CN113316455A - 用于离体扩增自然杀伤细胞的方法及其用途 - Google Patents
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Abstract
本发明提供用于扩增脐带血来源的自然杀伤细胞的离体方法以及其使用方法。实施方案的实例包括:在抗原呈递细胞(APC)和IL‑2存在下刺激来自脐带血的单核细胞,并用APC再刺激该所述细胞以产生经扩增的NK细胞。在特定实施方案中,该方法不使用人白细胞抗原(HLA)配型。
Description
本申请要求于2018年11月29日提交的美国临时专利申请系列号62/773,132的优先权,该申请通过引用完全结合在本申请中。
背景
1.技术领域
本发明大体上涉及细胞生物学、分子生物学、免疫学和医学领域。更具体地,本发明涉及用于扩增自然杀伤(NK)细胞的方法及其用途。
2.相关技术说明
对于患有数种不同的血液恶性肿瘤和实体瘤的患者而言,自然杀伤(NK)细胞正成为细胞免疫疗法令人兴奋的来源;然而,大部分使用过继转移的NK细胞的研究受到以下因素的限制:需要自体人白细胞抗原(HLA)配型供者或单倍体相同供者;扩增程序冗长且复杂;输注的细胞存留不足且在体内扩增性差;以及令人失望的抗肿瘤活性。
用于产生NK细胞的理想细胞源尚未完全明了。来自患者的外周血NK细胞(PB-NK细胞)(即,自体细胞)或来自成人同种异体供者的外周血NK细胞是最常用的;然而,此方法需要与进行白细胞去除术的受者最少3/6HLA分子配型的有意愿的供者。成人PB NK细胞的另一个缺点是过继转移之后的次佳体内增殖和存留。因此,脐带血(CB)是用于产生NK细胞的造血细胞具有吸引力的来源,因为全世界CB库中有超过一百万经冷冻且随时可用的CB单元的庞大全球库存。
已显示CB-NK细胞具有固有特性,包括与细胞周期、细胞分裂和DNA复制相关的基因的较高表达,该固有特性使得CB-NK细胞优于从外周血扩增的NK细胞而用于过继疗法。广泛使用CB的阻碍在于难以以临床相关的剂量从冷冻CB单元扩增功能性NK细胞。因此,对于从CB扩增NK细胞的改良方法存在未得到满足的需求。
发明内容
在一个实施方案中,本发明提供一种用于扩增自然杀伤(NK)细胞的离体方法,其包括:在抗原呈递细胞(APC)和IL-2存在下刺激来自脐带血的单核细胞(MNC);并且用APC再刺激所述细胞以产生经扩增的NK细胞,其中在至少一些情况下,该方法在生物反应器中进行。刺激步骤可将MNC导向NK细胞。再刺激步骤可或可不包含IL-2的存在。在特定方面中,该方法不包含在刺激步骤期间移除或添加任何培养基组分。在特定方面中,该方法在特定时间范围内进行,诸如在少于15天内,例如在14天内进行。
在某一实施方案中,本发明提供一种用于扩增自然杀伤(NK)细胞的离体方法,其包括:(a)从脐带血获得单核细胞(MNC)的起始群体;(b)在抗原呈递细胞(APC)和IL-2存在下刺激MNC;以及(c)用APC再刺激所述细胞以产生经扩增的NK细胞,其中该方法在生物反应器中进行并且符合良好作业规范(GMP)。步骤(b)的刺激可将MNC导向NK细胞。步骤(c)可或可不包含IL-2的存在。在特定方面中,该方法不包含在步骤(b)期间移除或添加任何培养基组分。在特定方面中,该方法在少于15天进行,诸如在14天内进行。
在一些方面中,该方法进一步包括耗尽一种或多种特定标志物(诸如CD3)阳性的细胞。在某些方面中,耗尽步骤在步骤(b)与(c)之间进行。在一些方面中,从生物反应器移出细胞以进行CD3耗尽,并且将该细胞放入生物反应器中以进行步骤(c)。
在某些方面中,从脐带血获得MNC的起始群体包括在葡聚糖、人血清白蛋白(HSA)、DNA酶和/或氯化镁存在下解冻脐带血。在特定方面中,从脐带血获得MNC的起始群体包括在葡聚糖和/或DNA酶存在下解冻脐带血。在特定方面中,在5至20%(诸如10%)葡聚糖存在下洗涤脐带血。在某些方面中,在诸如浓度为100至300mM(尤其200mM)的氯化镁存在下使脐带血悬浮。在一些方面中,获得步骤包括进行ficoll密度梯度离心以获得单核细胞(MNC)。
在某些方面中,生物反应器为透气式生物反应器。在特定方面中,透气式生物反应器为G-Rex100M或G-Rex100。在一些方面中,步骤(b)的刺激在3-5L的培养基,诸如3、3.5、4、4.5或5L的培养基中进行。
在一些方面中,APC经γ辐照。在某些方面中,APC经工程改造以表达膜结合的IL-21(mbIL-21)。在特定方面中,APC经工程改造以表达IL-21、IL-15和/或IL-2。在一些方面中,MNC和APC以1:2的比率进行培养。在一些方面中,IL-2的浓度为50-200IU/mL,诸如100IU/mL。在特定方面中,每2-3天补给IL-2。
在特定方面中,进行步骤(b)持续6-8天,诸如7天。在一些方面中,进行步骤(c)持续6-8天,诸如7天。在一些方面中,步骤(c)不包括使细胞分开(split)。在特定方面中,在步骤(c)期间向细胞中添加两次IL-2,且在特定情况下,在步骤(c)期间不添加或移除其他培养基组分。
在一些方面中,所述方法包括使用3、4、5或6个生物反应器。在特定方面中,所述方法包括使用少于10个生物反应器。
在特定方面中,NK细胞扩增至少500倍、800倍、1000倍、1200倍、1500倍、2000倍、2500倍、3000倍或5000倍。在特定方面中,与静态液体培养相比,在生物反应器中培养NK细胞产生超过1000倍的NK细胞。
在某些方面中,所述方法不包括人白细胞抗原(HLA)配型。在一些方面中,NK细胞的起始群体不是从单倍体相同的供者获得。
在一些方面中,与从外周血扩增的NK细胞相比,经扩增的NK细胞具有增强的抗肿瘤活性。在某些方面中,与从外周血扩增的NK细胞相比,经扩增的NK细胞具有一种或多种细胞周期基因、一种或多种细胞分裂基因和/或一种或多种DNA复制基因的较高表达。在一些方面中,与从外周血扩增的NK细胞相比,经扩增的NK细胞具有较高的增殖能力。在一些方面中,经扩增的NK细胞不表现出耗竭。在某些方面中,通过测量穿孔蛋白、颗粒酶、CD57、KLRG1和/或PD1的表达来检测耗竭。在一些方面中,经扩增的NK细胞具有穿孔蛋白和/或颗粒酶的高表达。在某些方面中,经扩增的NK细胞具有CD57、KLRG1和/或PD1的低表达或没有CD57、KLRG1和/或PD1的表达。
在一些方面中,经扩增的NK细胞包含临床相关剂量。在某些方面中,脐带血为冷冻脐带血。在特定方面中,已针对一种或多种传染疾病测试冷冻脐带血,所述传染疾病诸如甲型肝炎、乙型肝炎、丙型肝炎、克氏锥虫(Trypanosoma cruzi)、HIV、人类嗜T淋巴细胞病毒、梅毒、寨卡病毒(Zika virus)等等。在一些方面中,脐带血为经汇集的脐带血,诸如来自3、4、5、6、7或8个个体脐带血单元。
在一些方面中,NK细胞不是自体的,诸如相对于接受者个体而言不是自体的。在某些方面中,NK细胞不是同种异体的,诸如相对于接受者个体而言不是同种异体的。
在一些方面中,APC为通用抗原呈递细胞(uAPC)。在某些方面中,uAPC经工程改造以表达:(1)CD48和/或CS1(CD319);(2)膜结合的白介素-21(mbIL-21);和(3)41BB配体(41BBL)。在一些方面中,uAPC表达CD48。在某些方面中,uAPC表达CS1。在特定方面中,uAPC表达CD48和CS1。在一些方面中,uAPC基本上没有内源性HLA I类、HLA II类和/或CD1d分子的表达。在某些方面中,uAPC表达ICAM-1(CD54)和/或LFA-3(CD58)。在特定方面中,uAPC进一步定义为源自白血病细胞的aAPC,诸如K562细胞。
在额外方面中,所述方法进一步包括冷冻保存经扩增的NK细胞。
本文进一步提供一种药物组合物,其包含:由实施方案(例如,(a)从脐带血获得单核细胞(MNC)的起始群体;(b)在抗原呈递细胞(APC)和IL-2存在下刺激MNC;以及(c)用APC再刺激所述细胞以产生经扩增的NK细胞,其中该方法在生物反应器中进行且符合GMP)产生的NK细胞群体;和药学上可接受的载剂。
另一实施方案提供一种用于治疗受试者的疾病或病症的组合物,该组合物包含有效量的由实施方案(例如,(a)从脐带血获得单核细胞(MNC)的起始群体;(b)在抗原呈递细胞(APC)和IL-2存在下刺激MNC;以及(c)用APC再刺激所述细胞以产生经扩增的NK细胞,其中该方法在生物反应器中进行且符合GMP)产生的NK细胞。
另一实施方案提供一种组合物用于治疗受试者的免疫相关病症的用途,该组合物包含有效量的由实施方案(例如,(a)从脐带血获得单核细胞(MNC)的起始群体;(b)在抗原呈递细胞(APC)和IL-2存在下刺激MNC;以及(c)用APC再刺激所述细胞以产生经扩增的NK细胞,其中该方法在生物反应器中进行且符合GMP)产生的NK细胞。
在另一实施方案中,提供一种用于治疗疾病或病症的方法,其包括向受试者施用有效量的根据实施方案(例如,(a)从脐带血获得单核细胞(MNC)的起始群体;(b)在抗原呈递细胞(APC)和IL-2存在下刺激MNC;以及(c)用APC再刺激所述细胞以产生经扩增的NK细胞,其中该方法在生物反应器中进行且符合GMP)所述的经扩增的NK细胞。
在额外方面中,所述方法进一步包括施用化学疗法。在一些方面中,所述化学疗法在经扩增的NK细胞之前施用。在特定方面中,所述化学疗法是清髓性的。在其他方面中,所述化学疗法是非清髓性的。在一些方面中,所述化学疗法为淋巴细胞清除性化学疗法。在特定方面中,所述淋巴细胞清除性化学疗法为基于氟达拉宾的淋巴细胞清除性化学疗法。在特定方面中,所述化学疗法为来那度胺(lenalidomide)。
在特定方面中,所述方法不包括进行HLA配型。在特定方面中,受试者没有发展移植物抗宿主疾病或其他毒性。
在一些方面中,所述疾病或病症为免疫相关病症。在某些方面中,所述免疫相关病症为自体免疫病症、移植物抗宿主疾病、同种异体移植排斥或炎性病况。在一些方面中,所述疾病或病症为癌症,诸如多发性骨髓瘤。
在额外方面中,所述方法进一步包括施用至少第二治疗剂。在一些方面中,至少第二治疗剂包括化学疗法、免疫疗法、手术、放射疗法或生物疗法。在一些方面中,NK细胞和/或至少第二治疗剂经静脉内、腹膜内、气管内、瘤内、肌内、内窥镜方式、病灶内、经皮、皮下、区域性施用或通过直接注射或输注施用。
本发明的其他目的、特征和优势将通过以下详细描述而变得显而易见。然而,应理解,所述详细描述和具体实施例虽然指示本发明的优选实施方案,但仅以举例说明方式给出,因为本领域技术人员通过该详细描述容易知晓在本发明的精神和范围内的各种改变和修改。
附图说明
以下附图形成本说明书的一部分且包括在内以进一步展示本发明中的某些方面。参考这些附图中的一个或多个附图,结合本文中记载的特定实施方案的详细描述,可更好地理解本发明的方法和组合物。
图1A至图1E:相比于外周血(PB)NK细胞,脐带血(CB)NK细胞中参与细胞增殖(图1A)、细胞活化(图1B)、细胞粘附(图1C)、细胞周期(图1D)和DNA复制(图1E)的基因的较高表达。
图2:CB NK细胞相比于PB-NK细胞具有较高的增殖能力。
图3:快速离体扩增的CB NK细胞(RE-CB NK细胞)没有表现出耗竭的表型证据。
图4:如BLI成像(右侧图)和存活率(左侧图)所示,RE-CB NK细胞在多发性骨髓瘤(MM)的免疫缺陷小鼠模型中诱导出稳健的抗肿瘤活性。
具体实施方式
在某些实施方案中,本发明提供用于离体扩增NK细胞的方法。本发明方法提供由CB单元(诸如冷冻的CB单元)制造符合良好作业规范(GMP)且具有高度功能性的NK细胞的稳健且快速的扩增方案。因此,本发明方法可在没有活供者的情况下进行。稳健的NK细胞也可以由新鲜或冷冻的外周血细胞产生。该方法可以包括在抗原呈递细胞(APC)存在下进行扩增,所述抗原呈递细胞诸如可具有或可不具有NK细胞特异性扩增能力的通用抗原呈递细胞(uAPC)。快速离体扩增的CB NK细胞(RE-CB NK细胞)可以新鲜输注,或可使用优化的条件冷冻保存使得所述细胞可在日后使用。重要的是,该方法提供以临床剂量大规模扩增NK细胞。
NK细胞的扩增可在诸如生物反应器的封闭系统中进行。本研究表明,与静态液体培养系统相比,CB-NK细胞可以在更一致且稳健扩增的情况下产生,诸如超过1000倍。
在一些方面中,本发明符合GMP的程序包括使用已针对第一周和第二周NK细胞培养优化的特定培养条件。增加培养基体积且由此降低培养物中的细胞浓度对扩增的规模、进行培养所需的时间和物流以及过程成本具有显著影响。如针对前七天培养的表2A和针对第二周培养的表2B中所示,与较少培养基和较高细胞浓度(G-Rex 100)相比,在较大培养基体积和降低的细胞浓度(G-Rex 100M)的情况下获得显著更好的倍数扩增。优化的程序需要更少的生物反应器,且产生相同或较高NK细胞剂量需要较少的细胞。此情形展示于第7天,例如,此时需要用少四倍的细胞来接种各个G-Rex 100M以达成相同剂量。在第0至7天,不需要干预培养物,诸如不用如先前方法中那样向细胞中加料。使用优化的程序,在第7至14天,细胞不需要分开且仅向其中加料两次(但在替代方案中,向细胞中加料一次、三次或四次或更多次)。使用较少培养基和细胞因子以及较少技术人员时间,从而节省金钱且改善物流。重要的是,在第7至14天,培养物中需要最少干预(例如,仅添加两次IL2),这不仅节省技术时间而且明显降低微生物污染的机会。这与目前使用的当前NK细胞扩增程序不同,在当前NK细胞扩增程序中,培养物通常每隔一天分开,反复加料,从而增加了微生物污染风险。如表2C中所总结的,优化的方法将技术人员时间减少29%。
本研究表明,快速离体扩增的CB NK细胞(RE-CB NK)可在没有任何毒性或移植物抗宿主疾病风险的情况下,甚至在没有任何HLA配型的情况下安全输注。还表明,在输注RE-CB NK细胞前,施加化学疗法,诸如在存在或不存在干细胞挽救的情况下的清髓性、非清髓性或降低强度的化学疗法或淋巴细胞清除性化学疗法,促进CB-NK细胞的体内生长和活化。这些细胞由此成为真正“现成的”免疫疗法产物,从而允许对在输注前可能需要额外疗法的患者具有最大灵活性。
因此,本发明进一步提供用于治疗诸如血液恶性疾病和实体瘤的癌症的方法。该治疗可以包括施用NK细胞和化学疗法,该化学疗法诸如在存在或不存在干细胞挽救的情况下的清髓性、非清髓性或降低强度的化学疗法或淋巴细胞清除性化学疗法。化学疗法可在输注NK细胞前施加。NK细胞可与靶向NK细胞受体(诸如CD16)的治疗剂组合施用,从而将细胞重新导向至靶标,由此增加针对不同肿瘤的反应。靶向NK细胞受体(诸如CD16)的治疗剂可为单株抗体、双特异性抗体或三特异性抗体。在特定情况下,NK细胞不与化学疗法和/或其他免疫疗法组合。
I.定义
如本文所用,关于指定组分“基本上不含”在本文中用于意指没有任一种指定组分被有意配制在组合物中和/或仅作为污染物或以痕量存在。由组合物的任何非预期污染产生的指定组分的总量因此远低于0.05%,优选地低于0.01%。在特定情况下,存在这样的组合物,其中指定组分的量用标准分析方法检测不到。
当在本说明书中使用时,“一种”或“一个”可意指一种或多种或者一个或多个。当在权利要求书中与词语“包含”结合使用时,词语“一种”或“一个”可以意指一种或多于一种或者一个或多于一个。
尽管本申请支持“或”仅指备选物和“和/或”,但在权利要求书中使用时,术语“或”用来意指“和/或”,除非明确指示仅指备选物或备选物是相互排斥的。如本文中所用,“另一种”可意指至少第二种或更多种。术语“约”、“基本上”和“大约”一般意指所陈述值加或减5%。
“免疫病症”、“免疫相关病症”或“免疫介导的病症”是指其中免疫反应在疾病的发展或进展中起关键作用的病症。免疫介导的病症包括自体免疫病症、同种异体移植排斥、移植物抗宿主疾病和炎性病况以及过敏性病况。
“治疗”疾病或病况是指指执行方案,其可包括向患者施用一种或多种药物,以努力减轻基本的迹象或症状。所需的治疗效果包括降低疾病进展速率、改善或减轻疾病病况和缓解或改良预后。减轻可在疾病或病况的迹象或症状出现之前以及在它们出现之后发生。因此,“治疗”可以包括预防疾病或非所需的病况。另外,“治疗”不需要完全减轻迹象或症状,不需要治愈,且特别包括仅对患者具有边际效应的方案。
如在整个本申请中使用的术语“治疗效益”或“治疗有效的”是指相对于此病况的医学治疗促进或增强受试者的健康的任何事物。这包括但不限于疾病迹象或症状的频率或严重性的降低。例如,癌症治疗可涉及例如肿瘤尺寸减小、肿瘤侵袭性降低、癌症生长速率降低或预防转移。癌症治疗还可指延长癌症患者的存活期。
“受试者”和“患者”是指人类或非人类(诸如灵长类动物、哺乳动物和脊椎动物)。在特定实施方案中,受试者是人类。
词组“药学上或药理学上可接受的”是指在按需要向动物(诸如人类)施用时不产生不良、过敏或其他不适当反应的分子实体和组合物。依据本发明,包含抗体或额外活性成分的药物组合物的制剂将是本领域技术人员所知的。此外,对于动物(例如人类)施用,应理解,制剂应该满足FDA生物标准办公室(FDA Office of Biological Standards)所要求的无菌性、致热原性、一般安全性和纯度标准。
如本文所用,“药学上可接受的载剂”包括任何以及所有水性溶剂(例如,水,醇/水溶液,盐水溶液,肠胃外介质,诸如氯化钠、林格氏右旋糖(Ringer's dextrose)等)、非水溶剂(例如,丙二醇、聚乙二醇、植物油和可注射有机酯,诸如油酸乙酯)、分散介质、包衣、表面活性剂、抗氧化剂、防腐剂(例如,抗细菌剂或抗真菌剂、抗氧化剂、螯合剂和惰性气体)、等渗剂、吸收延迟剂、盐、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、流体和营养补充剂,类似物质以及它们的组合,这些是本领域普通技术人员已知的。根据熟知的参数调整药物组合物中的各种组分的pH和准确浓度。
术语“单倍体分型”、“HLA配型”或“组织分型”是指用于例如通过判定特定受试者的淋巴细胞上表达哪种HLA基因座(或哪些HLA基因座)来鉴别个体的单倍体型或组织型的方法。然而,在特定实施方案中,该方法不包括人白细胞抗原(HLA)配型。HLA基因位于作为6号染色体的短臂上的区域的主要组织相容性复合体(MHC)中,且参与细胞与细胞的相互作用、免疫反应、器官移植、癌症发展和疾病易感性。存在六个对移植重要的基因座,命名为HLA-A、HLA-B、HLA-C和HLA-DR、HLA-DP以及HLA-DQ。在各基因座处,可存在若干不同等位基因中的任一者。广泛用于单倍体分型的方法使用聚合酶链式反应(PCR)以将受试者的DNA与编码MHC抗原的基因的已知区段进行比较。这些基因的这些区域的可变性决定受试者的组织型或单倍体型。血清学方法亦用于检测细胞表面上的血清学定义的抗原。可通过已知血清学技术来测定HLA-A、HLA-B和HLA-C决定子。简言之,将来自受试者的淋巴细胞(从新鲜外周血分离)与识别所有已知HLA抗原的抗血清一起培育。使细胞铺展于具有含有各种抗血清的微孔的盘中。将细胞孵育30分钟,随后再进行60分钟的补体孵育(complementincubation)。如果淋巴细胞在其表面上具有由抗血清中的抗体识别的抗原,则淋巴细胞被裂解。可添加染料以显示细胞膜渗透性的变化和细胞死亡。通过裂解破坏的细胞的图案指示组织学不相容性的程度。举例而言,如果在含有针对HLA-A3的抗血清的孔中来自测试HLA-A3的个人的淋巴细胞受到破坏,则对于该抗原型测试为阳性。
术语“抗原呈递细胞(APC)”是指能够呈递呈可被免疫系统的特定效应细胞识别的肽-MHC复合物形式的一种或多种抗原、且由此诱导针对所呈递的一种或多种抗原的有效细胞免疫反应的一类细胞。术语“APC”涵盖完整细胞,诸如巨噬细胞、B细胞、内皮细胞、活化的T细胞和树突状细胞,或能够呈递抗原的自然存在的或合成的分子,诸如与β2-微球蛋白复合的纯化的MHC I类分子。
术语“功能性封闭的”是指通过气密性密封整个系统或通过在与收集系统的所有连接处提供无菌屏障过滤器来密封系统以确保流体无菌性。
术语“生物反应器”是指在封闭无菌系统中为细胞提供营养物且移除代谢物、并且提供有利于细胞生长的物理化学环境的大规模细胞培养系统。在特定方面中,生物学和/或生物化学过程在受监测和控制的环境和操作条件下进展,所述条件例如pH、温度、压力、营养物供应和废料移除。根据本发明,适合于与本发明方法一起使用的生物反应器的基本类型包括中空纤维生物反应器。
II.NK细胞扩增
在某些方面中,本发明涉及从CB扩增NK细胞。NK细胞可具有独特优势,所述优势与参与细胞周期、细胞分裂和DNA复制的基因的较高表达(如图1A-1E中所示)有关。由此,本发明方法提供用于增殖源自CB的NK细胞的符合GMP的快速扩增方案。
在示例性方案中,将脐带血单元(例如,20%或完整脐带血单元)解冻,且通过使用Ficoll密度梯度离心来分离单核细胞而获得NK细胞。可在解冻后和单核细胞分离后进行洗涤。然后将细胞与IL-2(100U/mL)和APC一起孵育,所述APC诸如经γ辐照(100Gy)的aAPC(例如,克隆9膜结合的IL-21(mbIL-21)aAPC)或uAPC。生物反应器(诸如G-Rex生物反应器)中NK细胞与aAPC的比例可为2:1。在第2天,向细胞培养物中加入IL-2并监测扩增率。在第6或7天,可诸如通过使用Miltenyi XS柱和SuperMACSTM分离器来排除CD3+细胞。随后将细胞与IL-2(100U/mL)一起孵育,添加IL-2,且随后在第14天收集细胞。
解冻可在37℃水浴中在无菌床中进行。培养基可以包括含有L-谷氨酰胺、Clicks培养基和人AB(例如10%)血清的RPMI 1640。可以通过以450xG离心10分钟来进行洗涤。洗涤溶液可包含0.1%至10%(诸如0.5%、1%、2%、3%、4%、5%、6%、7%、8%、9%或10%)HSA DPBS、10%葡聚糖DPBS、DNA酶和氯化镁。
可通过将经洗涤的CB细胞的均匀部分成层至试管中的Ficoll-Paque上来进行单核细胞分离。接着可以对细胞进行离心,且移除上层受到污染的血浆和血浆。可以进一步对细胞进行离心,移除上清液,且将细胞重悬在培养基中。
在特定方面中,在整个过程中通过进行细胞计数、生存率、嵌合性、免疫表型分型、无菌性、支原体PCR(mycoplasm PCR)、格兰氏染色、内毒素、铬测定和细胞因子测定分析来进行质量控制。
NK细胞可在经工程改造的饲养细胞(诸如APC)存在下扩增。APC可表达用于活化NK共刺激性分子和细胞因子的配体。例如,APC可为表达CD48、CS1、IL-21、IL-2和/或IL15的UAPC。
在某些实施方案中,通过本领域熟知的方法从脐带血衍生出NK细胞。在特定实施方案中,从CB(诸如汇集的CB)分离免疫细胞。具体地,本发明的快速扩增方案可以涉及从冷冻且解冻的CB单元或从选自临床CB库的新鲜CB单元分离并扩增NK细胞。CB可以由2个、3个、4个、5个、6个、7个、8个、10个或更多个单元汇集。NK细胞可以是自体的或同种异体的。经分离的NK细胞可以是与待施用细胞疗法的受试者配型的单倍体型。然而,在特定方面中,NK细胞不是自体的或HLA配型的。NK细胞可通过人体内的特定表面标记物,诸如CD16、CD56和CD8检测。
在某些方面中,NK细胞的起始群体可通过使用Ficoll密度梯度离心来分离单核细胞而获得。可以去除细胞培养物中表达CD3、CD14和/或CD19的任何细胞,且可以对细胞培养物进行表征以确定CD56+/CD3-细胞或NK细胞的百分比。
可以在存在本发明的APC(诸如UAPC)的情况下扩增细胞。扩增可持续约2至30天,诸如3至20天,特别是12至16天,诸如12、13、14、15、16、17、18或19天,特别约14天。NK细胞和APCS可以以约3:1至1:3,诸如2:1、1:1、1:2,特别约1:2的比率存在。扩增培养物可以进一步包含细胞因子以促进扩增,所述细胞因子诸如IL-2、IL-21和/或IL-18。细胞因子可以约10U/mL至500U/mL,诸如100U/mL至300U/mL,特别约200U/mL的浓度存在。可在扩增培养物中补给细胞因子,诸如每2至3天补给。可至少再次向培养物中添加APC,诸如在CAR转导的后再次添加。
在扩增之后,NK细胞可以立即进行输注或可以进行储存,诸如通过低温保存来储存。在某些方面中,NK细胞可以作为在约1、2、3、4、5天内的混合群体(bulk population)离体繁殖数天、数周或数月。
经扩增的NK细胞可以分泌I型细胞因子(诸如干扰素γ、肿瘤坏死因子α和颗粒细胞-巨噬细胞集落刺激因子(GM-CSF),它们活化先天性免疫细胞和适应性免疫细胞两者)以及其他细胞因子和趋化因子。这些细胞因子的测量可用于测定NK细胞的活化状态。另外,本领域中已知的用于测定NK细胞活化的其他方法可用于表征本发明的NK细胞。
A.生物反应器
NK细胞可在功能性封闭系统(诸如生物反应器)中扩增。扩增可以在透气式生物反应器中进行,所述透气式生物反应器诸如G-Rex细胞培养装置。生物反应器可以支持平均体积450mL中1x109至3x109个总细胞。
生物反应器可根据一般类别进行分组,包括:静态生物反应器、搅拌瓶式生物反应器、旋转壁容器式生物反应器、中空纤维生物反应器和直接灌注式生物反应器。在生物反应器内,细胞可以是游离的或固定化的、接种在多孔三维支架(水凝胶)上。
中空纤维生物反应器可以用于提高培养期间的质量转移。中空纤维生物反应器是基于中空纤维的3D细胞培养系统,所述中空纤维是以平行阵列布置的较小半透性毛细管膜,其典型截留分子量(molecular weight cut-off,MWCO)范围为10至30kDa。这些中空纤维膜通常捆扎且容纳于管状聚碳酸酯外壳内,从而形成中空纤维生物反应器筒。在还装配有入口端口和出口端口的筒内有两个隔室:中空纤维内的毛细管内(IC)空间和围绕中空纤维的毛细管外(EC)空间。
由此,对于本发明,生物反应器可为中空纤维生物反应器。中空纤维生物反应器可将细胞包埋在纤维的管腔内,在管腔外空间灌注培养基;或备选地,中空纤维生物反应器可经由中空纤维提供气体和培养基灌注,而细胞在管腔外空间内生长。
中空纤维应适合于在生物反应器中递送营养物以及移除废料。中空纤维可呈任何形状,例如可呈圆形和管状或呈同心环的形式。中空纤维可由可再吸收或不可再吸收的膜制成。例如,中空纤维的适合组分包括聚对二氧环己酮(polydioxanone)、聚乳酸交酯、聚乳酸羟基乙酸、聚乙醇酸、聚乳酸、聚乙醇酸/碳酸三亚甲酯、纤维素、甲基纤维素、纤维素聚合物、纤维素酯、再生纤维素、普洛尼克(pluronic)、胶原蛋白、弹性蛋白及其混合物。
生物反应器可在接种细胞之前预致敏。预致敏可包括用缓冲液(诸如PBS)冲洗。预致敏还可以包括用细胞外基质蛋白(诸如纤连蛋白)涂布生物反应器。接着可用培养基(诸如αMEM)洗涤生物反应器。
在特定实施方案中,本发明方法使用GRex生物反应器。GRex烧瓶的底部为透气膜,细胞驻留在该透气膜上。因此,细胞处于高度氧化的环境中,从而允许细胞生长至高密度。系统容易扩大规模,且需要较低频率的培养操作。GRex烧瓶与标准组织培养箱和细胞实验室设备兼容,从而减少开始过继细胞疗法(ACT)程序所需要的专用设备和资本投资。
细胞可以如下密度接种在生物反应器中:约100至1000个细胞/cm2,诸如约150个细胞/cm2,约200个细胞/cm2,约250个细胞/cm2,约300个细胞/cm2,诸如约350个细胞/cm2,诸如约400个细胞/cm2,诸如约450个细胞/cm2,诸如约500个细胞/cm2,诸如约550个细胞/cm2,诸如约600个细胞/cm2,诸如约650个细胞/cm2,诸如约700个细胞/cm2,诸如约750个细胞/cm2,诸如约800个细胞/cm2,诸如约850个细胞/cm2,诸如约900个细胞/cm2,诸如约950个细胞/cm2,或约1000个细胞/cm2。具体地,细胞可以约400至500个细胞/cm2,诸如约450个细胞/cm2的细胞密度接种。
接种在生物反应器中的细胞的总数目可为约1.0x106至约1.0x108个细胞,诸如约1.0x106至5.0.0x106、5.0x106至1.0x107、1.0x107至5.0x107、5.0x107至1.0x108个细胞。在特定方面中,接种在生物反应器中的细胞的总数目为约1.0x107至约3.0x107,诸如约2.0x107个细胞。
细胞可接种在任何适合的培养细胞的培养基中,许多此类培养基是可商购的。示例性培养基包括DMEM、RPMI、MEM、培养基199、HAMS等。在一个实施方案中,培养基为αMEM培养基,特别是补充有L-谷氨酰胺的αMEM。培养基可补充有以下中的一种或多种:生长因子、细胞因子、激素、或B27、抗生素、维生素和/或小分子药物。特定地,培养基可以不含血清。
在一些实施方案中,可在室温下孵育细胞。培养箱可以加湿,且具有约5%CO2和约1%O2的气氛。在一些实施方案中,CO2浓度可在约1-20%、2-10%或3-5%的范围内。在一些实施方案中,O2浓度可在约1-20%、2-10%或3-5%的范围内。
B.抗原呈递细胞
抗原呈递细胞包括巨噬细胞、B淋巴细胞和树突状细胞,它们通过各自对特定MHC分子的表达区分。APC内化抗原且在其外部细胞膜上再表达该抗原的一部分以及MHC分子。MHC是具有多个基因座的较大遗传复合物。MHC基因座编码两个主要类别的MHC膜分子,称为I类和II类MHC。T辅助淋巴细胞一般识别与MHC II类分子缔合的抗原,T细胞毒性淋巴细胞识别与MHC I类分子缔合的抗原。MHC在人类中称为HLA复合物,在小鼠中称为H-2复合物。
在某些情况下,aAPC适用于制备实施方案的治疗性组合物和细胞疗法产品。关于制备和使用抗原递呈系统的一般指导参见例如美国专利号6,225,042、6,355,479、6,362,001和6,790,662;美国专利申请公开号2009/0017000和2009/0004142;以及国际公开号WO2007/103009。
aAPC系统可以包含至少一种外源性辅助分子。可以采用任何合适数目和组合的辅助分子。辅助分子可选自诸如共刺激性分子和粘附分子的辅助分子。示例性共刺激性分子包括CD86、CD64(FcγRI)、41BB配体和IL-21。粘附分子可包括:碳水化合物结合糖蛋白,诸如选择素;跨膜结合糖蛋白,诸如整联蛋白;钙依赖性蛋白,诸如钙粘素;以及单次跨膜免疫球蛋白(Ig)超家族蛋白,诸如细胞间粘附分子(ICAM);所述粘附分子促进例如细胞与细胞或细胞与基质的接触。示例性粘附分子包括LFA-3和ICAM,诸如ICAM-1。用于选择、克隆、制备和表达示例性辅助分子(包括共刺激性分子和粘附分子)的技术、方法和试剂示例于例如美国专利号6,225,042、6,355,479和6,362,001。
C.通用抗原呈递细胞
本发明的一些实施方案涉及通用抗原呈递细胞(UAPC)的生产和用途。UAPC可用于扩增免疫细胞(诸如NK细胞和T细胞)。UAPC可以被工程改造以表达膜结合的IL-21(mbIL-21)和41BBL(CD137配体)。
UAPC可以被工程改造以表达CD137配体和/或膜结合的细胞因子。所述膜结合的细胞因子可为mIL-21或mIL-15。在特定实施方案中,UAPC被工程改造以表达CD137配体和mIL-21。APC可来源于癌细胞,诸如白血病细胞。APC可以不表达内源性HLA I类、HLA II类或CD1d分子。APC可以表达ICAM-1(CD54)和LFA-3(CD58)。特定地,APC可为K562细胞,诸如经工程改造成表达CD137配体和mIL-21的K562细胞。APC可以经辐照。工程改造可通过本领域中已知的任何方法(诸如反转录病毒转导)来进行。
细胞因子对整个种类的免疫细胞(包括NK细胞)施加非常强效的控制,影响细胞命运、活性及细胞反应功效。用于活化NK细胞的细胞因子刺激力证实其“自然”效应功能高度易受环境干预影响,且预致敏可调节体内NK细胞行为。
为解决获取临床上相关量的NK细胞的问题,本发明的方法使用白介素(IL-21)作为用于本发明的UAPC平台技术中的NK细胞扩增的驱动剂。在人体内,利用IL-10和IL-21进行的NK细胞刺激以STAT3依赖性方式诱导NKG2D表达。虽然细胞因子受体共享多种免疫细胞中的类似细胞信号传导组分,但NK细胞特异性信号传导取决于用于增殖的IL-21受体-STAT3连接。
细胞因子信号传导对于维持淋巴细胞存活和增殖是关键的。在体内,IL-2施用是唯一经FDA批准的用于扩增NK细胞的方法。另一种强效NK细胞活化剂IL-15作为IL-2的可能替代物进行I期临床试验,但预期在全身性施用后具有显著的毒性。除显著的毒性外,这些细胞因子还诱导T细胞增殖,同时限制NK细胞存留。尽管共享用于信号转导的同一受体,但IL-2、IL-4、IL-7、IL-9、IL-15和IL-21受体对多种多样的细胞具有独特且特异性的作用。
1.膜结合的IL-21
在某些实施方案中,对于特异性地给NK细胞供应能量,IL-21可用于生产本发明的UAPC。IL-21受体(IL21R)与IL-2受体β链(其能够通过其与共同细胞因子受体γ链(γ(c))二聚化而转导信号)紧密相关,在活化的人类NK细胞(易于触发的细胞)中上调。虽然I型细胞因子IL-21可以调节T细胞、B细胞和NK细胞功能,但我们发现仅人类NK细胞经由IL21受体信号传导路径活化而经历显著扩增(在21天内扩增1000倍)。相反地,IL21在CD8+veT细胞收缩中起重要作用1。
IL21R信号传导主要由STAT3(一种高度强效的细胞增殖活化因子)供以动力。IL21R-STAT3连接由与GAS结合的IL-21诱导的STAT3 DNA和顺式可诱导元件(cis-inducible element)驱动,如通过利用抗磷酸酪氨酸抗体进行的免疫沈淀法和蛋白质印迹验证的2。IL21介导的增殖的分子基础可特异性追溯至调控IL-21诱导的STAT1和STAT3磷酸化的IL21R上的酪氨酸510(Y510)3。该机制由Statl/Stat3双重敲除小鼠中的抑制的IL-21反应而得到强调。
IL21R信号传导对于NK细胞毒性是重要的。人类IL21R缺乏症与51Cr标记的K562靶细胞的细胞溶解受损有关,同时抗体依赖性细胞毒性未受到影响4。单基因性非胚致死性缺陷(IL21R的功能损失型突变)呈现极佳的机会描绘且因此适用于建模、增强和塑形先天性NK细胞溶解反应。
即使CD56dim细胞群体和CD56bright细胞群体两者均携带类似数目的表面IL21R,IL-21信号传导仍选择性地模制NK细胞子集。相对于CD56dim NK细胞,在CD56bright NK细胞中STAT1和STAT3磷酸化的IL-21诱导更高。相比之下,IL-21对作为也驱动T细胞扩增的IL-2活化路径的STAT5活化没有作用。除STAT3活化外,IL-21信号传导还涉及MAPK和PI3K路径,且诱导NK细胞中先天性免疫反应基因(包括IFN-γ、T-bet、IL-12Rβ2和IL-18R)的表达,对其预致敏以杀灭肿瘤细胞。
对于IL-21的有效利用,mbIL-21表达可用于集中且定位与NK细胞上的IL21R的反式相互作用。mbIL21的膜接近性确保在需要其的情况下的易获得性,因此,其可以在没有大量和大浓度的外源供应IL-21的情况下维持最佳的细胞增殖。与经辐照的K562-mb15-41BBL共培养诱导来自外周血的CD56+CD3-NK细胞中值为21.6倍的扩增。与仅用来自共享γc家族的可溶性细胞因子(包括单独或组合的IL-2、IL-12、IL-15、IL-21)进行的刺激相比,该扩增更高。通过比较,本发明的UAPC可在14至21天内使NK细胞扩增至少1000倍(3-log)。UAPC上的mbIL21表达还可以避免对外源性临床级细胞因子的需求。
2.4-1BBL(4-1BB配体、CD137配体、CD137L、TNFSF9)
除NK细胞功能的细胞因子预致敏的概念外,与NK细胞中的活化分子的直接物理相互作用引起增强的细胞增殖反应。CD137(4-1BB)是调控细胞增殖、分化和程序性细胞死亡(凋亡)的肿瘤坏死受体(TNF-R)基因家族的成员。首先表征鼠受体,随后表征人类同系物,它们在氨基酸水平上共享60%的同一性,在细胞质/信号传导结构域中具有显著的保守性。CD137主要在活化的T细胞和NK细胞中表达,且在炎症部位处的胸腺细胞、骨髓细胞和内皮细胞中具有不同可检测的量。生理学CD137信号传导通过以下调控:1)NF-κB,其经由Bcl-XL活化促进存活;和2)PI3K/ERK1/2路径,其特异性驱动细胞周期进展。
在活化的NK细胞中,CD137是细胞因子可诱导的共刺激性分子,其又通过增加细胞增殖和IFN-γ分泌来驱动NK细胞中的抗肿瘤反应。使用CD137L-/-敲除小鼠进行的研究阐明CD137/CD137L信号传导在发展抗肿瘤免疫细胞中的重要性。与对照小鼠相比,CD137-/-敲除小鼠的肿瘤癌转移频率高4倍。
作为TNF超家族的34kDa糖蛋白成员的CD137配体(CD137L,4-1BB配体)主要在活化抗原呈递细胞(APC)(包括B细胞、巨噬细胞和树突状细胞)上检测到,且在活化的T细胞上以低水平瞬时表达。与鼠对应物相比,人类CD137L仅具有36%同源性10。与拮抗性CD137抗体的抗肿瘤功效一致,已显示CD137L结合引发CTL和抗肿瘤活性。
因此,本发明的UAPC可以被工程改造以表达4-1BB配体,所述4-1BB配体是用于最佳刺激的针对CD137的生理学反受体。
3.SLAM/CD48
除细胞因子调理和4-1BBL共刺激外,NK细胞与靶细胞之间的直接物理相互作用也影响细胞反应,即靶细胞杀伤。在免疫系统中广泛表达并且在免疫系统中起关键作用的信号传导淋巴细胞性活化分子(SLAM,先前也称为CD2超家族)家族同源免疫球蛋白受体在细胞间相互作用方面尤其重要。
因此,本发明的UAPC可以表达一种或多种SLAM家族抗原。SLAM家族成员包括CD2、CD48、CD58(LFA-3)、CD244(2B4)、CD229(Ly9)、CD319(CS1(CD2子集1);CRACC(CD2样受体活化细胞毒性细胞))和CD352(NTB-A(NK-T-B抗原))。在特定方面中,UAPC表达CD48和/或CS1。NK细胞表达SLAM家族(SLAMF)的至少三个成员。所述成员为:2B4,NK、T和B细胞抗原(NTB-A)和CD2样受体活化细胞毒性细胞(CRACC),它们识别各自在靶细胞上和可能地在其他NK细胞上的配体CD48、NTB-A和CRACC。尽管SLAMF1、SLAMF3、SLAMF5、SLAMF6、SLAMF7、SLAMF8和SLAMF9均为嗜同性(自配体)受体,而SLAMF2和SLAMF4为彼此的反受体(嗜异性)。已知嗜同性亲和力(解离常数Kd<1μM至200μM)中的宽范围(三个数量级)指向用于针对SLAM糖蛋白的重叠但独特的信号传导机制的机制基础。
表1:SLAM家族成员结合亲和力。
在特定实施方案中,本发明的UAPC被工程改造以表达CD48从而支持细胞与细胞相互作用,进而增强NK细胞反应。CD48是在NK细胞、T细胞、单核细胞和嗜碱性细胞的表面上发现的糖磷脂酰肌醇锚定蛋白质(GPI-AP),且参与这些细胞中的粘附与活化路径。尽管其缺少细胞内结构域,但CD48刺激诱导脂筏(lipid raft)中的信号传导因子重排、Lck激酶活性和酪氨酸磷酸化。作为粘附和共刺激性分子,CD48诱导B淋巴细胞和T淋巴细胞、NK细胞、肥大细胞和嗜酸性细胞中的诸多效应。在人类NK细胞中,CD48是2B426(NK细胞的一种重要活化剂)的反受体。认为嗜异性相互作用竞争CD244与MHC-I的相互作用。因此,2B4/CD48相互作用诱导人类NK细胞中的活化信号,然而在鼠NK细胞中,其传送抑制性信号。
尽管同一群体的细胞之间的2B4-CD48相互作用(即NK细胞-NK细胞相互作用或T细胞-T细胞相互作用)通过在APC(诸如通常不含CD48的K562骨髓细胞系)上表达CD48引起增强的活化,但是UAPC可以在NK细胞上以反式形式开启强力2B4信号传导路径。
4.SLAM/CS1
在一些实施方案中,本发明的UAPC被工程改造以表达CS1(SLAM家族的另一成员)作为用以开启NK细胞杀伤能力的共刺激性分子。与反结合至2B4的CD48不同,CS1相互作用是嗜同性的,且可在顺式相对反式相互作用的情形下进行表征。通常不含CS1的K562细胞可被工程改造以表达CS1。
III.基因工程改造的抗原受体
本发明的NK细胞可以被基因工程改造以表达抗原受体,如工程改造的TCR和/或CAR。例如,NK细胞经修饰以表达具有针对癌症抗原的抗原特异性的TCR。在NK细胞中可以添加多种CAR和/或TCR(诸如针对不同抗原)。
合适的修饰方法在本领域中是已知的。例如,参见Sambrook和Ausubel,同前所述。例如,可以使用Heemskerk等人,2008和Johnson等人,2009所述的转导技术转导细胞,以使其表达具有针对癌症抗原的抗原特异性的TCR。
编码全长TCRα和β(或γ和和δ)链的RNA的电穿孔可用作替代方案,以克服关于反转录病毒转导的与内源性TCR链的配对所引起的自体反应性的长期问题。即使此替代配对在瞬时转染策略中出现,可能产生的自体反应性T细胞也将在一定时间后失去该自体反应性,原因在于所引入的TCRα和β链仅瞬时表达。当引入的TCRα和β链表达减弱时,仅正常的自体T细胞留下来。当通过稳定的反转录病毒转导来引入全长TCR链时,情况并非如此,稳定的反转录病毒转导从来不会失去所引入的TCR链,从而在患者中引起恒定存在的自体反应性。
在一些实施方案中,细胞包含一种或多种通过基因工程改造引入的编码一种或多种抗原受体的核酸和所述核酸的基因基因工程改造的产物。在一些实施方案中,所述核酸是异源的,即,通常不存在于细胞或从所述细胞获得的样品中,所述核酸如从另一种生物体或细胞获得的核酸,例如,在被工程改造的细胞和/或该细胞所来源的生物体中通常不发现所述核酸。在一些实施方案中,所述核酸不是天然存在的,诸如在自然中不能发现的核酸(例如,嵌合核酸)。
在一些实施方案中,CAR包含与抗原特异性结合的细胞外抗原识别结构域。在一些实施方案中,所述抗原是表达在细胞表面上的蛋白质。在一些实施方案中,CAR是TCR样CAR,抗原是经处理的肽抗原,诸如细胞内蛋白质的肽抗原,类似TCR,其在主要组织相容性复合体(MHC)分子的情形下在细胞表面上被识别。
示例性的抗原受体,包括CAR和重组TCR,以及用于工程改造受体和将所述受体引入细胞中的方法,包括例如在以下中记载的那些方法: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,和和/或Sadelain等人,2013;Davila等人,2013;Turtle等人,2012;Wu等人,2012中所述的那些。在一些方面中,基因工程改造的抗原受体包括美国专利号7,446,190中记载的CAR,和国际专利申请公开号WO/2014055668A1中记载的那些。
A.嵌合抗原受体
在一些实施方案中,CAR包含:a)细胞内信号传导结构域,b)跨膜结构域,和c)包含抗原结合区的细胞外结构域。
在一些实施方案中,经工程改造的抗原受体包括CAR,所述CAR包括活化或刺激性CAR、共刺激性CAR(参见WO2014/055668)和/或抑制性CAR(iCAR,参见Fedorov等人,2013)。CAR通常包括连接至(在一些方面中经由接头和/或跨膜结构域)一种或多种细胞内信号传导组分的细胞外抗原(或配体)结合结构域。此类分子通常模仿或近似通过天然抗原受体的信号、通过此类受体与共刺激性受体的组合的信号和/或通过单独的共刺激性受体的信号。
本发明的某些实施方案涉及核酸的用途,包括编码抗原特异性CAR多肽的核酸,包括已经人源化以降低免疫原性的CAR(hCAR),所述CAR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可识别包含一种或多种抗原之间的共享空间的表位。在某些实施方案中,结合区可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。在另一实施方案中,该特异性来源于结合至受体的肽(例如细胞因子)。
预期人类CAR核酸可以是用于增强用于人类患者的细胞免疫疗法的人类基因。在一个特定实施方案中,本发明包括全长CAR cDNA或编码区。抗原结合区或抗原结合结构域可以包含源于特定人类单克隆抗体的单链可变片段(scFv)的VH和VL链的片段,诸如美国专利7,109,304中记载的那些,该专利通过引用并入本文中。该片段也可以是人类抗原特异性抗体的任何数目的不同抗原结合域。在更特定的实施方案中,该片段是由针对用于在人类细胞中表达的人类密码子应用而优化的序列编码的抗原特异性scFv。
重排可以是多聚的,诸如双抗体或多聚体。多聚体最可能由轻链和重链的可变部分交叉配对为双抗体而形成。构建体的铰链部分可具有多种选择,从完全缺失至保留第一半胱氨酸、至脯氨酸取代而非丝氨酸取代、至截断至第一半胱氨酸。Fc部分可缺失。稳定和/或二聚化的任何蛋白质均可供用于此目的。人们可以仅使用Fc结构域中的一种,例如来自人类免疫球蛋白的CH2或CH3结构域。还可以使用已经修饰以改良二聚化的人类免疫球蛋白的铰链区、CH2区和CH3区。人们还可以仅使用免疫球蛋白的铰链部分。人们还可使用CD8α的部分。
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,所述共刺激性受体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)中的一种或多种。除了通过CD3ζ引发的初级信号以外,通过插入人类CAR中的人类共刺激性受体提供的额外信号对于NK细胞的完全活化具有重要性且可以帮助改良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经构建具有针对特定抗原(或标记物或配体)的特异性,所述特定抗原诸如在待由过继疗法靶向的特定细胞类型中表达的抗原,例如癌症标记物,和/或意欲诱导抑制反应的抗原,诸如在正常或非病变细胞类型上表达的抗原。因此,CAR在其细胞外部分中通常包含一种或多种抗原结合分子,诸如一种或多种抗原结合片段、结构域或部分,或一种或多种抗体可变结构域和/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(其可称为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。抗原包括通过模式识别受体(诸如Dectin-1)识别的碳水化合物抗原。肿瘤相关抗原可以是任何种类的,只要其在肿瘤细胞的细胞表面上表达。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p53、突变ras等等。在某些实施方案中,当存在低量的肿瘤相关抗原时,CAR可以与细胞因子共表达以改良持久性。例如,CAR可与IL-15共表达。
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,或可以经合成(例如经由PCR合成),或其组合。取决于基因组DNA的尺寸和内含子的数目,可能需要使用cDNA或其组合,原因在于:发现内含子使mRNA稳定。此外,可进一步有利地使用内源性或外源性非编码区来使mRNA稳定。
预期嵌合构建体可以作为裸DNA或在合适的载体中引入至免疫细胞中。通过电穿孔使用裸DNA稳定转染细胞的方法为本领域中已知的。参见例如美国专利号6,410,319。裸DNA一般指编码嵌合受体的DNA,该嵌合受体以对于表达适当的定向包含在质粒表达载体中。
备选地,病毒载体(例如反转录病毒载体、腺病毒载体、腺相关病毒载体或慢病毒载体)可以用于将嵌合构建体引入至免疫细胞中。根据本发明方法使用的适合的载体在免疫细胞中是非复制的。已知大量载体系基于病毒,其中维持在细胞中的病毒的拷贝数足够低以维持细胞活力,诸如例如基于HIV、SV40、EBV、HSV或BPV的载体。
在一些方面中,抗原特异性结合或识别组分连接至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包括融合至CAR的细胞外结构域的跨膜结构域。在一个实施方案中,使用与CAR中的一个结构域天然缔合的跨膜结构域。在一些情况下,跨膜结构域经选择或由氨基酸取代修饰以避免此类结构域结合至相同或不同表面膜蛋白质的跨膜结构域,以使与受体复合物的其他成员的相互作用降至最低。
在一些实施方案中,跨膜结构域来源于天然或合成来源。在天然来源的情况下,在一些方面中,结构域来源于任何膜结合的蛋白或跨膜蛋白。跨膜区包括来源于以下(即,至少包含以下的一个或多个跨膜区)的那些:T细胞受体的α、β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,跨膜结构域为合成的。在一些方面中,合成性跨膜结构域主要包含疏水性残基,诸如亮氨酸和缬氨酸。在一些方面中,将在合成性跨膜结构域的各端处发现苯丙氨酸、色氨酸和缬氨酸的三联体。
在某些实施方案中,本文所揭示的用于遗传修饰免疫细胞(诸如NK细胞)的平台技术包括:(i)使用电穿孔装置(例如核转染仪)的非病毒基因转移,(ii)经由胞内结构域(例如CD28/CD3-ζ、CD137/CD3-ζ或其他组合)传导信号的CAR,(iii)具有可变长度的胞外结构域的CAR,所述胞外结构域将抗原识别结构域连接至细胞表面,以及在一些情况下,(iv)能够稳健地且在数值上扩增CAR+免疫细胞的衍生自K562的人工抗原呈递细胞(aAPC)(Singh等人,2008;Singh等人,2011)。
B.T细胞受体(TCR)
在一些实施方案中,经基因工程改造的抗原受体包括重组TCR和/或从天然存在的T细胞克隆的TCR。“T细胞受体”或“TCR”指含有可变α和β链(也分别称为TCRα和TCRβ)或可变γ和δ链(也分别称为TCRγ和TCRδ)且能够特异性结合已与MHC受体结合的抗原肽的分子。在一些实施方案中,TCR呈αβ形式。
通常,以αβ或γδ形式存在的TCR一般在结构上是相似的,但是表达它们的T细胞可以具有不同的解剖位置或功能。TCR可存在于细胞表面上或以可溶性形式存在。一般而言,TCR存在于一般负责识别与主要组织相容性复合体(MHC)分子结合的抗原的T细胞(或T淋巴细胞)的表面上。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/或短胞质尾区(参见例如Janeway等人,1997)。例如,在一些方面中,TCR的各链可具有一个N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C端末端处的短胞质尾区。在一些实施方案中,TCR与参与调控信号转导的CD3复合物的恒定蛋白相缔合。除非另外说明,否则术语“TCR”应理解为涵盖其功能性TCR片段。该术语还涵盖完整或全长TCR,包括呈αβ形式或γδ形式的TCR。
因此,出于本发明的目的,提及TCR包括任何TCR或功能性片段,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。可互换使用的TCR的“抗原结合部分”或“原结合片段”是指含有TCR的结构性结构域的一部分但结合完全TCR所结合的抗原(例如MHC-肽复合物)的分子。在一些情况下,抗原结合部分含有TCR的可变结构域,诸如TCR的可变α链和可变β链,其足以形成结合位点用于结合至特异性MHC-肽复合物,诸如其中一般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以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分子的结合位点赋予抗原识别且决定肽特异性,并且决定肽特异性。通常,如免疫球蛋白,CDR由框架区(FR)分隔(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是负责识别经处理抗原的主要CDR,尽管α链的CDR1也已显示与抗原肽的N端部分相互作用,而β链的CDR1与肽的C端部分相互作用。认为CDR2识别MHC分子。在一些实施方案中,β链的可变区可含有另一高变(HV4)区。
在一些实施方案中,所述TCR链含有恒定结构域。例如,与免疫球蛋白类似,TCR链(例如,α-链、β-链)的细胞外部分可以含有两个免疫球蛋白结构域、一个在N端的可变结构域(例如,Va或Vp;通常是基于Kabat编号的氨基酸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)、以及一个与细胞膜相邻的恒定结构域(例如,α链恒定结构域或Ca,通常是基于Kabat的氨基酸117-259;β-链恒定结构域或Cp,通常是基于Kabat的氨基酸117-295)。例如,在某些情况下,由两条链形成的TCR的细胞外部分含有两个近膜端恒定结构域和两个含有CDR的远膜端可变结构域。TCR结构域的恒定结构域含有短连接序列,其中半胱氨酸残基形成二硫键,在两条链之间形成连接。在一些实施方案中,TCR可以具有在α链和β链的每一个中的额外半胱氨酸残基,使得TCR在恒定结构域中含有两个二硫键。
在一些实施方案中,所述TCR链可以含有一个跨膜结构域。在一些实施方案中,所述跨膜结构域是带正电荷的。在一些情况下,所述TCR链含有一个细胞质尾区。在一些情况下,所述结构允许TCR与其他分子(如CD3)结合。例如,含有具有跨膜区的恒定结构域的TCR可以将蛋白锚定在细胞膜中并与CD3信号传导器(apparatus)或复合物的恒定亚基结合。
一般来说,CD3是可以具有三条不同链(γ、δ和ε)(在哺乳动物中)和ζ链的多蛋白复合物。例如,在哺乳动物中,所述复合物可以含有一个CD3γ链、一个CD3δ链、两个CD3ε链以及CD3ζ链的同源二聚体。CD3γ、CD3δ和CD3ε链是含有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细胞受体链结合的特征。CD3γ、CD3δ和CD3ε链的胞内尾区各自含有单个保守基序(称为基于免疫受体酪氨酸的活化基序或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传送到细胞中发挥作用。CD3链和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,所述TCR可以是两条链α和β(或任选地γ和δ)的异源二聚体,或者它可以是单链TCR构建体。在一些实施方案中,所述TCR是含有例如通过一个或更多个二硫键连接的两条独立链(α和β链或γ和δ链)的异源二聚体。在一些实施方案中,鉴定针对靶抗原(例如癌症抗原)的TCR并将其引入细胞中。在一些实施方案中,编码TCR的核酸可从多种来源获得,例如通过公众可得到的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,例如获自细胞,例如获自T细胞(例如细胞毒性T细胞)、T细胞杂交瘤或其他公众可获得的来源。在一些实施方案中,T细胞可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)工程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,噬菌体展示用于分离针对靶抗原的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根据TCR序列的知识合成地产生。
C.抗原
在由经遗传工程改造的抗原受体靶向的抗原中的是在待通过过继细胞疗法靶向的疾病、病状或细胞类型的情形下表达的那些抗原。在疾病和病状中的是增殖性、赘生性和恶性疾病和病症,包括癌症和肿瘤,包括血液癌、免疫系统癌症,例如淋巴瘤、白血病和/或骨髓瘤,例如B、T和骨髓白血病、淋巴瘤和多发性骨髓瘤。在一些实施方案中,相比于正常或非靶向细胞或组织,抗原选择性地表达或过表达在疾病或病状的细胞(例如肿瘤或病原性细胞)上。在其他实施方案中,抗原表达在正常细胞上和/或表达在经工程改造的细胞上。
任何合适的抗原可用于本发明的方法中。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抗原(Linnemann等人,2015)。在特定方面中,抗原包括NY-ESO、EGFRvIII、Muc-1、Her2、CA-125、WT-1、Mage-A3、Mage-A4、Mage-A10、TRAIL/DR4和CEA。在特定方面中,两种或更多种抗原受体的抗原包括但不限于CD19、EBNA、WT1、CD123、NY-ESO、EGFRvIII、MUC1、HER2、CA-125、WT1、Mage-A3、Mage-A4、Mage-A10、TRAIL/DR4和/或CEA。这些抗原的序列在本领域中已知的,例如(均为登录号):CD19(登录号NG_007275.1)、EBNA(登录号NG_002392.2)、WT1(登录号NG_009272.1)、CD123(登录号NC_000023.11)、NY-ESO(登录号NC_000023.11)、EGFRvIII(登录号NG_007726.3)、MUC1(登录号NG_029383.1)、HER2(登录号NG_007503.1)、CA-125(登录号NG_055257.1)、WT1(登录号NG_009272.1)、Mage-A3(登录号NG_013244.1)、Mage-A4(登录号NG_013245.1)、Mage-A10(登录号NC_000023.11)、TRAIL/DR4(登录号NC_000003.12)和/或CEA(登录号NC_000019.10)。
肿瘤相关抗原可衍生自前列腺癌、乳腺癌、结肠直肠癌、肺癌、胰腺癌、肾癌、间皮瘤癌症、卵巢癌或黑素瘤癌症。示例性肿瘤相关抗原或肿瘤细胞衍生抗原包括MAGE1、3和MAGE4(或其他MAGE抗原,例如国际专利公开号WO99/40188中所公开的那些MAGE抗原);PRAME;BAGE;RAGE,Lage(还称为NY ESO 1);SAGE;和HAGE或GAGE。肿瘤抗原的这些非限制性实例表达于广泛的肿瘤类型,例如黑素瘤、肺癌、肉瘤和膀胱癌中。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,肿瘤抗原可为自身肽激素,例如全长促性腺激素释放激素(GnRH),一种用于治疗多种癌症的长度为10个氨基酸的短肽。
肿瘤抗原包括衍生自特征在于肿瘤相关抗原表达,例如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,例如黑素细胞-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质。举例说明性肿瘤相关抗原包括但不限于衍生自或包含以下中的任何一个或多个的肿瘤抗原:p53、Ras、c-Myc、细胞质丝氨酸/苏氨酸激酶(例如A-Raf、B-Raf和C-Raf、细胞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、BAGE、DAM-6、-10、GAGE-1、-2、-8、GAGE-3、-4、-5、-6、-7B、NA88-A、MART-1、MC1R、Gp100、PSA、PSM、酪氨酸酶、TRP-1、TRP-2、ART-4、CAMEL、CEA、Cyp-B、hTERT、hTRT、iCE、MUC1、MUC2、磷酸肌醇3-激酶(PI3K)、TRK受体、PRAME、P15、RU1、RU2、SART-1、SART-3、Wilms肿瘤抗原(WT1)、AFP、-连环蛋白/m、胱天蛋白酶-8/m、CEA、CDK-4/m、ELF2M、GnT-V、G250、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蛋白1(TACSTD1)TACSTD2、受体酪氨酸激酶(例如表皮生长因子受体(EGFR)(特别地,EGFRvIII)、血小板衍生生长因子受体(PDGFR)、血管内皮生长因子受体(VEGFR))、细胞质酪氨酸激酶(例如src-家族、syk-ZAP70家族)、整联蛋白连接激酶(ILK)、转录的信号转导蛋白和活化因子STAT3、STATS和STATE、低氧诱导因子(例如HIF-1和HIF-2)、核因子-κB(NF-B)、Notch受体(例如Notch1-4)、c-Met、雷帕霉素的哺乳动物靶标(mTOR)、WNT、细胞外信号调节激酶(ERK)和其调节亚基、PMSA、PR-3、MDM2、间皮素、肾细胞癌-5T4、SM22-α、碳酸酐酶I(CAI)和IX(CAIX)(还称为G250)、STEAD、TEL/AML1、GD2、蛋白酶3、hTERT、肉瘤移位断点、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、聚唾液酸、MYCN、RhoC、GD3、岩藻糖基GM1、间皮素(mesothelian)、PSCA、sLe、PLAC1、GM3、BORIS、Tn、GLoboH、NY-BR-1、RGsS、SART3、STn、PAX5、OY-TES1、精子蛋白17、LCK、HMWMAA、AKAP-4、SSX2、XAGE 1、B7H3、豆荚蛋白、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、LRRN1和个体基因型(idiotype)。
抗原可包括表位区或表位肽,其衍生自肿瘤细胞中突变的基因或衍生自相比于正常细胞在肿瘤细胞中以不同水平转录的基因,例如端粒酶、存活素、间皮素、突变ras、bcr/ab1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,例如N-乙酰氨基葡萄糖转移酶-V;在骨髓瘤和B细胞淋巴瘤中产生独特个体基因型的免疫球蛋白基因的克隆重排;包括衍生自肿瘤病毒过程的表位区或表位肽的肿瘤抗原,例如人类乳头状瘤病毒蛋白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,例如癌胚抗原和甲胎蛋白。
在其他实施方案中,抗原获自或衍生自病原性微生物或机会性病原性微生物(在本文中还称作传染病微生物),例如病毒、真菌、寄生物和细菌。在某些实施方案中,衍生自此类微生物的抗原包括全长蛋白质。
其抗原预期用于本文所述的方法的举例说明性病原性生物体包括人类免疫缺陷病毒(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)、A型、B型和C型流感、水泡性口炎病毒(VSV)、水泡性口炎病毒(VSV)、多瘤病毒(例如BK病毒和JC病毒)、腺病毒、包括抗甲氧西林金黄色葡萄球菌(Methicillin-resistantStaphylococcus aureus,MRSA)的葡萄球菌属(Staphylococcus)物种和包括肺炎链球菌(Streptococcus pneumoniae)的链球菌属(Streptococcus)物种。如本领域技术人员将理解的,衍生自这些和其他病原性微生物、用作如本文所描述的抗原的蛋白质和编码蛋白质的核苷酸序列可在出版物和公开数据库例如SWISS-和中确定。
衍生自人类免疫缺陷病毒(HIV)的抗原包括以下中的任一个:HIV病毒粒子结构蛋白(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。
衍生自单纯疱疹病毒(例如HSV1和HSV2)的抗原包括但不限于表达自HSV晚期基因的蛋白质。晚期基因的组主要编码形成病毒粒子的蛋白质。此类蛋白质包括形成病毒衣壳的五种蛋白质(UL):UL6、UL18、UL35、UL38和主要衣壳蛋白UL19、UL45和UL27,其中每一个可用作如本文所述的抗原。预期用作本文中的抗原的其他示例性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,各自编码可潜在地用作抗原的蛋白质。
衍生自巨细胞病毒(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。如本领域技术人员应该理解的,用作本文所述的抗原的CMV蛋白质可在公开数据库,例如SWISS-和中确定(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的衍生自埃巴病毒(Epstein-Ban virus,EBV)的抗原包括EBV溶解蛋白gp350和gp110、在潜伏周期感染期间产生的EBV蛋白,包括埃巴核抗原(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)。
预期用于本文中的衍生自呼吸道合胞病毒(RSV)的抗原包括由RSV基因组编码的十一种蛋白质或其抗原性片段中的任一个:NS1、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。
预期使用的衍生自水泡性口炎病毒(VSV)的抗原包括由VSV基因组编码的五种主要蛋白和其抗原性片段中的任一个: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)。
预期用于某些实施方案的衍生自流感病毒的抗原包括血凝素(HA)、神经氨酸苷酶(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、犬瘟热病毒多肽、埃博拉病毒多肽、肠病毒多肽、黄病毒多肽、肝炎病毒(AE)多肽(乙型型肝炎核心或表面抗原、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苷酶多肽)、副粘病毒多肽、细小病毒多肽、瘟病毒多肽、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、反转录病毒多肽和轮状病毒多肽。
在某些实施方案中,抗原可为细菌抗原。在某些实施方案中,感兴趣的细菌抗原可为分泌的多肽。在其他某些实施方案中,细菌抗原包括使多肽的一个或多个部分暴露于细菌的外细胞表面上的抗原。
预期使用的衍生自葡萄球菌属物种(包括抗甲氧西林金黄色葡萄球菌(MRSA))的抗原包括毒性调节子,例如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。可充当抗原的其他葡萄球菌蛋白质包括C1p蛋白质、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)。金黄色葡萄球菌的两个物种(N315和Mu50)的基因组已测序并且公开可用,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,用作抗原的葡萄球菌蛋白质还可在其他公开数据库例如Swiss-和中确定。
预期用于本文所述的某些实施方案的衍生自肺炎链球菌的抗原包括肺炎链球菌溶血素、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质也是本领域中已知的并且可在一些实施方案中用作抗原(参见例如Zysk等人,2000)。肺炎链球菌的毒性菌株的完整基因组序列已测序,并且如本领域技术人员应理解的,本文中所用的肺炎链球菌蛋白质还可在其他公开数据库例如SWISS-和中确定。用于根据本公开内容的抗原的尤其感兴趣的蛋白质包括预测暴露于肺炎双球菌表面的毒性因子和蛋白质(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、鲍特氏菌(Bordetella)多肽、巴尔通体(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、嗜二氧化碳噬细胞菌(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、埃利希体(Ehrlichia)多肽、埃希菌(Escherichia)多肽、弗朗西斯氏菌(Francisella)多肽、梭杆菌(Fusobacterium)多肽、血巴通氏体(Haemobartonella)多肽、嗜血杆菌(Haemophilus)多肽(例如b型流感嗜血杆菌外膜蛋白质)、螺旋杆菌(Helicobacter)多肽、克雷伯氏菌(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、奈瑟氏菌(Neisseria)多肽、新立克次体(Neorickettsia)多肽、诺卡氏菌(Nocardia)多肽、巴氏杆菌(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)(参见本文描述)、变形杆菌(Proteus)多肽、假单胞菌(Pseudomonas)多肽、立克次体(Rickettsia)多肽、罗克利马体(Rochalimaea)多肽、沙门氏菌(Salmonella)多肽、志贺菌(Shigella)多肽、葡萄球菌(Staphylococcus)多肽、A组链球菌(Streptococcus)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)多肽和耶尔森菌(Yersinia)多肽(例如鼠疫耶尔森菌(Y pestis)F1和V抗原)。
真菌抗原的实例包括但不限于犁头霉(Absidia)多肽、枝顶孢(Acremonium)多肽、交链孢(Alternaria)多肽、曲霉菌(Aspergillus)多肽、蛙粪霉菌(Basidiobolus)多肽、离蠕孢(Bipolaris)多肽、芽生菌(Blastomyces)多肽、念珠菌(Candida)多肽、球孢子菌(Coccidioides)多肽、耳霉(Conidiobolus)多肽、隐球菌(Cryptococcus)多肽、弯孢霉(Curvalaria)多肽、表皮癣菌(Epidermophyton)多肽、外瓶霉(Exophiala)多肽、地丝菌(Geotrichum)多肽、组织胞浆菌(Histoplasma)多肽、马杜拉分支菌(Madurella)多肽、马拉色菌(Malassezia)多肽、小孢子菌(Microsporum)多肽、丛梗孢(Moniliella)多肽、被孢霉(Mortierella)多肽、毛霉菌(Mucor)多肽、拟青霉菌(Paecilomyces)多肽、青霉菌(Penicillium)多肽、单胞瓶霉(Phialemonium)多肽、瓶霉(Phialophora)多肽、原壁菌(Prototheca)多肽、假霉样真菌(Pseudallescheria)多肽、假微座孢(Pseudomicrodochium)多肽、腐霉菌(Pythium)多肽、鼻孢子菌(Rhinosporidium)多肽、根霉菌(Rhizopus)多肽、齿梗孢(Scolecobasidium)多肽、孢子丝菌(Sporothrix)多肽、匍柄霉(Stemphylium)多肽、毛癣菌(Trichophyton)多肽、毛孢子菌(Trichosporon)多肽和木丝霉(Xylohypha)多肽。
原生动物寄生虫抗原的实例包括但不限于巴倍虫(Babesia)多肽、肠袋虫(Balantidium)多肽、贝诺虫(Besnoitia)多肽、隐胞子虫(Cryptosporidium)多肽、艾美球虫(Eimeria)多肽、脑胞内原虫(Encephalitozoon)多肽、内阿米巴(Entamoeba)多肽、梨形鞭毛虫(Giardia)多肽、哈蒙德虫(Hammondia)多肽、肝簇虫(Hepatozoon)多肽、等孢子球虫(lsospora)多肽、利什曼原虫(Leishmania)多肽、微孢子虫(Microsporidia)多肽、新孢子虫(Neospora)多肽、小孢子虫(Nosema)多肽、五鞭毛滴虫(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、血管圆线虫(Angiostrongylus)多肽、蛔虫(Ascaris)多肽、布鲁丝线虫(Brugia)多肽、仰口线虫(Bunostomum)多肽、毛细线虫(Capillaria)多肽、夏氏线虫(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、棘唇线虫(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、罗阿丝虫(Loa)多肽、曼森线虫(Mansonella)多肽、米勒线虫(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、旋尾线虫(Spirocerca)多肽、迭宫绦虫(Spirometra)多肽、冠丝虫(Stephanofilaria)多肽、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)环孢子(PfCSP))、孢子体表面蛋白2(PfSSP2)、肝状态抗原l的羧基末端(PfLSAl c-端)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、泰累尔梨浆虫(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;苍蝇,例如蠓、蚊子、白蛉、黑蝇、马蝇、角蝇、鹿蝇、采采蝇、螫蝇、引起蝇蛆病的蝇和库蠓;蚂蚁;蜘蛛,虱子;螨虫;以及蝽类(true bug),例如床虱和猎蝽。
D.自杀基因
本公开内容的免疫细胞的CAR可包含一种或多种自杀基因。如本文所用,术语“自杀基因”定义为在施用前药时实现基因产物向杀死其宿主细胞的化合物的转变的基因。可使用的自杀基因/前药组合的实例为单纯疱疹病毒-胸苷激酶(HSV-tk)和更昔洛韦、阿昔洛韦或FIAU;氧化还原酶和环己酰亚胺;胞嘧啶脱氨酶和5-氟胞嘧啶;胸苷激酶胸苷酸激酶(Tdk::Tmk)和AZT;和脱氧胞苷激酶和胞嘧啶阿拉伯糖苷。
可使用大肠杆菌(E.coli)嘌呤核苷磷酸化酶,一种所谓的自杀基因,其将前药6-甲基嘌呤脱氧核糖苷转化为有毒嘌呤6-甲基嘌呤。与前药疗法一起使用的自杀基因的其他实例是大肠杆菌胞嘧啶脱氨酶基因和HSV胸苷激酶基因。
示例性自杀基因包括CD20、CD52、EGFRv3或诱导性胱天蛋白酶9。在一个实施方案中,EGFR变体III(EGFRv3)的截短形式可用作可通过西妥昔单抗(Cetuximab)切除的自杀抗原。可用于本公开内容中的本领域已知的其他自杀基因包括:嘌呤核苷磷酸化酶(PNP)、细胞色素p450酶(CYP)、羧肽酶(CP)、羧酸酯酶(CE)、硝基还原酶(NTR)、鸟嘌呤核糖基转移酶(XGRTP)、糖苷酶、甲硫氨酸-α,γ-裂解酶(MET)和胸苷磷酸化酶(TP)。
E.递送方法
本领域技术人员将有能力通过标准重组技术(例如参见Sambrook等人,2001和Ausubel等人,1996)构建载体用于表达本公开内容的抗原受体。载体包括但不限于:质粒、黏粒、病毒(噬菌体、动物病毒和植物病毒)和人工染色体(例如,YAC),诸如反转录病毒载体(例如,来源于莫罗尼鼠类白血病病毒载体(MoMLV)、MSCV、SFFV、MPSV、SNV等的载体)、慢病毒载体(例如,来源于HIV-1、HIV-2、SIV、BIV、FIV等的载体)、腺病毒(Ad)载体(包括其复制胜任形式、复制缺陷形式和无肠形式)、腺相关病毒(AAV)载体、猴病毒40(SV-40)载体、牛乳头瘤病毒载体、埃巴病毒载体、疱疹病毒载体、牛痘病毒载体、哈维鼠肉瘤病毒(Harveymurine sarcoma virus)载体、鼠类乳房肿瘤病毒载体、劳斯肉瘤病毒(Rous sarcomavirus)载体、小病毒载体、脊髓灰质炎病毒载体、水泡性口炎病毒载体、maraba病毒载体和B组腺病毒enadenotucirev载体。
a.病毒载体
本发明的某些方面中可提供编码抗原受体的病毒载体。在生成重组病毒载体时,通常用异源(或非天然)蛋白质的基因或编码序列来替换非必需基因。病毒载体是利用病毒序列将核酸且有可能将蛋白质引入细胞中的一类表达构建体。某些病毒经由受体介导的内吞作用感染细胞或进入细胞并整合至宿主细胞基因组中并且稳定且有效表达病毒基因的能力使其成为用于将外源核酸转移至细胞(例如,哺乳动物细胞)中的有吸引力的候选者。下文描述可用于递送本发明的某些方面的核酸的病毒载体的非限制性实例。
慢病毒为复合反转录病毒,除常见反转录病毒基因gag、pol和env以外,慢病毒还含有其他具有调节或结构性功能的基因。慢病毒载体在本领域中是熟知的(参见例如美国专利6,013,516和5,994,136)。
重组慢病毒载体能够感染非分裂细胞,且可用于体内和体外基因转移以及核酸序列表达。例如,美国专利5,994,136中描述了能够感染非分裂细胞的重组慢病毒,其中适合的宿主细胞经两个或更多个具有包装功能(即gag、pol和env以及rev和tat)的载体转染,该专利通过引用并入本文中。
b.调节元件
包括在适用于本发明的载体中的表达盒尤其含有(在5’至3’方向上)可操作地连接于蛋白质编码序列的真核转录启动子、包括间隔序列的剪接信号和转录终止/聚腺苷酸化序列。控制真核细胞中的蛋白质编码基因的转录的启动子和增强子由多个基因元件构成。细胞机构能够聚集和整合由各元件输送的调节信息,从而允许不同基因进化不同的、通常为复合的转录调节模式。在本发明的上下文中所使用的启动子包括组成型、诱导型及组织特异型启动子。
(i)启动子/增强子
本文所提供的表达构建体包含驱动抗原受体表达的启动子。启动子一般包含用于定位RNA合成的起始位点的序列。其最佳已知实例为TATA盒,但在一些缺乏TATA盒的启动子,诸如哺乳动物末端脱氧核苷酸转移酶基因的启动子和SV40晚期基因的启动子中,叠加起始位点本身的离散元件有助于固定起始的位置。额外启动子元件调节转录起始频率。通常,这些元件位于起始位点上游30110bp区中,但许多启动子已显示也含有起始位点下游的功能元件。为使编码序列“处在启动子控制下”,将转录阅读框的转录起始位点的5’端置于所选择的启动子的“下游”(即3’端)。“上游”启动子刺激DNA的转录且促进所编码RNA的表达。
启动子元件之间的间距通常是灵活的,使得当元件相对彼此倒置或移动时保留启动子功能。在tk启动子中,启动子元件之间的间距可在活性开始下降前增加至相隔50bp。取决于启动子,个别元件似乎可以合作地或独立地起活化转录作用。启动子可以或可以不与“增强子”结合使用,增强子指参与核酸序列的转录活化的顺式作用调节序列。
启动子可为天然与核酸序列缔合的一种启动子,如可通过分离位于编码区段和/或外显子上游的5’非编码序列获得。此类启动子可称为“内源的”。类似地,增强子可为天然与核酸序列缔合、位于该序列下游或上游的一种增强子。备选地,某些优势将通过将编码核酸区段置于重组或异源启动子控制下来获得,重组或异源启动子指在其天然环境中通常不与核酸序列缔合的启动子。重组或异源增强子也指在其天然环境中通常不与核酸序列缔合的增强子。此类启动子或增强子可包括其他基因的启动子或增强子,以及自任何其他病毒或原核或真核细胞分离的启动子或增强子,和非“天然存在的”启动子或增强子,即含有不同转录调节区的不同元件和/或改变表达的突变。例如,最常用于重组DNA构建的启动子包括β内酰胺酶(青霉素酶)、乳糖及色氨酸(trp-)启动子系统。除合成地产生启动子和增强子的核酸序列以外,可结合本文所公开的组合物使用重组克隆和/或核酸扩增技术(包括PCRTM)产生序列。此外,预期也可以采用引导非核细胞器(诸如粒线体、叶绿体等)内的序列的转录和/或表达的控制序列。
自然地,使用有效引导在选择用于表达的细胞器、细胞类型、组织、器官或生物体中的DNA区段的表达的启动子和/或增强子将是重要的。分子生物学领域的技术人员一般知晓使用启动子、增强子和细胞型组合进行蛋白质表达(参见例如Sambrook等人,1989,其通过引用并入本文中)。所用启动子可以是组成型的、组织特异型的、诱导型的和/或适用于在适当条件下引导所引入的DNA区段的高水平表达,诸如在重组蛋白质和/或肽的大规模产生方面有利。启动子可以是异源的或内源的。
另外,任何启动子/增强子组合(根据例如真核启动子数据库(EukaryoticPromoter Data Base,EPDB),通过万维网epd.isb-sib.ch/访问)也可用于驱动表达。使用T3、T7或SP6细胞质表达系统是另一个可能的实施方案。如果提供适当的细菌聚合酶(作为递送复合物的一部分或作为额外的基因表达构建体),则真核细胞可以支持从某些细菌启动子的细胞质转录。
启动子的非限制性实例包括早期或晚期病毒启动子,诸如SV40早期或晚期启动子、巨细胞病毒(CMV)即时早期启动子、劳斯肉瘤病毒(RSV)早期启动子;真核细胞启动子,诸如β肌动蛋白启动子、GADPH启动子、金属硫蛋白启动子;和串联的反应元件启动子,诸如环状AMP反应元件启动子(cre)、血清反应元件启动子(sre)、佛波醇酯启动子(TPA)和靠近最小TATA盒的反应元件启动子(tre)。也有可能使用人类生长激素启动子序列(例如Genbank登录号X05244,核苷酸283-341所描述的人类生长激素最小启动子)或小鼠乳房肿瘤启动子(可购自ATCC,目录号ATCC 45007)。在某些实施方案中,启动子为CMV IE、dectin-1、dectin-2、人类CD11c、F4/80、SM22、RSV、SV40、Ad MLP、β-肌动蛋白、MHC I类或MHC II类启动子,然而适用于驱动治疗性基因表达的任何其他启动子可以适用于实施本发明。
在某些方面中,本发明的方法亦还涉及增强子序列,即增加启动子活性且具有以顺式方式起作用的潜能的核酸序列,且不考虑核酸序列的方向,甚至跨越相对较长距离(与靶启动子相距多达几千个碱基)。然而,增强子功能不一定受限于这样长的距离,因为其也可非常接近所给定的启动子起作用。
(ii)起始信号和连接表达
特定起始信号也可用于本发明中所提供的表达构建体中用以编码序列的有效翻译。这些信号包括ATG起始密码子或相邻序列。可能需要提供包括ATG起始密码子的外源性翻译控制信号。本领域普通技术人员将容易地能够判定此情形且提供必需的信号。熟知起始密码子必须在所要编码序列的阅读框的“框内”,以确保整个插入物的翻译。外源性翻译控制信号和起始密码子可为天然或合成的。表达效率可通过包括适当转录增强子元件来增强。
在某些实施方案中,使用内部核糖体进入位点(IRES)元件的用途产生多基因或多顺反子信息。IRES元件能够绕过5’甲基化封端依赖性翻译的核糖体扫描模型且在内部位点开始翻译。已描述来自小核糖核酸病毒家族的两个成员(脊髓灰质炎和脑心肌炎)的IRES元件以及来自哺乳动物信息的IRES。IRES元件可连接至异源开放阅读框。多个开放阅读框可转录在一起,各自通过IRES分隔,产生多顺反子信息。借助于IRES元件,各开放阅读框可接近核糖体以便有效翻译。可以使用单一启动子/增强子转录单一信息来有效表达多个基因。
另外,某些2A序列元件可用于在本发明中所提供的构建体中产生基因的连接表达或共表达。例如,裂解序列可用于通过连接开放阅读框以形成单一顺反子来共表达基因。示例性裂解序列为F2A(口蹄疫病毒2A)或“2A样”序列(例如,Thosea asigna病毒2A;T2A)。
(iii)复制起点
为了在宿主细胞中繁殖载体,其可含有一个或多个复制位点起点(常常称为“ori”),例如,对应于如上文所描述的EBV的oriP,或在程序化中具有类似或提高功能的经基因工程改造的oriP的核酸序列,其为复制起始的特定核酸序列。备选地,可以采用如上文所述的其他染色体外复制病毒或自主复制序列(ARS)的复制起点。
c.选择和可筛选标记物
在一些实施方案中,含有本发明的构建体的细胞可通过在表达载体中包括标记物进行体外或体内鉴别。此类标记物将赋予细胞可鉴别的变化,允许容易地鉴别含有所述表达载体的细胞。一般而言,选择标记物是赋予允许选择的特性的一种标记物。阳性选择标记物是该标记物的存在允许其选择的一种标记物,而阴性选择标记物是其存在阻止其选择的一种标记物。阳性选择标记物的实例为抗药性标记物。
通常包含药物选择标记物有助于克隆和鉴定转化体,例如,赋予对新霉素、嘌呤霉素、潮霉素、DHFR、GPT、博来霉素(zeocin)和组氨醇的抗性的基因是有用的选择标记物。除了赋予允许基于条件的实施区分转化体的表型的标记物之外,还预期了其他类型的标记物,包括可筛选标记物,例如以比色分析为基础的GFP。备选地,可以使用可筛选的酶作为阴性选择标记物,例如单纯疱疹病毒胸苷激酶(tk)或氯霉素乙酰转移酶(CAT)。本领域技术人员还知晓如何使用免疫标记物,可能与FACS分析结合使用。所使用的标记物被认为并不重要,只要它能够与编码基因产物的核酸同时表达即可。选择和可筛选标记物的其他例子是本领域技术人员公知的。
d.核酸递送的其他方法
除病毒递送编码抗原受体的核酸以外,以下为将重组基因递送至给定宿主细胞的其他方法,且由此被视为在本发明中。
如本文所描述或如本领域普通技术人所知晓的,可使用任何适合的用于转化细胞的核酸递送方法来将诸如DNA或RNA的核酸引入本发明的免疫细胞中。此类方法包括但不限于:直接递送DNA,诸如通过离体转染、通过注射,包括显微注射;通过电穿孔;通过磷酸钙沈淀;通过使用DEAE-葡聚糖接着使用聚乙二醇;通过直接音波加载;通过脂质体介导的转染和受体介导的转染;通过微弹轰击;通过与碳化硅纤维一起进行搅拌;通过农杆菌介导的转化;通过干化/抑制介导的DNA摄取;以及这些方法的任何组合。经由应用诸如这些方法的技术,可以稳定或暂时地转化细胞器、细胞、组织或生物体。
IV.治疗方法
本发明方法可有助于从脐带血或外周血产生大量高度功能性NK细胞,以用于NK细胞免疫疗法。本发明方法也可用于增强CAR-NK细胞疗法的功能性。由此,本文提供用于治疗疾病的方法,其通过过继输注仅NK细胞或NK细胞与单克隆、双特异性和三特异性抗体的组合,所述抗体结合CD16或NK细胞上的其他受体且将细胞重新导向至靶标,从而增加针对不同肿瘤的反应。
在一些实施方案中,本公开内容提供用于免疫疗法的方法,其包括施用有效量的本公开内容的NK细胞,在一些实施方案中,医学疾病或病症通过转移引发免疫反应的NK细胞群体来治疗。在本公开内容的某些实施方案中,癌症或感染通过转移引发免疫反应的NK细胞群体来治疗。本文提供用于治疗个体的癌症或延缓其进展的方法,其包括向个体施用有效量的NK细胞疗法。本发明的方法可以应用于治疗免疫病症、实体癌症、血液癌症和病毒感染。
本发明的治疗方法适用的肿瘤包括任何恶性细胞类型,诸如发现于实体肿瘤或血液肿瘤中的那些恶性细胞。示例性实体肿瘤可以包括但不限于选自由以下组成的组的器官的肿瘤:胰脏、结肠、盲肠、胃、大脑、头部、颈部、卵巢、肾、喉、肉瘤、肺、膀胱、黑素瘤、前列腺和乳房。示例性血液肿瘤包括骨髓肿瘤、T细胞或B细胞恶性疾病、白血病、淋巴瘤、母细胞瘤、骨髓瘤等。可使用本文所提供的方法治疗的癌症的其他实例包括但不限于肺癌(包括小细胞肺癌、非小细胞肺癌、肺腺癌及肺鳞状癌)、腹膜癌、胃癌(包括胃肠癌和胃肠基质癌)、胰脏癌、宫颈癌、卵巢癌、肝癌、膀胱癌、乳腺癌、结肠癌、结肠直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌、各种类型的头颈癌和黑素瘤。
所述癌症可具体说来具有以下组织学类型,不过其不限于这些:赘生物,恶性的;癌瘤;癌瘤,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,恶性的;胆管癌;肝细胞癌;联合肝细胞癌与胆管癌;小梁状腺癌;腺样囊性癌;腺瘤性息肉腺癌;腺癌,家族性结肠息肉病;实体癌;类癌瘤,恶性的;细支气管肺泡腺癌;乳头状腺癌;嫌色细胞癌;嗜酸细胞癌;嗜酸性腺癌;嗜碱细胞癌;透明细胞腺癌;粒细胞癌;滤泡状腺癌;乳头状和滤泡状腺癌;无包膜形成的硬化性癌;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,乳房;腺泡细胞癌;腺鳞状上皮癌;腺癌伴鳞状化生;胸腺瘤,恶性的;卵巢间质肿瘤,恶性的;泡膜细胞瘤,恶性的;颗粒细胞瘤,恶性的;睾丸母细胞瘤,恶性的;塞尔托利细胞癌;莱迪希细胞瘤,恶性的;脂质细胞瘤,恶性的;副神经节瘤,恶性的;乳房外副神经节瘤,恶性的;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;雀斑型恶性黑素瘤;肢端雀斑样黑素瘤(acral lentiginous melanomas);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;蓝痣,恶性的;肉瘤;纤维肉瘤;纤维组织细胞瘤,恶性的;粘液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎性横纹肌肉瘤;泡状横纹肌肉瘤;间质性肉瘤;混合肿瘤,恶性的;米勒管混合肿瘤;肾母细胞瘤;肝母细胞瘤;癌肉瘤;间质瘤,恶性的;布伦纳瘤,恶性的;叶状肿瘤,恶性的;滑膜肉瘤;间皮瘤,恶性的;无性细胞瘤;胚胎癌;畸胎瘤,恶性的;卵巢甲状腺瘤,恶性的;绒膜癌;中肾瘤,恶性的;血管肉瘤;血管内皮瘤,恶性;卡波西肉瘤;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;间叶性软骨肉瘤;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;成釉细胞纤维肉瘤;松果体瘤,恶性;脊索瘤;神经胶质瘤,恶性;室鼓膜瘤;星形细胞瘤;原浆性星形细胞瘤;纤维型星形细胞瘤;星形母细胞瘤;成胶质细胞瘤;少突神经胶质瘤;成少突神经胶质细胞瘤;原始神经外胚层;小脑肉瘤;节细胞神经母细胞瘤;神经母细胞瘤;视网膜母细胞瘤;嗅神经源性肿瘤;脑膜瘤,恶性;神经纤维肉瘤;神经鞘瘤,恶性;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,小淋巴细胞性;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氏淋巴瘤;B-细胞淋巴瘤;低级/滤泡性非霍奇金淋巴瘤(NHL);小淋巴细胞性(SL)NHL;中级/滤泡性NHL;中级弥漫性NHL;高级免疫母细胞性NHL;高级淋巴母细胞性NHL;高级小非分裂细胞NHL;大包块病NHL;套细胞淋巴瘤;AIDS-相关的淋巴瘤;Waldenstrom巨球蛋白血症;恶性组织细胞病;多发性骨髓瘤;肥大细胞肉瘤;免疫增生性小肠病;白血病;淋巴性白血病;浆细胞性白血病;红白血病;淋巴肉瘤细胞白血病;骨髓性白血病;嗜碱细胞性白血病;嗜酸粒性白血病;单核细胞性白血病;肥大细胞白血病;巨核母细胞白血病;骨髓肉瘤;毛细胞白血病;慢性淋巴细胞性白血病(CLL);急性淋巴母细胞性白血病(ALL);急性髓性白血病(AML);和慢性髓母细胞性白血病。
特定实施方案涉及白血病的治疗方法。白血病为血液或骨髓癌症且特征在于血细胞(通常白血细胞(白细胞))的异常增殖(倍增产生)。其为称为血液赘瘤的广泛群组的疾病的一部分。白血病为广义术语,涵盖一系列疾病。白血病在临床上及病理上分成其急性和慢性形式。
在本发明的某些实施方案中,NK细胞递送至有需要的个体,诸如患有癌症或感染的个体。随后,细胞增强个体的免疫系统以攻击各个癌细胞或病原性细胞。在一些情况下,向个体提供一次或多次剂量的免疫细胞。在向个体提供两次或更多次剂量的免疫细胞的情况下,施用之间的持续时间应足以允许在个体中繁殖的时间,且在特定实施方案中,剂量的间的持续时间为1、2、3、4、5、6、7天或更多天。
本公开内容的某些实施方案提供治疗或预防免疫调节病症的方法。在一个实施方案中,受试者患有自体免疫疾病。自体免疫疾病的非限制性实例包括:斑秃,强直性脊柱炎,抗磷脂综合征,自身免疫性艾迪生病,肾上腺的自身免疫性疾病,自身免疫性溶血性贫血,自身免疫性肝炎,自身免疫性卵巢炎和睾丸炎,自身免疫性血小板减少症,白塞氏病,大疱性类天疱疮,心肌病,乳糜泻性皮炎(celiac spate-dermatitis),慢性疲劳免疫功能障碍综合症(CFIDS),慢性炎症性脱髓鞘性多发性神经病,Churg-Strauss综合征,瘢痕性类天疱疮,CREST综合征,冷凝集素病,克罗恩病,盘状狼疮,原发性混合性冷球蛋白血症,纤维肌痛-纤维肌炎,肾小球肾炎,格雷夫斯病,格林-巴利病,桥本氏甲状腺炎,特发性肺纤维化,特发性血小板减少性紫癜(ITP),IgA神经病,青少年关节炎,扁平苔藓,红斑性狼疮,美尼尔病,混合性结缔组织病,多发性硬化,1型或免疫介导的糖尿病,重症肌无力,肾病综合征(例如微小病变,局灶性肾小球硬化或膜性肾病),寻常型天疱疮,恶性贫血,结节性多动脉炎,多发性软骨炎,多腺综合征,风湿性多发性肌痛,多发性肌炎和皮肌炎,原发性无丙种球蛋白血症,原发性胆汁性肝硬化,银屑病,银屑病关节炎,雷诺现象,雷特综合症,类风湿性关节炎,结节病,硬皮病,干燥综合征,僵人综合征,系统性红斑狼疮,红斑狼疮,溃疡性结肠炎,葡萄膜炎,血管炎(例如结节性多动脉炎,大动脉炎,颞动脉炎/巨细胞性动脉炎或疱疹样皮炎性血管炎),白癜风和韦格纳肉芽肿病。因此,可以使用本文公开的方法治疗的自身免疫性疾病的一些实例包括但不限于多发性硬化症,类风湿性关节炎,系统性红斑狼疮,I型糖尿病,克罗恩病;溃疡性结肠炎,重症肌无力,肾小球肾炎,强直性脊柱炎,血管炎或银屑病。受试者还可以患有过敏性疾病,例如哮喘。
在另一个实施方案中,受试者是移植的器官或干细胞的接受者,并且NK细胞用于预防和/或治疗排斥。移植物可以是复合移植物,例如面部的组织。NK细胞可以在移植之前、与移植同时或在移植之后施用。在一些实施方案中,NK细胞在移植前施用,例如在移植前至少1小时,至少12小时,至少1天,至少2天,至少3天,至少4天,至少5天,至少6天,至少1周,至少2周,至少3周,至少4周或至少1个月施用。在一个具体的非限制性实例中,治疗有效量的NK细胞的施用在移植前3-5天进行。
在一些实施方案中,可以在NK细胞疗法之前向受试者施用非清髓性淋巴清除性化学疗法(nonmyeloablative lymphodepleting chemotherapy)。非清髓性淋巴清除性化学疗法可以是任何合适的此类疗法,其可以通过任何合适的途径进行施用。非清髓性淋巴清除性化学疗法可包括,例如,施用环磷酰胺和氟达拉滨,特别是如果癌症是黑素瘤(其可以是转移性的)时。施用环磷酰胺和氟达拉滨的示例性途径是静脉内。同样,可以施用任何合适剂量的环磷酰胺和氟达拉滨。在特定方面,施用约60mg/kg的环磷酰胺两天,此后施用约25mg/m2的氟达拉滨五天。
在某些实施方案中,将促进NK细胞的生长和活化的生长因子与NK细胞同时或在NK细胞后施用至受试者。免疫细胞生长因子可以是促进NK细胞的生长和活化的任何合适的生长因子。合适的免疫细胞生长因子的实例包括白介素(IL)-2、IL-7、IL-15和IL-12,它们可以单独使用或以多种组合(例如IL-2和IL-7,IL-2和IL-15,IL-7和IL-15,IL-2、IL-7和IL-15,IL-12和IL-7,IL-12和IL-15或IL-12和IL2)使用。
治疗有效量的NK细胞可以通过多种途径施用,包括肠胃外施用,例如静脉内、腹膜内、肌内、胸骨内或关节内注射或输注。
用于过继细胞疗法的NK细胞的治疗有效量是在被治疗的受试者中达到期望效果的量。例如,这可以是抑制进展或引起自身免疫或同种免疫疾病的消退所必需的或能够缓解由自身免疫疾病引起的症状(例如疼痛和炎症)的NK细胞的量。它可能是缓解与炎症相关的症状(例如疼痛、水肿和体温升高)所必需的量。它也可以是减少或防止移植的器官的排斥所必需的量。
可以以与用于疾病相一致的治疗方案施用NK细胞群体,例如在一到几天内单次或几次剂量以改善疾病状态或在延长的时间内的定期剂量以抑制疾病进展并预防疾病复发。制剂中使用的精确剂量还取决于施用途径以及疾病或病症的严重性,并且应根据从业者的判断和每个患者的情况来决定。NK细胞的治疗有效量将取决于所治疗的受试者、病痛的严重程度和类型以及施用方式。在一些实施方案中,可用于治疗人受试者的剂量范围为至少3.8×104、至少3.8×105、至少3.8×106、至少3.8×107、至少3.8×108、至少3.8×109、或至少3.8×1010个NK细胞/m2。在某些实施方案中,用于治疗人受试者的剂量范围为约3.8×109至约3.8×1010个NK细胞/m2。在另外的实施方案中,NK细胞的治疗有效量可以为约5×106个细胞/kg体重至约7.5×108个细胞/kg体重,例如约2×107个细胞至约5×108个细胞/kg体重,或约5×107个细胞至约2×108个细胞/kg体重。NK细胞的确切数量由本领域技术人员根据受试者的年龄、体重、性别和生理状况来容易地确定。可以从由体外或动物模型测试系统得出的剂量反应曲线外推得出有效剂量。
NK细胞可以与一种或多种其他治疗剂组合施用以治疗免疫介导的病症。组合疗法可包括但不限于一种或多种抗微生物剂(例如,抗生素、抗病毒剂和抗真菌剂),抗肿瘤剂(例如,氟尿嘧啶,甲氨蝶呤,紫杉醇,氟达拉滨,依托泊苷,阿霉素或长春新碱),免疫消耗剂(例如氟达拉滨,依托泊苷,阿霉素或长春新碱),免疫抑制剂(例如,硫唑嘌呤或糖皮质激素,例如地塞米松或泼尼松),抗炎剂(例如,糖皮质激素,例如氢化可的松、地塞米松或泼尼松,或非甾体抗炎剂,例如乙酰水杨酸、布洛芬或萘普生钠),细胞因子(例如白介素10或转化生长因子-β),激素(例如雌激素)或疫苗。另外,可以施用免疫抑制剂或致耐受剂,包括但不限于钙调神经磷酸酶抑制剂(例如,环孢菌素和他克莫司);mTOR抑制剂(例如,雷帕霉素);霉酚酸酯,抗体(例如识别CD3、CD4、CD40、CD154、CD45、IVIG或B细胞);化疗剂(例如,甲氨蝶呤,苏消安,白消安);辐照;或趋化因子,白介素或其抑制剂(例如BAFF,IL-2,抗IL-2R,IL-4,JAK激酶抑制剂)。取决于所需的效果,可以在施用NK细胞之前、期间或之后施用此类另外的药剂。细胞和试剂的这种施用可以通过相同的途径或通过不同的途径,并且可以在相同的部位或在不同的部位施用。
B.药物组合物
本文还提供包含NK细胞和药学上可接受的载剂的药物组合物和制剂。
本文所述的药物组合物和制剂可通过将具有所需纯度的活性成分(例如抗体或多肽)与一种或多种任选的药学上可接受的载剂(Remington's Pharmaceutical Sciences第22版,2012)混合来制备,其呈冻干制剂或水溶液的形式。药学上可接受的载剂通常在所采用的剂量和浓度下对接受者无毒,并且包括但不限于:缓冲液,例如磷酸盐、柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(例如十八烷基二甲基苄基氯化铵;六甲基氯化铵;苯扎氯铵;苄索氯铵;苯酚、丁醇或苄醇;对羟基苯甲酸烷基酯(alkylparaben),例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;邻苯二酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(少于约10个残基)多肽;蛋白质,例如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,例如聚乙烯吡咯烷酮;氨基酸,例如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,例如EDTA;糖,例如蔗糖、甘露醇、海藻糖或山梨糖醇;盐形成抗衡离子(counter-ion),例如钠;金属配合物(例如锌蛋白配合物);和/或非离子表面活性剂,例如聚乙二醇(PEG)。本文的示例性药学上可接受的载剂进一步包括间质药物分散剂,例如可溶性中性活性透明质酸酶糖蛋白(sHASEGP),例如人可溶性PH-20透明质酸酶糖蛋白,例如rHuPH20(Baxter International,Inc.)。某些示例性sHASEGP(包括rHuPH20)和使用方法描述于美国专利公开号2005/0260186和2006/0104968中。一方面,将sHASEGP与一种或多种另外的糖胺聚糖酶例如软骨素酶组合。
C.组合疗法
在某些实施方案中,本实施方案的组合物和方法涉及与至少一种另外的疗法组合的NK细胞群。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、骨髓移植、纳米疗法、单克隆抗体疗法或前述的组合。另外的疗法可以是辅助治疗或新辅助疗法的形式。
在一些实施方案中,另外的疗法是小分子酶抑制剂或抗转移剂的施用。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,例如抗恶心剂等)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路径疗法、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(例如免疫检查点疗法)在之前、期间、之后或以各种组合施用NK细胞疗法。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另外的治疗剂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小时内为患者提供抗体疗法和抗癌疗法。在某些情况下,可能期望将治疗时间显著延长,其中在各自施用之间经过几天(2、3、4、5、6或7天)至几周(1、2、3、4、5、6、7或8周)。
可以采用各种组合。对于下面的实例,NK细胞疗法为“A”,和抗癌疗法为“B”:
A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B
B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A
B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A
考虑到试剂的毒性(如果有的话),本实施方案的任何化合物或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,存在监测归因于组合疗法的毒性的步骤。
1.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”是指使用药物治疗癌症。“化学治疗剂”用于意指在癌症治疗中施用的化合物或组合物。这些试剂或药物通过其在细胞内的活性模式分类,例如其是否并且在哪一阶段影响细胞周期。备选地,试剂可基于其直接交联DNA、插入DNA中或通过影响核酸合成来诱导染色体和有丝分裂失常的能力来表征。
化学治疗剂的实例包括:烷化剂诸如塞替派和环磷酰胺;磺酸烷基酯诸,如白消安、英丙舒凡和哌泊舒凡;氮丙啶类,诸如苯佐替派(benzodopa)、卡波醌、美妥替派(meturedopa)和乌瑞替派(uredopa);乙烯亚胺和甲基蜜胺,包括六甲蜜胺、三亚乙基蜜胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲基蜜胺;番荔枝内酯(acetogenin)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱(包括合成的类似物托泊替康);苔藓抑素;卡利他汀(callystatin);CC-1065(包括它的合成类似物阿多来新、卡泽来新和比泽来新);念珠藻环肽(尤其是念珠藻环肽1和念珠藻环肽8);多拉司他汀;杜卡霉素(包括合成类似物KW-2189和CB1-TM1);软珊瑚醇;水鬼蕉碱(pancratistatin);sarcodictyin;海绵抑素;氮芥类,诸如苯丁酸氮芥、萘氮芥、氯磷酰胺(cholophosphamide)、雌莫司汀、异环磷酰胺、氮芥、盐酸氧化氮芥、美法仑、新氮芥、苯芥胆甾醇、泼尼莫司汀、曲磷胺和乌拉莫司汀;硝基脲类,诸如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀和雷莫司汀;抗生素类,诸如烯二炔抗生素(例如卡奇霉素,尤其是卡奇霉素γlI和卡奇霉素ωI1);达内霉素,包括达内霉素A;二膦酸盐类,诸如氯膦酸盐;埃斯波霉素;以及新制癌菌素生色团和有关的色蛋白烯二炔抗生素生色团、阿克拉霉素(aclacinomysin)、放线菌素、氨茴霉素(authrarnycin)、偶氮丝氨酸、博来霉素、放线菌素C、卡柔比星(carabicin)、洋红霉素、嗜癌霉素、色霉素、更生霉素、柔红霉素、地托比星、6-重氮基-5-氧代-L-正亮氨酸、多柔比星(包括吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉代-多柔比星和脱氧多柔比星)、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素类诸如丝裂霉素C、麦考酚酸、诺拉霉素、橄榄霉素、培洛霉素、泊非霉素(potfiromycin)、嘌罗霉素、三铁阿霉素、罗多比星、链黑霉素、链佐星、杀结核菌素、乌苯美司、净司他丁、佐柔比星;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、蝶罗呤和三甲曲沙;嘌呤类似物,诸如氟达拉滨、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、阿糖胞苷、二脱氧尿苷、去氧氟尿苷、依诺他滨和氟尿苷;雄激素类,诸如卡普睾酮、屈他雄酮丙酸盐、环硫雄醇、美雄烷和睾内酪;抗肾上腺类,诸如米托坦和曲洛司坦;叶酸补充剂,诸如亚叶酸(frolinic acid);醋葡醛内酯;醛磷酰胺糖苷;氨基酮戊酸;恩尿嘧啶;安吖啶;bestrabucil;比生群;依达曲沙(edatraxate);地磷酰胺(defofamine);秋水仙胺;地吖醌;依氟鸟氨酸(elformithine);依利醋铵;埃博霉素;依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明;美坦辛类,诸如美坦辛和安丝菌素;米托胍腙;米托蒽醌;莫哌达醇;尼曲吖啶;喷司他丁;蛋氨氮芥;吡柔比星;洛索蒽醌;鬼臼酸;2-乙基酰肼;丙卡巴肼;PSK多糖复合物;雷佐生;根霉素;西佐喃;锗螺胺;替奴佐酸;三亚胺醌;2,2′,2″-三氯三乙胺;单端孢霉烯类(尤其是T-2毒素、疣孢菌素(verracurin)A、杆孢菌素A和蛇行菌素);乌拉坦(urethan);长春地辛;达卡巴嗪;甘露莫司汀;二溴甘露醇;二溴卫矛醇;哌泊溴烷;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;替尼泊苷;依达曲沙;道诺霉素;氨基蝶呤;希罗达;伊班膦酸盐;伊立替康(例如,CPT-11);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);维A酸类,诸如视黄酸;卡培他滨;卡铂、丙卡巴肼、普卡霉素、吉西他滨、诺维本、法呢基-蛋白转移酶抑制剂、反铂,和上述任一种的药学上可接受的盐、酸或衍生物。
2.放射疗法
造成DNA损伤并已广泛使用的其他因素包括通常被称为γ射线、X射线的那些和/或放射性同位素向肿瘤细胞的定向递送。还考虑了其他形式的DNA损伤因素,例如微波、质子束照射(美国专利5,760,395和4,870,287)和UV照射。最可能的是,所有这些因素对DNA、DNA前体、DNA的复制和修复以及染色体的组装和维持造成宽范围的损害。X射线的剂量范围为从以50-200伦琴的日剂量持续长时间段(3至4周)至2000-6000伦琴的单次剂量。放射性同位素的剂量范围宽泛地变化,并且取决于同位素的半衰期、发射的辐射的强度和类型以及肿瘤细胞的摄取。
3.免疫疗法
熟练的技术人员会理解,另外的免疫疗法可以与实施方案的方法组合或结合使用。在癌症治疗的情形下,免疫治疗剂通常依赖于使用免疫效应细胞和分子以靶向并破坏癌细胞。利妥昔单抗是这样的一个实例。免疫效应物可以是例如对肿瘤细胞表面上的一些标记物特异性的抗体。所述抗体单独地可以充当治疗的效应物,或者它可以募集其他细胞以实际影响细胞杀伤。抗体还可以与药物或毒素(化学治疗剂、放射性核素、蓖麻蛋白A链、霍乱毒素、百日咳毒素等)缀合并且充当靶向剂。靶向地,效应物可以是直接地或间接地与肿瘤细胞靶标相互作用的携带表面分子的淋巴细胞。多种效应细胞包括细胞毒性T细胞和NK细胞。
已经出现抗体-药物缀合物作为癌症治疗剂开发的突破性方案。癌症是世界上死亡的主要原因之一。抗体-药物缀合物(ADC)包含与杀死细胞的药物共价连接的单克隆抗体(MAb)。该方案将MAb针对其抗原靶标的高特异性与高效细胞毒性药物组合,从而产生将货物(药物)递送至具有富集水平抗原的肿瘤细胞的“武装”MAb。药物的靶向递送还使其在正常组织中的暴露最小化,从而导致降低的毒性和提高的治疗指数。FDA对两种ADC药物的批准(2011年(本妥昔单抗(Brentuximab vedotin))和2013年(曲妥珠单抗美坦新或T-DM1))验证了该方案。目前存在超过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-货物优化变得越来越成熟,新ADC的发现和开发越来越依赖于适合于该方案的新靶标的鉴定和验证以及靶向MAb的产生。ADC靶标的两个标准是在肿瘤细胞中上调的/高水平的表达和稳健内化。
在免疫疗法的一个方面,肿瘤细胞必须带有一些适合靶向的标记物,即,所述标记物不存在于大多数其他细胞上。存在许多肿瘤标记物,并且这些肿瘤标记物中的任一种可能适合用于在本发明实施方案的上下文中的靶向。常见的肿瘤标记物包括CD20、癌胚抗原、酪氨酸酶(p97)、gp68、TAG-72、HMFG、唾液酸基路易斯抗原、MucA、MucB、PLAP、层粘连蛋白受体、erb B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组合。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。
目前在研究或在使用中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)、二硝基氯苯和芳族化合物(美国专利5,801,005和5,739,169;Hui和Hashimoto,1998;Christodoulides等人,1998);细胞因子疗法,例如,干扰素α、β和γ、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)。考虑一种或更多种抗癌疗法可以与本文所述的抗体疗法一起使用。
在一些实施方案中,所述免疫疗法可以是免疫检验点抑制剂。免疫检验点调高信号(例如共刺激性分子)或调低信号。可通过免疫检验点阻断而靶向的抑制性免疫检验点包括:腺苷A2A受体(A2AR)、B7-H3(也被称作CD276)、B和T淋巴细胞衰减剂(BTLA)、细胞毒性T-淋巴细胞相关的蛋白4(CTLA-4、也被称作CD152)、吲哚胺2,3-双加氧酶(IDO)、杀伤细胞免疫球蛋白(KIR)、淋巴细胞活化基因-3(LAG3)、程序性死亡1(PD-1)、T-细胞免疫球蛋白结构域和粘蛋白结构域3(TIM-3)和T细胞活化的V结构域Ig抑制剂(VISTA)。具体地,免疫检验点抑制剂靶向PD-1轴和/或CTLA-4。
免疫检验点抑制剂可以是药物,例如小分子、重组形式的配体或受体,或者特别是抗体,例如人抗体(例如,国际专利公开WO2015016718;Pardoll,Nat Rev Cancer,12(4):252-64,2012;二者通过引用并入本文)。可以使用免疫检验点蛋白或其类似物的已知抑制剂,特别是可以使用嵌合的、人源化的或人形式的抗体。如技术人员将知晓的,替代和/或等同名称可以用于在本公开内容中提及的某些抗体。在本公开内容的上下文中,这样的替代和/或等同名称是可互换的。例如已知的是,帕姆单抗(lambrolizumab)也以替代和等同名称MK-3475和帕博丽珠单抗(pembrolizumab)为人所知。
在一些实施方案中,所述PD-1结合拮抗剂是抑制PD-1与其配体结合配偶体结合的分子。在一个具体的方面,所述PD-1配体结合配偶体是PDL1和/或PDL2。在另一个实施方案中,PDL1结合拮抗剂是抑制PDL1与其结合配偶体结合的分子。在一个具体的方面,PDL1结合配偶体是PD-1和/或B7-1。在另一个实施方案中,PDL2结合拮抗剂是抑制PDL2与其结合配偶体结合的分子。在一个具体的方面,PDL2结合配偶体是PD-1。拮抗剂可以是抗体、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。示例性抗体描述于美国专利号US8735553、US8354509和US8008449中,它们都通过引用并入本文。用于用在本文提供的方法中的其他PD-1轴拮抗剂是本领域已知的,例如描述于美国专利申请号US20140294898、US2014022021和US20110008369中,它们都通过引用并入本文。
在一些实施方案中,所述PD-1结合拮抗剂是抗-PD-1抗体(例如,人抗体、人源化抗体或嵌合抗体)。在一些实施方案中,所述抗-PD-1抗体选自纳武单抗(nivolumab)、帕博丽珠单抗(pembrolizumab)和CT-011。在一些实施方案中,所述PD-1结合拮抗剂是免疫粘附素(例如,含有与恒定区(例如,免疫球蛋白序列的Fc区)融合的PDL1或PDL2的细胞外或PD-1结合部分的免疫粘附素)。在一些实施方案中,所述PD-1结合拮抗剂是AMP-224。纳武单抗(也被称作MDX-1106-04、MDX-1106、ONO-4538、BMS-936558和)是在WO2006/121168中描述的抗-PD-1抗体。帕博丽珠单抗(也被称作MK-3475、Merck 3475、帕姆单抗、和SCH-900475)是在WO2009/114335中描述的抗-PD-1抗体。CT-011(也被称作hBAT或hBAT-1)是在WO2009/101611中描述的抗-PD-1抗体。AMP-224(也被称作B7-DCIg)是在WO2010/027827和WO2011/066342中描述的PDL2-Fc融合可溶性受体。
可以在本文提供的方法中被靶向的另一种免疫检验点是细胞毒性T-淋巴细胞-相关的蛋白4(CTLA-4),也被称作CD152。人CTLA-4的完整cDNA序列具有Genbank登录号L15006。CTLA-4存在于T细胞表面上并且当与抗原呈递细胞表面上的CD80或CD86结合时充当“关闭”开关。CTLA4是免疫球蛋白超家族的一个成员,其在辅助性T细胞的表面上表达并向T细胞传递抑制信号。CTLA4与T细胞共刺激性蛋白CD28类似,并且这两种分子都结合抗原呈递细胞上的CD80和CD86(也分别称为B7-1和B7-2)。CTLA4向T细胞传递抑制信号,而CD28传递刺激信号。细胞内CTLA4也存在于调节性T细胞中并且可能对其功能是重要的。通过T细胞受体和CD28的T细胞活化会导致增加的CTLA-4(B7分子的抑制性受体)表达。
在一些实施方案中,所述免疫检验点抑制剂是抗-CTLA-4抗体(例如,人抗体、人源化抗体或嵌合抗体)、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。
使用本领域众所周知的方法,可以产生适用于本发明方法的抗-人-CTLA-4抗体(或由此衍生出的VH和/或VL结构域)。备选地,可以使用本领域公认的抗-CTLA-4抗体。例如,在以下文献中公开的抗-CTLA-4抗体可以用在本文公开的方法中:US 8,119,129,WO01/14424,WO 98/42752;WO 00/37504(CP675,206,也被称作曲美木单抗;以前的替西木单抗),美国专利号6,207,156;Hurwitz等人(1998)Proc Natl Acad Sci USA 95(17):10067-10071;Camacho等人(2004)J Clin Oncology 22(145):摘要号2505(抗体CP-675206);和Mokyr等人(1998)Cancer Res 58:5301-5304。每篇上述公开物的教导通过引用并入本文。也可以使用与这些本领域公知的抗体中的任一种竞争结合CTLA-4的抗体。例如,在国际专利申请号WO2001014424、WO2000037504和美国专利号8,017,114(都通过引用并入本文)中描述了人源化的CTLA-4抗体。
一种示例性的抗-CTLA-4抗体是伊匹木单抗(也被称作10D1、MDX-010、MDX-101和)或其抗原结合片段及变体(参见,例如,WO 01/14424)。在其他实施方案中,所述抗体包含伊匹木单抗的重链和轻链CDR或VR。因此,在一个实施方案中,所述抗体包含伊匹木单抗的VH区域的CDR1、CDR2和CDR3结构域,以及伊匹木单抗的VL区域的CDR1、CDR2和CDR3结构域。在另一个实施方案中,所述抗体与上述抗体竞争结合CTLA-4上的相同表位和/或结合至CTLA-4上的相同表位。在另一个实施方案中,所述抗体与上述抗体具有至少约90%可变区氨基酸序列同一性(例如,与伊匹木单抗具有至少约90%、95%或99%的可变区同一性)。
用于调节CTLA-4的其他分子包括例如在美国专利号US5844905、US5885796和国际专利申请号WO1995001994和WO1998042752(都通过引用并入本文)中描述的CTLA-4配体和受体,以及例如在美国专利号US8329867(通过引用并入本文)中描述的免疫粘附素。
4.手术
大约60%的患有癌症的人将经历某种类型的手术,包括预防性、诊断性或分期、治愈性和姑息性手术。治愈性手术包括其中将全部或一部分癌性组织物理去除、切除和/或破坏的切除术,并且可以与其他疗法(例如本发明实施方案的治疗、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。肿瘤切除术表示至少一部分肿瘤的物理去除。除肿瘤切除术之外,通过手术的治疗包括激光手术、冷冻手术、电手术和用显微镜控制的手术(Mohs氏手术)。
在切除一部分或全部癌性细胞、组织或肿瘤之后,可以在体内形成腔。通过灌注、直接注射或向该区域局部施用另外的抗癌疗法,可以实现治疗。可以重复这样的治疗,例如每1、2、3、4、5、6或7天,或者每1、2、3、4和5周,或者每1、2、3、4、5、6、7、8、9、10、11或12个月。这些治疗也可以具有不同剂量。
5.其他药剂
考虑可以将其他药剂与本发明实施方案的某些方面组合使用以提高治疗的治疗效果。这些其他药剂包括影响细胞表面受体和GAP连接的上调的药剂、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细胞凋亡诱导剂的敏感性的药剂或其他生物药剂。通过提高GAP连接数目实现的细胞间信号传导的增加,会增加对相邻过度增殖细胞群体的抗过度增殖作用。在其他实施方案中,细胞生长抑制剂或分化剂可以与本发明实施方案的某些方面组合使用以提高治疗的抗过度增殖效力。考虑细胞粘附抑制剂以提高本发明实施方案的效力。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。进一步考虑增加过度增殖细胞对细胞凋亡的敏感性的其他试剂(例如抗体c225)可以与本发明实施方案的某些方面组合使用以提高治疗效力。
V.制品或试剂盒
本文还提供了包含NK细胞的制品或试剂盒。制品或试剂盒可进一步包括包装插页,该包装插页包含用于使用NK细胞以治疗或延迟个体中癌症的进展或增强患有癌症的个体的免疫功能的说明。本文所述的任何抗原特异性NK细胞可包括在制品或试剂盒中。合适的容器包括例如瓶子、小药瓶、袋子和注射器。容器可以由多种材料(例如玻璃、塑料(例如聚氯乙烯或聚烯烃)或金属合金(例如不锈钢或哈氏合金))形成。在一些实施方案中,容器容纳制剂,并且在容器上或与容器相关的标签可以指示使用说明。制品或试剂盒还可以包括从商业和用户角度来看合乎需要的其他材料,包括其他缓冲液,稀释剂,过滤器,针头,注射器和带有使用说明的包装插页。在一些实施方案中,制品还包括一种或多种其他药剂(例如化学治疗剂和抗肿瘤剂)。用于一种或多种药剂的合适容器包括例如瓶子、小药瓶、袋子和注射器。
VI.实施例
包括以下实施例以证明本发明的优选实施方案。本领域技术人员应该理解,以下实施例中公开的技术代表本发明人发现的在本发明的实践中发挥良好作用的技术,因此可以认为构成本发明实践的优选方式。然而,根据本公开内容,本领域技术人员应当理解,可以在不背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-NK细胞的扩增
已研究NK细胞作为潜在的抗肿瘤效应物,但许多障碍限制其治疗性利用,主要与所述NK细胞的数目少有关,因此需要离体扩增以用于过继免疫疗法。来自患者的外周血NK细胞(PB-NK细胞)或来自成人同种异体供者的外周血NK细胞是最常用的;然而,该方法需要与进行白细胞清除术的接受者最少3/6HLA分子匹配的有意愿的供者。成人PB NK细胞的另一个缺点是过继转移后的次优体内增殖和存留。
本发明的研究显示,由CB产生的NK细胞可具有独特优势,所述优势与参与细胞增殖、细胞活化、细胞粘附、细胞周期和DNA复制的基因的较高表达(图1A至1E)有关。因此,研发出符合GMP的快速扩增方案,以用于使用经工程改造的饲养细胞(诸如表达4-1BB配体、IL21或IL-15和活化NK共刺激性分子的配体(诸如CD48或CS1)的饲养细胞)来增殖源自CB的NK细胞。
从冷冻并解冻的CB单元或从选自临床CB库的新鲜CB单元分离且扩增NK细胞。本发明策略的独特方面在于不要求供者与接受者之间HLA匹配,从而允许得到真正“现成的”细胞疗法产品。在可能的情况下,基于与接受者的KIR-配体错配来选择CB单元。
如图2中所示,在2周培养期内,获得中值803倍的扩增(范围为346至5547),该扩增倍数显著高于用PB NK细胞获得的扩增倍数(中值380倍,范围为99至1515;P=0.036),这表明CB-NK细胞的固有增殖特性。RE-CB NK细胞呈现功能性表型(图3),没有耗竭的迹象,如穿孔蛋白和颗粒酶的高表达以及CD57、KLRG1和PD1的表达缺乏所示。
RE-CB NK细胞针对体外肿瘤细胞系具有高度细胞毒性,且在辐照后的免疫缺陷小鼠中诱导出稳健的抗肿瘤活性(图4)。另外,在高剂量化学疗法联合自体干细胞挽救、清髓性、非清髓性或降低强度的化学疗法联合同种异体干细胞移植后以及基于氟达拉滨的淋巴细胞清除性化学疗法后,向超过60个患有血液癌的患者施用RE-CB NK细胞产物(6个HLA等位基因中有1-5个匹配),并且没有显示移植物抗宿主疾病或其他毒性。
本发明方法经优化,以改良进行培养所需的时间和物流且降低程序的成本。优化包含增加培养基体积且由此降低细胞在培养基中的浓度。如针对前七天培养的表2A和针对第二周培养的表2B中所示,与较少培养基和较高细胞浓度(G-Rex 100)相比,在较大培养基体积和降低的细胞浓度(G-Rex 100M)的情况下获得显著更好的倍数扩增。优化的程序需要更少生物反应器,且产生相同或较高NK细胞剂量需要较少细胞。在第7天显示出此情形,此时需要少四倍的细胞来接种各G-Rex 100M以达到相同剂量。在第0至7天,不需要干预培养物(与先前程序至少加料两次相比)。
利用优化的程序,在第7至14天,细胞不需要分开且仅加料两次。使用较少培养基和细胞因子以及较少技术专家时间,所有这些均节省金钱且改善物流。另外,在第7至14天,培养物中需要最少干预(仅添加两次IL2),这不仅节省技术时间而且明显减少微生物污染的机会。这与现今使用的最新NK细胞扩增程序不同,在最新NK细胞扩增程序中,培养物通常每隔一天进行分开,反复加料增加了微生物污染的风险。如表2C中所总结的,优化的方法将技术人员时间减少29%。
除经优化的培养物流(culture logistics)、成本和微生物污染风险降低以外,本发明方法还具有几种其他新颖且重要的特征。如图2中所示,在2周培养期内,获得中值803倍的扩增(范围为346至5547),该扩增倍数显著高于用PB NK细胞获得的扩增倍数(中值380倍,范围为99至1515;P=0.036),这表明CB-NK细胞的固有增殖特性。RE-CB NK细胞呈现功能性表型(图3),没有“耗竭”的迹象,如穿孔蛋白α和颗粒酶的高表达以及CD57、KLRG1和PD1的表达缺乏所示。RE-CB NK细胞针对体外肿瘤细胞系具有高度细胞毒性,且在辐照后的免疫缺陷小鼠中诱导出稳健的抗肿瘤活性(图4)。另外,在高剂量化学疗法联合自体干细胞挽救、清髓性、非清髓性或降低强度的化学疗法联合同种异体干细胞移植后以及基于氟达拉滨的淋巴细胞清除性化学疗法后,向超过80个血液癌患者施用快速扩增的(RE)-CB NK细胞产物(6个HLA等位基因中有1-5个匹配),其不具有移植物抗宿主疾病或其他毒性。更具体地,60个多发性骨髓瘤患者安全地接受了与化学疗法(美法仑和来那度胺)和自体移植结合的CB-NK细胞。如表3中所示,与153个接受标准护理(SOC)与美法仑和自体移植的多发性骨髓瘤(MM)和高风险MM(HRMM)患者相比,42个接受CB NK细胞的MM患者和HRMM患者(参加方案2011-0379)经历较高的≥非常好的部分反应(VGPR)和完全反应(CR)率。
表3.多发性骨髓瘤和高风险多发性骨髓瘤患者的反应率
单克隆抗体elotuzamab刺激NK细胞并使NK细胞靶向多发性骨髓瘤细胞,如下文所述:
·Elotuzamab经由CD16结合且通过直接连接NK细胞上的SLAMF7而增强NK细胞抗体依赖性细胞毒性(ADCC)
·离体扩增的NK细胞相比于非扩增细胞展示较高的elotuzamab介导的细胞毒性
·向来那度胺添加elotuzamab进一步增强针对SLAMF7hi抗NK细胞骨髓瘤细胞系的CB-NK ADCC
基于该数据,向化学疗法制剂(美法仑和来那度胺)中添加elotuzamab,且用CB NK细胞来治疗15个另外的HRMM患者。如表4中所示,与未接受NK细胞的患者相比,接受NK细胞的这些高风险患者的≥VGPR和CR率更高,且接受NK细胞加elotuzamab的那些患者的≥VGPR和CR率甚至更高。在第100天,针对接受NK细胞的两个组而言,骨髓活检的微小残留病(MRD)阴性反应率也是优异的。迄今为止,所有15个患者均存活,且仅有一个患者在移植一年时具有进行性骨髓瘤迹象;该患者是在第100天时骨髓呈MRD阳性的极少数患者中的一个。15个患者中有十四个保持没有进展。清楚地,本发明的基于CB NK的疗法对于患有高风险多发性骨髓瘤的患者有效。
表4.接受含有或不含elotuzamab的NK细胞的患者的反应率
*p-值=0.011;**p-值=0.0092
对于另一个试验(2015-0751),14个患有难治性/复发性非霍奇金淋巴瘤的患者在不考虑与患者的HLA配型的情况下接受经扩增的CB NK细胞。所有这些患者均安全地接受了CB NK细胞,不具有输注性或其他毒性且不具有任何GVHD。超过一半的这些难治性患者(57%)实现完全缓解,且在该治疗后一年保持无进展。这些结果强调了以下事实:这些CBNK细胞可用作现成的产物,而无需对患者或CB单元进行耗时且昂贵的HLA分型。对于第三个试验(2012-0819),19个患者接受了与同种异体移植结合的CB NK细胞。所述患者对这些细胞产物的耐受性极佳,且看起来与接受类似治疗但未接受CB NK细胞的患者相比具有更少的白血病复发。这些数据证实经扩增的CB NK细胞在各种不同临床配置中的安全性及功效。
因此,本发明方法可用于扩增来自脐带血的NK细胞,以获得符合GMP的临床剂量。
依据本公开内容,本文所公开和要求保护的所有方法可在不进行不当实验的情况下进行和执行。虽然已根据优选实施方案描述了本发明的组合物和方法,但对于本领域技术人员显而易见的是,可在不背离本发明的概念、精神和范围的情况下,在本文所描述的方法中和方法的步骤中或步骤顺序方面应用变化。更确切而言,显而易知化学上和生理学上均相关的某些药剂可取代本文所描述的药剂,同时获得相同或类似的结果。对本领域技术人员显而易见的所有此类类似取代和修改视为在由后附权利要求书所定义的本发明的精神、范围和概念内。
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Claims (78)
1.一种用于扩增自然杀伤(NK)细胞的离体方法,所述方法包括:
(a)从脐带血获得单核细胞(MNC)的起始群体;
(b)在抗原呈递细胞(APC)和IL-2存在下刺激所述MNC;以及
(c)用APC再刺激所述细胞以产生经扩增的NK细胞,其中所述方法在生物反应器中进行并且符合良好作业规范(GMP)。
2.根据权利要求1所述的方法,其中所述方法进一步包含耗尽CD3阳性的细胞。
3.根据权利要求2所述的方法,其中所述耗尽在步骤(b)与(c)之间进行。
4.根据权利要求3所述的方法,其中从生物反应器移出所述细胞。
5.根据权利要求1所述的方法,其中从脐带血获得MNC的起始群体包括在葡聚糖、人血清白蛋白(HSA)、DNA酶和/或氯化镁存在下解冻脐带血。
6.根据权利要求1所述的方法,其中从脐带血获得MNC的起始群体包括在葡聚糖和DNA酶存在下解冻脐带血。
7.根据权利要求5所述的方法,其中在10%葡聚糖存在下洗涤所述脐带血。
8.根据权利要求5或7所述的方法,其中在氯化镁存在下使所述脐带血悬浮。
9.根据权利要求8所述的方法,其中所述氯化镁的浓度为200mM。
10.根据权利要求1-9中任一项所述的方法,其中获得包括进行ficoll密度梯度离心以获得单核细胞(MNC)。
11.根据权利要求1-10中任一项所述的方法,其中所述方法不包括在步骤(b)期间移除或添加任何培养基组分。
12.根据权利要求1-11中任一项所述的方法,其中所述生物反应器是透气式生物反应器。
13.根据权利要求12所述的方法,其中所述透气式生物反应器是G-Rex100M。
14.根据权利要求13所述的方法,其中步骤(b)的刺激在3-5L的培养基中进行。
15.根据权利要求1-13中任一项所述的方法,其中所述APC经γ辐照。
16.根据权利要求15所述的方法,其中所述APC经工程改造以表达膜结合的IL-21(mbIL-21)。
17.根据权利要求1-16中任一项所述的方法,其中所述APC经工程改造以表达IL-21、IL-15、IL-7、IL-18和/或IL-2。
18.根据权利要求1-16中任一项所述的方法,其中所述MNC和APC以1:2的比率进行培养。
19.根据权利要求1-18中任一项所述的方法,其中所述IL-2的浓度为50-200IU/mL。
20.根据权利要求19所述的方法,其中所述IL-2的浓度为100IU/mL。
21.根据权利要求1-20中任一项所述的方法,其中每2-3天补给IL-2。
22.根据权利要求1-20中任一项所述的方法,其中进行步骤(b)持续6-8天。
23.根据权利要求22所述的方法,其中进行步骤(b)持续7天。
24.根据权利要求1-23中任一项所述的方法,其中步骤(b)不包括使细胞分开。
25.根据权利要求24所述的方法,其中向所述细胞添加两次IL-2。
26.根据权利要求1-25中任一项所述的方法,其中所述方法包括使用3、4、5或6个生物反应器。
27.根据权利要求26所述的方法,其中所述方法包括使用少于10个生物反应器。
28.根据权利要求1-27中任一项所述的方法,其中所述NK细胞扩增至少500倍、800倍、1000倍、3000倍或5000倍。
29.根据权利要求1-28中任一项所述的方法,其中与静态液体培养相比,在生物反应器中培养NK细胞产生超过1000倍的NK细胞。
30.根据权利要求1-29中任一项所述的方法,其中所述方法不包括人白细胞抗原(HLA)配型。
31.根据权利要求30所述的方法,其中所述NK细胞的起始群体不是从单倍体相同的供者获得。
32.根据权利要求1-31中任一项所述的方法,其中所述方法在少于15天内进行。
33.根据权利要求32所述的方法,其中所述方法在14天内进行。
34.根据权利要求1-33中任一项所述的方法,其中与从外周血扩增的NK细胞相比,所述经扩增的NK细胞具有增强的抗肿瘤活性。
35.根据权利要求34所述的方法,其中与从外周血扩增的NK细胞相比,所述经扩增的NK细胞具有细胞周期基因、细胞分裂基因和/或DNA复制基因的较高表达。
36.根据权利要求1-34中任一项所述的方法,其中与从外周血扩增的NK细胞相比,所述经扩增的NK细胞具有较高的增殖能力。
37.根据权利要求1-36中任一项所述的方法,其中所述经扩增的NK细胞不表现出耗竭。
38.根据权利要求37所述的方法,其中通过测量穿孔蛋白、颗粒酶、CD57、KLRG1和PD1的表达来检测耗竭。
39.根据权利要求38所述的方法,其中所述经扩增的NK细胞具有穿孔蛋白和颗粒酶的高表达。
40.根据权利要求38所述的方法,其中所述经扩增的NK细胞具有CD57、KLRG1和PD1的低表达或没有CD57、KLRG1和PD1的表达。
41.根据权利要求1-40中任一项所述的方法,其中所述经扩增的NK细胞包含临床相关剂量。
42.根据权利要求1-41中任一项所述的方法,其中所述脐带血为冷冻脐带血。
43.根据权利要求42所述的方法,其中已针对传染疾病测试所述冷冻脐带血。
44.根据权利要求1-43中任一项所述的方法,其中所述脐带血为经汇集的脐带血。
45.根据权利要求44所述的方法,其中所述脐带血从3、4、5、6、7或8个个体脐带血单元汇集。
46.根据权利要求1-45中任一项所述的方法,其中所述NK细胞不是自体的。
47.根据权利要求1-46中任一项所述的方法,其中所述NK细胞不是同种异体的。
48.根据权利要求1-47中任一项所述的方法,其中所述APC为通用抗原呈递细胞(uAPC)。
49.根据权利要求48所述的方法,其中所述uAPC经工程改造以表达:(1)CD48和/或CS1(CD319),(2)膜结合的白介素-21(mbIL-21),和(3)41BB配体(41BBL)。
50.根据权利要求48所述的方法,其中所述uAPC表达CD48。
51.根据权利要求48所述的方法,其中所述uAPC表达CS1。
52.根据权利要求48所述的方法,其中所述uAPC表达CD48和CS1。
53.根据权利要求48所述的方法,其中所述uAPC基本上没有内源性HLAI类、HLAII类或CD1d分子的表达。
54.根据权利要求48所述的方法,其中所述uAPC表达ICAM-1(CD54)和LFA-3(CD58)。
55.根据权利要求1-54中任一项所述的方法,其中所述uAPC进一步定义为源自白血病细胞的aAPC。
56.根据权利要求55所述的方法,其中所述源自白血病细胞的aAPC进一步定义为K562细胞。
57.根据权利要求1-56中任一项所述的方法,所述方法进一步包括冷冻保存所述经扩增的NK细胞。
58.一种药物组合物,其包含通过权利要求1-57中任一项所产生的NK细胞群体和药学上可接受的载剂。
59.一种组合物,其包含有效量的通过权利要求1-57中任一项所产生的NK细胞,所述组合物用于治疗受试者的疾病或病症。
60.组合物用于治疗受试者的免疫相关病症的用途,所述组合物包含有效量的通过权利要求1-57中任一项所产生的NK细胞。
61.一种用于治疗疾病或病症的方法,所述方法包括向受试者施用有效量的根据权利要求1-57中任一项所述的经扩增的NK细胞。
62.根据权利要求61所述的方法,其进一步包括施用化学疗法。
63.根据权利要求62所述的方法,其中所述化学疗法在所述经扩增的NK细胞之前施用。
64.根据权利要求62或63所述的方法,其中所述化学疗法是清髓性的。
65.根据权利要求62或63所述的方法,其中所述化学疗法是非清髓性的。
66.根据权利要求62或63所述的方法,其中所述化学疗法是淋巴细胞清除性化学疗法。
67.根据权利要求66所述的方法,其中所述淋巴细胞清除性化学疗法是基于氟达拉宾的淋巴细胞清除性化学疗法。
68.根据权利要求62-67中任一项所述的方法,其中所述化学疗法是来那度胺。
69.根据权利要求62-68中任一项所述的方法,其中所述方法不包括进行HLA配型。
70.根据权利要求62-69中任一项所述的方法,其中所述疾病或病症是免疫相关病症。
71.根据权利要求70所述的方法,其中所述免疫相关病症是自体免疫病症、移植物抗宿主疾病、同种异体移植排斥或炎性病况。
72.根据权利要求61-69中任一项所述的方法,其中所述疾病或病症是癌症。
73.根据权利要求72所述的方法,其中所述癌症是多发性骨髓瘤。
74.根据权利要求61-73中任一项所述的方法,其中所述受试者没有发展移植物抗宿主疾病或其他毒性。
75.根据权利要求61-74中任一项所述的方法,其进一步包括施用有效量的至少第二治疗剂。
76.根据权利要求75所述的方法,其中所述至少第二治疗剂包括化学疗法、免疫疗法、手术、放射疗法或生物疗法。
77.根据权利要求75所述的方法,其中所述NK细胞和/或至少第二治疗剂经静脉内、腹膜内、气管内、瘤内、肌内、内窥镜方式、病灶内、经皮、皮下、区域性施用或通过直接注射或输注施用。
78.根据权利要求75-77中任一项所述的方法,其中所述第二治疗剂包括elotuzamab。
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