肌内、腹膜内、皮下、囊内、舌下方式、通过吸入(例如气溶胶吸入)、注射、输注、连续输注、直接局限化灌流浸浴靶细胞、借助导管、借助灌洗、以脂质组合物(例如、脂质体)或通过其他方法或前述方式的任何组合施用,如本领域普通技术人员将已知(见例如,Remington'sPharmaceutical Sciences,第18版,Mack Printing Company,1990,所述文献通过引用方式并入本文)。
向受试者施用的本发明组合物的实际剂量可以由身体和生理因素如体重、病状严重性、正在治疗的疾病的类型、先前或同时存在的治疗性介入、患者特发病决定并且取决于施用途径。在任何情况下,负责施用的执业者将决定用于单个受试者的组合物中的有效成分浓度及适宜剂量。
在某些实施方案中,药物组合物可以包含例如至少约0.1%的活性化合物。在其他实施方案中,活性化合物可以例如占到约2%至约 75%之间、或约25%至约60%之间以及其间任何可推导范围的单位重量。在其他非限制性例子中,剂量也可以包括每次施用约1μg/kg/ 体重、约5μg/kg/体重、约10μg/kg/体重、约50μg/kg/体重、约100 μg/kg/体重、约200μg/kg/体重、约350μg/kg/体重、约500μg/kg/体重、约1mg/kg/体重、约5mg/kg/体重、约10mg/kg/体重、约50 mg/kg/体重、约100mg/kg/体重、约200mg/kg/体重、约350mg/kg/ 体重、约500mg/kg/体重至约1000mg/kg/体重或更多,及其间任何可推导范围。在从本文中列出的数值可推导的范围的非限制性例子中,基于上文描述的数值,可以施用约5mg/kg/体重至约100mg/kg/ 体重、约5微克/kg/体重至约500毫克/kg/体重的范围。
在任何情况下,组合物可以包含各种抗氧化剂以迟滞一种或多种组分的氧化。额外地,可以通过防腐剂,如各种抗菌剂和抗真菌剂,包括但不限于尼泊金酯(例如,尼泊金甲酯、尼泊金丙酯)、氯丁醇、苯酚、山梨酸、硫柳汞或其组合,实现对微生物作用的预防。
在其中组合物为液体形式的实施方案中,载体可以是溶剂或分散介质、其包括但不限于水、乙醇、多元醇(例如,甘油、丙二醇、液体聚乙二醇)、脂类(例如,甘油三酯、植物油、脂质体)和其组合。在许多情况下,将优选包括等渗剂,例如,糖、氯化钠或其组合。
通过以下方式制备无菌可注射溶液剂:将靶向APA的部分或其缀合物以所要求的量连同上文列举的多种其他成分一起并入适宜的溶剂中,根据需要,随后过滤消毒。通常,通过将多种消毒的有效成分并入无菌溶媒中来制备分散体,所述无菌溶媒含有基础分散介质和/ 或其他成分。在用于现场制备无菌可注射溶液剂、混悬剂或乳剂的无菌粉末情况下,优选的制备方法是真空干燥或冷冻干燥技术,所述技术产生有效成分的粉末,外加来自其事先无菌过滤的液体介质中的任何额外所需成分。如果需要,应当合适地缓冲液体介质并且首先用足够的盐水或葡萄糖使液体稀释剂在注射之前等渗。也构思制备用于直接注射的组合物,其中构思使用DMSO作为溶剂以导致极端快速的渗透、递送高浓度的有效药物至微小区域。
组合物必须在制造和储存条件下是稳定的;因此,受到保护以免微生物如细菌和真菌的污染作用。可以理解应当最小地保持内毒素污染处于安全水平,例如,小于0.5ng/mg蛋白质。
VII.联合疗法
在本发明的某些实施方案中,用于临床方面的本发明方法与有效治疗过度增殖性疾病的其他药剂如抗癌药组合。“抗癌药”能够例如通过以下方式在受试者中不利地影响癌症:杀伤癌细胞、在癌细胞中诱导凋亡、降低癌细胞的生长速率、降低转移的发生率或数目、减少肿瘤尺寸、抑制肿瘤生长、减少通向肿瘤或癌细胞的血液供应、促进针对癌细胞或肿瘤的免疫反应、阻止或抑制癌症进展、或增加癌症受试者的寿命。更一般地,将以有效杀伤细胞或抑制其增殖的合并量提供这些其他组合物。这种方法可以涉及使癌细胞与表达构建体和药物或多种因子同时接触。这可以通过以下方式实现:使细胞与包括两种药物的单一组合物或药理学制剂接触,或使细胞与两种不同的组合物或制剂同时接触,其中一种组合物包含表达构建体而另一种组合物包含第二药物。
抵抗化疗药物和放疗药物的肿瘤细胞代表临床肿瘤学中的一个主要问题。当前癌症研究的一个目标是找出通过与基因治疗组合改善化疗法和放疗法功效的方式。例如,单纯疱疹病毒胸苷激酶(HS-tK)基因,在通过逆转录病毒载体***递送至脑肿瘤时,成功地诱导对抗病毒药更昔洛韦的敏感性(Culver等人,1992)。在本发明的上下文中,构思除了其他促凋亡或细胞周期调节剂之外,细胞疗法可以类似地与化疗性、放疗性或免疫治疗性介入治疗结合使用。
可选地,本发明疗法可以在其他药物之前或在其之后以范围从数分钟至数周的间隔时间施用。在其他药物和本发明分别施加至个体的实施方案中,通常将确保充足的时间段在每次递送的时间之间不失效,从而该药物和本发明疗法将仍能够对细胞发挥有利联合的效应。在这类情况下,构思可以使细胞与两种药物在约12-24小时内彼此接触并且更优选地6-12小时内彼此接触。然而,在一些情况下,可能合乎需要显著延长治疗时间,其中在相应的施用之间逝去几日(2、 3、4、5、6或7日)至几周(1、2、3、4、5、6、7或8周)。
可以使用各种组合,本发明是“A”和第二种药剂如放疗或化疗是“B”:
预期治疗循环将根据需要重复。也构思各种标准疗法以及手术介入可以与本发明的细胞疗法组合应用。
A.化疗
癌症疗法也包括采用基于化学和辐射的治疗法的多种组合疗法。组合化疗法例如包括abraxane、六甲蜜胺、多西紫杉醇、赫赛汀、甲氨蝶呤、米托蒽醌、诺雷德、顺铂(CDDP)、卡铂、丙卡巴肼、氮芥、环磷酰胺、喜树碱、异环磷酰胺、美法仓、苯丁酸氮芥、白消安、亚硝基脲、更生霉素、佐柔比星、多柔比星、博来霉素、普卡霉素(plicomycin)、丝裂霉素、依托泊苷(VP16)、他莫昔芬、雷洛昔芬、***受体结合剂、紫杉酚、吉西他滨(gemcitabien)、长春瑞滨、法呢基蛋白质转移酶抑制剂、反式铂、5-氟尿嘧啶、新长春碱、长春碱和甲氨蝶呤、或前述药物的任何类似物或衍生变体。
B.放疗
造成DNA损伤并已经广泛使用的其他因素包括公知作为γ-射线、X射线和/或向肿瘤细胞定向递送放射性同位素。也构思其他形成的DNA损伤因素,如微波和UV-照射。最可能的是,全部这些因素对DNA、对DNA前体、对DNA复制和修复和对染色体装配和维持造成宽范围的损伤。X射线的剂量范围是从每日剂量50至200伦琴持续延长的时间段(3至4周)至单剂量的2000至6000伦琴。放射性同位素的剂量范围广泛地变动并且取决于同位素半寿期、所发射的辐射的强度和类型和肿瘤细胞的摄取量。
当适用于细胞时,术语“接触”和“暴露”在本文中用来描述借以递送治疗性构建体和化疗或放疗药至靶细胞或将它们直接置于靶细胞附近的过程。为了实现细胞杀伤或停滞,将两种药物以有效杀伤细胞或防止它***的联合量递送至细胞。
C.免疫疗法
免疫治疗药总体上依赖于使用免疫效应细胞和分子以靶向和摧毁癌细胞。免疫效应子可以例如是对肿瘤细胞表面上的一些标记特异的抗体。抗体单独可以充当疗法的效应子或它可以招募实际实现细胞杀伤的其他细胞。抗体也可以与药物或毒素(化疗、放射性核素、蓖麻毒蛋白A链、霍乱毒素、百日咳毒素等)缀合并且仅起到导引剂的作用。可选地,效应子可以是携带与肿瘤细胞靶直接或间接相互作用的表面分子的淋巴细胞。各种效应细胞包括细胞毒T细胞和NK细胞。
因此,免疫疗法可以作为联合疗法的一部分与本发明的细胞疗法结合使用。下文讨论联合疗法的一般方案。总体上,肿瘤细胞必须携带能够进行靶向(即,大多数其他细胞上不存在的)的一些标记。存在许多肿瘤标记并且这些肿瘤标记的任一者可以适合于本发明情境下的靶向。常见的肿瘤标记包括癌胚抗原、***特异性抗原、尿路肿瘤相关抗原、胚胎抗原、酪氨酸酶(p97)、gp68、TAG-72、HMFG、唾液酸化路易斯抗原、MucA、MucB、PLAP、***受体、层粘连蛋受体、erb B和p155。
D.基因
在又一个实施方案中,第二治疗是其中在本发明临床实施方案之前、之后或与之同时施用治疗性多核苷酸的基因治疗。本发明中包括多种表达产物,包括细胞增殖的诱导物、细胞增殖的抑制剂或程序性细胞死亡的调节物。
E.手术
大约60%患有癌症的人将经历某种类型的手术,所述手术包括预防、诊断或分期、治愈性和姑息性手术。治愈性手术是可以结合其他疗法如本发明疗法、化疗法、放疗法、激素疗法、基因治疗、免疫疗法和/或替代性疗法使用的癌症疗法。
治愈性手术包括其中物理摘除、切除和/或摧毁全部或部分癌组织的切除术。肿瘤切除指物理摘除至少部分的肿瘤。除肿瘤切除之外,手术治疗包括激光手术、低温手术、电外科手术和显微镜下控制的手术(Mohs手术)。进一步构思本发明可以与摘除浅表癌、初癌或附带量的正常组织结合使用。
一旦切除全部癌细胞、组织或肿瘤的部分,则可以在身体内形成空腔。可以通过用额外的抗癌疗法灌流、直接注射或局部施加该区域实现治疗。这种治疗可以重复,例如,每隔1、2、3、4、5、6或7 日,或每隔1、2、3、4和5周或每隔1、2、3、4、5、6、7、8、9、 10、11或12个月重复。这些治疗也可以变动剂量。
F.其他药剂
构思了其他药剂可以与本发明组合使用以改善疗法的治疗功效。这些额外药剂包括免疫调节剂、影响细胞表面受体和缝隙连接上调的药剂、细胞稳定及分化剂、细胞黏附抑制剂或增加过度增殖性细胞对凋亡诱导物的灵敏度的药剂。免疫调节剂包括肿瘤坏死因子;干扰素α、β、和γ;IL-2和其他细胞因子;F42K和其他细胞因子类似物;或MIP-1、MIP-1β、MCP-1、RANTES和其他趋化因子。进一步构思,细胞表面受体或其配体如Fas/Fas配体、DR4或DR5/TRAIL的上调将通过对过度增殖性细胞上建立自分泌或旁分泌效应,激动本发明的凋亡诱导能力。通过提高缝隙连接的数目增加胞间信号传导将增加对相邻过度增殖性细胞群的抗过度增殖作用。在其他实施方案中,细胞稳定或分化剂可以与本发明组合使用以改善疗法的抗过度增殖功效。构思细胞黏附抑制剂改善本发明的功效。细胞黏附抑制剂的例子是局部黏着斑激酶(FAK)抑制剂和洛伐他汀。还构思了增加过度增殖性细胞对凋亡的灵敏度的其他药剂(如抗体c225)可以与本发明组合使用以改善治疗功效。
激素疗法也可以与本发明结合或与前述任何其他癌症疗法组合使用。激素的用途可以用于治疗某些癌症如乳腺癌、***癌、卵巢癌、或***以降低某些激素如睾酮或***的水平或阻断其作用。这种治疗经常与至少一个其他癌症疗法组合使用作为治疗选项或以便降低转移风险。
DNA甲基转移酶抑制剂和/或组蛋白脱乙酰酶抑制剂示例性DNA 甲基转移酶抑制剂包括例如5-氮杂胞苷、5-氮杂-2'-脱氧胞苷、1-β-D- ***呋喃糖基-5-氮杂胞嘧啶和二氢-5-氮杂胞苷。示例性HDAC抑制剂包括异羟肟酸,如曲古抑菌素A;环四肽(如trapoxinB),和酯肽;苯甲酰胺;亲电酮类;和脂族酸化合物如苯基丁酸酯和丙戊酸。
G.程序性细胞死亡的调节物
凋亡或程序性细胞死亡,是正常胚胎发育、维持成体组织中稳态和抑制癌发生的重要过程(Kerr等人,1972)。已经展示Bcl-2蛋白家族和ICE样蛋白酶是其他***中凋亡的重要调节物和效应子。发现与滤泡淋巴瘤相关的Bcl-2蛋白在控制凋亡和增强应答于各种凋亡性刺激的细胞存活方面发挥突出作用(Bakhshi等人,1985;Cleary和Sklar, 1985;Cleary等人,1986;Tsujimoto等人,1985;Tsujimoto和Croce, 1986)。现在认为进化上保守的Bcl-2蛋白是相关蛋白质家族的成员,所述成员可以归类为死亡激动剂或死亡拮抗剂。
在其发现后,显示Bcl-2发挥作用以抑制多种刺激触发的细胞死亡。另外,现在已知存在分享共有结构和序列同源性的Bcl-2细胞死亡调节蛋白家族。这些不同的家族成员已经显示拥有与Bcl-2相似的功能(例如,BclXL、BclW、BclS、Mcl-1、A1、Bfl-1)或对抗Bcl-2功能并促进细胞死亡(例如,Bax、Bak、Bik、Bim、Bid、Bad、 Harakiri)。
H.生血管抑制剂
在某些实施方案中,本发明可以涉及施用与抗血管生成剂有效连接的靶向部分,所述抗血管生成剂是如血管紧张素、层粘连蛋肽、纤连蛋白肽、纤维蛋白溶酶原激活物抑制剂、组织金属蛋白酶抑制剂、干扰素、白介素12、血小板因子4、IP-10、Gro-β、血小板应答蛋白、2-甲氧基***、增殖蛋白相关蛋白、羧胺*** (carboxiamidotriazole)、CM101、马立马司他(Marimastat)、硫酸戊聚糖聚酯、血管生成素2(Regeneron)、干扰素-α、除莠霉素A、PNU145156E、16K催乳素片段、利诺胺、沙立度胺、己酮可可碱、染料木黄酮、TNP-470、内皮抑素、紫杉醇、accutin、血管抑制素、西多福韦、长春新碱、博来霉素、AGM-1470、血小板因子4或米诺环素。
肿瘤细胞增殖非常依赖于广泛的肿瘤血管化,这伴随癌症进展。因此,已经引入采用抗血管生成剂抑制新血管形成和定向破坏既有血管作为有效和相对无毒的肿瘤治疗方案。(Arap等人,1998;Arap等人,1998;Ellerby等人,1999)。多种抗血管生成剂和/或血管抑制剂是已知的(例如,Folkman,1997;Eliceiri和Cheresh,2001)。
I.细胞毒剂
化疗(细胞毒)剂可以用来治疗各种疾病状态,包括癌症。可能使用的化疗(细胞毒)剂包括但不限于5-氟尿嘧啶、博来霉素、白消安、喜树碱、卡铂、苯丁酸氮芥、顺铂(CDDP)、环磷酰胺、更生霉素、佐柔比星、多柔比星、***受体粘合剂、依托泊苷(VP16)、法呢基转移酶抑制剂、吉西他滨、异环磷酰胺、氮芥、美法仓、丝裂霉素、长春瑞滨、亚硝基脲、普卡霉素(plicomycin)、丙卡巴肼、雷洛昔芬、他莫昔芬、紫杉酚、替莫唑胺(temazolomide)(含水形式的 DTIC)、反式铂、长春碱和甲氨蝶呤、长春新碱或前述药物的任何类似物或衍生变体。大部分化疗药术语以下类别:烷基化剂、抗代谢物、抗肿瘤抗生素、皮质类固醇激素、有丝***抑制剂、和亚硝基脲类、激素药、其他药剂和任何类似物或其衍生变体。
化疗药和施用方法、剂量等是本领域技术人员熟知的(见例如,“Physicians DeskReference”,Goodman&Gilman's“The Pharmacological Basis of Therapeutics”以及在“Remington's Pharmaceutical Sciences”第15版,第1035-1038页和第1570-1580 页中,所述文献通过引用方式以相关部分并入本文),并且可以根据与本文公开内容与本发明公开。取决于正在接受治疗的患者的状况,剂量的一些变动将必然地出现。在任何情况下,负责施用的人将决定各个受试者的适宜剂量。当然,本文所述的全部剂量和药剂是示例性的,而非限制的,并且其他剂量或药剂可以由技术人员用于特定患者或应用。在这些点之间的任何剂量或其中可推导的范围也预期用于本发明中。
J.烷基化剂
烷基化剂是直接与DNA基因组相互作用以阻止细胞增殖的药物。这类的化疗药物代表影响细胞周期全部阶段的药剂,即,它们不是阶段特异性的。烷基化剂,可以包括但不限于氮芥、乙烯亚胺 (ethylenimene)、甲基蜜胺、烷基磺酸酯、亚硝基脲或三嗪类。它们包括但不限于:白消安、苯丁酸氮芥、顺铂、环磷酰胺(cytoxan)、达卡巴嗪、异环磷酰胺、氮芥(mustargen)和美法仑。
K.抗代谢物
抗代谢物破坏DNA和RNA合成。不同于烷基化剂,它们特别地影响S期期间的细胞周期。抗代谢物可以划分成各种类别,如叶酸类似物、嘧啶类似物和嘌呤类似物和相关的抑制性化合物。抗代谢物包括但不限于5-氟尿嘧啶(5-FU)、阿糖胞苷(Ara-C)、氟达拉滨、吉西他滨和甲氨蝶呤。
L.天然产物
天然产物通常指最初从天然来源分离并经鉴定具有药理学活性的化合物。这类化合物、其类似物和衍生物可以从天然来源分离、化学合成或通过本领域技术人员已知的任何技术重组地产生。天然产物包括这些类别,如有丝***抑制剂、抗肿瘤抗生素、酶和生物反应调节物。
有丝***抑制剂包括植物生物碱和可以抑制细胞***或有丝***所需要的蛋白质合成的其他天然物质。它们在细胞周期期间的特定阶段期间起作用。有丝***的抑制剂包括例如多西紫杉醇、依托泊苷 (VP16)、替尼泊苷、紫杉醇、紫杉酚、长春碱、长春新碱和长春瑞滨。
紫杉醇类化合物是从灰树短叶红豆杉(Taxus brevifolia)的树皮分离的一类相关化合物。紫杉醇类化合物包括但不限于诸如多西紫杉醇和紫杉醇之类的化合物。紫杉醇与微管蛋白结合(在不同于长春碱类生物碱所利用的位点处)且促进微管的装配。
蔓长春花属生物碱是经鉴定具有药物活性的一类植物生物碱。它们包括这类化合物如长春碱(VLB)和长春新碱。
M.抗生素
某些抗生素具有抗微生物活性和细胞毒活性。通过化学地抑制酶和有丝***或改变细胞膜,这些药物也干扰DNA。这些药物不是阶段特异性的,因此它们在细胞周期全部阶段中发挥作用。细胞毒性抗生素的例子包括但不限于博来霉素、更生霉素、佐柔比星、多柔比星 (阿霉素)、普利霉素(光神霉素)和伊达比星。
N.其他药剂
不属于前述分类的其他细胞毒药物包括但不限于铂配位络合物、蒽二酮类、取代脲、甲基肼衍生物、安吖啶、L-天冬酰胺酶,和维甲酸(tretinoin)。铂配位络合物包括这类化合物如卡铂和顺铂(顺 -DDP)。示例性蒽二酮是米托蒽醌。示例性取代脲是羟基脲。示例性甲基肼衍生物是丙卡巴肼(N-甲基肼,MIH)。这些实例不是限制性的,并且构思任何已知的细胞毒剂、细胞稳定剂或杀细胞剂可以与靶向肽连接并且施用至本发明范围内的所靶向的器官、组织或细胞类型。
VIII.本发明的试剂盒
可以在试剂盒中包含本文所述的任何组合物。在非限制性实例中,包含嵌合细胞因子受体的修饰细胞和/或产生这类细胞的试剂可以包含于试剂盒中。这类试剂包括细胞、核酸载体、缓冲剂、核苷酸、寡核苷酸等中的一种或多种。试剂盒将在一个或多个适合的容器中包含其任何组分。
试剂盒的组分可以在含水介质中或以冻干形式包装。试剂盒的容器装置通常将包括至少一个小瓶、试管、烧瓶、瓶、注射器或其他容器装置,其中可以安置并且优选地适当等分组分。在试剂盒中存在多于一种组分的情况下,试剂盒通常也将含有其中可以分别放置额外组分的第二、第三或其他额外容器。然而,可以在小瓶中包含组分的各种组合。本发明的试剂盒一般也将包括以用于商业销售的密封含有组分的装置。这类容器可以包括留置所需小药瓶的注塑或吹塑成型塑料容器。试剂盒的组分可以作为干燥粉末提供。当试剂和/或组分作为干燥粉末提供时,可以通过添加合适的溶剂使粉末复水。构思了也可以在另一个容器装置中提供溶剂。
实施例
将如下实施例包括在内以阐述本发明的优选实施方案。本领域技术人员应当理解,以下的实施例中公开的技术代表由发明人发现的在实施本发明时发挥良好作用的技术,并且因此可以视为构成其实施的优选模式。然而,根据本公开,本领域技术人员应当理解可以在公开的具体实施方案中产生许多变化并且仍获得类似或相似的结果而不脱离本发明的精神和范围。
实施例1
使用嵌合细胞因子受体逆转肿瘤微环境的影响
胰腺癌仍是发达国家中第四种最常见的癌症死亡原因。临床表现发生晚并且疾病早期转移,发生率和死亡率已经保持几乎相同超过 50年(Sweeney等人,2009;Wong等人,2009)。因此需要基于理解疾病生物学的改进治疗策略。由恶性细胞表达的肿瘤相关抗原(TAA)可以具有免疫原性,并因此是免疫破坏的潜在靶(Tassi等人,2008;Han 等人,2009;Rong等人,2009;Li等人,2008;Plate,2007)。体外扩充的TAA特异性细胞毒T淋巴细胞(CTL)的过继转移可以有效地***,例如包括霍奇金淋巴瘤和黑色素瘤(Bollard等人,2007;Morgan 等人,2006)。尽管输注靶向胰腺癌表达的TAA的CTL具有治疗潜力,这些肿瘤利用多种免疫逃避机制,包括下调抗原表达,和释放有利于形成Th2而非细胞毒性Th1型免疫反应的可溶性免疫调节细胞因子和其他物质(Leen等人,2007;Selcean等人,2009;Formentini等人, 2009;Kornmann等人,1999;Prokopchuk等人,2005;Seruga等人, 2008)。
为了克服这些障碍并且开发对抗胰腺癌的有效免疫治疗策略,本发明的实施方案涉及生成靶向恶性细胞上表达的抗原的CTL系,并且工程化这些CTL以表达嵌合分子,所述嵌合分子含有与传递Th1 信号的IL2Rγ和IL7Rα的胞内结构域连接的IL13α受体(IL13Rα1)和 IL4Rα的细胞因子结合性胞外结构域(Formentini等人,2009; Prokopchuk等人,2005)。在本发明的特定实施方案中,这些操作使得CTL抵抗极化Th2的肿瘤微环境并且反而维持Th1信号传导至靶向TAA的CTL(Vera等人,2009)。可以通过检验来自癌症患者(如胰腺癌患者)的活组织检查和血清样品来开始,并记录TAA表达模式和产生的Th2细胞因子的水平和模式。随后可以确定是否可以扩充针对来自患者PBMC的已表达抗原的CTL并且修饰这些CTL的作用,从而它们仍保持极化成Th1活性,甚至在诱导Th2的肿瘤微环境下也是如此。在本发明的实施方案中,针对反应性胰腺癌相关抗原的T细胞可以从患者的PBMC产生并且受到修饰以保留Th1功能,甚至在肿瘤的Th2细胞因子环境下也是如此。这类实施方案可以由三种示例性方法表征:1)记录TAA表达模式和评估初次活组织检查样品的细胞因子谱;2)产生对多种胰腺癌靶抗原特异的肿瘤反应性CTL并且体外评价它们的特异性和功能;和3)通过强制性表达嵌合细胞因子受体,保护CTL免受Th2细胞因子的信号传导抑制性作用。
背景和意义
胰腺癌.胰腺癌在世界范围造成每年估计213,000例死亡(Wong 等人,2009)。手术切除仍是唯一治愈性疗法,导致15-20%的5年存活率,但是这种选项不可用于诊断患有局部晚期或转移性疾病的绝大部分患者(Sweeney等人,2009;Tanis等人,2009)。常规化疗和放疗法几乎不产生实质益处,这强调对新治疗药的需要。
用于病毒相关性恶性肿瘤的过继免疫疗法.发明人已经常规地产生病毒特异性CTL用于过继转移(Leen等人,2006;Leen等人, 2009),并且在超过100位干细胞细胞接受者中的研究已经显示供体衍生的EBV-CTL可以安全地保护患者对抗EBV驱动的淋巴瘤并且治愈甚至存在严重已建立病情的患者(Heslop等人,2009;Heslop等人, 1996;Rooney等人,1995)。这种方案也已经显示成功治疗免疫功能健全个体中的EBV+ve肿瘤(Bolard等人,2007;Louis等人,2009; Straathof等人,2005;Bollard等人,2004)。在最近一项I期试验中,在高风险EBV+veHL或NHL缓解时接受治疗的9/10患者仍处于缓解,而5/6存在活跃复发病情的患者具有肿瘤缓解,所述肿瘤缓解在 4位患者中是完全的(Bollard等人,2007)。这些研究展示,EBV特异的功能性T细胞在输注后在患者血液中频率增加(暗示体内扩充)、寻的至肿瘤组织并消除肿瘤细胞。
用于病毒非依赖性恶性肿瘤的过继免疫疗法.利用过继转移的 CTL治疗病毒非依赖性癌症的努力已经受阻于(i)关于TAA表达的信息有限,(ii)鉴于循环的反应性T细胞经常遭遇失能或耐受,缺少可重复方法以产生针对已表达抗原的CTL系,和(iii)肿瘤利用的免疫逃避策略,这些策略限制过继转移的T细胞的体内活性。这些策略包括下调表达的靶抗原和分泌抑制性细胞因子,所述抑制性细胞因子起到招募调节性免疫细胞至肿瘤并直接抑制和/或使细胞毒性Th1T细胞针对无效Th2表型再极化的作用(Selcean等人,2009;Formentini等人, 2009;Prokopchuk等人,2005)。使用优化的抗原呈递细胞(APC)和增强性细胞因子以产生TAA-CTL,发明人已经开发了活化遭失能/耐受的T细胞的策略(Kaka等人,2009;Foster等人,2007;Kaka等人, 2008)。
发明人在下文提供多种策略以鉴定胰腺癌表达的靶并调节体外产生的TAA-CTL对肿瘤微环境存在的细胞因子的反应;开发这些策略以便使用过继免疫疗法靶向胰腺癌。
确定TAA表达模式.已经存在由胰腺癌活组织检查样品表达的 TAA的有限报道。因此,可以例如使用免疫组织化学(IHC)和 RT-PCR,全面记录胰腺癌中的TAA表达。
体外产生TAA特异性CTL.发明人已经开发了使用表达完整抗原(pepmix或编码TAA的质粒)的DC作为APC从患者PBMC中产生 TAA-CTL并且以最佳细胞因子混合物共培养的方案(表1)。也可以确定这种策略是否可以适用于产生靶向胰腺癌相关抗原的TAA-CTL。
克服肿瘤免疫逃避策略.对于有效免疫疗法,必须表征和规避肿瘤免疫逃避策略。IL13和IL4均对抑制和再极化Th1效应子T细胞作出主要贡献,所述Th1效应子T细胞对胰腺癌中消除肿瘤至关重要 (Formentini等人,2009;Prokopchuk等人,2005)。可以用嵌合细胞因子受体表征武装性TAA-CTL,所述嵌合细胞因子受体结合这些抑制性细胞因子并且使得它们的胞内结果转换成Th1信号,因此改进 CTL的功效。
示例性结果
检测癌症活组织检查样品上的TAA.为了将该方案初步建模,从源自TCH的病理科、Methodist医院和儿童肿瘤学组织的霍奇金疾病或滤泡性B细胞淋巴瘤患者获得石蜡包埋的4μm***切片。将切片脱石蜡和复水。Triton-X-100和Digest ALL1(Zymed)用于抗原修复。切片用针对MAGE-A4、PRAME和存活素的第一抗体染色。用(i)针对兔或小鼠第一抗体的powervision+试剂盒(immunovision)或(ii)针对其他第一抗体的ABC试剂盒(vectorlabs)成功地检测到抗原表达。全部抗体均使用阳性对照和阴性对照切片和含有非癌组织的组织阵列验证。
使用pepmix刺激的或质粒胞核转染的APC产生同时对多种TAA具有特异性的TAA- CTL.发明人通过以下方式优化CTL产生方案:使用以涵盖示例性淋巴瘤相关抗原SSX2、存活素和MAGEA4的 pepmix主混合物刺激的DC作为APC并且在IL7(10ng/ml)、IL12(10 ng/ml)、IL15(10ng/ml)和IL6(1000U/ml)存在下共培养(表1)。
组 | Th1极化 | 增殖/存活 | 抑制调节性T细胞(Tregs) |
1 | IL-12 | IL7;IL-15 | |
2 | IL-12 | IL7;IL-15 | IL-6 |
3 | IL-12,IL-27 | IL7;IL-15 | |
4 | IL-12,IL-27 | IL7;IL-15 | IL-6 |
生成对全部三种刺激抗原同时具有特异性的TAA-CTL。重要地,使用相同抗原从相同供体产生,但是使用次优细胞因子组合所培养的CTL(表1;组1、3、4)产生针对免疫优势SSX2抗原的单特异性 CTL,因此在至少某些实施方案中展示了优化细胞因子组合以产生多种TM-CTL的用途。通过使用以编码SSX2、存活素和MAGEA4的 DNA质粒经核转染的DC从6/6供体产生多种TM-CTL,证实该***的一致性和稳健性。发明人也产生同时靶向白血病表达的抗原 WT1、PRAME、存活素和蛋白酶3(n=3)以及示例性肝细胞表达的抗原MAGE1、MAGE3和AFP(n=3)的多种TAA-CTL。这些多种 TAA-CTL是有功能的,如通过IFNγELispot和细胞毒性测定法所评估。可以采用这项技术来产生靶向最频繁表达的胰腺癌表达抗原的多种TAA-CTL。
逆转Th2信号传导对CTL的作用并且确保暴露于这些细胞因子而非维持Th1型反 应.工程化2种逆转录病毒中间构建体和在转基因 CTL中的初步测试。已经报道以共有组分与受体结合的Th2细胞因子IL4和IL13在患有胰腺癌的受试者中抑制Th1免疫力(Formentini 等人,2009;Prokopchuk等人,2005)。IL13受体由IL4Rα链和 IL-13Rα1链组成。IL13细胞因子以低亲和力与IL13α1链结合,随后招募IL4Rα链以增加结合亲和力。相反,IL4首先结合IL4Rα,后者随后招募IL13Rα1或IL2Rγc链(图1)。来自两种受体复合体的信号由 IL4Rα链转导,从而IL4和IL13招募相同的Janus激酶(JAK)信号传导者和转录激活物(Stat6)途径。作为结果,暴露于任一种细胞因子具有重叠的免疫抑制结果(Formentini等人,2009;Prokopchuk等人, 2005)。为了对抗在Th1TAA-CTL上的这些作用,发明人构建了两种示例性第一代逆转录病毒载体。如图2A中所述,构建体#1编码经 IRES与GFP连接的IL13Rα1胞外结构域与IL2Rγ胞内结构域 (IL-13Rα1/IL-2Rγ)的融合蛋白。构建体#2编码与mOrange连接的 IL4Rα胞外结构域与IL7Rα胞内结构域(IL-4Rα/IL-7Rα)的融合蛋白。因此,在本发明的具体实施方案中,一旦结合IL4或IL13细胞因子,则共表达两种构建体的细胞诱导胞内Th1信号。为了评估逆转录病毒转导的效率,在双重转导的抗原特异性CTL上评价GFP或 mOrange的表达。如预期,这产生表达构建体#1(GFP阳性-右下侧四分图)、构建体#2(mOrange阳性-左上侧四分图)或双阳性 (GFP/mOrange-右上四分图)(图2B)的CTL的混合群体。通过测量 StatS暴露于IL2(50U/ml)、IL-4(1000U/ml)或IL13(5ng/ml)后的磷酸化,证实转基因的功能。仅在施用IL2后的对照细胞中检测到磷酸化 Stat5;相反,在暴露于3种细胞因子中任一种后的共表达两种构建体的转基因细胞中检测到磷酸化Stat5(图2C)。使用显微分析,证实这些细胞因子作为生长因子发挥作用(图2D)。
示例性实验设计和方法
胰腺癌是预后不良的侵袭性疾病。虽然存在肿瘤特异性T细胞免疫力的证据(Tassi等人,2008;rong等人,2009;Plate,2007;Alters 等人,1997;Cappello等人,2009;Lepoisto等人,2008;Kawaoka等人,2008;Kondo等人,2008),但是肿瘤环境中的免疫阻抑性细胞因子限制T细胞的有效性(Selcean等人,2009;Formentini等人,2009; Kornmann等人,1999;Prokopchuk等人,2005)。在特定的实施方案中,输注离体扩充的TAA-CTL产生临床益处并且提供针对胰腺癌的新治疗性选项,其中所述TAA-CTL已经(i)在Th1极性细胞因子存在下培养以逆转失能,(ii)经选择而对多种TAA特异,以最小化因表位丧失所致的逃逸,和(iii)使其抵抗体内存在的抑制性可溶性因子。
在第一方案中,可以进行以下操作:a)评估胰腺肿瘤的细胞因子谱,和b)记录它们的TAA表达模式。可以建立患者血清中Th1和 Th2/抑制性细胞因子的模式以及从培养的原代肿瘤样品中释放的细胞因子的模式,使用例如IHC和RT-PCR确定活组织检查样品中的TAA表达模式,并且产生编码最频繁表达的抗原的DNA质粒库用于下文描述的CTL刺激方案。来自这个方案的数据允许设计用于过继免疫疗法的T细胞,其中可以使所述T细胞靶向肿瘤抗原并且变得抵抗肿瘤抑制作用。
示例性方法如下。
细胞因子分析.可以记录例如30-50份入库患者血清样品的细胞因子谱,并且使用Th1/Th2细胞因子阵列,将这些血清样品与从例如 30位健康供体采集的血清比较,所述Th1/Th2细胞因子阵列检测 IL1β、IL2、IL4、IL5、IL6、IL7、IL8、IL10、IL12、IL13、 IFNγ、GM-CSF和TNFα;可以通过ELISA测量TGFβ。也可以采集新鲜的活组织检查样品,在RPMI+5%HuS中培养4-5日并且使用相同的细胞因子分析上清液。这允许评估完整范围的在这些患者中循环和由肿瘤产生的抑制性和刺激性细胞因子。
TAA表达.可以通过IHC和RT-PCR对活组织检查样品筛查 TAA表达,包括先前声称与胰腺癌相关的那些TAA(CEA、MUC1、 MUC2、MUC5AC、MUC6和端粒酶)(Han等人,2009;Li等人,2008) 以及PRAME、MAGEA、SSX2/4、NY-ESO和存活素。
产生DNA质粒库.可以产生质粒,所述质粒编码在筛查中最频繁检测到的7种抗原(举例)。这些抗原可以克隆至p-Max表达质粒中处在CMV启动子的控制下,所述CMV启动子确保高水平的转基因表达并且将随GFP共表达以可能评估核转染效率。发明人先前已经验证DNA质粒作为产生病毒(Gerdemann等人,2009)和肿瘤特异性 CTL的抗原的有效来源。
在本发明的特定实施方案中,在患者血清中和来自培养的活组织检查样品的上清液中检测Th2/抑制性细胞因子IL13和IL4占优势,因为这两种细胞因子均由胰细胞系过量产生并且由肿瘤用作自分泌生长因子。在特定的实施方案中,在患者活组织检查样品上检测TAA 表达。公布的报道表明,大部分肿瘤是CEA阳性的,大约60%表达 MUC-1,同时较低频率地检测到MUC-6(<15%),并且可以进一步表征TAA表达的频率和强度。可以产生表达最频繁检测到的TAA的质粒库。
表2:示例性组织样品
组织 | 样品数目 |
血细胞 | 232 |
囊肿液 | 22 |
正常组织 | 701 |
胰液 | 66 |
血浆 | 574 |
血清 | 559 |
肿瘤组织 | 780 |
胰腺炎 | 178 |
总计 | 3092 |
这些描述的实施方案提供由胰腺肿瘤表达的TAA和抑制性细胞因子的概况,从而允许设计靶向策略和保护策略。
在第二方案中,可以产生对多种胰腺癌相关性靶抗原特异的肿瘤特异性CTL并体外评价它们的特异性和功能。可以确定是否可以从患有胰腺癌的受试者扩充针对胰腺癌TAA的CTL。基于其他癌症中取得成功,可以产生CTL,首先用单一抗原特异性和随后采用多种抗原特异性,意图在于使肿瘤抗原丧失变体介导的免疫逃避最小化。
示例性方法如下:可以例如获得,40-50ml将作为APC和应答者T细胞的来源的患者血液。例如可以从20-25位患者产生CTL系。
DC产生:通过在CellGenix DC培养基中在GM-CSF和IL-4存在下培养,从CD14选择的单核细胞中分化出DC。将CD14阳性细胞冷冻用于后续刺激。使培养的DC再成熟24小时,例如使用如上文所述产生的编码不同抗原的DNA质粒进行核转染,随后使其成熟另外 24小时。通过使用流式细胞术测量成熟分子CD80、CD83、CD86、 HLA-Dr和GFP的表达评估表型和核转染效率。
CTL刺激:为了活化抗原特异性T细胞,将核转染的DC与 CD14阳性PBMC以R:S比率10:1在CTL培养基(45%Click's、45%高级RPMI、5%人血清和5mM L-glutamax)中,在促进最佳CTL存活和扩充的优化细胞因子混合物(IL-7、IL-12、IL15和IL6)(表1)存在下共培养。为了产生多种TAA-CTL,可以用多种质粒同时转染 DC。将扩充的细胞在第9日用核转染的DC再刺激并且随IL7一起培养并且从第12日起每周二次给予IL-2(50U/ml)。通过台盼蓝拒染法评估CTL扩充和生存力。在3次刺激后,可以使用包括CD4、CD8、 CD56、CD16、CD45RA、CD45RO、CD25、CD28、CD27和 CD62L的标记分析细胞表型以确定CTL的活化和记忆(效应子与中枢记忆)状态。可以使用ELispot或胞内细胞因子染色法,测量应答于刺激(或者肽或核转染的DC)的Th1(IFN-γ、TNFα、IL2)和Th2(IL4、 IL5、IL13、IL10和TGFβ)细胞因子的产生。通过ELispot评估表位宽度,例如,使用重叠肽汇集物来刺激经CD4和CD8选择的细胞并且确定在每种蛋白质内部识别出哪种CD4和CD8表位。使用表达 TAA的APC、HLA匹配的胰细胞系以及自体肿瘤作为靶细胞,通过 Cr51释放测定法评估溶细胞功能。
在本发明的特定实施方案中,使用核转染的DC作为APC,从患者PBMC容易地产生多克隆多种TAA-CTL。在某些情况下,并非全部抗原在全部供体中均有免疫原性,虽然在特定情况下,可以一致地为每位受试者产生识别至少2种抗原的多种TAA-CTL。基于在CTL 系中的研究结果结合如上文所述鉴定的TAA表达谱,可以鉴定用于未来免疫疗法的最佳4-5个靶(例如)。扩充的细胞可以是多克隆的 (CD4+和CD8+),具有中枢记忆(CD62L+)和效应子记忆(CD62L-)群体和终端分化的效应子。在优化的细胞因子混合物存在下,在具体实施方案中,CTL将具有Th1细胞因子谱并且一旦刺激,将产生 TNFα、IFNγ和IL2,从而允许鉴定每种抗原的一组CD4+和CD8+T 细胞表位。在本发明的一些实施方案中,扩充的细胞保留针对全部刺激抗原的特异性和活性,如通过例如流式细胞术、胞内细胞因子染色法和溶细胞测定法测量。
在其中可能使用核转染的DC作为APC无法产生TAA-CTL的情况下,可以将pepmixe用作抗原刺激。在其中可能用多种TAA特异性无法产生同时活化扩充CTL的情况下,就病毒抗原而言,并非全部TAA均同等地具有免疫原性并且可以见到抗原性竞争和在多个轮次刺激后针对较弱抗原的特异性丧失。然而,优化的细胞因子组合使得在细胞系内部维持多特异性成为可能。在可能存在TAA-CTL体外增殖不良的情况下(虽然这是不太可能,因为发明人在16日的培养时间范围内在G-Rex生物反应器中一致实现20-40倍TAA-CTL扩充; Vera等人,2009),但是如果这种扩充得不到维持,则可以将IL15替换为增进增殖而特异性不丧失的IL2(Quintarelli等人,2007)。在反应性T细胞的频率低于IFNγELispot和胞内染色测定法检测限的情况下,虽然这不太可能,因为ELlspot可以检测少至1/100,000分泌细胞因子的细胞,但是可以分析已经多次刺激过的(并且每次刺激例如重复7-10次)的CTL,因此将期望T细胞的频率充分放大以允许检测。如果不是如此,可以重新刺激。
在本发明的实施方案中,开发了制造多克隆CTL的可重复技术,所述多克隆CTL针对癌(至少包括胰腺癌)中表达的多个肿瘤抗原内的多个表位具有特异性。
在第三方案中,可以通过强制性表达嵌合细胞因子受体,保护 CTL免受Th2细胞因子信号传导的抑制作用。在具体的实施方案中,例如产生单一双顺反子构建体,所述构建体编码与IL2Rγ和/或 IL7Rα的胞内结构域连接的IL13Rα和/或IL4Rα的胞外结构域。
由胰腺癌使用的一种肿瘤免疫逃避策略例如是释放Th2抑制性细胞因子,如IL13和IL4,所述细胞因子i)增强癌细胞增殖和ii)减弱 TAA特异性Th1-CTL并使其再极化成Th2细胞。因此为了改善过继转移的多种TAA-CTL的功效,可以使用嵌合细胞因子受体,使它们抵抗IL13和IL4的抑制作用,其中所述嵌合细胞因子受体连接结合这些Th2细胞因子的受体的胞外结构域至两种刺激性(Th1)细胞因子受体的信号传导胞内结构域。
示例性方法如下:发明人已经制备并测试了2种示例性有功能的逆转录病毒中间载体;构建体#1编码IL-13Rα1/IL-2Rγ-IRES-GFP和构建体#2编码IL-4Rα/IL-7Rα-IRES-mOrange(图2)。包含相容性单一限制性酶位点(Xhol-Mlul)以允许将构建体#1中的GFP容易替换成来自构建体#2的IL4Rα/IL7Rα融合蛋白(图2a),目的在于产生编码 hIL4受体和IL13受体连同信号转导IL2和IL7受体的胞外结构域的单一双顺反子构建体(#3)(图3a)。可以通过本领域标准手段验证其功能。可以使用293T细胞的瞬时转染制备逆转录病毒上清液并且CTl 转导可以遵循公布的方案进行(Vera等人,2009;Quintarelli等人, 2007;Vera等人,2006;Savoldo等人,2007)。可以通过FACS分析 IL13Rα和IL4Rα,评价重组蛋白的表达,并且在IL2、IL4或IL13 存在下通过磷酸化Stat5分析,评价IL2Rγ胞内结构域和IL7Rα胞内结构域的功能性。可以随后产生PG-13稳定生产细胞系,其以反式方式含有Gag和Pol序列,从而允许稳定产生病毒。可以分离单一细胞克隆并检测它们的功能滴度,并分离复制型载体。
在本发明的特定实施方案中,存在IL13Rα1和IL4Rα的相等表达,如通过FACS评价,并且IL2Rγ和IL7Rα胞内结构域将传递通过磷酸化Stat5分析法可检测的Th1信号。例如存在大于20%的T细胞靶转导,并且通过在IL4或IL13存在下培养随时间推移选择转导的细胞(Vera等人,2009;Bollard等人,2007;Savoldo等人,2007)。
在一些情况下,在IL13Rα1胞外结构域和CTL上微弱表达的野生型IL4Rα之间可能存在交叉配对,并且这可能导致低水平背景 Stat6信号传导。然而,高比率的转基因:野生型受体表达降低这种情况发生的概率。在某些方面,IL4Rα胞外结构域与野生型IL2Rγ的交叉配对也可能发生,但是在这个情况下是可接受的,因为Th1信号将被传递(图3)。
在本发明的一些实施方案中,产生一种双顺反子构建体及稳定生产系,这使得CTL支持Th1活性信号成为可能,甚至当暴露于正常情况下诱导Th2转换的IL4或IL13时也是如此。
可以评估在IL13和IL4存在下培养的基因修饰的多种TAA-CTL 的离体转导效率和功能。这种形式的体外比较允许确定每种融合蛋白是否多种TAA-CTL中功能地表达、转基因表达是否持久以及这类表达是否改变转导细胞的表型,或不利地影响它们的抗肿瘤活性。
示例性方法如下:如上文所述生成多种TAA-CTL,例如用例如构建体#3转导。可以测量未转导和转导的细胞的扩充。可以使用已经用构建体#1或#2单一转导的CTL作为对照。在IL2、IL4和IL13 存在下培养CTL。可以使用FACS和台盼蓝拒染法测量细胞表型、数目和生存力的变化,并且使用多重途径信号传导试剂盒测量细胞信号传导的变化。此外,在短期(4小时Cr51,测定法)和长期(4日共培养) 研究中,使用表达自体TAA的APC、HLA匹配的胰细胞系和自体肿瘤细胞作为靶在IL2、IL13和IL4的存在下比较抗肿瘤活性。
在本发明的具体方面,检测两种融合蛋白的功能性水平,并且未转导的CTL的培养物或用构建体#1在伴有除IL2之外的任何细胞因子情况下转导的CTL的培养物对CTL功能、增殖和存活产生负向作用。在一个具体实施方案中,用构建体#2转导的CTL在IL4的存在下增殖并且维持它们的功能,因为这种示例性嵌合构建体可以与野生型IL2Rγ二聚化。最后,在本发明的特定实施方案中,用构建体#3 转导的CTL在全部三种细胞因子存在下传递Th1信号、增殖、存活和发挥功能(图3)。表3中显示示例性结果的汇总表。
表3:示例性构建体的预测结果
+IL2 | +IL4 | +IL13 | |
生长/功能 | 生长/功能 | 生长/功能 | |
未转导 | +++ | - | - |
#1(IL13Rα/IL2Rγ) | +++ | - | - |
#2(IL4Rα/IL7Rα) | +++ | ++ | - |
#3(融合) | +++ | ++++ | ++++ |
在本发明的实施方案中,开发靶向肿瘤的多特异性CTL疗法用于癌症,如胰腺癌,并且使这些细胞抵抗由肿瘤采用的重要免疫逃避策略。可以在临床研究中产生和融合基因修饰的多种TAA-CTL以在患有胰腺癌的个体中评价它们的安全性和抗肿瘤功效。
实施例2
作为实例用IL4Rα/IL7Rα对CAR修饰的T细胞进行基因修饰
肿瘤已经演变出复杂机制以破坏细胞免疫反应,包括表达在效应子T细胞中诱导失能或凋亡的FasL或PD-L1。微环境中包括招募调节性T细胞和分泌抑制T细胞增殖的TGF-β和其他免疫阻抑性细胞因子。存在肿瘤和调节性树突细胞的吲哚胺2,3-双加氧酶(IDO)组成型表达,这耗尽色氨酸,导致T细胞失能和MHC和共刺激分子的下调或调节。T细胞可以受肿瘤微环境存在的多种因子(包括至少IL10、TGF-β、IL13和IL-4)抑制。如果细胞因子受体胞外结构域与非天然胞内结构域一起用来武装T细胞以抵抗抑制性肿瘤微环境,则可以克服这个问题。
在本发明的实施方案中,通过强制性表达人工IL4/IL7细胞因子受体保护多种TAA-CTL免受Th2细胞因子的抑制作用。可以产生示例性转基因构建体,如图4中的那一种,其显示为IL4Rα/IL7Rα的融合物并且包含报道基因,如mOrange,不过在一些情况下,构建体缺少报道基因。图5显示转基因受体的稳定表达,如通过检测转导细胞上IL4R表达和mOrange共表达的流式细胞术所检测。图6显示转基因受体是有功能的,如通过检测当暴露于IL4细胞因子时转基因细胞中的磷酸化STAT5(pSTAT5)所评估,所述IL4在野生型条件下将诱导pSTAT6。图7表明嵌合4/7R的转基因表达并未不利地影响CTL 功能,如使用检测靶细胞特异性裂解的铬释放测定法评估,并且图8 显示表达4/7R的转基因T细胞在IL2(用来诱导T细胞增殖的标准生长因子)或IL-4存在下体外增殖,同时从相同供体产生但是不表达4/7R的CTL仅能够在生长因子IL2存在下增殖。图9显示表达4/7R 的CTL可以耗尽来自从肿瘤细胞系收集的上清液中的IL4,这表明转基因受体实际上可以利用肿瘤产生的细胞因子并且可以潜在地使肿瘤缺少以前的生长因子。图10显示表达4/7R的CTL抵抗其他免疫阻抑性细胞因子,如通过暴露于所示细胞因子条件后细胞计数所评估;维持CTL特异性和功能,如通过ELIspot评估。
显示将免疫阻抑性细胞因子的信号传导改变成T细胞生长因子 (图11)。图12-14显示4/7R CTL在异体移植物小鼠模型中控制肿瘤生长其中SCID小鼠植入产生IL4的肿瘤,所述肿瘤共表达FFLuc以允许体内成像。随后,动物用未转导的或4/7R修饰的CTL治疗。用4/7R CTL治疗的动物具有比对照组显著更小的肿瘤,这导致总生存期的增加。图15显示在某些实施方案中,可以调节患者衍生的 CAR-PSCA修饰的T细胞以例如共表达4/7R。图16显示经修饰以共表达4/7R的CAR-PSCA T细胞保留它们杀伤肿瘤靶的能力。
这个实施例显示T细胞可以经修饰以共表达不同的转基因。通过用靶向示例性肿瘤抗原PSCA的嵌合抗原受体进行基因修饰向T细胞赋予抗原特异性。随后,修饰相同细胞以共表达4/7R。采用4/7R修饰并未不利地影响T细胞识别肿瘤细胞的能力。
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虽然已经详述了本发明及其优点,但是应当理解可以在本文中做出各种变化、替换和改变而不脱离如所附权利要求书所定义的本发明精神和范围。另外,本申请的范围不意在限于本说明书中描述的过程、机器、制造法、物质组合物、手段、方法和步骤的具体实施方案。如本领域普通技术人员将从本发明的公开容易地领会,可以根据本发明使用目前存在或稍后开发的过程、制造法、物质组合物、手段、方法或步骤,它们基本上履行与本文所述的相应实施方案相同的功能或基本上实现与之相同的结果。因而,所附权利要求书意图将在这类过程、制造法、物质组合物、手段、方法或步骤纳入其范围内。
本发明的一些实施方案如下:
1.一种免疫***细胞,其包含嵌合细胞因子受体,所述嵌合细胞因子受体包含细胞因子结合胞外结构域和信号转导胞内结构域,其中所述胞外结构域选自IL10胞外结构域、IL4胞外结构域、IL13胞外结构域TGFβ胞外结构域、IL6胞外结构域、IL8胞外结构域及其组合,并且其中所述胞内结构域选自IL2胞内结构域、IL7胞内结构域、 IL15胞内结构域及其组合。
2.根据实施方案1所述的细胞,其中所述细胞选自原代T细胞、 T淋巴细胞和NK细胞。
3.根据实施方案2所述的细胞,其中所述T淋巴细胞是天然存在的肿瘤抗原特异性细胞毒T淋巴细胞。
4.根据实施方案1所述的细胞,其中所述细胞靶向选自CEA、 MUC1、MUC5AC、MUC6、端粒酶、PRAME、MAGEA、SSX2/4、 NY-ESO和存活素的肿瘤相关抗原。
5.产生根据实施方案1所述的细胞的方法,其包括步骤:
提供或获得免疫细胞;
用编码嵌合受体的表达载体转染所述细胞。
6.根据实施方案5所述的方法,其中所述免疫细胞来自需要癌症治疗的个体。
7.根据实施方案5所述的方法,其中所述载体是逆转录病毒载体、慢病毒载体或转座子质粒。
8.根据实施方案5所述的方法,还包括向所述个体提供多个细胞的步骤。
9.根据实施方案5所述的方法,其中所述个体患有选自胰腺癌、肺癌、乳腺癌、脑癌、***癌、皮肤癌、卵巢癌、睾丸癌、胆囊癌、脾癌、胃癌、结肠癌、直肠癌、食管癌、***、膀胱癌、子宫内膜癌、肾癌、血液癌、甲状腺和胃癌的癌症。
10.治疗个体中癌症的方法,包含向所述个体递送治疗有效量的根据实施方案1所述的细胞的步骤。
11.根据实施方案10所述的方法,其中所述细胞相对于个体是自体或同种异型的。
12.根据实施方案10所述的方法,其中所述个体患有选自胰腺癌、肺癌、乳腺癌、脑癌、***癌、皮肤癌、卵巢癌、睾丸癌、胆囊癌、脾癌、胃癌、结肠癌、直肠癌、食管癌、***、膀胱癌、子宫内膜癌、肾癌、血液癌、甲状腺癌和胃癌的癌症。
13.根据实施方案10所述的方法,其中所述细胞通过静脉内递送向所述个体递送。
Claims (12)
1.一种免疫***细胞,其包含嵌合细胞因子受体,所述嵌合细胞因子受体包含细胞因子结合胞外结构域和信号转导胞内结构域,
其中所述胞外结构域为IL13受体胞外结构域且所述胞内结构域为IL2受体胞内结构域,并且其中所述细胞选自原代T细胞、T淋巴细胞和NK细胞。
2.根据权利要求1所述的细胞,其中所述T淋巴细胞是天然存在的肿瘤抗原特异性细胞毒T淋巴细胞。
3.根据权利要求1所述的细胞,其中所述细胞靶向选自CEA、MUC1、MUC5AC、MUC6、端粒酶、PRAME、MAGEA、SSX2/4、NY-ESO和存活素的肿瘤相关抗原。
4.产生根据权利要求1所述的细胞的方法,其包括步骤:
提供或获得免疫细胞;
用编码所述嵌合受体的表达载体转染所述细胞。
5.根据权利要求4所述的方法,其中所述免疫细胞来自需要癌症治疗的个体。
6.根据权利要求4所述的方法,其中所述载体是逆转录病毒载体、慢病毒载体或转座子质粒。
7.根据权利要求4所述的方法,还包括提供多个细胞的步骤。
8.根据权利要求5所述的方法,其中所述个体患有选自胰腺癌、肺癌、乳腺癌、脑癌、***癌、皮肤癌、卵巢癌、睾丸癌、胆囊癌、脾癌、结肠癌、直肠癌、食管癌、***、膀胱癌、子宫内膜癌、肾癌、血液癌、甲状腺癌和胃癌的癌症。
9.治疗有效量的根据权利要求1所述的细胞在制备用于治疗个体中癌症的药物组合物中的用途,其中IL13存在于所述癌症的微环境中。
10.根据权利要求9所述的用途,其中所述细胞相对于所述个体是自体或同种异型的。
11.根据权利要求9所述的用途,其中所述个体患有选自胰腺癌、肺癌、乳腺癌、脑癌、***癌、皮肤癌、卵巢癌、睾丸癌、胆囊癌、脾癌、结肠癌、直肠癌、食管癌、***、膀胱癌、子宫内膜癌、肾癌、血液癌、甲状腺癌和胃癌的癌症。
12.根据权利要求9所述的用途,其中所述细胞通过静脉内递送向所述个体递送。
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US10548921B2 (en) | 2020-02-04 |
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