CN115003801A - 用于克服肿瘤微环境中的免疫抑制的改造的t细胞和肿瘤浸润性淋巴细胞 - Google Patents
用于克服肿瘤微环境中的免疫抑制的改造的t细胞和肿瘤浸润性淋巴细胞 Download PDFInfo
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Abstract
本公开的实施方案提供了促进癌症治疗的方法和组合物,包括至少因为它们涉及逃避肿瘤微环境的疗法。在具体实施方案中,组合物被用于利用肿瘤浸润性淋巴细胞和/或改造的T细胞的疗法,所述肿瘤浸润性淋巴细胞和/或改造的T细胞被保护免受来自肿瘤微环境的免疫抑制,因为它们被改造成减少或消除转化生长因子‑β受体2和/或T‑细胞‑Ig‑和‑ITIM‑结构域和/或CD7基因的表达。
Description
本申请要求于2019年11月27日提交的美国临时专利申请系列号62/941,670的优先权,该申请的全部内容通过引用并入本文。
序列表
本申请包含序列表,该序列表已经以ASCII格式电子提交,并且其全部内容通过引用并入本文。于2020年11月12日生成的所述ASCII拷贝命名为UTSC_P1200WO_SL.txt,大小为3,664字节。
技术领域
本公开的实施方案至少涉及细胞生物学、分子生物学、免疫学和医学领域。
背景技术
细胞免疫疗法对于癌症的治疗具有相当大的前景。然而,某些细胞疗法因来自癌症细胞或肿瘤微环境中的细胞的抑制性信号而获得有限的成功。例如,诱导微环境中的细胞(例如,调节性T细胞或骨髓-来源的抑制细胞)释放抑制免疫应答和促进肿瘤细胞增生和存活的物质(诸如转化生长因子-β(TGFβ)和腺苷)。因此,对于细胞免疫疗法的改进方法存在着尚未得到满足的需求。
发明内容
本公开的实施方案包括用于过继细胞疗法癌症治疗的方法和组合物。本公开特别地提供了与不存在所公开的各种方法和组合物的情况相比使得肿瘤浸润性淋巴细胞(TIL)和改造的T细胞更有效地用于癌症治疗的方法和组合物。在具体实施方案中,本公开提供了与在缺少所公开的方法和组合物的情况下使用TIL和/或改造的T细胞相比,使得改造的TIL和/或改造的T细胞在肿瘤微环境中更有效的方法和组合物。在特定实施方案中,TIL和/或改造的T细胞对于接受者个体是自体的,尽管在一些情况下,TIL和/或改造的T细胞是接受者个体同种异体的。
本公开提供了癌症免疫疗法的改进方式,特别是关于使用改造的TIL和/或改造的T细胞。在特定实施方案中,敲除TIL或T细胞中的一个或多个特定基因或敲低TIL和/或T细胞中的一个或多个特定基因克服了肿瘤微环境中的免疫抑制。在具体实施方案中,被敲除的一个或多个基因有利于肿瘤微环境中的免疫抑制,因为它们允许改造的TIL或改造的T细胞逃避肿瘤微环境中或来自肿瘤微环境的一个或多个抑制性信号。在具体实施方案中,改造的TIL和/或改造的T细胞具有以下的表达减少或消除:转化生长因子-β受体2(TGFBR2)和/或T-细胞-Ig-和-ITIM-结构域(TIGIT)内源基因和/或CD7和/或程序性细胞死亡蛋白1(PD-1)和/或含T-细胞免疫球蛋白和粘蛋白结构域-3(TIM-3)。尽管改造的TIL和/或改造的T细胞可以使用任何合适的手段编辑细胞中的内源基因来改造,但在具体实施方案中利用CRISPR。
在本公开的特定方面,自体TIL和/或T细胞用于患有肿瘤的个体,尽管在备选实施方案中,所述个体患有血液系统恶性病。在特定实施方案中,TIL和/或T细胞获自需要癌症疗法的个体,诸如获自个体自身的癌症(肿瘤)。在一些情况下,所述个体可以已知患有癌症并且从癌症获取细胞用于获得TIL。在其他情况下,个体可以未知患有癌症,并且在被诊断癌症(例如,通过活检)后从所述癌症获得TIL。在任何情况下,TIL可以取自个体的癌症,扩增至合适数目的扩增的TIL,改造成具有以下的敲除或敲低:TGFBR2和/或TIGIT和/或CD7和/或PD-1和/或TIM-3,并且递送回初始获得所述TIL的所述个体。
本公开的实施方案包括组合物,包含(a)改造的肿瘤浸润性淋巴细胞(TIL),其中所述TIL包含下列中的一种或多种:(1)转化生长因子-β受体2(TGFBR2)的表达和/或活性的破坏;(2)T-细胞-Ig-和-ITIM-结构域(TIGIT)的表达和/或活性的破坏;(3)CD7的表达和/或活性的破坏;(4)PD-1的表达的破坏;和(5)TIM-3的表达的破坏,所述转化生长因子-β受体2(TGFBR2)、所述T-细胞-Ig-和-ITIM-结构域(TIGIT)、所述CD7、所述PD-1和所述TIM-3均是所述TIL内源的;和/或
(b)改造的T细胞,其中所述T细胞包括下列中的一种或多种:(1)所述TIL内源性转化生长因子-β受体2(TGFBR2)的表达和/或活性的破坏;(2)T-细胞-Ig-和-ITIM-结构域(TIGIT)的表达和/或活性的破坏;和(3)CD7的表达和/或活性的破坏;(4)PD-1的表达的破坏;和(5)TIM-3的表达的破坏,所述TIGIT、所述CD7、所述PD-1和所述TIM-3均是所述T细胞内源的。
在具体实施方案中,TIL是经扩增的TIL。对TGFBR2、TIGIT、CD7、PD-1和TIM-3中的一种或多种的表达和/或活性的破坏可以包括核酸、肽、蛋白、小分子或其组合。所述核酸可以包括分别对应于TGFBR2、TIGIT、CD7、PD-1或TIM-3的siRNA、shRNA、反义寡核苷酸或用于CRISPR的向导RNA。在具体实例中,TIL和/或T细胞包含TGFBR2、TIGIT、CD7、PD-1和/或TIM-3的表达的破坏。所述T细胞可以包含靶向一个或多个癌症抗原的异源抗原受体,诸如T细胞受体、嵌合抗原受体、趋化因子受体、嵌合细胞因子受体或其混合物。
在一些实施方案中,提供了本公开的组合物的细胞群体,包括其中所述群体处于药学上可接受的承载体中。
在一个实施方案中,提供了制备本文所涵盖的细胞的方法,包括分别利用下列各项电穿孔TIL和/或T细胞的步骤:(a)Cas9或编码Cas9的核酸;以及(b)、(c)、(d)中的一个或多个:(b)用于CRISPR的TGFBR2向导RNA;(c)用于CRISPR的TIGIT向导RNA;(d)用于CRISPR的CD7向导RNA;(e)用于CRISPR的PD-1向导RNA;或(f)用于CRISPR的TIM-3向导RNA。在具体实施方案中,所述方法进一步限定为包括两个或更多个电穿孔步骤,其中第一电穿孔步骤使所述TIL和/或T细胞接受TGFBR2向导RNA、TIGIT向导RNA、CD7向导RNA、PD-1向导RNA和TIM-3向导RNA中的一种或多种,并且第二电穿孔步骤使所述TIL和/或T细胞接受在所述第一电穿孔步骤中未使用的针对TGFBR2、TIGIT、CD7、PD-1或TIM-3中的一种或多种的向导RNA。在其中采用第三电穿孔步骤来靶向第三基因的实施例中,所述第三电穿孔步骤使所述TIL和/或T细胞接受在第一和第二电穿孔步骤中使用的那些向导RNA以外的向导RNA,等等,当需要时包括第四和第五电穿孔步骤。所述方法可以进一步包括至少一个扩增所述TIL和/或T细胞的步骤。在具体实例中,在电穿孔步骤前存在对所述TIL和/或T细胞的扩增步骤和/或在电穿孔步骤后存在对所述TIL和/或T细胞的扩增步骤。
在一个实施方案中,提供了一种杀死个体中的癌症细胞的方法,包括向所述个体递送治疗有效量的本公开的组合物的步骤。所述癌症可以是血液系统癌症或包括实体肿瘤。在具体实施方案中,所述TIL和/或T细胞相对于所述个体是同种异体的或是自体的。所述方法可以进一步限定为:(a)从所述个体获得癌症细胞;(b)从所述癌症细胞扩增TIL以产生经扩增的TIL;(c)改造所述经扩增的TIL以具有:(1)所述TIL内源性TGFBR2的表达或活性的破坏;和/或(2)TIGIT的表达或活性的破坏以产生改造的细胞;和/或(3)CD7的表达或活性的破坏;和/或(4)PD-1的表达的破坏;和/或(5)TIM-3的表达的破坏;以及(d)向所述个体施用有效量的经改造的细胞。所述方法可以进一步限定为:(a)从所述个体获得癌症细胞;(b)扩增T细胞以产生经扩增的T细胞;(c)改造所述经扩增的T细胞以具有:(1)所述TIL内源性TGFBR2的表达或活性的破坏;和/或(2)TIGIT的表达或活性的破坏以产生改造的细胞;和/或(3)CD7的表达或活性的破坏;和/或(4)PD-1的表达的破坏;和/或(5)TIM-3的表达的破坏;以及(d)向所述个体施用有效量的经改造的细胞。
在一些情况下,向所述个体递送额外的癌症疗法,诸如手术、辐射、化学疗法、激素疗法、免疫疗法或它们的组合。
前面已经相当广泛地概括了本公开的特征和技术优点以便可以更好地理解下面的详述。下文要描述的其他特征和优点形成本文权利要求书的主题。本领域技术人员要理解的是所公开的概念和具体实施方案可以容易地被用作修改或设计用于执行本设计的相同目的的其他结构的基础。本领域技术人员还要认识到此类等效的构造没有偏离如附带的权利要求书所给出的精神和范围。从下面的描述并结合附图考虑时将更好地理解新颖性的特征以及更多的目的和优点,这些新颖性的特征据信是本文公开的设计的特征,以及关于组织和操作方法的特征。然而,要明确地理解提供每一张附图仅用于说明和描述的目的,不意在是对本公开的限制的定义。
附图说明
为了更完全地理解本公开,现在结合附图参照下列的描述。
图1:使用基于电穿孔的转染将Cas9核糖核蛋白(RNP)复合物有效递送到T细胞用于基因编辑。此图证明了在电穿孔后几乎所有细胞是Cas9RNP复合物阳性的。
图2.在基于电穿孔递送Cas9 RNP复合物后5天敲除鼠T细胞中的模型基因(Selplg)。
图3.使用基于电穿孔递送Cas9 RNP复合物敲除鼠T细胞中的TIGIT。在此提供的数据显示通过RT-PCR评估在RNA水平的TIGIT敲除。
图4.离体扩增的患者来源的TIL的转染效率。通过电穿孔转移TIGIT-特异性RNP复合物产生了76.5%的细胞递送效率(阳性细胞百分比)。
图5.利用靶向TIGIT的Cas9 RNP复合物转染之前扩增的TIL产生了显著的敲除。提供了在对照例(未转染)和实施例(用TIGIT-特异性RNP转染)中全部TIGIT阳性活TIL的百分比。
图6A-6B.通过体内混合shRNA筛选鉴定调节T细胞浸润到肿瘤中的基因。图6A.实验设计的示意性图示。用靶向编码细胞表面上表达的蛋白质的300个基因的混合shRNA文库转导激活的pmel T细胞,细胞过继转移(ACT)到经辐射的荷B16肿瘤小鼠。ACT后7天,从B16肿瘤和脾配对样品分离pmel T细胞,进行DNA分离和测序。图6B.密度图。密度图中的箭头指示与脾T细胞和参照(ACT前获取的样品)相比TIL群体中的富集发夹序列。对每组2-3个样品完成分析。显示了代表性的表面T细胞筛选。
图7.基于shRNA条形码通过Cd7敲低与脾相比较肿瘤中的T细胞浸润增强。显示了在脾和肿瘤样品(每种n=6)中对于靶向Cd7的10种不同的shRNA构建体中的每一种shRNA条形码读数的数目。大多数构建体显示与脾样品相比在肿瘤样品中有富集。
图8.基于单个基因敲低,与脾相比在肿瘤中Cd7敲低Pmel的富集。单独用含有Cd7shRNA的慢病毒载体或非靶向对照(NTC)载体转导Pmel T细胞,在ACT进荷瘤小鼠之前FACS分选载体表达的GFP并扩增。在ACT后12天从肿瘤分离全部肿瘤浸润性免疫淋巴细胞(TIL)并计数。与未转导或NTC构建体转导的Pmel T细胞相比发现了较高数目的Cd7敲低Pmel,证实了在shRNA筛选中发现的效应。
图9.使用T细胞受体α链基因(TRAC)作为模型靶标,使用各种电穿孔脉冲参数(表示为EH100、EN138、EH115和EO115)和两个不同的Cas9输入量(5μg和10μg),优化患者来源的TIL中的CRISPR基因敲除。
图10.优化对患者来源的TIL中TIGIT的CRISPR基因敲除。利用各种向导RNA序列(表示为TIGIT AA、AB、AC、AD和AE)接受TIGIT敲除的TIL显示TIGIT表面表达减少。
图11.优化对患者来源的TIL中TGFBR2的CRISPR基因敲除。使用靶向TGFBR2的向导RNA(不同的向导RNA序列,表示为TGFBR2 AA、AB、AC和AD)对TIL基因修饰。
图12.已经经历对TGFBR2的CRISPR基因敲除的TIL对外源性TGF-β刺激的效应有抗性。使用靶向TGFBR2的向导RNA(不同的向导RNA序列,表示为TGFBR2 AA、AB、AC和AD)对TIL进行基因修饰。
表1.用来靶向人T细胞中的TIGIT和TGFBR2的向导RNA序列。
图13.已经经历对TGFBR2的CRISPR基因敲除的TIL对外源性TGF-β刺激的效应有抗性。未修饰和修饰的TIL在TGF-β的存在下培养3天。数据呈现为来自TGF-β-处理(10ng/ml)的TIL与媒介物处理的TIL的细胞因子浓度的倍数变化(比率)。数据来自从两个独立供体分离的TIL。
图14A-14C.RNP转染在激活的小鼠CD8+T细胞中诱导高度有效的Cas9/CRISPR-介导的PD-1敲除。在转染后6天,通过流式细胞术评价的PD-1蛋白表达;基于FMO确定的阳性表达(图14A)。(图14B)使用抗-CD3和白介素(IL)-2的体外激活上调CD8 T细胞中的PD-1细胞表面表达(利用非靶向对照RNP转染的对照细胞,NTC条件)。(图14C)用靶向PD-1的Cas9/gRNA RNP(PD-1KO条件)转染的T细胞显示了PD-1表达的减少。
具体实施方式
如本说明书中所用,“一个”或“一种”可以意指一个或多个/一种或多种。如在权利要求中所用,当结合词语“包含”使用时,词“一个”或“一种”可以意指一个或多于一个/一种或多于一种。如本文所用,“另一个”可以意指至少第二个或更多个。此外,术语“具有”、“包括”、“含有”和“包含”是可互换的,并且本领域技术人员要认识到这些术语是开放式的术语。在具体实施方案中,例如,本公开的各个方面可以“基本上由本公开的一个或多个序列组成”或“由本公开的一个或多个序列组成”。本发明的一些实施方案可以由或基本上由本公开的一个或多个要素、方法步骤和/或方法组成。考虑本文所述的任何方法或组合物可以相对于本文所述的任何其他方法或组合物来实现。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、物质组合物、手段、方法和步骤的特定实施方案。如本文所用,术语“或”和“和/或”用来描述多个组分的组合或彼此互斥。例如,“x、y和/或z”可以指单独“x”,单独“y”,单独“z”,“x、y和z”,“(x和y)或z”,“x或(y和z)”,或“x或y或z”。具体考虑x,y或z可以从实施方案中被具体排除。
在整个本说明书中提到“一个实施方案”、“实施方案”、“特定实施方案”、“相关实施方案”、“某个实施方案”、“另外的实施方案”或“进一步的实施方案”或其组合意指结合该实施方案描述的特定的特征、结构或特性包括在本公开的至少一个实施方案中。因此,在整个本说明书中在各个地方出现前述短语不一定全部是指相同的实施方案。此外,所述特定的特征、结构或特性可以在一个或多个实施方案中以任何合适的方式组合。
短语“治疗有效量”当在本文中使用时意指有效产生一些期望治疗效应的化合物、材料或包含本公开的化合物的组合物的量,所述治疗效应例如,以可应用于任何医学治疗的合理收益/风险比治疗(即,预防和/或减轻)受试者中的癌症,或直接或间接抑制TGF-β与其他分子的相互作用。在一个实施方案中,治疗有效量足以减少或消除至少一个症状。本领域技术人员认识到即使癌症没有被完全根除而是部分改善,量也可以被认为是治疗有效的。例如,癌症的扩散可以停止或减少或延缓发生,来自癌症的副作用可以部分减少或完全消除或延缓发生,受试者的寿命可以增加,受试者可以经历较少的疼痛,受试者的生活质量可以改善,等等。
短语“药学上可接受的”在本文中用来指在规范的医学判断范围内,与合理的收益/风险比相称,适合用于接触人类和动物组织而没有过多的毒性、刺激、变态反应,或其他问题或并发症的那些化合物、材料、组合物和/或剂型。
如本文所用,“哺乳动物”是本发明的方法的适宜受试者。哺乳动物可以是高级脊椎动物哺乳动物纲的任何成员,包括人类;其特征在于活产、有体毛、和雌性的分泌乳汁用于喂养幼儿的乳腺。另外,哺乳动物的特征在于不管气候条件如何改变,它们维持恒定体温的能力。哺乳动物的实例为人、猫、犬、牛、小鼠、大鼠、马、山羊、绵羊和黑猩猩。哺乳动物可以称为“患者”或“受试者”或“个体”。
如本文所用,基因的“破坏”是指与没有破坏时基因产物的表达水平相比,细胞中由主题基因编码的一个或多个基因产物的表达消除或减少。示例性基因产物包括mRNA和由该基因编码的蛋白产物。在一些情况下破坏是暂时的或可逆的,并且在其他情况下,是永久的。在一些情况下破坏是功能性的或全长蛋白或mRNA的破坏,尽管存在以下的事实:可以产生截短的或无功能的产物。在本文的一些实施方案中,与表达相反,基因活性或功能被破坏。基因破坏通常通过人工方法诱导,即,通过添加或引入化合物、分子、复合物或组合物,和/或通过破坏基因的核酸或与该基因相关的核酸,诸如在DNA水平。示例性的基因破坏方法包括:基因沉默,敲低,敲除和/或基因破坏技术,诸如基因编辑。实例包括反义技术,诸如RNAi,siRNA,shRNA和/或核酶,它们通常导致表达的瞬时减少,以及基因编辑技术,其导致被靶向基因失活或破坏,例如,通过诱导断裂和/或同源重组。实例包括插入、突变和缺失。破坏典型地导致由基因编码的正常或“野生型”产物的表达的遏制和/或完全缺失。此类基因破坏的实例是插入、移码和错义突变、缺失、敲入和敲除基因或部分基因,包括缺失整个基因。此类破坏可以发生在编码区,例如,在一个或多个外显子中,导致不能产生全长产物、功能产物或任何产物,诸如通过插入终止密码子。此类破坏还可以通过启动子或增强子或影响转录激活的其他区中的破坏发生,从而防止基因的转录。基因破坏包括基因靶向,包括通过同源重组对靶向基因的失活。
术语“改造的(engineered)”当在本文中使用时是指通过人工产生的实体,包括细胞、核酸、多肽、载体等。在至少一些情况下,改造的实体是合成的并且包含非天然存在的或以在本公开中使用的方式构造的元件。在一些情况下,该术语是指已经被人工修饰以携带或表达在自然界中未发现的一个或多个分子的细胞。
关于异源抗原受体,术语“改造的”当在本文中使用时是指通过人工生成的并且在自然界中未发现的抗原受体,该抗原受体不是表达它的细胞内源的。例如,所述受体可以是通过标准重组技术合成产生的。该术语包括生成包含在自然界中未发现的组分的融合蛋白,包括在同一分子中。实例包括T细胞受体、嵌合抗原受体、嵌合细胞因子受体等。术语“异源”当在本文中使用时是指源自与接受者不同的细胞类型或不同的物种。在具体实例中,它是指合成的和/或不是来自T细胞或TIL的基因或蛋白。该术语还指合成衍生的基因或基因构建体。例如,关于T细胞或TIL,细胞因子可以被认为是异源的,即使该细胞因子天然由所述T细胞或TIL产生,因为它是合成衍生的,诸如通过基因重组,包括处于携带编码该细胞因子的核酸序列的载体中提供给T细胞或TIL。
本公开涉及对用于患有癌症和需要癌症治疗的个体的细胞疗法的改进。所述细胞是非天然的并且通过人工改造以具有对细胞的内源基因的一个或多个基因修饰。在特定实施方案中,所述细胞是肿瘤浸润性淋巴细胞(TIL)和/或T细胞。在特定情形中,存在敲除或敲低编码TIL细胞和/或T细胞上的抑制性受体的基因以改善这些细胞的治疗功能,包括在过继细胞疗法的情形中。在具体方面,本公开提供了对TIL疗法和/或T细胞疗法的改进,诸如其中所述细胞从患者的肿瘤分离,扩增至合适的数目,并回输到同一患者中。在具体实施方案中,敲除TGFBR2和/或TIGIT和/或CD7和/或PD-1和/或TIM-3允许这些细胞克服肿瘤微环境中的关键免疫抑制信号。在至少某些实例中,敲除通过利用包含Cas9蛋白和靶向每个感兴趣基因的gRNA的Cas9核糖核蛋白(RNP)复合物转染TIL细胞和/或T细胞来进行。如本文所涵盖的,使用此方法有效地敲除了人和小鼠T细胞和TIL和/或T细胞中的基因。
I.改造的肿瘤浸润性淋巴细胞
本公开的实施方案提供一种或多种用于治疗任何癌症的细胞组合物。所述细胞组合物可以包含基因修饰的TIL(诸如与天然突变相反,具有人工产生的一种或多种内源基因的表达减少)并且包括用于施用于需要癌症治疗的个体的制剂。所述组合物可以被配制或不被配制用于储存、运输和/或递送。
本公开的实施方案包括用于免疫疗法的细胞,其包括被改造成比没有改造的TIL更有效地治疗癌症的TIL。在一些实施方案中,TIL被改造成具有:(1)内源性TGF-β受体2(TGFBR2)的表达减少或消除和/或所表达的蛋白的活性减少或消除;和/或(2)内源性T-细胞-Ig-和-ITIM-结构域(TIGIT)的表达减少或消除和/或所表达的蛋白的活性减少或消除;和/或(3)内源性CD7的表达减少或消除和/或所表达的蛋白的活性减少或消除;和/或(4)内源性PD-1的表达的减少或消除和/或所表达的蛋白的活性减少或消除;和/或(5)内源性TIM-3的表达减少或消除和/或所表达的蛋白的活性减少或消除。这种改造可以通过任何合适的方式发生。因此,TIL可以被基因编辑,并且基因编辑可以通过任何手段发生。基因编辑可以是或可以不是暂时的;在具体实例中,基因编辑是永久的。
在一些实施方案中,通过对一个或多个期望基因实施破坏来进行基因破坏,作为一些实例,诸如敲除,插入,错义或移码突变,包括双等位基因移码突变,全部或部分基因的缺失,例如,一个或多个外显子或其部分的缺失,和/或敲入。在某些实例中,破坏可以影响序列特异性或靶向的核酸酶,包括结合DNA的靶向核酸酶诸如锌指核酸酶(ZFN)和转录激活物样效应子核酸酶(TALEN)和RNA-导向核酸酶诸如CRISPR-相关核酸酶(Cas),具体被设计为靶向TGFBR2基因或其部分的序列或TIGIT基因或其部分或CD7基因或其部分或PD-1基因或其部分或TIM-3基因或其部分。
在一些实施方案中,TGFBR2基因破坏和/或TIGIT基因破坏和/或CD7基因破坏和/或PD-1基因破坏和/或TIM-3基因破坏通过诱导基因中的一个或多个双链断裂和/或一个或多个单链断裂来进行,包括以靶向的方式进行。在一些实施方案中,双链或单链断裂通过核酸酶形成,所述核酸酶例如核酸内切酶,诸如基因靶向核酸酶。在一些方面,在基因的编码区中(例如,在外显子中)诱导断裂。例如,在一些实施方案中,在编码区的N-末端部分附近发生诱导,例如,在第一外显子中,在第二外显子中,或在后续的外显子中。
在一些实施方案中,使用反义技术实现基因破坏,包括通过RNA干扰(RNAi)、短干扰RNA(siRNA)、短发夹(shRNA)和/或核酶用来选择性地抑制或遏制基因的表达。siRNA技术属于RNAi,它采用具有与从基因转录的mRNA的核苷酸序列同源的序列和与所述核苷酸序列互补的序列的双链RNA分子。siRNA通常与从基因转录的mRNA的一个区域同源/互补,或可以是包括与不同区域同源/互补的多个RNA分子的siRNA。在一些方面,siRNA包括在多顺反子构建体中。
对于使用靶基因或基因产物的序列知识的技术的破坏,TIGIT核酸序列的实例为登记号EU675310,其对应蛋白为登记号ACD74757。TGFBR2核酸序列的一个实例为登记号NM_001024847,其对应蛋白序列的实例为登记号NP_001020018。CD7核酸序列的一个实例为登记号NM_006137,其对应蛋白序列的实例为登记号NP_006128。PD-1核酸序列的一个实例为登记号L27440,其对应蛋白序列的实例为登记号AAC41700.1。TIM-3核酸序列的一个实例为登记号JX049979,其对应蛋白序列的实例为登记号AFO66593.1。
在一些实施方案中,使用DNA靶向分子实现破坏,所述DNA靶向分子诸如DNA结合蛋白或DNA结合核酸、或者包含它们的复合物、化合物或组合物,其分别特异性地结合或杂交到TGFBR2基因或TIGIT基因或CD7基因或PD-1基因或TIM-3基因。在一些实施方案中,DNA靶向分子包含DNA结合结构域,例如,锌指蛋白(ZFP)DNA结合结构域,转录激活物样蛋白(TAL)或TAL效应子(TALE)DNA结合结构域,规律成簇的间隔短回文重复(CRISPR)DNA结合结构域,或来自大范围核酸酶的DNA结合结构域。锌指、TALE和CRISPR系统结合结构域可以被改造成结合到预定的核苷酸序列,例如,通过改造(改变一个或多个氨基酸)天然存在的锌指或TALE蛋白的识别螺旋区。改造的DNA结合蛋白(锌指或TALE)是非天然存在的蛋白。设计的理性标准包括应用置换原则和计算机化算法用于处理储存了现有ZFP和/或TALE设计和结合数据的信息的数据库中的信息。
在通过诱导基因中的一个或多个双链断裂和/或一个或多个单链断裂进行基因改变的情况下,所述双链或单链断裂可以通过细胞修复过程经历修复,诸如通过非同源末端连接(NHEJ)或同源性定向修复(HDR)。在一些方面,修复过程是易错的,并且导致基因的破坏,诸如移码突变,例如,双等位基因移码突变,它可以导致基因的完全敲除。例如,在一些方面,破坏包括诱导缺失、突变和/或插入。在一些实施方案中,破坏导致早期终止密码子的存在。在一些方面,插入、缺失、易位、移码突变和/或提前终止密码子的存在导致基因的表达、活性和/或功能的破坏。
在一些实施方案中,使用一个或多个DNA结合核酸进行所述改变,诸如通过RNA导向的核酸内切酶(RGEN)的改变。例如,所述改变可以使用规律成簇的间隔短回文重复(CRISPR)和CRISPR-相关(Cas)蛋白来进行。通常,“CRISPR系统”笼统指参与CRISPR-相关("Cas")基因的表达或引导CRISPR-相关("Cas")基因的活性的转录物和其他元件,包括编码Cas基因的序列,tracr(反式激活CRISPR)序列(例如,tracrRNA或有活性的部分tracrRNA),tracr-配对序列(在内源性CRISPR系统的情况下涵盖“直接重复序列”和tracrRNA-加工的部分直接重复序列),向导序列(在内源性CRISPR系统的情况下也称作“间隔区”)和/或来自CRISPR基因座的其他序列和转录物。
CRISPR/Cas核酸酶或CRISPR/Cas核酸酶系统可以包括非编码RNA分子(向导)RNA(其序列特异性地结合到DNA)和Cas蛋白(例如Cas9)(具有核酸酶功能性(例如,两个核酸酶结构域))。CRISPR系统的一个或多个元件可以衍生自I型、II型或III型CRISPR系统,例如,衍生自包含内源性CRISPR系统的特定生物体,诸如酿脓链球菌(Streptococcuspyogenes)。
TIL中可以引入向导RNA和CRISPR酶,或编码CRISPR酶的mRNA。对于CRISPR-介导的破坏,向导RNA和核酸内切酶可以通过本领域中已知的任何手段被引入到TIL以允许向细胞和亚细胞小室内递送药剂/化学物质和分子(蛋白质和核酸),可以使用的手段包括脂质体递送手段、聚合物承载体、化学承载体、脂质体复合物(lipoplexes)、聚合物复合物(polyplexes,)、树状聚合物、纳米粒子、乳液、天然吞噬作用或吞噬作用通路作为非限制性实例,以及物理方法诸如电穿孔。在具体的方面,使用电穿孔来引入向导RNA和核酸内切酶,或编码核酸内切酶的核酸。
在一个示例性的方法中,用于CRISPR敲除多个基因的方法可以包括从个体的癌症分离TIL,包括从肿瘤分离。当从个体获得用于自体目的时,TIL可以通过任何合适的方法获得,诸如通过活检或任何类型的常规样品采集,包括从血液、骨髓等获取。在其中TIL相对于接受者个体是同种异体的情况下,TIL的来源可以来自储存、来自商业来源,来自供体的新鲜来源,等等。
在其中TIL被扩增的实施方案中,它们可以通过任何合适的方法扩增,诸如通过在IL-2中培养对来自肿瘤碎块的TIL的初始扩增,接着进行快速扩增流程,所述快速扩增流程涉及在外周血单个核细胞(PBMC)或人工抗原递呈细胞的存在下,通过CD3交联和IL-2的刺激,具有或不具有通过4-1BB/CD137的额外共刺激。
在扩增之前或之后,TIL可以接受改造以实现TIGIT和/或TGFBR2和/或CD7和/或PD-1和/或TIM-3的敲低或敲除。在其中利用CRISPR的情况下,对TIGIT和/或TGFBR2和/或CD7和/或PD-1和/或TIM-3的改造可以发生在同一电穿孔步骤或在相继的电穿孔步骤中。当电穿孔步骤是相继的时候,TIGIT、TGFBR2、CD7、PD-1和TIM-3中的一个或多个的敲除/敲低可以分别在还没有被敲低或敲除的TIGIT、TGFBR2、CD7、PD-1和TIM-3中之一的敲除/敲低之前或之后。TIGIT、TGFBR2、CD7、PD-1和TIM-3的敲除/敲低的任意组合可以以任何次序发生,例如各个期望基因以2、3、4或5个电穿孔步骤的组合编辑。仅作为一个具体实施例,TIGIT和TGFBR2可以在第一电穿孔步骤中编辑,CD7可以在第二或后续电穿孔步骤中编辑(以及其任意组合,包括关于PD-1和TIM-3的步骤)。在CRISPR编辑TIL后,它们可以接受或不接受额外的扩增步骤,例如,通过经CD3交联和IL2刺激的再刺激。
在一些方面,Cas核酸酶和gRNA(包括对靶序列特异的crRNA和固定的tracrRNA的融合体)被引入至TIL中。通常,gRNA的5'末端处的靶位点将Cas核酸酶靶向至该靶位点,例如,TGFBR2基因或TIGIT基因或CD7基因或PD-1基因或TIM-3基因,使用互补碱基配对进行。靶位点可以基于其紧接前间隔序列邻近基序(PAM)序列的5’的位置选择,诸如典型地为NGG或NAG。就此而言,通过将向导RNA的前20、19、18、17、16、15、14、14、12、11或10个核苷酸修饰为对应靶DNA序列,gRNA被靶向至期望序列。通常,CRISPR系统的特征在于促进在靶序列的位点处形成CRISPR复合物的元件。典型地,“靶序列”通常是指这样的序列:向导序列被设计成具有对该序列的互补性,其中在靶序列和向导序列之间的杂交促进CRISPR复合物的形成。不一定需要完全互补性,条件是存在足够的互补性以引起杂交并促进CRISPR复合物的形成。
CRISPR系统可以诱导靶位点处的双链断裂(DSB),接着是如本文所讨论的破坏或改变。在其他实施方案中,Cas9变体,称为“切口酶”,用于在靶位点处在单链上切口。可以使用成对的切口酶,例如,用来提高特异性,每个切口酶由一对不同的gRNA靶向序列引导,使得在同时引入切口时,引入5’突出端。在其他实施方案中,无催化活性的Cas9与异源效应子结构域融合以影响基因表达,所述异源效应子结构域诸如转录阻遏物或激活物。
靶序列可以包括任何多核苷酸,诸如DNA或RNA多核苷酸。靶序列可以位于细胞的核或细胞质中,诸如,在细胞的细胞器内。通常,可以用于重组到包含靶序列的靶基因座中的序列或模板称为“编辑模板”或“编辑多核苷酸”或“编辑序列”。在一些方面,外源模板多核苷酸可以称为编辑模板。在一些方面,重组是同源重组。
典型地,在内源性CRISPR系统的情况下,CRISPR复合物(包含与靶序列杂交并与一个或多个Cas蛋白复合的向导序列)的形成导致靶序列内或附近(例如,在1、2、3、4、5、6、7、8、9、10、20、50个或更多个碱基对内)的一条或两条链的裂解。Tracr序列可以包含野生型tracr序列的全部或一部分(例如,野生型tracr序列的大约或超过大约20、26、32、45、48、54、63、67、85或更多个核苷酸序列)或由野生型tracr序列的全部或一部分组成,其也可以形成CRISPR复合物的一部分,诸如通过沿tracr序列的至少一部分与tracr配对序列的全部或一部分杂交,所述tracr配对序列可操作地连接到向导序列。tracr序列与tracr配对序列具有足够的互补性从而杂交并参与形成CRISPR复合物,诸如当最佳比对时沿tracr配对序列的长度至少50%、60%、70%、80%、90%、95%或99%的序列互补性。
可以将驱动CRISPR系统的一个或多个元件的表达的一个或多个载体引入到细胞中使得CRISPR系统的元件的表达引导在一个或多个靶位点处形成CRISPR复合物。组分还可以作为蛋白和/或RNA递送到细胞。例如,Cas酶、与tracr-配对序列连接的向导序列和tracr序列可以各自可操作地连接到单独载体上的单独调控元件。备选地,从相同的或不同的调控元件表达的两个或更多个元件可以组合在单个载体中,一个或多个额外的载体提供在未包括在第一载体中的CRISPR系统的任何组分。所述载体可以包含一个或多个插入位点,诸如限制性核酸内切酶识别序列(也称作“克隆位点”)。在一些实施方案中,一个或多个插入位点位于一个或多个载体的一个或多个序列元件的上游和/或下游。当使用多个不同的向导序列时,可以使用单个表达构建体将CRISPR活性靶向细胞内的多个不同的对应靶序列。
载体可以包括与编码CRISPR酶(诸如Cas蛋白)的酶编码序列可操作连接的调控元件。Cas蛋白的非限制性实例包括Cas1、Cas1B、Cas2、Cas3、Cas4、Cas5、Cas6、Cas7、Cas8、Cas9(也称作Csn1和Csx12)、Cas10、Csy1、Csy2、Csy3、Cse1、Cse2、Csc1、Csc2、Csa5、Csn2、Csm2、Csm3、Csm4、Csm5、Csm6、Cmr1、Cmr3、Cmr4、Cmr5、Cmr6、Csb1、Csb2、Csb3、Csx17、Csx14、Csx10、Csx16、CsaX、Csx3、Csx1、Csx15、Csfl、Csf2、Csf3、Csf4、其同源物,或其修饰形式。这些酶时已知的;例如,酿脓链球菌Cas9蛋白的氨基酸序列可以参见SwissProt数据库中的登记号Q99ZW2。
CRISPR酶可以是Cas9(例如,来自酿脓链球菌或肺炎链球菌(S.pneumonia))。CRISPR酶可以引导靶序列位置处的一条或两条链的裂解,诸如在靶序列内和/或靶序列的互补链内。载体可以编码相对于对应野生型酶有突变的CRISPR酶使得突变的CRISPR酶缺少裂解包含靶序列的靶多核苷酸的一条或两条链的能力。例如,来自酿脓链球菌的Cas9的RuvC I催化结构域中的天冬氨酸-丙氨酸置换(D10A)将来自裂解两条链的核酸酶的Cas9转变成切口酶(裂解单链)。可以利用被突变以具有减少的脱靶编辑的CRISPR酶,诸如来自Integrated DNA Technologies,Inc.。在一些实施方案中,Cas9切口酶可以与一个或多个向导序列组合使用,例如,与两个向导序列(它们分别靶向DNA靶标的有义链和反义链)组合使用。此组合允许两条链都被切开并且用来诱导NHEJ或HDR。
在一些实施方案中,编码CRISPR酶的酶编码序列进行密码子优化以用于在特定细胞(诸如真核细胞)中表达。真核细胞可以是源自特定生物体的那些,诸如哺乳动物,包括但不限于人、小鼠、大鼠、兔、犬或非人灵长类动物。通常,密码子优化是指通过用在感兴趣的宿主细胞的基因中更频繁或最频繁使用的密码子替换天然序列的至少一个密码子同时保持天然氨基酸序列来修饰核酸序列以在所述宿主细胞中增强表达的过程。各种物种表现出对特定氨基酸的某些密码子的特殊偏好。密码子偏好(生物体之间的密码子使用差异)经常与信使RNA(mRNA)的翻译效率相关,而信使RNA(mRNA)的翻译效率又被认为尤其取决于被翻译的密码子的性质和特定转移RNA(tRNA)分子的可用性。细胞中所选择的tRNA的优势通常是肽合成中最频繁使用的密码子的反映。因此,可以基于密码子优化来定制基因以用于在给定生物体中的最佳基因表达。
通常,向导序列是与靶多核苷酸序列具有足够的互补性从而与靶序列杂交并引导CRISPR复合物与靶序列序列特异性结合的任何多核苷酸序列。在一些实施方案中,当使用合适的比对算法最佳比对时,向导序列和其对应的靶序列之间的互补性程度为约或超过约50%、60%、75%、80%、85%、90%、95%、97%、99%、或更高。
最佳比对可以使用任何合适的用于比对序列的算法来确定,所述算法的非限制性实例包括Smith-Waterman算法,Needleman-Wunsch算法,基于Burrows-Wheeler变换(例如,Burrows Wheeler Aligner)、Clustal W、Clustal X、BLAT、Novoalign(NovocraftTechnologies,ELAND(Illumina,San Diego,Calif.)、SOAP(可在soap.genomics.org.cn获得)和Maq(可在maq.sourceforge.net获得)的算法。
CRISPR酶可以是包含一个或多个异源蛋白结构域的融合蛋白的一部分。CRISPR酶融合蛋白可以包含任何附加的蛋白序列,并且任选地在任何两个结构域之间的接头序列。可以与CRISPR酶融合的蛋白质结构域的实例包括,但不限于:表位标签,报告基因序列,和具有下列活性中的一种或多种的蛋白质结构域:甲基化酶活性,去甲基化酶活性,转录激活活性,转录阻遏活性,转录释放因子活性,组蛋白修饰活性,RNA裂解活性和核酸结合活性。表位标签的非限制性实例包括组氨酸(His)标签、V5标签、FLAG标签、流感血凝素(HA)标签、Myc标签、VSV-G标签和硫氧还蛋白(Trx)标签。报告基因的实例包括,但不限于:谷胱甘肽-5-转移酶(GST)、辣根过氧化物酶(HRP)、氯霉素乙酰转移酶(CAT)β半乳糖苷酶、β-葡糖苷酸酶、萤光素酶、绿色荧光蛋白(GFP)、HcRed、DsRed、青色荧光蛋白(CFP)、黄色荧光蛋白(YFP)、和包括色蓝荧光蛋白(BFP)的自发荧光蛋白。CRISPR酶可以融合到编码蛋白或蛋白片段的基因序列,所述蛋白或蛋白片段结合DNA分子或结合其它细胞分子,包括但不限于麦芽糖结合蛋白(MBP)、S-标签、Lex A DNA结合结构域(DBD)融合体、GAL4A DNA结合结构域融合体和单纯疱疹病毒(HSV)BP16蛋白融合体。可以形成包含CRISPR酶的融合蛋白的一部分的另外的结构域描述于US 20110059502中,其通过引用并入本文。
在一些实施方案中,TGFBR2和/或TIGIT基因和/或CD7基因和/或PD-1基因和/或TIM-3基因的表达、活性和/或功能的改变通过破坏相应基因来进行。在一些方面,所述基因被修饰使得其表达与缺少所述基因修饰时的表达或缺少被引入以实施所述修饰的组分的情况下的表达相比减少至少为或约20、30或40%,通常至少为或约50、60、70、80、90、91、92、93、94、95、96、97、98、99或100%。
在特定实施方案中,除了TGFBR2、TIGIT、CD7、PD-1和TIM-3中的一种或多种的表达减少以外,TIL可以被进一步人工修饰。
在一些实施方案中,在产生改造的TIL的过程之前或期间,通过对一个或多个标志物的阴性或阳性选择来富集TIL。
II.改造的T细胞
本公开的实施方案提供了一种或多种用于治疗任何癌症的T细胞组合物。所述细胞组合物可以包含基因修饰的T细胞(诸如,与天然突变相反,具有人工产生的一种或多种内源基因的表达减少)并且包括用于施用于需要癌症治疗的个体的制剂。所述组合物可以被配制或不被配制以用于储存、运输和/或递送。
在某些实施方案中,T细胞被修饰以具有一种或多种内源基因的减少表达或无表达。在特定实施方案中,T细胞被改造以表达一种或多种异源抗原受体,诸如改造的TCR、CAR、嵌合细胞因子受体、趋化因子受体,或其组合,等等。所述异源抗原受体通过人工合成产生。在特定实施方案中,T细胞被修饰以表达对一种或多种癌症抗原有抗原特异性的CAR和/或TCR。可以将多种CAR和/或TCR(诸如针对不同抗原)加入到T细胞。在一些方面,T细胞通过在特定基因基因座处敲入CAR或TCR而被改造以表达CAR或TCR,诸如通过使用CRISPR进行。在一些实施方案中,T细胞被改造以具有一种或多种内源基因的表达减少并且被改造以表达一种或多种异源抗原受体。
在一些实施方案中,T细胞来源于血液、骨髓、淋结、脐带和/或淋巴器官。在一些方面,细胞是人细胞。所述细胞典型地是原代细胞,诸如从受试者直接分离的那些和/或从受试者分离并冷冻的那些。在一些实施方案中,所述细胞包括T细胞或其他细胞类型的一个或多个亚群,诸如全T细胞群体,CD4+细胞,CD8+细胞,及其亚群,诸如通过功能、激活状态、成熟度、分化潜力、扩增、再循环、定植、和/或持久能力、抗原特异性、抗原受体类型、存在于特定器官或小室、标志物或细胞因子分泌谱和/或分化程度定义的那些。在一些实施方案中,所述方法包括从受试者分离细胞,制备,加工,培养,将它们改造以表达合成抗原受体(诸如非天然TCR),将它们改造以具有TGRBR2、TIGIT、CD7、PD-1和/或TIM-3的表达减少或消除,以及在冷冻保存之前或之后将它们再引入至相同和/或不同的受试者。此类步骤可以以该特定顺序发生,或不以该特定顺序发生。例如,T细胞可以被改造以具有一种或多种内源基因的基因编辑,接着改造经基因编辑的细胞以表达合成抗原受体。
在特定的实施方案中,某些CRISPR核酸试剂可以在T细胞中使用,包括下列(且还参见表1):
TGFBR2(外显子5)GACGGCTGAGGAGCGGAAGA(gRNA1)(SEQ ID NO:11)
TGTGGAGGTGAGCAATCCCC(gRNA2)(SEQ ID NO:12)
小鼠序列的实例:
Mm.Cas9.TGFBR2.1.AA:ACGGCCACGCAGACTTCATG(SEQ ID NO:13)
Mm.Cas9.TGFBR2.1.AB:GGACTTCTGGTTGTCGCAAG(SEQ ID NO:14)
在T细胞亚型和亚群(例如,CD4+和/或CD8+T细胞)中,有幼稚T(TN)细胞、效应T细胞(TEFF)、记忆性T细胞及其亚型,诸如干细胞记忆性T细胞(TSCM)、中枢记忆性T细胞(TCM)、效应记忆性T细胞TEM)、或终末分化效应记忆性T细胞、肿瘤浸润性淋巴细胞(TIL)、未成熟T细胞、成熟T细胞、辅助性T细胞、细胞毒性T细胞、粘膜相关不变T(MAIT)细胞、天然存在的和获得性调节性T(Treg)细胞、辅助性T细胞、诸如TH1细胞、TH2细胞、TH3细胞、TH17细胞、TH9细胞、TH22细胞、滤泡辅助性T细胞、α/βT细胞和δ/γT细胞。
在一些实施方案中,富集或消耗一种或多种改造的T细胞群中对特异性标志物阳性(诸如表面标志物)或对特异性标志物阴性的细胞。在一些情况下,此类标志物是在T细胞的某些群体(例如,非记忆性细胞)上不存在的或以相对低水平表达但在T细胞的某些其他群体(例如,记忆性细胞)上存在或以相对较高的水平表达的标志物。
在一些实施方案中,通过在非T细胞上表达的标志物的阴性选择从PBMC样品中分离T细胞,所述非T细胞诸如B细胞、单核细胞、或其他血液白细胞,所述标志物诸如CD14。在一些方面,CD4+或CD8+选择步骤用来分离CD4+辅助性和CD8+细胞毒性T细胞。此类CD4+和CD8+群体可以通过对在一种或多种幼稚、记忆性和/或效应T细胞亚群上表达或以相对较高程度表达的标志物的阳性或阴性选择进一步分选成亚群。
在一些实施方案中,对CD8+T细胞进一步富集或消耗幼稚、中枢记忆性细胞、效应记忆性细胞和/或中枢记忆性干细胞,诸如通过基于与各个亚群相关的表面抗原的阳性或阴性选择。在一些实施方案中,执行对中枢记忆性T(TCM)细胞的富集以增加功效,诸如改善施用后的长期存活率、扩增和/或移植,在一些方面,这在此类亚群中是特别稳健的。
在一些实施方案中,改造的T细胞是自体T细胞。在此方法中,肿瘤样品获自需要癌症治疗的个体,并且可以获得或不获得单细胞悬液。单细胞悬液可以以任何合适的方式获得,例如,机械(使用例如gentleMACSTM分离器(Miltenyi Biotec,Auburn,Calif.)解离肿瘤)或酶法(例如,胶原酶或DNA酶)。肿瘤酶法消化的单细胞悬液可以与一种或多种特异性白介素诸如IL-2一起培养。
培养的T细胞可以汇集在一起并快速扩增。快速扩增提供了抗原特异性T细胞的数目在约10天至约14天的时期内至少约50倍(例如,50倍、60倍、70倍、80倍、90倍或100倍,或更高)的增加。更优选地,快速扩增提供了在约10天至约14天的时期内至少约200倍(例如,200倍、300倍、400倍、500倍、600倍、700倍、800倍、900倍或更高)的增加。
扩增可以通过本领域中已知的众多方法中的任一种来实现。例如,T细胞可以在饲养淋巴细胞和IL-2或IL-15的存在下使用非特异性T细胞受体刺激来快速扩增。非特异性T细胞受体刺激可以包括约30ng/ml OKT3,其是一种小鼠单克隆抗-CD3抗体(可获自Raritan,N.J.)。备选地,T细胞可以通过在T细胞生长因子的存在下,诸如300IU/ml IL-2或IL-15,优选IL-2,利用癌症的一种或多种抗原(包括其抗原部分,诸如一个或多个表位,或细胞)体外刺激外周血单核细胞(PBMC)来快速扩增,所述抗原可以任选地从载体表达,诸如人白细胞抗原A2(HLA-A2)结合肽。体外诱导的T-细胞通过用癌症的相同抗原对表达HLA-A2的抗原递呈细胞脉冲再刺激来快速扩增。备选地,例如,T-细胞可以利用辐照的自体淋巴细胞或利用辐照的HLA-A2+同种异体淋巴细胞和IL-2再刺激。
除了具有TGFBR2、TIGIT、CD7、PD-1、和TIM-3中的一种或多种的表达减少以及一种或多种异源抗原受体以外,T细胞可以被修饰以表达促进T细胞的生长和激活的一种或多种T细胞生长因子。合适的T细胞生长因子包括,例如,IL-2、IL-7、IL-15和IL-12。合适的修饰方法在本领域中是已知的。参见,例如,Sambrook等人,Molecular Cloning:A LaboratoryManual,第3版,Cold Spring Harbor Press,Cold Spring Harbor,N.Y.2001;和Ausubel等人,Current Protocols in Molecular Biology,Greene Publishing Associates andJohn Wiley&Sons,NY,1994。在特定的方面,修饰的自体T细胞以高水平表达T细胞生长因子。T细胞生长因子编码序列,诸如IL-12的编码序列,在本领域中很容易得到,启动子也是一样,启动子与T细胞生长因子编码序列的可操作连接促进高水平表达。
A.T细胞受体
在一些实施方案中,改造的异源抗原受体包括重组TCR和/或从天然存在的T细胞克隆的TCR。“T细胞受体”或“TCR”是指包含可变的α和β链(也分别称作TCRα和TCRβ)或可变的γ和δ链(也分别称作TCRγ和TCRδ)的分子,其能够特异性地结合到与MHC受体结合的抗原肽。在一些实施方案中,TCR为αβ形式。
典型地,以αβ和γδ形式存在的TCR在基因结构上是相似的,但表达它们的T细胞可以具有截然不同的解剖位置或功能。TCR可以存在于细胞的表面上或为可溶形式。通常,TCR存在于T细胞(或T淋巴细胞)的表面上,在此其通常负责识别与主要组织相容性复合物(MHC)分子结合的抗原。在一些实施方案中,TCR还可以包含恒定结构域、跨膜结构域和/或短的细胞质尾部(参见,例如,Janeway等人,1997)。例如,在一些方面,TCR的每条链可以具有一个N-末端免疫球蛋白可变结构域、一个免疫球蛋白恒定结构域、跨膜区和在C-末端处的短的细胞质尾部。在一些实施方案中,TCR与参与调控信号转导的CD3复合物的不变蛋白缔合。除非另外说明,否则术语“TCR”应当理解为涵盖其功能性TCR片段。该术语还涵盖完整的或全长TCR,包括αβ形式或γδ形式的TCR。
因此,为了本文的目的,提到TCR则包括任何TCR或功能片段,诸如与结合在MHC分子中的特定抗原肽(即MHC-肽复合物)结合的TCR的抗原结合部分。TCR的“抗原结合部分”或“抗原结合片分段”可以互换使用,是指含有TCR的结构上结构域的一部分但结合完整TCR所结合的抗原(例如MHC-肽复合物)的分子。在一些实例中,抗原结合部分包含TCR的可变结构域,诸如TCR的可变α链和可变β链,足以形成用于结合到特异性MHC-肽复合物的结合位点,诸如通常其中每条链含有三个互补决定区。
在一些实施方案中,TCR链的可变结构域缔合形成环,或类似于免疫球蛋白的互补决定区(CDR),其通过形成TCR分子的结合位点来赋予抗原识别并决定肽特异性,并且决定肽特异性。典型地,像免疫球蛋白一样,CDR被构架区(FR)隔开(参见,例如,Jores等人,1990;Chothia等人,1988;Lefranc等人,2003)。在一些实施方案中,CDR3是负责识别经加工抗原的主要CDR,尽管α链的CDR1也已经显示与抗原肽的N-末端部分相互作用,而β链的CDR1与抗原肽的C-末端部分相互作用。CDR2被认为识别MHC分子。在一些实施方案中,β-链的可变区可以包含另一超变(HV4)区。
在一些实施方案中,TCR链包含恒定结构域。例如,像免疫球蛋白一样,TCR链的细胞外部分(例如,a-链,β-链)可以包含两个免疫球蛋白结构域,N-末端处的可变结构域(例如,Va或Vp;典型地基于Kabat编号系统的氨基酸1-116,Kabat等人,"Sequences ofProteins of Immunological Interest,US Dept.Health and Human Services,PublicHealth Service National Institutes of Health,1991,第5版),和邻近细胞膜的一个恒定结构域(例如,a-链恒定结构域或Ca,典型地基于Kabat的氨基酸117-259,β-链恒定结构域或Cp,典型地基于Kabat的氨基酸117-295)。例如,在一些实例中,由两条链形成的TCR的细胞外部分包含两个膜-近侧恒定结构域和两个包含CDR的膜-远侧可变结构域。TCR结构域的恒定结构域包含短连接序列,其中半胱氨酸残基形成二硫键,形成两条链之间的连接。在一些实施方案中,TCR可以在α和β链的每一条链中具有另外的半胱氨酸残基使得TCR在恒定结构域中包含两个二硫键。
在一些实施方案中,TCR链可以包含跨膜结构域。在一些实施方案中,跨膜结构域带正电荷。在一些实例中,TCR链包含细胞质尾部。在一些实例中,所述结构允许TCR与其他分子如CD3缔合。例如,包含具有跨膜区的恒定结构域的TCR可以将蛋白质锚定在细胞膜中,并与CD3信号传导器或复合物的不变亚基缔合。
通常,CD3是多蛋白复合物,其可以具有在哺乳动物中的三个不同的链(γ、δ和ε)以及ζ-链。例如,在哺乳动物中,所述复合物可以包含CD3γ链、CD3δ链、两个CD3ε链、和CD3ζ链的同型二聚体。CD3γ、CD3δ和CD3ε链是包含单个免疫球蛋白结构域的免疫球蛋白超家族的高度相关的细胞表面蛋白。CD3γ、CD3δ和CD3ε链的跨膜区带负电荷,这是允许这些链与带正电荷的T细胞受体链缔合的特性。CD3γ、CD3δ和CD3ε链的细胞内尾部各自包含单个保守基序(该基序称为基于免疫受体酪氨酸的激活基序或ITAM),而每个CD3ζ链具有三个保守基序。通常,ITAM参与TCR复合物的信号传导能力。这些辅助分子具有带负电荷的跨膜区并在将信号从TCR传送到细胞中具有一定作用。CD3-和ζ-链与TCR一起形成所谓的T细胞受体复合物。
在一些实施方案中,TCR可以是两条链α和β(或任选地γ和δ)的异二聚体或它可以是单链TCR构建体。在一些实施方案中,TCR是包含连接在一起的两条单独链(α和β链,或γ和δ链)的异二聚体,诸如通过一个二硫键或多个二硫键连接在一起。在一些实施方案中,鉴定针对靶抗原(例如,癌症抗原)的TCR,并将其引入到细胞中。在一些实施方案中,编码TCR的核酸可以获自各种来源,诸如通过对公共可获得的TCR DNA序列的聚合酶链式反应(PCR)扩增。在一些实施方案中,TCR获自生物来源,诸如来自细胞诸如来自T细胞(例如,细胞毒性T细胞)、T细胞杂交瘤或其他公共可获得的来源。在一些实施方案中,T细胞可以获自体内分离的细胞。在一些实施方案中,可以从患者分离高亲和力T细胞克隆,并分离TCR。在一些实施方案中,T细胞可以是培养的T细胞杂交瘤或克隆。在一些实施方案中,已经在用人免疫系统基因(例如,人白细胞抗原系统,或HLA)改造的转基因小鼠中产生了针对靶抗原的TCR克隆。参见,例如,肿瘤抗原(参见,例如,Parkhurst等人,2009和Cohen等人,2005)。在一些实施方案中,使用噬菌体展示来分离针对靶抗原的TCR(参见,例如,Varela-Rohena等人,2008和Li,2005)。在一些实施方案中,TCR或其抗原结合部分可以根据TCR序列的知识合成产生。
B.嵌合抗原受体(CAR)
在一些实施方案中,T细胞被改造以表达一个或多个包含一个或多个特异性结合抗原的细胞外抗原识别结构域的CAR。在一些实施方案中,抗原是在细胞的表面上表达的蛋白。在一些实施方案中,CAR是TCR-样CAR并且所述抗原是经加工的肽抗原,诸如细胞内蛋白的肽抗原,像TCR一样,在主要组织相容复合物(MHC)分子的情况下所述肽抗原在细胞表面上被识别。
在一些实施方案中,CAR包含:a)一个或多个细胞内信号传导结构域,b)跨膜结构域,和c)包含一个或多个抗原结合区的细胞外结构域,在具体实施方案中,所述抗原结合区是结合抗原的scFv。
示例性的抗原受体,包括CAR和重组TCR,以及改造和将所述受体引入至细胞中的方法,包括在下列中所述的那些:例如,国际专利申请公开号WO200014257、WO2013126726、WO2012/129514、WO2014031687、WO2013/166321、WO2013/071154、WO2013/123061,美国专利申请公开号US2002131960、US2013287748、US20130149337,美国专利号:6,451,995、7,446,190、8,252,592、8,339,645、8,398,282、7,446,179、6,410,319、7,070,995、7,265,209、7,354,762、7,446,191、8,324,353和8,479,118,以及欧洲专利申请号EP2537416,和/或Sadelain等人,2013;Davila等人,2013;Turtle等人,2012;Wu等人,2012所述的那些。在一些方面,基因改造的抗原受体包括美国专利号7,446,190中所述的CAR,以及国际专利申请公开号WO/2014055668 A1中所述的那些。
在一些实施方案中,CAR包括激活或刺激性CAR、共刺激性CAR(参见WO2014/055668)和/或抑制性CAR(iCAR,参见Fedorov等人,2013)。CAR通常包括连接到一个或多个细胞内信号传导组分的细胞外抗原(或配体)结合结构域,在一些方面,经由接头和/或跨膜结构域连接。此类分子典型地模拟或近似于通过天然抗原受体传导的信号、通过此类受体与共刺激性受体组合传导的信号、和/或通过共刺激性受体单独传导的信号。
本公开的某些实施方案涉及核酸的应用,包括编码抗原特异性CAR多肽的核酸,在一些实例中包括已经被人源化以减少免疫原性的CAR(hCAR),其包含细胞内信号传导结构域、跨膜结构域、和包含一个或多个信号传导基序的细胞外结构域。在某些实施方案中,CAR可以识别包含一个或多个抗原之间的共用空间的表位。在某些实施方案中,结合区可以包含单克隆抗体的互补决定区、单克隆抗体的可变区、和/或其抗原结合片段。在另一个实施方案中,特异性源自结合受体的肽(例如,细胞因子)。
考虑人CAR核酸可以是用来增强用于人类患者的细胞免疫疗法的人类基因。在具体实施方案中,本公开包括全长CAR cDNA或编码区。抗原结合区或结构域可以包含来源于特定人单克隆抗体的单链可变片段(scFv)的VH和VL链的片段,诸如在美国专利7,109,304中描述的那些,该专利通过引用并入本文。所述片段还可以是人抗原特异性抗体的任何数目的不同的抗原结合结构域。在更具体的实施方案中,所述片段是由针对用于在人类细胞中表达的人密码子应用进行优化的序列编码的抗原特异性scFv。
排列可以是多聚体的,诸如双抗体或多聚体。多聚体最可能通过将轻链和重链的可变部分交叉配对成双抗体来形成。构建体的铰链部分可以具有多种替代物,从完全缺失,到保留第一半胱氨酸,到脯氨酸而非丝氨酸置换,到被截短至第一半胱氨酸。Fc部分可以缺失。稳定的和/或二聚化的任何蛋白可以用于此目的。可以仅使用Fc结构域之一,例如,来自人免疫球蛋白的CH2或CH3结构域。还可以使用已经被修饰以改善二聚化的人免疫球蛋白的铰链、CH2和CH3区。还可以仅使用免疫球蛋白的铰链部分。还可以使用CD8α部分。
在一些实施方案中,CAR核酸包含编码其他共刺激性受体的序列,诸如跨膜结构域和经修饰的CD28细胞内信号传导结构域。其他共刺激性受体包括,但不限于,CD28、CD27、OX-40(CD134)、DAP10、DAP12、和4-1BB(CD137)中的一个或多个。除了由CD3ζ引发的初级信号以外,由插入在人CAR中的人共刺激性受体提供的额外信号对于T细胞的完全激活是很重要的,并且可以有助于改善过继免疫疗法的体内持久性和治疗成功性。
在一些实施方案中,CAR被构建具有针对特定抗原(或标志物或配体)的特异性,所述特定抗原诸如待被过继疗法靶向的在特定细胞类型中表达的抗原,例如,癌症标志物,和/或意在诱导抑制应答的抗原,诸如在正常或非患病细胞类型上表达的抗原。因此,CAR典型地在其细胞外部分中包括一个或多个抗原结合分子,诸如一个或多个抗原结合片段、结构域或部分,或一个或多个抗体可变结构域,和/或抗体分子。在一些实施方案中,CAR包括抗体分子的一个或多个抗原结合部分,诸如来源于单克隆抗体(mAb)的可变重链(VH)和可变轻链(VL)的单链抗体片段(scFv)。
在嵌合抗原受体的某些实施方案中,受体的抗原特异性部分(可以称作包含抗原结合区的细胞外结构域)包含肿瘤相关抗原或病原体特异性抗原结合结构域。抗原包括被模式识别抗体识别的糖类抗原,诸如Dectin-1。肿瘤相关抗原可以是任何类型的,只要它在肿瘤细胞的细胞表面上表达即可。肿瘤相关抗原的示例性实施方案包括CD19、CD20、癌胚抗原、甲胎蛋白、CA-125、MUC-1、CD56、EGFR、c-Met、AKT、Her2、Her3、上皮肿瘤抗原、黑素瘤相关抗原、突变的p53、突变的ras等。在某些实施方案中,CAR可以与一种或多种细胞因子共表达以改善持久性,例如当存在少量的肿瘤相关抗原时。例如,CAR可以与一种或多种细胞因子共表达,所述细胞因子诸如IL-7、IL-2、IL-15、IL-12、IL-18、IL-21或其组合。
编码嵌合受体的开放阅读框的序列可以获自基因组DNA来源,cDNA来源,或可以合成获得(例如,通过PCR),或其组合。取决于基因组DNA的大小和内含子的数目,可以期望使用cDNA或其组合,因为发现内含子使mRNA稳定。此外,使用内源性或外源性非编码区来稳定mRNA可能是进一步有利的。
考虑嵌合构建体可以作为裸DNA或在合适的载体中被引入到免疫细胞中。使用裸DNA通过电穿孔稳定转染细胞的方法在本领域中是已知的。参见,例如,美国专利号6,410,319。裸DNA通常是指以适宜方向包含在质粒表达载体中用于表达的编码嵌合受体的DNA。
备选地,病毒载体(例如,逆转录病毒载体、腺病毒载体、腺相关病毒载体或慢病毒载体)可以用来将嵌合构建体引入到免疫细胞中。根据本公开的方法使用的合适载体在免疫细胞中是不复制的。大量基于病毒的载体是已知的,其中在细胞中维持的病毒的拷贝数足够低以维持细胞的活力,诸如,例如基于HIV、SV40、EBV、HSV、或BPV的载体。
在一些方面,抗原特异性结合或识别组分连接到一个或多个跨膜和细胞内信号传导结构域。在一些实施方案中,CAR包括与CAR的细胞外结构域融合的跨膜结构域。在一个实施方案中,使用天然与CAR中的一个结构域缔合的跨膜结构域。在一些情况下,选择跨膜结构域或通过氨基酸置换修饰跨膜结构域,以避免这些结构域与相同或不同表面膜蛋白的跨膜结构域结合,从而使与受体复合物的其他成员的相互作用最小化。
在一些实施方案中,跨膜结构域来源于天然来源或合成来源。在来源为天然的情况下,在一些方面,所述结构域来源于任何膜结合蛋白或跨膜蛋白。跨膜区包括来源于以下的那些(即,至少包括它们的跨膜区):T-细胞受体的α链、β链或ζ链,CD28,CD3ζ,CD3ε,CD3γ,CD3δ,CD45,CD4,CD5,CD8,CD9,CD 16,CD22,CD33,CD37,CD64,CD80,CD86,CD 134,CD137,CD154,ICOS/CD278,GITR/CD357,NKG2D和DAP分子。备选地,在一些实施方案中,跨膜结构域是合成的。在一些方面,合成的跨膜结构域主要包含疏水残基,诸如亮氨酸和缬氨酸。在一些方面,苯丙氨酸、色氨酸和缬氨酸的三联体存在于合成的跨膜结构域的每一个末端处。
在某些实施方案中,本文公开的用于基因修饰T细胞的平台技术包括:(i)使用电穿孔装置(例如,细胞核转染仪(nucleofector))的非病毒基因转移,(ii)通过胞内结构域(例如,CD28/CD3-ζ、CD137/CD3-ζ或其他组合)信号传导的CAR,(iii)具有可变长度的将抗原识别结构域连接到细胞表面的细胞外结构域的CAR,和在某些情况下,(iv)能够稳定地和在数值上扩增CAR+免疫细胞的来源于K562的人工抗原递呈细胞(aAPC)(Singh等人,2008;Singh等人,2011)。
C.抗原
由经基因改造的异源抗原受体靶向的抗原包括在待通过过继细胞疗法靶向的疾病、病况或细胞类型的情形中表达的抗原。疾病和病况包括增生性、赘生性和恶性疾病和病症,包括癌症和肿瘤,包括血液系统癌症,免疫系统癌症,诸如淋巴瘤、白血病和/或骨髓瘤,诸如B、T和髓样白血病,淋巴瘤和多发性骨髓瘤。在一些实施方案中,与正常或非靶向细胞或组织相比,抗原在疾病或病况的细胞(例如,肿瘤或致病细胞)上选择性表达或过表达。在其他实施方案中,抗原在正常细胞上表达和/或在改造的细胞上表达。
在本方法中可以靶向任何合适的抗原。在一些实例中,所述抗原可以与某些癌症细胞相关联,但与非癌性细胞无关。示例性抗原包括,但不限于,来自感染原的抗原分子、自体/自身抗原、肿瘤/癌症相关抗原,和肿瘤新生抗原(Linnemann等人,2015)。在特定方面,抗原包括:CD19,EBNA,CD123,HER2,CA-125,TRAIL/DR4,CD20,癌胚抗原,甲胎蛋白,CD56,AKT,Her3,上皮性肿瘤抗原,CD319(CS1),ROR1,叶酸结合蛋白,HIV-1包膜糖蛋白gp120,HIV-1包膜糖蛋白gp41,CD5,CD23,CD30,HERV-K,IL-11Rα,κ链,λ链,CSPG4,CD33,CD47,CLL-1,U5snRNP200,CD200,BAFF-R,BCMA,CD99,p53,突变的p53,Ras,突变的ras,c-Myc,胞质丝氨酸/苏氨酸激酶(例如,A-Raf,B-Raf,和C-Raf,周期蛋白依赖性激酶),MAGE-A1,MAGE-A2,MAGE-A3,MAGE-A4,MAGE-A6,MAGE-A10,MAGE-A12,MART-1,黑素瘤相关抗原,BAGE,DAM-6、-10,GAGE-1、-2、-8,GAGE-3、-4、-5、-6、-7B,NA88-A,MC1R,mda-7,gp75,Gp100,PSA,PSM,酪氨酸酶,酪氨酸酶相关蛋白,TRP-1,TRP-2,ART-4,CAMEL,CEA,Cyp-B,hTERT,hTRT,iCE,MUC1,MUC2,磷脂酰肌醇3-激酶(PI3K),TRK受体,PRAME,P15,RU1,RU2,SART-1,SART-3,肾母细胞瘤抗原(WT1),AFP,-连环蛋白/m,胱天蛋白酶-8/m,CDK-4/m,ELF2M,GnT-V,G250,HAGE,HSP70-2M,HST-2,KIAA0205,MUM-1,MUM-2,MUM-3,肌球蛋白/m,RAGE,SART-2,TRP-2/INT2,707-AP,膜联蛋白II,CDC27/m,TPI/mbcr-abl,BCR-ABL,干扰素调节因子4(IRF4),ETV6/AML,LDLR/FUT,Pml/RAR,肿瘤相关钙信号转导子1(TACSTD1)TACSTD2,受体酪氨酸激酶(例如,表皮生长因子受体(EGFR)(具体地,EGFRvIII),血小板衍生生长因子受体(PDGFR),血管内皮生长因子受体(VEGFR)),VEGFR2,胞质酪氨酸激酶(例如,src-家族,syk-ZAP70家族),整合素连接激酶(ILK),转录信号转导物和激活物STAT3、STATS和STATE,缺氧诱导因子(例如,HIF-1和HIF-2),核因子-κB(NF-B),Notch受体(例如,Notch1-4),NY ESO 1,c-Met,哺乳动物雷帕霉素靶蛋白(mTOR),WNT,细胞外信号调节激酶(ERK),和它们的调节亚基,PMSA,PR-3,MDM2,间皮素,肾细胞癌-5T4,SM22-α,碳酸酐酶I(CAI)和IX(CAIX)(也称作G250),STEAD,TEL/AML1,GD2,蛋白酶3,hTERT,肉瘤易位断裂点,EphA2,ML-IAP,EpCAM,ERG(TMPRSS2 ETS融合基因),NA17,PAX3,ALK,雄激素受体,细胞周期蛋白B1,多聚唾液酸,MYCN,RhoC,GD3,岩藻糖基GM1,间皮素,PSCA,sLe,PLAC1,GM3,BORIS,Tn,GLoboH,NY-BR-1,RGsS,SAGE,SART3,STn,PAX5,OY-TES1,精子蛋白17,LCK,HMWMAA,AKAP-4,SSX2,XAGE 1,B7H3,legumain,TIE2,Page4,MAD-CT-1,FAP,MAD-CT-2,fos相关抗原1,CBX2,CLDN6,SPANX,TPTE,ACTL8,ANKRD30A,CDKN2A,MAD2L1,CTAG1B,SUNC1,和LRRN1。
抗原的序列在本领域中是已知的,例如,在数据库中,包括下列实例:CD19(登记号NG_007275.1),EBNA(登记号NG_002392.2),WT1(登记号NG_009272.1),CD123(登记号NC_000023.11),NY-ESO(登记号NC_000023.11),EGFRvIII(登记号NG_007726.3),MUC1(登记号NG_029383.1),HER2(登记号NG_007503.1),CA-125(登记号NG_055257.1),WT1(登记号NG_009272.1),Mage-A3(登记号NG_013244.1),Mage-A4(登记号NG_013245.1),Mage-A10(登记号NC_000023.11),TRAIL/DR4(登记号NC_000003.12),和/或CEA(登记号NC_000019.10)。
例如,肿瘤相关抗原可以来源于前列腺癌、乳腺癌、结肠直肠癌、肺癌、胰腺癌、肾癌、间皮瘤癌症、卵巢癌、肝癌、脑癌、骨癌、胃癌、脾脏癌症、睾丸癌、宫颈癌、肛门癌、胆囊癌、甲状腺癌或黑素瘤癌症。示例性的肿瘤相关抗原或肿瘤细胞来源的抗原包括MAGE 1、3和MAGE 4(或其他MAGE抗原,诸如国际专利公开号WO99/40188中所公开的那些);PRAME;BAGE;RAGE,Lage(也称为NY ESO 1);SAGE;和HAGE或GAGE。肿瘤抗原的这些非限制性实例在多种肿瘤类型(诸如,黑素瘤、肺癌、肉瘤和膀胱癌)中表达。参见,例如,美国专利号6,544,518。前列腺癌肿瘤相关抗原包括例如,前列腺特异性膜抗原(PSMA),前列腺特异性抗原(PSA)、前列腺酸性磷酸盐、NKX3.1和前列腺的六跨膜上皮抗原(STEAP)。
其他肿瘤相关抗原包括Plu-1、HASH-1、HasH-2、Cripto和Criptin。另外,肿瘤抗原可以是自身肽激素,诸如全长促性腺激素释放激素(GnRH),其是一种短的10个氨基酸长的肽,可用于治疗许多癌症。
肿瘤抗原包括来源于特征在于肿瘤相关抗原表达(诸如,HER-2/neu表达)的癌症的肿瘤抗原。感兴趣的肿瘤相关抗原包括谱系特异性肿瘤抗原,诸如黑素细胞-黑素瘤谱系抗原MART-1/Melan-A、gp100、gp75、mda-7、酪氨酸酶和酪氨酸酶相关蛋白。
抗原可以包括表位区或表位肽,所述表位区或表位肽来源于肿瘤细胞中突变的基因或来源于在肿瘤细胞中以与正常细胞相比不同的水平转录的基因,诸如端粒酶,存活蛋白,间皮素,突变的ras,bcr/abl重排,Her2/neu,突变或野生型p53,细胞色素P450 1B1和异常表达的内含子序列,诸如N-乙酰氨基葡萄糖氨基转移酶-V;免疫球蛋白基因的克隆重排,其在骨髓瘤和B细胞淋巴瘤中产生独特的独特型;包括来源于致癌病毒过程的表位区或表位肽的肿瘤抗原,诸如人乳头瘤病毒蛋白E6和E7;埃巴病毒蛋白LMP2;具有肿瘤选择性表达的非突变癌胚蛋白,诸如癌胚抗原和甲胎蛋白。
在其他实施方案中,抗原获自或来源于病原微生物或机会性病原微生物(在本文中也称为传染病微生物),诸如病毒、真菌、寄生虫和细菌。在某些实施方案中,来源于此类微生物的抗原包括全长蛋白质。
其抗原预期用于本文描述的方法的示例性病原性生物包括:人免疫缺陷病毒(HIV),单纯疱疹病毒(HSV),呼吸道合胞病毒(RSV),巨细胞病毒(CMV),埃巴病毒(EBV),甲型、乙型和丙型流感,水疱性口炎病毒(VSV),水疱性口炎病毒(VSV),多瘤病毒(例如,BK病毒和JC病毒),腺病毒,葡萄球菌属(Staphylococcus)物种,包括耐甲氧西林金黄色葡萄球菌(Methicillin-resistant Staphylococcus aureus,MRSA),和链球菌属(Streptococcus)物种,包括肺炎链球菌(Streptococcus pneumoniae)。如本领域技术人员将理解的,来源于这些和其他病原微生物的用作如本文所述的抗原的蛋白质以及编码所述蛋白质的核苷酸序列可以在出版物和公共数据库(诸如,和)中鉴定。
来源于人免疫缺陷病毒(HIV)的抗原包括以下任一种:HIV病毒体结构蛋白(例如,gp120、gp41、p17、p24),蛋白酶,逆转录酶或由tat、rev、nef、vif、vpr和vpu编码的HIV蛋白。
来源于单纯疱疹病毒(例如,HSV 1和HSV2)的抗原包括但不限于,从HSV晚期基因表达的蛋白质。后一组基因主要编码形成病毒体颗粒的蛋白质。这样的蛋白质包括来自形成病毒衣壳的(UL)的五种蛋白质:UL6、UL18、UL35、UL38和主要衣壳蛋白UL19、UL45和UL27,它们各自可以用作本文所述的抗原。预期在本文中用作抗原的其他示例性HSV蛋白包括ICP27(H1,H2)、糖蛋白B(gB)和糖蛋白D(gD)蛋白。HSV基因组包含至少74个基因,每个基因编码可能被用作抗原的蛋白质。
来源于巨细胞病毒(CMV)的抗原包括:CMV结构蛋白,在病毒复制的即刻早期和早期阶段期间表达的病毒抗原,糖蛋白I和III,衣壳蛋白,外壳蛋白,低基质蛋白pp65(ppUL83),p52(ppUL44),IE1和1E2(UL123和UL122),来自UL128-UL150的基因簇的蛋白质产物(Rykman等人,2006),包膜糖蛋白B(gB),gH,gN和pp150。如本领域技术人员将理解的,可用作本文描述的抗原的CMV蛋白可在诸如和的公共数据库中鉴定(参见,例如,Bennekov等人,2004;Loewendorf等人,2010;Marschall等人,2009)。
预期用于某些实施方案中的来源于Epstein-Ban病毒(EBV)的抗原包括:EBV裂解蛋白gp350和gp110,在潜伏期感染期间产生的EBV蛋白,包括Epstein-Ban核抗原(EBNA)-1,EBNA-2,EBNA-3A,EBNA-3B,EBNA-3C,EBNA-前导蛋白(EBNA-LP)和潜伏膜蛋白(LMP)-1,LMP-2A和LMP-2B(参见,例如,Lockey等人,2008)。
预期用于本文的来源于呼吸道合胞病毒(RSV)的抗原包括由RSV基因组编码的11种蛋白质中的任何一种或其抗原片段:NS 1,NS2,N(核衣壳蛋白),M(基质蛋白)SH,G和F(病毒外壳蛋白),M2(第二基质蛋白),M2-1(延伸因子),M2-2(转录调节),RNA聚合酶和磷蛋白P。
预期使用的来源于水疱性口炎病毒(VSV)的抗原包括VSV基因组编码的五种主要蛋白质中的任何一种及其抗原片段:大蛋白(L),糖蛋白(G),核蛋白(N),磷蛋白(P)和基质蛋白(M)(参见,例如,Rieder等人,1999)。
预期在某些实施方案中使用的来源于流感病毒的抗原包括:血凝素(HA),神经氨酸酶(NA),核蛋白(NP),基质蛋白M1和M2,NS1,NS2(NEP),PA,PB1,PB1-F2和PB2。
示例性病毒抗原还包括但不限于:腺病毒多肽,甲病毒多肽,杯状病毒多肽(例如杯状病毒衣壳抗原),冠状病毒多肽,瘟热病毒多肽,埃博拉病毒多肽,肠病毒多肽,黄病毒多肽,肝炎病毒(AE)多肽(乙型肝炎病毒核心或表面抗原,丙型肝炎病毒E1或E2糖蛋白、核心或非结构蛋白),疱疹病毒多肽(包括单纯疱疹病毒或水痘带状疱疹病毒糖蛋白),感染性腹膜炎病毒多肽,白血病病毒多肽,马尔堡病毒多肽,正粘病毒多肽,乳头瘤病毒多肽,副流感病毒多肽(例如血凝素和神经氨酸酶多肽),副粘病毒多肽,细小病毒多肽,瘟病毒多肽,微小核糖核酸病毒多肽(例如脊髓灰质炎病毒衣壳多肽),痘病毒多肽(例如,牛痘病毒多肽),狂犬病病毒多肽(例如,狂犬病病毒糖蛋白G),呼肠孤病毒多肽,逆转录病毒多肽和轮状病毒多肽。
在某些实施方案中,抗原可以是细菌抗原。在某些实施方案中,感兴趣的细菌抗原可以是分泌的多肽。在其他某些实施方案中,细菌抗原包括具有暴露于细菌的外细胞表面上的多肽的一个或多个部分的抗原。
预期使用的来源于葡萄球菌属物种(包括耐甲氧西林金黄色葡萄球菌(MRSA))的抗原包括毒力调节剂,诸如,Agr系统,Sar和Sae,Arl系统,Sar同系物(Rot,MgrA,SarS,SarR,SarT,SarU,SarV,SarX,SarZ和TcaR),Srr系统和TRAP。可以充当抗原的其他葡萄球菌蛋白包括Clp蛋白,HtrA,MsrR,顺乌头酸酶,CcpA,SvrA,Msa,CfvA和CfvB(参见,例如,Staphylococcus:Molecular Genetics,2008Caister Academic Press,Ed.JodiLindsay)。已经对金黄色葡萄球菌的两个种(N315和Mu50)的基因组进行了测序,并可公开获得,例如在PATRIC(PATRIC:The VBI PathoSystems Resource Integration Center,Snyder等人,2007)。如本领域技术人员将理解的,还可以在其他公共数据库(诸如和)中鉴定用作抗原的葡萄球菌蛋白。
预期用于本文所述的某些实施方案中的来源于肺炎链球菌的抗原包括:肺炎球菌溶血素,PspA,胆碱结合蛋白A(CbpA),NanA,NanB,SpnHL,PavA,LytA,Pht和菌毛蛋白(RrgA;RrgB;RrgC)。肺炎链球菌的抗原性蛋白在本领域中也是已知的,并且在一些实施方案中可用作抗原(参见,例如,Zysk等人,2000)。已经对肺炎链球菌的毒株的完整基因组序列进行了测序,并且如本领域技术人员将理解的,用于本文的肺炎链球菌蛋白也可以在其他公共数据库诸如和中鉴定。根据本公开内容,对于抗原特别感兴趣的蛋白质包括毒力因子和被预测在肺炎球菌表面暴露的蛋白质(参见,例如,Frolet等人,2010)。
可用作抗原的细菌抗原的实例包括,但不限于:放线菌(Actinomyces)多肽,芽孢杆菌(Bacillus)多肽,拟杆菌(Bacteroides)多肽,博德特氏菌(Bordetella)多肽,巴尔通氏体(Bartonella)多肽,疏螺旋体(Borrelia)多肽(例如伯氏疏螺旋体(B.burgdorferi)OspA),布鲁氏菌(Brucella)多肽,弯曲杆菌(Campylobacter)多肽,二氧化碳噬纤维菌(Capnocytophaga)多肽,衣原体(Chlamydia)多肽,棒状杆菌(Corynebacterium)多肽,柯克斯氏体(Coxiella)多肽,嗜皮菌(Dermatophilus)多肽,肠球菌(Enterococcus)多肽,埃利希氏体(Ehrlichia)多肽,埃希氏杆菌(Escherichia)多肽,弗朗西斯氏菌(Francisella)多肽,梭杆菌(Fusobacterium)多肽,血巴尔通氏体(Haemobartonella)多肽,嗜血杆菌(Haemophilus)多肽(例如b型流感嗜血杆菌外膜蛋白),螺杆菌(Helicobacter)多肽,克雷伯菌(Klebsiella)多肽,L型细菌多肽,钩端螺旋体(Leptospira)多肽,李斯特菌(Listeria)多肽,分枝杆菌(Mycobacteria)多肽,支原体(Mycoplasma)多肽,奈瑟菌(Neisseria)多肽,新立克次体(Neorickettsia)多肽,诺卡氏菌(Nocardia)多肽,巴斯德氏菌(Pasteurella)多肽,消化球菌(Peptococcus)多肽,消化链球菌(Peptostreptococcus)多肽,肺炎球菌(Pneumococcus)多肽(即肺炎链球菌(S.pneumoniae)多肽),变形杆菌(Proteus)多肽,假单胞菌(Pseudomonas)多肽,立克次体(Rickettsia)多肽,罗卡利马体(Rochalimaea)多肽,沙门氏菌(Salmonella)多肽,志贺氏菌(Shigella)多肽,葡萄球菌多肽,A组链球菌多肽(例如酿脓链球菌(S.pyogenes)M蛋白),B组链球菌(无乳链球菌(S.agalactiae))多肽,密螺旋体(Treponema)多肽和耶尔森氏菌(Yersinia)多肽(例如,鼠疫耶尔森氏菌(Y pestis)F1和V抗原)。
真菌抗原的实例包括但不限于:犁头霉属(Absidia)多肽,支顶孢属(Acremonium)多肽,链格孢属(Alternaria)多肽,曲霉属(Aspergillus)多肽,蛙粪霉属(Basidiobolus)多肽,双极霉属(Bipolaris)多肽,芽生菌属(Blastomyces)多肽,念珠菌属(Candida)多肽,球孢子菌属(Coccidioides)多肽,耳霉属(Conidiobolus)多肽,隐球菌属(Cryptococcus)多肽,弯孢属(Curvalaria)多肽,表皮癣菌属(Epidermophyton)多肽,外瓶霉属(Exophiala)多肽,地丝菌属(Geotrichum)多肽,组织胞浆菌属(Histoplasma)多肽,马杜拉分枝菌属(Madurella)多肽,马拉色菌属(Malassezia)多肽,小孢霉属(Microsporum)多肽,小丛梗孢属(Moniliella)多肽,被孢霉属(Mortierella)多肽,毛霉属(Mucor)多肽,拟青霉属(Paecilomyces)多肽,青霉菌属(Penicillium)多肽,单胞瓶霉属(Phialemonium)多肽,瓶霉属(Phialophora)多肽,原壁菌属(Prototheca)多肽,假阿利什霉菌属(Pseudallescheria)多肽,假小托菌属(Pseudomicrodochium)多肽,腐霉属(Pythium)多肽,鼻孢子虫属(Rhinosporidium)多肽,根霉菌属(Rhizopus)多肽,线状担子菌属(Scolecobasidium)多肽,孢子丝菌属(Sporothrix)多肽,匍柄霉属(Stemphylium)多肽,发癣菌属(Trichophyton)多肽,毛孢子菌属(Trichosporon)多肽和木丝霉属(Xylohypha)多肽。
原生动物寄生虫抗原的实例包括,但不限于,巴贝西虫(Babesia)多肽,肠袋虫(Balantidium)多肽,贝诺孢子虫(Besnoitia)多肽,隐孢子虫(Cryptosporidium)多肽,艾美球虫(Eimeria)多肽,脑胞内原虫(Encephalitozoon)多肽,内变形虫(Entamoeba)多肽,贾第鞭毛虫(Giardia)多肽,哈蒙德虫(Hammondia)多肽,肝簇虫(Hepatozoon)多肽,等孢子球虫(Isospora)多肽,利什曼虫(Leishmania)多肽,微孢子虫(Microsporidia)多肽,新孢子虫(Neospora)多肽,小孢子虫(Nosema)多肽,五毛滴虫(Pentatrichomonas)多肽,疟原虫(Plasmodium)多肽。蠕虫寄生虫抗原的实例包括,但不限于,棘唇线虫(Acanthocheilonema)多肽,猫圆线虫(Aelurostrongylus)多肽,钩虫(Ancylostoma)多肽,管圆线虫(Angiostrongylus)多肽,蛔虫(Ascaris)多肽,布鲁格丝虫(Brugia)多肽,仰口线虫(Bunostomum)多肽,毛细线虫(Capillaria)多肽,夏伯特虫(Chabertia)多肽,古柏线虫(Cooperia)多肽,环体线虫(Crenosoma)多肽,网尾线虫(Dictyocaulus)多肽,膨结线虫(Dioctophyme)多肽,双瓣线虫(Dipetalonema)多肽,裂头绦虫(Diphyllobothrium)多肽,Diplydium多肽,恶丝虫(Dirofilaria)多肽,龙线虫(Dracunculus)多肽,蛲虫(Enterobius)多肽,类丝虫(Filaroides)多肽,血矛线虫(Haemonchus)多肽,兔唇蛔虫(Lagochilascaris)多肽,Loa多肽,曼森线虫(Mansonella)多肽,缪勒线虫(Muellerius)多肽,侏体吸虫(Nanophyetus)多肽,板口线虫(Necator)多肽,细颈线虫(Nematodirus)多肽,结节线虫(Oesophagostomum)多肽,盘尾丝虫(Onchocerca)多肽,后睾吸虫(Opisthorchis)多肽,奥斯特线虫(Ostertagia)多肽,副丝虫(Parafilaria)多肽,并殖吸虫(Paragonimus)多肽,副蛔虫(Parascaris)多肽,泡翼线虫(Physaloptera)多肽,原圆线虫(Protostrongylus)多肽,腹腔丝虫(Setaria)多肽,尾旋线虫(Spirocerca)多肽,迭宫绦虫(Spirometra)多肽,冠丝虫(Stephanofilaria)多肽,粪类圆线虫(Strongyloides)多肽,圆线虫(Strongylus)多肽,吸吮线虫(Thelazia)多肽,弓蛔线虫(Toxascaris)多肽,弓蛔虫(Toxocara)多肽,旋毛虫(Trichinella)多肽,毛圆线虫(Trichostrongylus)多肽,鞭虫(Trichuris)多肽,钩虫(Uncinaria)多肽和吴策线虫(Wuchereria)多肽。(例如恶性疟原虫(P.falciparum)环子孢子(PfCSP))、子孢子表面蛋白2(PfSSP2)、肝状态抗原1的羧基末端(PfLSA1 c-term)和输出蛋白1(PfExp-1),肺囊虫(Pneumocystis)多肽,肉孢子虫(Sarcocystis)多肽,血吸虫(Schistosoma)多肽,泰勒虫(Theileria)多肽,弓形虫(Toxoplasma)多肽和锥虫(Trypanosoma)多肽。
体外寄生虫抗原的实例包括,但不限于,来自以下的多肽(包括抗原以及过敏原):跳蚤;蜱,包括硬蜱和软蜱;蝇类,诸如蠓,蚊子,沙蝇,黑蝇,马蝇,角蝇,鹿蝇,采采蝇,厩螫蝇,引起蝇蛆病的蝇类和库蠓;蚂蚁;蜘蛛,虱子;螨;和蝽象(true bug),诸如床虱和猎蝽。
III.本公开的方法
本公开的实施方案包括改良的用于治疗或预防任何类型的医学病况的免疫治疗方法,所述医学病况至少包括癌症,包括血液系统恶性病或实体肿瘤,通过使用TIL和/或T细胞作为所述治疗的至少一部分。血液系统恶性病至少包括骨髓的癌症、T或B细胞恶性病,白血病,淋巴瘤,母细胞瘤,骨髓瘤等。具体实例至少包括:急性髓细胞白血病,B-细胞急性成淋巴细胞白血病,T-细胞急性成淋巴细胞白血病,骨髓增生异常综合征,慢性淋巴细胞白血病/小淋巴细胞性淋巴瘤,滤泡性淋巴瘤,淋巴浆细胞性淋巴瘤,弥漫性大B细胞淋巴瘤,套细胞淋巴瘤,毛细胞白血病,浆细胞骨髓瘤或多发性骨髓瘤,成熟T/NK细胞瘤等。实体肿瘤的实例包括脑肿瘤、肺肿瘤、乳腺肿瘤、前列腺肿瘤、胰腺肿瘤、胃肿瘤、肛门肿瘤、头颈部肿瘤、骨肿瘤、皮肤肿瘤、肝肿瘤、肾肿瘤、甲状腺肿瘤、睾丸肿瘤、卵巢肿瘤、子宫内膜肿瘤、胆囊肿瘤、腹膜肿瘤、子宫颈肿瘤、结肠肿瘤、直肠肿瘤、女阴肿瘤、脾肿瘤,它们的组合等。
癌症可以具体地是以下组织学类型,尽管不限于这些:赘生物,恶性;癌;癌,未分化的;巨细胞和梭形细胞癌;小细胞癌;乳头状癌;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛基质癌;移行细胞癌;乳头状移行细胞癌;腺癌;胃泌素瘤,恶性;胆管癌;肝细胞癌;合并的肝细胞癌和胆管癌;小梁腺癌;腺样囊性癌;腺瘤息肉中的腺癌;腺癌,家族性结肠息肉病;实体癌;类癌瘤,恶性;支气管肺泡腺癌;乳头状腺癌;嫌色细胞癌;嗜酸细胞癌;嗜氧腺癌;嗜碱性细胞癌;透明细胞腺癌;颗粒细胞癌;滤泡腺癌;乳头状和滤泡状腺癌;非包膜硬化性癌;肾上腺皮质癌;子宫内膜样癌;皮肤附属器癌;大汗腺腺癌;皮脂腺癌;盯聍腺腺癌;粘液表皮样癌;囊腺癌;乳头状囊腺癌;乳头状浆液性囊腺癌;粘液性囊腺癌;粘液腺癌;印戒细胞癌;浸润性导管癌;髓样癌;小叶癌;炎性癌;佩吉特氏病,乳腺;腺泡细胞癌;腺鳞癌;腺癌伴鳞状化生;胸腺瘤,恶性;卵巢间质瘤,恶性;卵泡膜细胞瘤,恶性;颗粒细胞瘤,恶性;睾丸母细胞瘤,恶性;塞尔托利氏细胞癌;莱迪希细胞瘤,恶性;脂质细胞瘤,恶性;副神经节瘤,恶性;乳腺外副神经节瘤,恶性;嗜铬细胞瘤;血管球肉瘤;恶性黑素瘤;无黑素性黑素瘤;浅表扩散性黑素瘤;恶性雀斑黑素瘤;肢端雀斑黑素瘤;结节性黑素瘤;巨大色素痣中的恶性黑素瘤;上皮样细胞黑素瘤;蓝色痣,恶性;肉瘤;纤维肉瘤;纤维组织细胞瘤,恶性;粘液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎横纹肌肉瘤;肺泡横纹肌肉瘤;基质肉瘤;混合性肿瘤,恶性;苗勒管混合瘤;肾母细胞瘤;肝母细胞瘤;癌肉瘤;间质瘤,恶性;布伦纳瘤,恶性;叶状肿瘤,恶性;滑膜肉瘤;间皮瘤,恶性;无性细胞瘤;胚胎癌;畸胎瘤,恶性;甲状腺肿样卵巢瘤,恶性;绒毛膜癌;中肾瘤,恶性;血管肉瘤;血管内皮瘤,恶性;卡波西氏肉瘤;血管外皮细胞瘤,恶性;淋巴管肉瘤;骨肉瘤;皮质旁骨肉瘤;软骨肉瘤;软骨母细胞瘤,恶性;间质软骨肉瘤;骨巨细胞瘤;尤因氏肉瘤;牙源性肿瘤,恶性;成釉细胞牙肉瘤;成釉细胞瘤,恶性;成釉细胞牙肉瘤;松果体瘤,恶性;脊索瘤;神经胶质瘤,恶性;室管膜瘤;星形细胞瘤;原生质星形细胞瘤;纤维性星形细胞瘤;星形母细胞瘤;胶质母细胞瘤;少突胶质细胞瘤;成少突胶质细胞瘤;原始神经外胚层瘤;小脑肉瘤;神经节神经母细胞瘤;成神经细胞瘤;视网膜母细胞瘤;嗅觉神经源性肿瘤;脑膜瘤,恶性;神经纤维肉瘤;神经鞘瘤,恶性;颗粒细胞瘤,恶性;恶性淋巴瘤;霍奇金氏病;霍奇金氏;副肉芽肿;恶性淋巴瘤,小淋巴细胞;恶性淋巴瘤,大细胞,弥漫性;恶性淋巴瘤,滤泡性;蕈样真菌病;其他指定的非霍奇金淋巴瘤;B细胞淋巴瘤;低等级/滤泡性非霍奇金淋巴瘤(NHL);小淋巴细胞性(SL)NHL;中等级/滤泡性NHL;中等级弥散性NHL;高等级免疫母细胞性NHL;高等级淋巴母细胞性NHL;高等级小非裂解细胞NHL;大体积疾病(bulky disease)NHL;套细胞淋巴瘤;AIDS相关淋巴瘤;Waldenstrom巨球蛋白血症;恶性组织细胞增生症;多发性骨髓瘤;肥大细胞肉瘤;免疫增生性小肠疾病;白血病;淋巴性白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;髓细胞性白血病;嗜碱性粒细胞白血病;嗜酸性粒细胞白血病;单核细胞白血病;肥大细胞白血病;成巨核细胞白血病;髓样肉瘤;毛细胞白血病;慢性淋巴细胞性白血病(CLL);急性成淋巴细胞性白血病(ALL);急性髓细胞性白血病(AML);和慢性成髓细胞性白血病。
本公开的方法涵盖免疫疗法,所述免疫疗法包括用于治疗癌症的过继细胞疗法,使用TIL(无论是否经过扩增)和/或T细胞(无论是否经过扩增)进行,其中通过抑制释放的抑制性TGF-β(诸如来自癌症细胞)或抑制相关的相互作用,诸如TGF-β和整合素之间的关系,或抑制TGF-β结合免疫细胞的能力(通过敲除细胞中的其受体)来改进所述免疫疗法以获得免疫疗法的更大功效。对TIL和/或T细胞的此类修饰允许在癌症治疗中获得更大功效。
在一些实施方案中,本公开提供了免疫治疗方法,包括施用有效量的本公开的TIL和/或T细胞,其中TIL和/或T细胞被特定地修饰。在一个实施方案中,至少通过在接受者中引起免疫应答的特定的TIL和/或T细胞治疗医学疾病或病症。在本公开的某些实施方案中,通过转移引起免疫应答的特异性TIL和/或T细胞群治疗任何癌症。本文提供了治疗或延缓个体的癌症进展的方法,包括向所述个体施用有效量的抗原特异性细胞疗法,其中所述TIL和/或T细胞包含可以靶向期望抗原的分子,诸如异源抗原受体。
在本公开的特定实施方案中,将有效量的TIL和/或T细胞递送到有需要的个体,诸如患有任何类型癌症的个体。然后所述细胞增强所述个体的免疫系统以攻击癌症细胞。在一些情况下,向所述个体提供一个或多个剂量的TIL和/或改造的T细胞。在其中向所述个体提供两个或更多个剂量的TIL和/或T细胞的情形中,施用之间的持续时间应当足以允许在所述个体中的繁殖时间,并且在具体实施方案中,剂量之间的持续时间可以为l、2、3、4、5、6、7天或更多天。在量上连续剂量可以彼此相同或不同。在一些情况下,连续剂量随时间推移递减或随时间推移递增。
本公开的方法涵盖递送有效量的组合物,所述组合物包含被改造用于敲除TGFBR2和/或TIGIT和/或CD7和/或PD-1和/或TIM-3的TIL和/或T细胞。在一些情况下,存在多种细胞的群体,在每一个群体中单个TIL和/或单个T细胞已经敲除了TGFBR2和TIGIT和CD7和PD-1和TIM-3,而在其他情况下,所述群体是已经敲除了TGFBR2和/或敲除了TIGIT和/或敲除了CD7和/或敲除了PD-1和/或敲除了TIM-3的TIL细胞和/或T细胞的混合物。在其中期望两种或更多种组分的递送顺序的情况下,所述顺序可以是任何类型的顺序,只要所述递送是治疗上有效的即可。在具体实施方案中,包含一种或多种期望基因的敲除的TIL细胞和/或T细胞的递送发生在第二种疗法之前,使得所述第二种疗法比没有初始TIL和/或改造的T细胞步骤的情况更有效。
在其中改造的TIL和改造的T细胞两者均施用于有需要的个体的实施方案中,改造的TIL和改造的T细胞可以处于或不处于同一制剂中。在其中改造的TIL和改造的T细胞处于同一制剂中的情况下,它们在量上可以基本上相同或不同。例如,改造的TIL和改造的T细胞可以利用特定的比率。在具体实例中,所述比率可以为1:1、1:2、1:5、1:10、1:25、1:50、1:100、1:250、1:1000、1:10000,以及这些之间可导出的任何比率。当改造的TIL和改造的T细胞不处于同一制剂中时,它们可以同时或不同时施用于个体。无论它们是否同时施用于个体,它们可以通过或不通过相同的施用途径递送。在具体实例中,改造的TIL和改造的T细胞经静脉内施用,包括在同一制剂中。当它们单独施用时,可以以任何顺序。对于单独施用,施用之间的持续时间可以为任何合适的持续时间,诸如在1-60秒内,1-60分钟内,1-7天内,1-4周内,1-12个月内,或更长时间,以及它们之间可导出的任何持续时间。
在其中改造的TIL和改造的T细胞两者均施用于个体的一些实施方案中,关于治疗所述个体中的癌症,它们的综合效应可以是加成的或协同的。
IV.药物组合物
本公开的药物组合物包含溶解或分散在药学上可接受的承载体中的有效量的具有改变的TGFBR2和/或TIGIT和/或CD7和/或PD-1和/或TIM-3的表达的改造的TIL和/或改造的T细胞(和/或离体或体内产生它们的试剂)。短语“药学上或药理学上可接受的”是指当施用于动物(诸如,例如,人)时不产生不良反应,变态反应或其他不利反应的分子实体和组合物,视情况而定。根据本公开,包含改造的TIL和/或改造的T细胞(和/或离体或体内产生它们的试剂)的药学组合物的制剂是本领域技术人员已知的,以Remington:The Science andPractice of Pharmacy,第21版,Lippincott Williams and Wilkins,2005为例,该书通过引用并入本文。此外,对于动物(例如,人)施用,要理解制剂应当满足如由FDA生物制剂标准办公室(FDA Office of Biologics standards)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,“药学上可接受的承载体”包括:任何和所有溶剂,分散介质,包衣,表面活性剂,抗氧化剂,防腐剂(例如,抗细菌剂,抗真菌剂),等渗剂,吸收延迟剂,盐类,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,调味剂,染料,类似此类的材料及其组合,如本领域普通技术人员将已知的(参见,例如,Remington'sPharmaceutical Sciences,第18版,Mack Printing Company,1990,1289-1329页,该书通过引用并入本文)。任何常规载体除非与活性成分不相容,否则预期将它们用于药物组合物中。
药物组合物可以包含不同类型的承载体,取决于是否待以固体、液体或气溶胶形式施用,以及是否需要是无菌的以用于诸如注射的施用途径。本文公开的组合物可以经静脉内、皮内、透皮、鞘内、动脉内、腹膜内、经鼻内、经阴道内、经直肠内、局部地、肌内、皮下、经粘膜、经口、局部地、局灶地、吸入(例如,雾化吸入)、注射、输注、连续输注、局部灌注直接浸泡靶细胞,通过导管,通过灌洗,在精华液中,在脂质组合物(例如,脂质体)中,或通过其他方法或前述各项的任何组合施用,如本领域普通技术人员已知的那样。
改造的TIL和/或改造的T细胞(和/或离体或体内产生它们的试剂)可以配制成游离碱、中性或盐形式的组合物。药学上可接受的盐类,包括酸加成盐,例如,与蛋白性组合物的游离氨基形成的那些,或与无机酸(诸如,例如,盐酸或磷酸)或有机酸(诸如乙酸、草酸、酒石酸或扁桃酸)形成的那些。与游离羧基形成的盐也可来自于无机碱(诸如例如钠、钾、铵、钙或三价铁的氢氧化物),或有机碱(诸如异丙胺、三甲胺、组氨酸或普鲁卡因)。在配制后,溶液将以与剂量制剂相容的方式且以治疗有效的量施用。所述制剂容易以各种各样的剂型施用,诸如配制用于肠胃外施用,诸如可注射溶液,或用于递送至肺的气雾剂,或配制用于消化道施用,诸如药物释放胶囊等。
进一步根据本公开,适合用于施用的本公开的组合物提供在含有或不含有惰性稀释剂的药学上可接受的承载体中。所述承载体应当是可吸收的并且包括液体、半固体(即,糊状物)或固体承载体。除非任何常规介质、药剂、稀释剂或承载体对接受者不利或对包含在其中的组合物的疗效不利,否则它们适宜在用于实施本发明的方法的可施用组合物中使用。承载体或稀释剂的实例包括脂肪、油、水、盐水溶液、脂类、脂质体、树脂、粘合剂、填料等、或其组合。所述组合物还可以包含各种氧化剂以延迟一种或多种组分的氧化。另外,预防微生物的作用可以通过防腐剂来获得,诸如各种抗细菌剂和抗真菌剂,包括但不限于,对羟基苯甲酸酯(例如,对羟基苯甲酸甲酯、对羟基苯甲酸丙酯)、氯丁醇、酚、山梨酸、硫柳汞或其组合。
根据本公开,所述组合物与承载体以任何方便和实用的方式组合,即,通过溶液、混悬液、乳化、混合、包封、吸收等。此类程序对于本领域技术人员来说是常规的。
在本公开的具体实施方案中,所述组合物与半固体或固体承载体充分组合或混合。所述混合可以以任何方便的方式执行,诸如研磨。也可以在混合过程中加入稳定剂,以保护所述组合物不丧失治疗活性,即,在胃内变性。在所述组合物中使用的稳定剂的实例包括:缓冲剂,氨基酸诸如甘氨酸和赖氨酸,糖类诸如右旋糖、甘露糖、半乳糖、果糖,乳糖、蔗糖、麦芽糖、山梨醇、甘露醇等。
在进一步的实施方案中,本公开还涉及使用药物脂质媒介物组合物,其包括改造的TIL和/或改造的T细胞(和/或离体或体内产生它们的试剂)和任选的水性溶剂。如本文所用,术语“脂质”将被定义为包括特征是不溶于水并且可用有机溶剂萃取的广泛范围的物质中的任一者。这个广泛化合物类别为本领域技术人员所熟知,并且当术语“脂质”在本文中使用时,它不限于任何特定结构。实例包括含有长链脂族烃的化合物和它们的衍生物。脂质可为天然存在的或合成的(即由人设计或产生)。然而,脂质通常是生物物质。生物脂质在本领域中是熟知的,并且包括例如中性脂肪、磷脂、磷酸甘油酯、类固醇、萜烯、溶血脂质、糖鞘脂、糖脂、硫脂、具有醚和酯连接的脂肪酸的脂质和可聚合脂质,及其组合。当然,除本文具体描述的那些以外的由本领域技术人员理解为脂质的化合物也由本发明的组合物和方法涵盖。
本领域普通技术人员将熟悉可用于使组合物分散在脂质媒介物中的技术的范围。例如,可使改造的TIL和/或改造的T细胞(和/或离体或体内产生它们的试剂)分散于含有脂质的溶液中,用脂质溶解,用脂质乳化,与脂质混合,与脂质组合,共价键合于脂质,以混悬液形式含于脂质中,含于胶束或脂质体中或与胶束或脂质体复合,或另外通过为本领域普通技术人员所知的任何手段与脂质或脂质结构缔合。分散可或可不导致形成脂质体。
向动物患者施用的本发明组合物的实际剂量可由身体和生理因素决定,所述因素诸如体重、病状的严重性、所治疗的疾病的类型、先前或并行治疗干预、患者的特发病和施用途径。视施用剂量和途径而定,优选剂量和/或有效量的施用次数可根据受试者的响应而变化。在任何情况下,负责施用的从业者都将确定组合物中活性成分的浓度和适于个体受试者的剂量。
在某些实施方案中,药物组合物可包含例如至少约0.1%的活性化合物。在其他实施方案中,活性化合物可占单位的重量的约2%至约75%,或例如约25%至约60%,以及其中可导出的任何范围。当然,可以使得将以任何给定单位剂量的化合物获得适合剂量的方式制备各治疗有用组合物中的活性化合物的量。诸如溶解性、生物利用度、生物半衰期、施用途径、产品储存期限以及其他药理学考虑事项的因素将由制备此类药物制剂的领域中的技术人员考虑,因此,多种剂量和治疗方案可以是合乎需要的。
在一些实施方案中,可以利用8-150x109个细胞的剂量。在其他非限制性实例中,剂量也可包括每次施用约1微克/kg/体重、约5微克/kg/体重、约10微克/kg/体重、约50微克/kg/体重、约100微克/kg/体重、约200微克/kg/体重、约350微克/kg/体重、约500微克/kg/体重、约1毫克/kg/体重、约5毫克/kg/体重、约10毫克/kg/体重、约50毫克/kg/体重、约100毫克/kg/体重、约200毫克/kg/体重、约350毫克/kg/体重、约500毫克/kg/体重,直至约1000mg/kg/体重或更多,以及其中可导出的任何范围。在可从本文所列的数值导出的范围的非限制性实例中,基于上述数值,可施用约5mg/kg/体重至约100mg/kg/体重、约5微克/kg/体重至约500毫克/kg/体重等的范围。
A.消化组合物和制剂
在本公开的一个实施方案中,配制改造的TIL和/或改造的T细胞(和/或离体或体内产生它们的试剂)以通过消化途径来施用。消化途径包括其中组合物与消化道直接接触的所有可能的施用途径。具体来说,本文公开的药物组合物可经口、经颊、经直肠或舌下施用。因此,可将这些组合物与惰性稀释剂一起或与可吸收食用承载体一起配制,或可将它们封闭在硬壳或软壳明胶胶囊中,或可将它们压制成片剂,或可将它们直接与膳食的食物掺和。
在某些实施方案中,可将活性化合物与赋形剂掺和,并且以可摄取片剂、颊含片、锭剂、胶囊、酏剂、混悬液、糖浆剂、糯米纸囊剂等形式使用(Mathiowitz等,1997;Hwang等,1998;美国专利号5,641,515;5,580,579和5,792,451,各自通过引用整体明确并入本文)。片剂、锭剂、丸剂、胶囊剂等也可含有以下各物:粘合剂,诸如例如,黄蓍胶、阿拉伯胶、玉米淀粉、明胶或其组合;赋形剂,诸如例如,磷酸二钙、甘露糖醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁或其组合;崩解剂,诸如例如,玉米淀粉、马铃薯淀粉、海藻酸或其组合;润滑剂,诸如例如,硬脂酸镁;甜味剂,诸如例如,蔗糖、乳糖、糖精或其组合;调味剂,诸如例如,薄荷、冬青油、樱桃味调味剂、橙味调味剂等。当剂量单位形式是胶囊时,除以上类型的物质之外,它也可含有液体承载体。各种其他物质可作为包衣存在或可存在以其他方式改进剂量单位的物理形式。举例来说,片剂、丸剂或胶囊剂可用虫胶、糖或两者包覆。当剂型是胶囊剂时,除以上类型的物质之外,它也可含有诸如液体承载体的承载体。明胶胶囊、片剂或丸剂可被肠溶性包衣包覆。肠溶性包衣防止组合物在其中pH是酸性的胃或肠上部中变性。参见例如美国专利号5,629,001。在到达小肠后,其中的碱性pH使包衣溶解,并且容许组合物释放以及由特化细胞例如上皮肠上皮细胞和派尔斑(Peyer's patch)M细胞吸收。糖浆剂或酏剂可含有活性化合物、作为甜味剂的蔗糖、作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、染料和调味剂诸如樱桃味或橙味调味剂。当然,用于制备任何剂量单位形式的任何物质都应是药学上纯净的,并且在所用量下大致上无毒。此外,可将活性化合物掺入缓释制备物和制剂中。
对于经口施用,本公开的组合物可以备选地与一种或多种赋形剂掺和成嗽口剂、洁牙剂、颊含片、口腔喷雾剂或舌下经口施用制剂的形式。举例来说,可制备嗽口剂,将活性成分以所需量掺入适当溶剂诸如硼酸钠溶液(多贝尔氏溶液(Dobell's Solution))中。备选地,可将活性成分掺入经口溶液诸如含有硼酸钠、甘油和碳酸氢钾的经口溶液中,或分散于洁牙剂中,或以治疗有效量添加至可包括水、粘合剂、磨蚀剂、调味剂、起泡剂和保湿剂的组合物中。备选地,可将组合物塑造成可被放置在舌下或另外溶解于口腔中的片剂或溶液形式。
适于其他消化施用模式的额外制剂包括栓剂。栓剂是具有各种重量和形状,通常含药,用于插入直肠中的固体剂型。在插入之后,栓剂软化,熔融,或溶解于腔液中。一般来说,对于栓剂,传统承载体可包括例如聚亚烷基二醇、甘油三酯或其组合。在某些实施方案中,栓剂可由含有例如在约0.5%至约10%,并且优选是约1%至约2%的范围内的活性成分的混合物形成。
B.胃肠外组合物和制剂
在进一步的实施方案中,组合物可通过胃肠外途径来施用。如本文所用,术语“胃肠外”包括绕过消化道的途径。具体来说,本文公开的药物组合物可以例如但不限于经静脉内、真皮内、肌肉内、动脉内、鞘内、皮下或腹膜内的方式施用(美国专利号6,613,308;5,466,468;5,543,158;5,641,515;和5,399,363,各自通过引用整体明确并入本文)。
可在水中适当地混合表面活性剂诸如羟丙基纤维素来制备作为游离碱或药理学上可接受的盐形式的活性化合物的溶液。也可在甘油、液体聚乙二醇及其混合物中以及在油中制备分散液。在一般储存和使用条件下,这些制剂含有防腐剂以防止微生物生长。适于可注射使用的药物形式包括无菌水溶液或分散液以及用于临时制备无菌可注射溶液或分散液的无菌粉末(美国专利5,466,468,通过引用整体明确并入本文)。在所有情况下,形式必须无菌,并且就存在容易可注射性而言必须是流体。它在制造和储存条件下必须是稳定的,并且必须对抗诸如细菌和真菌的微生物的污染作用加以保存。承载体可为溶剂或分散介质,其含有例如水、乙醇、多元醇(即甘油、丙二醇和液体聚乙二醇等)、其适合混合物、和/或植物油。适当流动性可例如通过使用包覆剂诸如卵磷脂,在分散液的情况下通过维持所需粒径,以及通过使用表面活性剂加以维持。防止微生物作用可通过各种抗细菌剂和抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等)来达成。在许多情况下,将优选的是包括等渗剂,例如糖或氯化钠。延长可注射组合物的吸收可通过在组合物中使用延迟吸收的药剂(例如单硬脂酸铝和明胶)来达成。
对于以水溶液进行胃肠外施用,举例来说,如果必要,那么溶液应适当缓冲,并且首先用足够盐水或葡萄糖致使液体稀释剂等渗。这些特定水溶液尤其适于静脉内、肌肉内、皮下和腹膜内施用。就此而论,根据本公开可采用的无菌水性介质将为本领域技术人员所知。举例来说,可将一个剂量溶解于等渗NaCl溶液中,并且添加至皮下灌注液中,或在提议的输注部位处注射(参见例如"Remington's Pharmaceutical Sciences"第15版,第1035-1038和1570-1580页)。取决于所治疗受试者的状况,剂量的一些变化将必然存在。在任何情况下,负责施用的人士都将确定适于个体受试者的剂量。此外,对于人施用,制剂应满足如由FDA生物制剂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。
无菌可注射溶液通过将活性化合物以所需量与以上列举的各种其他成分一起掺入在适当溶剂中来制备,根据需要,随后进行过滤灭菌。通常,分散液通过将各种经灭菌的活性成分掺入至含有基本分散介质和来自以上列举的那些的所需其他成分的无菌媒介物中来制备。在用于制备无菌可注射溶液的无菌粉末的情况下,优选制备方法是真空干燥和冷冻干燥技术,这些技术从先前经无菌过滤的活性成分的溶液产生活性成分外加任何额外期望成分的粉末。使粉状组合物与液体承载体(诸如例如水或盐水溶液)在有或无稳定剂下组合。
C.杂项药物组合物和制剂
在本发明的其他优选实施方案中,改造的TIL和/或改造的T细胞(和/或离体或体内产生它们的试剂)可配制成通过各种杂项途径(例如经局部(即透皮)施用、经粘膜施用(鼻内、经阴道等)和/或吸入)来施用。
用于局部施用的药物组合物可包括被配制用于含药应用(诸如软膏剂、糊剂、霜剂或粉剂)的活性化合物。软膏剂包括用于局部应用的所有油性、吸附、乳化和水溶性基质的组合物,而霜剂和洗剂是仅包括乳化基质的那些组合物。局部施用的药物可含有渗透增强剂以促进活性成分透过皮肤进行吸收。合适的渗透增强剂包括甘油、醇、烷基甲基亚砜、吡咯烷酮和月桂氮酮(luarocapram)。用于局部应用的组合物的可能基质包括聚乙二醇、羊毛脂、冷霜和矿脂以及任何其他适合的吸附、乳化或水溶性软膏基质。局部制剂也可包括如为保存活性成分和提供均质混合物所必需的乳化剂、胶凝剂和抗微生物防腐剂。本发明的透皮施用也可包括使用“贴片”。举例来说,贴片可在固定时期内以预定速率以及以连续方式供应一种或多种活性物质。
在某些实施方案中,药物组合物可通过滴眼剂、鼻内喷雾剂、吸入和/或其他气雾剂递送媒介物来递送。用于通过经鼻气雾喷雾剂来直接向肺递送组合物的方法已例如描述于美国专利号5,756,353和5,804,212(各自通过引用整体明确并入本文)中。同样,使用鼻内微粒树脂(Takenaga等,1998)和溶血磷脂酰基-甘油化合物(美国专利号5,725,871,通过引用整体明确并入本文)递送药物在药物领域中也是熟知的。同样,以聚四氟乙烯载体基质形式进行透粘膜药物递送描述于美国专利号5,780,045(通过引用整体明确并入本文)中。
术语气雾剂是指细碎固体或液体粒子分散于液化或加压气体推进剂中的胶体系统。用于吸入的本发明的典型气雾剂将由活性成分于液体推进剂或液体推进剂和适合溶剂的混合物中的混悬液组成。适合的推进剂包括烃和烃醚。适合的容器将根据推进剂的压力要求而变化。气雾剂的施用将根据受试者的年龄、体重以及症状的严重性和响应而变化。
V.联合疗法
在某些实施方案中,本实施方案的组合物和方法涉及除包含改造的TIL和/或改造的T细胞的组合物以外的癌症疗法。另外的疗法可以是放射疗法、手术(例如,肿块切除术和乳房切除术)、化学疗法、基因疗法、DNA疗法、病毒疗法、RNA疗法、免疫疗法(除本公开内容以外)、骨髓移植、纳米疗法、单克隆抗体疗法、激素疗法或前述的组合。另外的疗法可以是辅助疗法或新辅助疗法的形式。
在一些实施方案中,另外的疗法是一种或多种小分子酶抑制剂和/或一种或多种抗转移剂的施用。在一些实施方案中,另外的疗法是副作用限制剂(例如,旨在减少治疗的副作用的发生和/或严重性的药剂,诸如抗恶心剂等)的施用。在一些实施方案中,另外的疗法是放射疗法。在一些实施方案中,另外的疗法是手术。在一些实施方案中,另外的疗法是放射疗法和手术的组合。在一些实施方案中,另外的疗法是γ辐照。在一些实施方案中,另外的疗法是靶向PBK/AKT/mTOR途径疗法、HSP90抑制剂、微管蛋白抑制剂、细胞凋亡抑制剂和/或化学预防剂。另外的疗法可以是本领域已知的一种或多种化学治疗剂。
可以相对于另外的癌症疗法(诸如免疫检查点疗法)在其之前、期间、之后或以各种组合施用免疫细胞疗法(除了本公开的TIL疗法和/或改造的T细胞疗法以外)。施用间隔可以从同时至数分钟至数天至数周。在其中免疫细胞疗法与本公开的组合物分开地提供给患者的实施方案中,通常将确保在每次递送的时间之间不会度过相当长的一段时间,使得这两种化合物将仍然能够发挥对患者有利的联合作用。在这样的情况下,预期可以在彼此约12至24或72小时内,更具体地在彼此约6-12小时内为患者提供免疫疗法治疗和本公开的组合物。在一些情况下,可能期望将治疗时间显著延长,其中在各自施用之间间隔几天(2、3、4、5、6或7天)至几周(1、2、3、4、5、6、7或8周)。
考虑到药剂的毒性(如果有的话),本实施方案的任何化合物或细胞疗法向患者的施用将遵循用于施用此类化合物的一般方案。因此,在一些实施方案中,存在监测归因于联合疗法的毒性的步骤。
A.化学疗法
根据本发明的实施方案,可以使用多种化学治疗剂。术语“化学疗法”是指使用药物来治疗癌症。“化学治疗剂”用于表示在癌症的治疗中施用的化合物或组合物。这些药剂或药物根据它们在细胞内的活动方式(例如,它们是否影响细胞周期以及在什么阶段影响细胞周期)进行分类。备选地,药剂可以基于其直接交联DNA、插入DNA或通过影响核酸合成来诱导染色体和有丝分裂畸变的能力来进行表征。
化疗剂的实例包括:烷化剂,诸如噻替派(thiotepa)和环磷酰胺;烷基磺酸酯,诸如白消安,英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶,诸如苯佐替派(benzodopa),卡波醌(carboquone),美妥替派(meturedopa)和乌瑞替派(uredopa);乙烯亚胺和甲基蜜胺(methylamelamines),包括六甲蜜胺(altretamine),三亚乙基蜜胺(triethylenemelamine),三亚乙基磷酰胺(trietylenephosphoramide),三亚乙基硫代磷酰胺(triethiylenethiophosphoramide)和三羟甲基蜜胺(trimethylolomelamine);番荔枝内酯(acetogenins)(特别是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱(包括合成类似物托泊替康(topotecan));苔藓抑素;卡利他汀(callystatin);CC-1065(包括其阿多来新(adozelesin)、卡泽来新(carzelesin)和比泽来新(bizelesin)合成类似物);念珠藻环肽(cryptophycin)(特别是念珠藻环肽1和念珠藻环肽8);多拉司他汀(dolastatin);杜卡霉素(duocarmycin)(包括合成类似物KW-2189和CB1-TM1);软珊瑚醇(eleutherobin);水鬼蕉碱(pancratistatin);sarcodictyin;海绵抑素(spongistatin);氮芥类,诸如苯丁酸氮芥,萘氮芥(chlornaphazine),氯磷酰胺(cholophosphamide),雌莫司汀(estramustine),异环磷酰胺(ifosfamide),氮芥(mechlorethamine),盐酸氧化氮芥(mechlorethamine oxidehydrochloride),美法仑(melphalan),新恩比兴(novembichin),苯芥胆甾醇(phenesterine),泼尼莫司汀(prednimustine),曲磷胺(trofosfamide),和乌拉莫司汀;亚硝基脲,诸如卡莫司汀(carmustine),氯脲霉素(chlorozotocin),福莫司汀(fotemustine),洛莫司汀(lomustine),尼莫司汀(nimustine)和雷莫司汀(ranimnustine);抗生素,诸如烯二炔抗生素(例如,卡奇霉素(calicheamicin),特别是卡奇霉素γlI和卡奇霉素ωI1);达内霉素(dynemicin),包括达内霉素A;二膦酸盐,诸如氯膦酸盐;埃斯波霉素(esperamicin);以及新制癌菌素生色团和相关的色蛋白烯二炔类抗生素生色团,阿克拉霉素(aclacinomysin),放线菌素(actinomycin),氨茴霉素(authrarnycin),偶氮丝氨酸,博来霉素(bleomycins),放线菌素C(cactinomycin),卡柔比星(carabicin),洋红霉素(carminomycin),嗜癌菌素(carzinophilin),色霉素(chromomycinis),更生霉素(dactinomycin),柔红霉素(daunorubicin),地托比星(detorubicin),6-重氮-5-氧代-L-正亮氨酸,多柔比星(doxorubicin)(包括吗啉代-多柔比星,氰基吗啉代-多柔比星,2-吡咯啉并-多柔比星,和脱氧多柔比星),表柔比星(epirubicin),依索比星(esorubicin),伊达比星(idarubicin),麻西罗霉素(marcellomycin),丝裂霉素诸如丝裂霉素C,麦考酚酸,诺拉霉素(nogalarnycin),橄榄霉素(olivomycins),培洛霉素(peplomycin),泊非霉素(potfiromycin),嘌罗霉素,三铁阿霉素(quelamycin),罗多比星(rodorubicin),链黑菌素(streptonigrin),链佐星(streptozocin),杀结核菌素(tubercidin),乌苯美司(ubenimex),净司他丁(zinostatin),和佐柔比星(zorubicin);抗代谢药,诸如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸,蝶罗呤(pteropterin),和三甲曲沙(trimetrexate);嘌呤类似物,诸如氟达拉滨(fludarabine),6-巯基嘌呤,硫咪嘌呤,和硫鸟嘌呤;嘧啶类似物,诸如安西他滨,阿扎胞苷,6-氮杂尿苷,卡莫氟(carmofur),阿糖胞苷,二脱氧尿苷,去氧氟尿苷,依诺他滨(enocitabine),和氟尿苷;雄激素类,诸如卡普睾酮(calusterone),丙酸屈他烷酮(dromostanolone propionate),环硫雄醇(epitiostanol),美雄烷(mepitiostane),和睾内酪(testolactone);抗肾上腺类,诸如米托坦(mitotane)和曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸;醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamideglycoside);氨基酮戊酸;恩尿嘧啶(eniluracil);安吖啶(amsacrine);阿莫司汀(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);依氟鸟氨酸(elfornithine);依利醋铵;埃博霉素(epothilone);依托格鲁(etoglucid);硝酸镓;羟基脲;香菇多糖(lentinan);氯尼达明(lonidainine);美坦辛类(maytansinoids),诸如美坦辛(maytansine)和安丝菌素(ansamitocins);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidanmol);尼曲吖啶(nitraerine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基酰肼;丙卡巴肼;PSK多糖复合物;雷佐生(razoxane);根霉素(rhizoxin);西佐喃(sizofiran);锗螺胺(spirogermanium);替奴佐酸(tenuazonic acid);三乙胺醌;2,2',2”-三氯三乙胺;单端孢霉烯类(特别是T-2毒素,疣孢菌素A,杆孢菌素A和蛇形菌素(anguidine));乌拉坦(urethan);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇;二溴卫矛醇;哌泊溴烷(pipobroman);加西托星(gacytosine);阿糖胞苷(“Ara-C”);环磷酰胺;紫杉烷类,例如紫杉醇和多西他赛吉西他滨;6-硫鸟嘌呤;巯基嘌呤;铂配位络合物,诸如顺铂、奥沙利铂和卡铂;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨;诺肖林(novantrone);替尼泊苷(teniposide);依达曲沙(edatrexate);道诺霉素;氨基蝶呤;希罗达(xeloda);伊班膦酸盐;伊利替康(irinotecan)(例如CPT-11);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视黄醇,诸如视黄酸;卡培他滨(capecitabine);卡铂,丙卡巴肼(procarbazine),普卡霉素(plicomycin),吉西他滨,诺维本(navelbine),法呢基-蛋白转移酶抑制剂,反铂(transplatinum),和上述任何一种的药学上可接受的盐、酸或衍生物。
B.放射疗法
引起DNA损伤并已被广泛使用的其他因素包括普遍已知的γ射线、X射线和/或放射性同位素向肿瘤细胞的定向递送。也可以考虑其他形式的DNA损伤因素,诸如微波、质子束辐照(美国专利5,760,395和4,870,287)和UV辐照。最有可能的是,所有这些因素影响对DNA、DNA前体、DNA的复制和修复以及染色体的装配和维持的广泛损害。X射线的剂量范围从长时间(3-4周)的50至200伦琴的每日剂量到2000至6000伦琴的单次剂量。放射性同位素的剂量范围广泛变化,并且取决于同位素的半衰期、所发射的辐射的强度和类型以及肿瘤细胞的摄取。
C.免疫疗法
本领域技术人员将理解,其他免疫疗法(所公开的改造的TIL细胞疗法和/或改造的T细胞疗法以外)可以与实施方案的方法组合或结合使用。在癌症治疗的背景下,免疫疗法通常依靠使用免疫效应细胞和分子来靶向和破坏癌症细胞。利妥昔单抗是这样的实例。免疫效应物可以是例如对肿瘤细胞表面上的某些标志物具有特异性的抗体。抗体单独可以充当疗法的效应物,或者它可以募集其他细胞来实际影响细胞杀伤。抗体也可以与药物或毒素(化疗剂、放射性核素、蓖麻毒蛋白A链、霍乱毒素、百日咳毒素等)缀合,并充当靶向剂。备选地,效应物可以是携带直接或间接与肿瘤细胞靶标相互作用的表面分子的淋巴细胞。除了敲低或敲除TGFBR2和/或TIGIT的那些以外,各种效应细胞包括细胞毒性T细胞和NK细胞。
已经出现抗体-药物缀合物作为开发癌症治疗剂的突破性方法。抗体-药物缀合物(ADC)包含与杀细胞药物共价连接的单克隆抗体(MAb)。这种方法将MAb针对其抗原靶标的高特异性与高效的细胞毒性药物结合在一起,从而产生了“经武装的”MAb,其可将有效载荷(药物)递送至具有富集水平抗原的肿瘤细胞。药物的靶向递送还将其在正常组织中的暴露降至最低,从而降低了毒性并提高了治疗指数。FDA批准的两种ADC药物,2011年的(本妥昔单抗(brentuximab vedotin))和2013年的(曲妥珠单抗美坦新(trastuzumab emtansine)或T-DM1)验证了这种方式。目前,有超过30种ADC药物候选物处于癌症治疗的临床试验的各个阶段(Leal等人,2014)。随着抗体工程和接头-有效载荷优化的日趋成熟,新型ADC的发现和开发越来越依赖于对适用于所述方式的新靶标的鉴定和验证以及靶向MAb的产生。ADC靶标的两个标准是肿瘤细胞中上调/高水平的表达和稳健内在化。
在免疫疗法的一个方面,肿瘤细胞必须带有一些易于靶向的标志物,即,所述标志物在大多数其他细胞上不存在。存在许多肿瘤标志物,并且在本发明的实施方案的背景下,这些肿瘤标志物中的任何一种都可能适于靶向。常见的肿瘤标志物包括CD20、癌胚抗原、酪氨酸酶(p97)、gp68、TAG-72、HMFG、唾液酸化的路易斯抗原、MucA、MucB、PLAP、层粘连蛋白受体、erbB和p155。免疫疗法的一个替代方面是将抗癌作用与免疫刺激作用相结合。还存在免疫刺激性分子,包括:细胞因子,诸如IL-2、IL-4、IL-12、GM-CSF、γ-IFN,趋化因子,诸如MIP-1、MCP-1、IL-8,和生长因子,诸如FLT3配体。
目前正在研究或使用的免疫疗法的实例是免疫佐剂,例如牛分枝杆菌(Mycobacterium bovis)、恶性疟原虫(Plasmodium falciparum)、二硝基氯苯和芳香族化合物(美国专利5,801,005和5,739,169;Hui和Hashimoto,1998;Christodouulides等人,1998);细胞因子疗法,例如任何类型的干扰素、IL-1、GM-CSF和TNF(Bukowski等人,1998;Davidson等人,1998;Hellstrand等人,1998);基因疗法,例如TNF、IL-1、IL-2和p53(Qin等人,1998;Austin-Ward和Villaseca,1998;美国专利5,830,880和5,846,945);和单克隆抗体,例如抗CD20、抗神经节苷脂GM2和抗p185(Hollander,2012;Hanibuchi等人,1998;美国专利5,824,311)。预期可以将一种或多种抗癌疗法与本文所述的抗体疗法一起使用。
在一些实施方案中,免疫疗法可以是免疫检查点抑制剂。免疫检查点调高信号(例如共刺激性分子)或调低信号。可通过免疫检查点阻断而靶向的抑制性免疫检查点包括:腺苷A2A受体(A2AR),B7-H3(也称为CD276),B和T淋巴细胞衰减因子(BTLA),细胞毒性T淋巴细胞相关蛋白4(CTLA-4,也称为CD152),吲哚胺2,3-双加氧酶(IDO),杀伤细胞免疫球蛋白(KIR),淋巴细胞激活基因-3(LAG3),程序性死亡蛋白1(PD-1),T细胞免疫球蛋白结构域和粘蛋白域3(TIM-3)和T细胞激活的V-结构域Ig抑制剂(VISTA)。特别地,免疫检查点抑制剂靶向PD-1轴和/或CTLA-4。
D.手术
大约60%的癌症患者将接受某种类型的手术,包括预防性、诊断或分期、治愈和姑息手术。治愈手术包括切除(其中全部或部分癌组织被物理移除、切除和/或破坏),并且可以与其他疗法(诸如本实施方案的治疗,化学疗法,放射疗法,激素疗法,基因疗法,免疫疗法和/或替代疗法)结合使用。肿瘤切除术是指肿瘤的至少一部分的物理去除。除肿瘤切除术外,手术治疗还包括激光手术、冷冻手术、电手术和用显微控制的手术(莫氏手术)。
在切除部分或全部癌性细胞、组织或肿瘤后,可能在体内形成空腔。可以通过使用其他抗癌疗法对该区域进行灌注、直接注射或局部应用来完成治疗。例如,可以每1、2、3、4、5、6或7天,或者每1、2、3、4和5周或每1、2、3、4、5、6、7、8、9、10、11或12个月重复这种治疗。这些治疗也可以具有不同的剂量。
E.其他药剂
预期可以将其他药剂与本实施方案的某些方面组合使用以改善治疗的疗效。这些另外的药剂包括影响细胞表面受体的上调和GAP连接的药剂,细胞生长抑制剂和分化剂,细胞粘附抑制剂,增加过度增殖细胞对凋亡诱导剂的敏感性的药剂或其他生物药剂。通过增加GAP连接数增加细胞间信号传导将增加对邻近的过度增殖细胞群的抗过度增殖作用。在其他实施方案中,细胞生长抑制剂或分化剂可以与本实施方案的某些方面结合使用以改善治疗的抗过度增殖功效。预期细胞粘附的抑制剂可改善本发明实施方案的功效。细胞粘附抑制剂的实例是粘着斑激酶(FAK)抑制剂和洛伐他汀。进一步考虑了可以将增加过度增殖细胞对凋亡的敏感性的其他药剂(诸如抗体c225)与本发明实施方案的某些方面组合使用以改善治疗功效。
VI.本公开的试剂盒
本文公开的任一种组合物可以包含在试剂盒中。在非限制性实例中,TIL和/或T细胞(和/或用于产生它们的改造形式的试剂),和这些可以包含在本公开的试剂盒中的合适容器装置中。
提供制品或试剂盒,其包括改造的TIL和/或改造的T细胞,和/或用于产生它们的一种或多种试剂。TIL和/或T细胞可以来自任何来源,并且在具体实施方案中,TIL和/或T细胞已经通过本文所涵盖的方法产生。在具体实施方案中,TIL和/或T细胞已经被基因编辑,并且可以提供在试剂盒中使得它们可以被进一步修饰以表达一个或多个异源抗原受体。在具体实施方案中,TIL和/或T细胞已经被修饰以表达一个或多个异源抗原受体并且可以在试剂盒中提供使得它们可以进一步被修饰以进行基因编辑。在具体实施方案中,在试剂盒中提供用于生成TIL和/或T细胞的一种或多种试剂,诸如靶向特定基因的试剂,包含异源抗原受体的试剂(用于产生所述异源抗原受体的一种或多种试剂),或其组合。在一般实施方案中,所述试剂可以包含核酸(包括DNA或RNA),蛋白质,培养基,缓冲液,盐类,辅因子,等等。在具体实例中,所述试剂盒包含一种或多种CRISPR相关试剂,包括用于靶向特定期望基因。
可将试剂盒的组分包装在水性介质中或以冻干形式包装。试剂盒的容器装置将通常包括至少一个小瓶、试管、烧瓶、瓶、注射器或其他容器装置,可向其中放置一种或多种组分,并且优选的是所述一种或多种组分以适合方式等分。当试剂盒中存在超过一种组分时,所述试剂盒也可以通常含有可向其中单独放置额外组分的第二、第三或其他额外容器。然而,组分的各种组合可包含在一个小瓶中。本公开的试剂盒也典型地包括用于含有改造的TIL和/或改造的T细胞(和/或用于生成它们的试剂)的装置,和任何其他试剂容器,它们紧密密封以进行商业销售。此类容器可包括注塑或吹塑塑料容器,所需小瓶被保持在该注塑或吹塑塑料容器中。
当试剂盒的组分以一种和/或多种液体溶液形式提供时,液体溶液是水溶液,其中无菌水溶液是特别优选的。所述组合物还可以配制成可注射组合物。在所述情况下,容器装置可自身是注射器、吸移管和/或其他这样类似器具,制剂可从其向身体的感染区域施加,向动物中注射,和/或甚至向试剂盒的其他组分中施加和/或与试剂盒的其他组分混合。
然而,试剂盒的组分可以干燥粉末形式提供。当试剂和/或组分以干燥粉末形式提供时,粉末可通过添加适合溶剂来复配。设想溶剂也可提供在另一容器装置中。
无论容器的数目有多少和/或是何类型,本公开的试剂盒还可以包括用于协助注射/施用和/或将最终的组合物放置在动物体内的工具,和/或与所述工具包装在一起。此类工具可以是注射器、吸移管、镊子和/或任何此类批准医用的递送器具。在一些实施方案中,试剂或设备或容器包括在试剂盒中用于离体使用。
实施例
包括以下实施例以证明本发明的优选实施方案。本领域技术人员应当理解,以下实施例中公开的技术代表发明人发现的在本发明的实践中发挥良好作用的技术,以及因此可以认为构成其实践的优选方式。然而,鉴于本公开内容,本领域技术人员应当理解,可以在不脱离本发明的精神和范围的情况下在所公开的特定实施方案中进行许多改变,并且仍可获得类似或相似的结果。
实施例1
敲除肿瘤浸润性淋巴细胞中的基因以克服肿瘤微环境中的免疫抑制
本实施例证明了在TIL中的基因编辑给它们提供了在肿瘤微环境中增强的活性。在具体方法中,所述TIL被敲除TIL中的一个或多个特定内源基因。本实施例证明了递送已经与特定gRNA种类复合的Cas9蛋白可以用来有效地在免疫细胞中进行CRISPR基因编辑,所述免疫细胞包括鼠T细胞和人TIL。此方式用来产生TGFBR2和/或TIGIT和/或CD7的表达减少或消除的TIL。作为初步研究,图1显示了使用基于电穿孔的转染将Cas9RNP复合物(包含Alt-R S.p.Cas9核酸酶V3,CRISPR-Cas9 tracrRNA–ATTOTM 550,和对Selplg基因特异的两个不同的crRNA(命名为AA和AB))有效递送到T细胞中用于基因编辑(作为一个实例),其中CRISPR-Cas9 tracrRNA–ATTOTM 550被利用用于转染细胞的荧光追踪。使用此技术在小鼠CD8+T细胞中实现的转染效率为>97%(即,在电穿孔后24小时,>97%的细胞为RNP复合物阳性)。将该方法应用到模型基因(选择素P配体;Selplg),其中在基于电穿孔递送含有靶向Selplg基因的两个不同crRNA种类(命名为AA和AB)的Cas9 RNP复合物(图2)后5天,鼠T细胞中的基因90%敲除。
作为实例,所述方法用于敲除鼠T细胞中感兴趣基因。图3证明了使用基于电穿孔递送Cas9 RNP复合物敲除鼠T细胞中TIGIT的能力。本文提供的数据显示了通过RT-PCR评估在RNA水平的TIGIT敲除。在图4中,发明人显示了对TIL的有效改造。在离体扩增的患者来源的TIL中,实现了对TIGIT的敲除,转染效率>75%。通过电穿孔转移TIGIT-特异性RNP复合物导致的细胞递送效率为76.5%(阳性细胞百分比)。最后,利用靶向TIGIT的Cas9 RNP复合物转染事先扩增的TIL产生了相当可观的敲除。在此显示了在对照例(未转染)和实施例(利用TIGIT-特异性RNP转染)中TIGIT阳性的全部活TIL的百分比。在特定实施方案中,所述方法用于敲除TIL中不同的基因,诸如,例如,TGF-βR2。
图6A-6B显示了在体内通过混合shRNA筛选对调节T细胞浸润到肿瘤中的基因的鉴定。图6A.实验设计的示意性图示。用靶向300个编码细胞表面上表达的蛋白质的基因的混合shRNA文库转导激活的pmel T细胞,细胞过继转移(ACT)到经辐射的荷B16肿瘤小鼠。ACT后7天,从B16肿瘤和脾配对样品分离pmel T细胞,进行DNA分离和测序。图6B.密度图。密度图中的箭头指示与脾T细胞和参照(ACT前获取的样品)相比TIL群体中的富集的发夹序列。对每组2-3个样品进行分析。显示了代表性的表面T细胞筛选。
图7显示了基于shRNA条形码通过Cd7敲低与脾相比较肿瘤中的T细胞浸润的增强。显示了在脾和肿瘤样品(每种n=6)中对于靶向Cd7的10种不同的shRNA构建体中的每一种的shRNA条形码读数的数目。大多数构建体显示:与脾样品相比,在肿瘤样品中有富集。
图8显示了基于单个基因敲低,与脾相比在肿瘤中Cd7敲低Pmel的富集。单独用含有Cd7 shRNA的慢病毒载体或非靶向对照(NTC)载体转导Pmel T细胞,在ACT进荷瘤小鼠之前FACS分选载体表达的GFP并扩增。在ACT后12天从肿瘤分离全部肿瘤浸润性免疫淋巴细胞(TIL)并计数。与未转导或NTC构建体转导的Pmel T细胞相比,发现了较高数目的Cd7敲低Pmel,证实了在shRNA筛选中发现的效应。
单独用含有Cd7 shRNA的慢病毒载体或非靶向对照(NTC)载体转导Pmel T细胞,在ACT进荷瘤小鼠之前FACS分选载体表达的mCherry并扩增。在ACT前一天,Cd7 shRNA-转导的Pmel T细胞表达93.9%mCherry,并且通过mCherry和活/死流式细胞术分析为95.1%有活力。qRT-PCR分析证实与NTC-转导的Pmel T细胞相比,Cd7 mRNA表达减少达84%。
使用T细胞受体α链基因(TRAC)作为模型靶标在患者来源的TIL中优化CRISPR基因敲除(图9)。在几种不同的电穿孔脉冲参数(标为EH100、EN138、EH115和EO115)和两个不同的Cas9输入量(5μg和10μg)下,实现了对αβT细胞受体的稳健消除(>90%)。这些数据证明使用临床相关的转染方案在人T细胞中的稳健CRISPR基因编辑。
图10涉及对在患者来源的TIL中TIGIT的CRISPR基因敲除的优化。未修饰的TIL显示94.3%的TIGIT表面表达阳性。利用各种向导RNA序列(标为TIGIT AA、AB、AC、AD和AE)接受TIGIT敲除的TIL显示TIGIT表面表达减少。标识为“TIGIT AB”和“TIGIT AC”的向导RNA序列(仅作为实例)的使用显示了最强敲除效率,在CRISPR基因编辑后,<2%的细胞仍为TIGIT表面表达阳性。
图11证明了对患者来源的TIL中TGFBR2的CRISPR基因敲除的优化。使用靶向TGFBR2的向导RNA(不同的向导RNA序列,标为TGFBR2 AA、AB、AC和AD,作为实例)对TIL进行基因修饰。基因修饰的TIL的特征在于,与用Cas9假模拟物(mock)转染的TIL相比,在CRISPR切口位点处野生型TGFBR2序列的水平基本上较低。利用标为“TGFBR2 AC”和“TGFBR2 AD”的向导RNA进行的基因修饰显示了最稳健的野生型DNA消除。
已经经历对TGFBR2的CRISPR基因敲除的TIL对外源性TGF-β刺激的效应有抗性(图12)。当暴露于外源性TGF-β时,未修饰的TIL表达高水平的磷酸化SMAD-2和SMAD-3。相反,已经经历CRISPR基因编辑以消除TGFBR2的TIL对TGF-β-诱导的SMAD磷酸化相对有抗性。使用靶向TGFBR2的向导RNA(不同的向导RNA序列,标为TGFBR2 AA、AB、AC和AD,作为实例)对TIL进行基因修饰。用命名为“TGFBR2 AC”和“TGFBR2AD”的向导RNA修饰的TIL证明对SMAD磷酸化有最强的抗性。在几个独立的患者来源的TIL细胞系间,这些结果是可再现的。
附图中的表1提供了用于在人T细胞中靶向TIGIT和TGFBR2的向导RNA序列的实例。使用Integrated DNA Technologies(IDT)网络工具来设计向导RNA。
在图13中,已经经历对TGFBR2的CRISPR基因敲除的TIL对外源性TGF-β刺激的效应有抗性。当在TGF-β的存在下培养3天时,未修饰的TIL分泌的几种促炎细胞因子的水平降低(如通过来自TGF-β:媒介物处理的细胞的细胞因子浓度的倍数变化<1.0证明)。相反,当在存在或缺少TGF-β的情况下培养时,使用靶向TGFBR2的向导RNA(不同的向导RNA序列,标注为TGFBR2 AC和AD)基因修饰的TIL分泌大致等量的促炎细胞因子(如通过TGF-β:媒介物的倍数变化~1.0证明)。数据呈现为来自TGF-β-处理(10ng/ml)的TIL与媒介物处理的TIL的细胞因子浓度的倍数变化(比率)。数据来自从两个独立供体分离的TIL。
在图14中,RNP转染在激活的小鼠CD8+T细胞中诱导高度有效的Cas9/CRISPR-介导的PD-1敲除。(图14B)在CD8 T细胞中利用抗-CD3和IL-2体外激活上调了PD-1的细胞表面表达(利用非靶向对照RNP转染的对照细胞,NTC条件)。(图14C)用靶向PD-1的Cas9/gRNA RNP(PD-1KO条件)转染的T细胞,显示了PD-1表达的减少,对应于与NTC表达相比97%的敲除效率。在转染后6天,通过流式细胞术评价的PD-1蛋白表达;基于FMO确定的阳性表达(图14A)。
参考文献
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尽管已经详细地描述了本公开及其优势,但应当理解在不背离如由附带的权利要求所限定的设计的精神和范围的前提下可以对本文做出各种变化、替代和改变。此外,本申请的范围不意在限于在说明书中描述的过程、机器、制造、物质组合物、手段、方法和步骤的特定实施方案。如本领域普通技术人员从本公开中容易理解的,可以根据本公开利用目前现有的或以后待开发的执行与本文所述的相应实施方案基本上相同的功能或实现基本上相同的结果的过程、机器、制造、物质组合物、手段、方法或步骤。因此,附带的权利要求旨在在其范围内包括此类过程、机器、制造、物质组合物、手段、方法或步骤。
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<130> UTSC.P1200WO-1001143829
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Claims (34)
1.一种组合物,包含:
(a)改造的肿瘤浸润性淋巴细胞(TIL),其中所述TIL包含下列中的一种或多种:(1)转化生长因子-β受体2(TGFBR2)的表达和/或活性的破坏;(2)T-细胞-Ig-和-ITIM-结构域(TIGIT)的表达和/或活性的破坏;(3)CD7的表达和/或活性的破坏,所述转化生长因子-β受体2(TGFBR2)、所述T-细胞-Ig-和-ITIM-结构域(TIGIT)和所述CD7均是所述TIL内源的;(4)程序性细胞死亡蛋白1(PD-1)的表达的破坏;和(5)含T-细胞免疫球蛋白和粘蛋白结构域-3(TIM-3)的表达的破坏;和/或
(b)改造的T细胞,其中所述T细胞包含下列中的一种或多种:(1)所述TIL内源性转化生长因子-β受体2(TGFBR2)的表达和/或活性的破坏;(2)T-细胞-Ig-和-ITIM-结构域(TIGIT)的表达和/或活性的破坏;(3)CD7的表达和/或活性的破坏;(4)PD-1的表达的破坏;和(5)TIM-3的表达的破坏,所述T-细胞-Ig-和-ITIM-结构域(TIGIT)、所述CD7、所述PD-1和所述TIM-3均是所述T细胞内源的。
2.权利要求1所述的组合物,其中所述TIL是经扩增的TIL和/或其中所述T细胞是经扩增的T细胞。
3.权利要求1或2所述的组合物,其中TGFBR2、TIGIT、CD7、PD-1和TIM-3中的一种或多种的表达和/或活性的破坏包括核酸、肽、蛋白、小分子或其组合。
4.权利要求3所述的组合物,其中所述核酸包括分别对应于TGFBR2、TIGIT、CD7、PD-1和TIM-3的siRNA、shRNA、反义寡核苷酸或用于CRISPR的向导RNA。
5.权利要求1-4中任一项所述的组合物,其中所述TIL包含TGFBR2的表达的破坏。
6.权利要求1-5中任一项所述的组合物,其中所述TIL包含TIGIT的表达的破坏。
7.权利要求1-6中任一项所述的组合物,其中所述TIL包含CD7的表达的破坏。
8.权利要求1-7中任一项所述的组合物,其中所述TIL包含PD-1的表达的破坏。
9.权利要求1-8中任一项所述的组合物,其中所述TIL包含TIM-3的表达的破坏。
10.权利要求1-9中任一项所述的组合物,其中所述T细胞包含TGFBR2的表达的破坏。
11.权利要求1-10中任一项所述的组合物,其中所述T细胞包含TIGIT的表达的破坏。
12.权利要求1-11中任一项所述的组合物,其中所述T细胞包含CD7的表达的破坏。
13.权利要求1-12中任一项所述的组合物,其中所述T细胞包含PD-1的表达的破坏。
14.权利要求1-13中任一项所述的组合物,其中所述T细胞包含TIM-3的表达的破坏。
15.权利要求1、2、3、4、10、11、12、13或14中任一项所述的组合物,其中所述TIL或T细胞包含靶向一种或多种癌症抗原的一种或多种异源抗原受体。
16.权利要求15所述的组合物,其中所述异源抗原受体是T细胞受体、嵌合抗原受体、趋化因子受体、嵌合细胞因子受体或它们的混合物。
17.权利要求1-16中任一项所述的组合物的细胞的群体。
18.一种组合物,包含权利要求17所述的群体。
19.权利要求18所述的组合物,其中所述群体处在药学上可接受的承载体中。
20.一种制备权利要求1-16中任一项所述的细胞的方法,包括分别利用下列各项电穿孔TIL和/或T细胞的步骤:
(a)Cas9或编码Cas9的核酸;以及(b)、(c)、(d)、(e)和(f)中的一个或多个:
(b)一种或多种用于CRISPR的TGFBR2向导RNA;
(c)一种或多种用于CRISPR的TIGIT向导RNA;或
(d)一种或多种用于CRISPR的CD7向导RNA;
(e)一种或多种用于CRISPR的PD-1向导RNA;和
(f)一种或多种用于CRISPR的TIM-3向导RNA。
21.权利要求18所述的方法,进一步限定为包括两个或更多个电穿孔步骤,其中第一电穿孔步骤使所述TIL和/或改造的T细胞接受TGFBR2向导RNA、TIGIT向导RNA、CD7向导RNA、PD-1向导RNA和TIM-3向导RNA中的一种或多种,并且第二电穿孔步骤使所述TIL和/或改造的T细胞接受在所述第一电穿孔步骤中未使用的针对TGFBR2、TIGIT、CD7、PD-1和TIM-3中的一种或多种的向导RNA。
22.权利要求20-21中任一项所述的方法,进一步包括至少一个扩增所述TIL和/或T细胞的步骤。
23.权利要求22所述的方法,其中在电穿孔步骤前存在对所述TIL和/或T细胞的扩增步骤。
24.权利要求22或23所述的方法,其中在电穿孔步骤后存在对所述TIL和/或T细胞的扩增步骤。
25.权利要求20-24中任一项所述的方法,进一步包括修饰所述T细胞或TIL以表达一种或多种异源抗原受体的步骤。
26.权利要求25所述的方法,其中所述异源抗原受体是T细胞受体、嵌合抗原受体、趋化因子受体、嵌合细胞因子受体或它们的混合物。
27.权利要求25或26所述的方法,其中所述异源抗原受体被定制为靶向个体的癌症细胞上的癌症抗原。
28.一种杀死个体中的癌症细胞的方法,包括向所述个体递送治疗有效量的权利要求1-16中任一项所述的组合物的步骤。
29.权利要求28所述的方法,其中所述癌症是血液系统癌症或包括实体肿瘤。
30.权利要求28-29中任一项所述的方法,其中所述TIL和/或T细胞与所述个体是同种异体的。
31.权利要求28-29中任一项所述的方法,其中所述TIL和/或T细胞是所述个体自体的。
32.权利要求28、29或31中任一项所述的方法,进一步限定为:
(a)从所述个体获得癌症细胞;
(b)从所述癌症细胞扩增TIL以产生经扩增的TIL;
(c)改造所述经扩增的TIL以具有:(1)所述TIL内源性TGFBR2的表达或活性的破坏;和/或(2)所述TIL内源性TIGIT的表达或活性的破坏;和/或(3)所述TIL内源的CD7的表达或活性的破坏;和/或(4)所述TIL内源的PD-1的表达或活性的破坏;和/或(5)所述TIL内源的TIM-3的表达或活性的破坏;以及
(d)向所述个体施用有效量的经改造的细胞。
33.权利要求28-32中任一项所述的方法,其中向所述个体递送额外的癌症疗法。
34.权利要求33所述的方法,其中所述额外的癌症疗法包括手术、辐射、化学疗法、激素疗法、免疫疗法或它们的组合。
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