CN116600818A - 靶向免疫细胞中的src-3作为治疗癌症的免疫调节治疗剂 - Google Patents
靶向免疫细胞中的src-3作为治疗癌症的免疫调节治疗剂 Download PDFInfo
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Abstract
本公开涉及与癌症治疗相关的方法和组合物,包括靶向免疫细胞(包括T细胞,例如T调节细胞)中的SRC‑3。特别是靶向T调节细胞中的SRC‑3对于根除哺乳动物中的肿瘤是有效的。在特定情况下,对T调节细胞进行离体CRISPR,以产生适合过继性细胞转移的细胞。在一些情况下,将一种或多种靶向SRC‑3的试剂也施用给个体和/或在施用前暴露于细胞。
Description
本申请要求于2020年10月28日提交的美国临时申请序列号63/106770的优先权,该申请通过引用整体并入本文。
关于联邦赞助的研究或开发的声明
本发明是在美国国防部授予的W81XWH-13-1-0285和美国国立卫生研究院授予的HD008188的政府支持下完成的。政府对本发明有一定的权利。
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,包括癌症医学。
发明背景
类固醇受体共激活因子-3(SRC-3)作用为乳腺癌症(BC)增殖、转移和对基于内分泌的标准癌症疗法的耐受性的关键驱动因素。作为一种癌基因,SRC-3作为核受体和多种其他转录因子的多效性共激活因子起作用,驱动癌症细胞增殖和转移所需的程序。重要的是,SRC-3在宿主免疫系统的调节中也发挥着重要作用。
本公开通过以独特的方式靶向SRC-3来提供有效的癌症疗法,满足了本领域长期以来的需求。
发明内容
本公开涉及用于对任何类型癌症进行治疗、延缓进展、延缓发病或降低患病风险的系统、方法和组合物。在特定实施方案中,本公开涉及过继性细胞转移,其中施用给有此需要的个体的细胞是免疫细胞,所述免疫细胞(1)具有内源性SRC-3表达的破坏;和/或(2)已经暴露于一种或多种靶向SRC-3的试剂。在特定实施方案中,免疫细胞是CD4+细胞,包括是CD4+T调节细胞(Treg)。
目前Treg靶向免疫检查点抑制剂主要集中在破坏其与其他免疫细胞的细胞表面相互作用的表面蛋白(受体)上。本公开与此不同,因为作为Treg基因靶标的SRC-3是以调节Treg核基因表达程序发挥功能的核蛋白。由于SRC-3作为转录主调节因子的作用,本文表明在小鼠遗传模型中消除SRC-3可以以促进肿瘤根除的方式调节Treg功能,同时避免对已建立的免疫检查点抑制剂经常观察到的其他严重副作用。在具体实施方案中,本公开涉及一种基于CRISPR的方法,以靶向免疫细胞(包括遗传修饰的Treg细胞)中的SRC-3基因,用于过继性转移到癌症患者体内。因此,本公开提供了一种独特的方式来支持基于免疫系统的肿瘤根除。
在一个实施方案中,有一种工程化的免疫细胞,其包含类固醇受体共激活因子-3(SRC-3)的破坏。在特定的实施方案中,免疫细胞是T细胞,例如T调节细胞。T细胞可以是CD4+、CD25+和/或FOXP3+。在某些实施方案中,破坏进一步限定为免疫细胞经遗传修饰以具有降低的SRC-3表达水平或基本上不具有SRC-3表达。在特定情况下,使用一种或多种引导RNA和Cas9酶来工程化免疫细胞。对于个体而言,免疫细胞可以是自体的、同种异体的或同基因的。
在某些实施方案中,有一种组合物,其包含:(a)本文所涵盖的任何免疫细胞;和(b)一种或多种靶向SRC-3的试剂。在某些情况下,(a)和(b)在不同的制剂中,但它们也可以在相同的制剂中。在具体实施方案中,靶向SRC-3的试剂是小分子抑制剂、抗体、蛋白质、核酸或其组合。SRC-3的小分子抑制剂可以是蟾毒灵、棉酚、疣孢菌素A、SI-2、SI-10、SI-12、其功能衍生物或其组合。抗体可以是单克隆抗体或多克隆抗体,并且具体实例包括5E11、LS-C801929、PA1-845、AX15.3、PA5-29854、EPR4374(3)或其组合。
在一个实施方案中,有一种治疗个体癌症的方法,包括向个体施用治疗有效量的本文中包含的任何细胞的步骤。癌症可能是SRC-3+癌症。癌症可以是乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、胃癌、多发性骨髓瘤、甲状腺癌症或胰腺癌。
在一些情况下,在施用步骤之前,将细胞离体暴露于有效量的一种或多种靶向SRC-3的试剂,例如小分子抑制剂(蟾毒灵、棉酚、疣孢菌素A、SI-2、SI-10、SI-12、其功能衍生物、其组合)、抗体(单克隆抗体或多克隆或片段,如scFv)、蛋白质、核酸或其组合。具体抗体包括5E11、LS-C801929、PA1-845、AX15.3、PA5-29854、EPR4374(3)或其组合。在某些情况下,向个体施用治疗有效量的附加癌症疗法,例如手术、放疗、化疗、激素疗法、药物疗法、蛋白质疗法、免疫疗法或其组合。附加癌症疗法可以包括一种或多种靶向SRC-3的试剂。可以在基本上相同的时间或不同的时间向个体施用细胞和附加癌症疗法。细胞和附加癌症疗法可以在相同的制剂中,或不在相同的制剂中。可以静脉内、腹膜内、动脉内、局部、通过吸入、肌肉内、胸骨内、通过关节内注射或通过输注施用细胞。可以施用细胞一次或多次,当它们被多次施用时,施用之间的持续时间在1-24小时、1-7天、1-4周或1-12个月内。
在一个实施方案中,有一种治疗个体的癌症的方法,包括向个体施用治疗有效量的本文所涵盖的任何组合物的步骤,包括这样的组合物,所述组合物包含(a)本文所涵盖的任何免疫细胞;和(b)一种或多种靶向SRC-3的试剂。在这种情况下,(a)和(b)可以在或可以不在不同的试剂中和/或在相同或不同的时间施用给个体。当在不同时间施用时,(a)和(b)的施用之间的持续时间可以在1-24小时、1-7天、1-4周或1-12个月内。可以一次或多次将组合物施用给个体,并且当多次将组合物施用给个体时,施用之间的持续时间在1-24小时、1-7天、1-4周或1-12个月内。癌症可以是SRC-3+。癌症可以属于乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、胃癌、多发性骨髓瘤、甲状腺癌或胰腺癌。在特定情况下,在施用步骤之前,将(a)中的细胞离体暴露于有效量的一种或多种靶向SRC-3的试剂。
在一个实施方案中,有一种产生本文所涵盖的任何免疫细胞的方法,包括破坏免疫细胞中的SRC-3表达的步骤。
免疫细胞可以是T细胞,包括Treg。在特定情况下,该方法进一步限定为:(a)分别获得CD4+T细胞或CD4+Treg;和(b)将CD4+T细胞或CD4+Treg分别暴露于一种或多种分别破坏T细胞或Treg中内源性SRC-3表达的试剂。在特定实施方案中,T细胞或Treg从脾脏、骨髓、血液、血浆或其组合获得。该方法可以进一步包括从CD4+T细胞获得T调节细胞的步骤。在特定情况下,T调节细胞是CD25+和/或Fox3p+。在特定情况下,一种或多种破坏T细胞中内源性SRC-3表达的试剂包括核酸。在特定方面,一种或多种破坏T细胞中内源性SRC-3表达的试剂包括CRISPR试剂。该方法可以进一步包括将免疫细胞离体暴露于有效量的一种或多种靶向SRC-3的试剂的步骤。
为了更好地理解下面的详细描述,前面已经相当广泛地概述了本公开的特征和技术优势。下文将描述构成本文权利要求主题的附加特征和优点。本领域技术人员应当理解,所公开的概念和具体实施方案可以容易地用作修改或设计其他结构以实现本设计的相同目的的基础。本领域技术人员还应该意识到,这样的等效构造不脱离所附权利要求中所阐述的精神和范围。当结合附图考虑时,根据以下描述,将更好地理解被认为是本文公开的设计特有的新颖特征,包括操作的组织和方法,以及进一步的目的和优点。然而,要明确理解的是,提供每个附图仅仅是为了示例说明和描述的目的,而不是意图作为本公开的限制的定义。
附图说明
为了更全面地理解本公开,现在参考结合附图进行的以下描述。
图1:Src-3基因敲除(KO)小鼠的综合免疫表型分型显示广泛的淋巴细胞增多症。对来自老年(16-20个月)Src-3 KO小鼠(-/-,n=6)和野生型同窝小鼠(+/+,n=7)的外周血进行免疫表型分型。在SRC-3敲除小鼠中,T细胞和B细胞以及特定亚型显著升高。粒细胞、单核细胞、嗜酸性粒细胞、巨噬细胞、树突状细胞和NK细胞在统计学上没有显著差异(数据未显示)。
图2A-2B:SRC-3的表达在T调节细胞(Treg)中高度富集并与Foxp3相关。图2A:BioGPS基因组学平台(10)中来自选定组织的Ncoa3(Src-3)探针强度(使用两种探针)的代表图,显示Src-3在T细胞谱系中高度表达,在Foxp3+CD4+T细胞(Treg)中表达最高。图2B:使用批量校正的共表达数据库Immuno Navigator(12)进行296个NURSA管理的共调节因子与Treg中Foxp3表达的相关性。Ncoa3与Treg中Foxp3的表达密切相关。
图3A-3B:SRC-3调节人Treg中的FOXP3表达。图3A:在人类Treg(来自健康供体)中沉默SRC-3降低Treg标志物基因和免疫检查点调节子的mRNA表达。用表达针对萤光素酶(shLuc)或SRC-3的shRNA的慢病毒载体感染供体Treg,并通过RT-qPCR测量mRNA水平。图3B:SRC-3可以刺激FOXP3启动子功能。SRC-3在瞬时转染测定中共激活FoxP3启动子驱动的报告基因活性。用FoxP3启动子萤光素酶报告基因(GR Lee实验室馈赠,Hwang等人2016,Nat.Commun.)和增加浓度的SRC-3表达质粒来转染293T细胞。
图4A-4C:E0771 BC肿瘤在基因工程化的小鼠模型中被根除,其中SRC-3在表达Foxp3的Treg细胞中被特异性缺失。图4A:将floexd SRC-3小鼠回交10代至C57BL/6J背景下,并与同样在C57BL/6J背景下的Foxp3-EGFP/CRE/ERT2敲入小鼠杂交。他莫昔芬处理导致Cre的激活和SRC-3基因外显子11和12的切除。图4B:C57BL/6J对照小鼠和Treg:SRC-KO小鼠用他莫昔芬处理五天,然后在另外三周后将1x106个表达萤光素酶的E0771 BC肿瘤细胞注射到清洁的乳腺脂肪垫中。图4C:在32天的时间内测量肿瘤体积(左图)。右图显示了研究结束时的肿瘤和脾脏图像。
图5:在基于CRISPR的SRC-3基因靶向后,大量T淋巴细胞中SRC-3(NcoA3)mRNA的定量。以下引物用于以上进行的RT-qPCR测定。NCoA3引物(探针103):左:AAG ACT CTT TAGGAC CGC TTT TAC T(SEQ ID NO:1)。右:ACA CTG CGC CAT GGT TAA T(SEQ ID NO:2)。GAPDH引物(探针52):左:GGG TTC CTA TAA ATA CGG ACT GC(SEQ ID NO:3)。右:CCA TTTTGT CTA CGG GAC GA(SEQ ID NO:4)。(PE-)-非靶向细胞;(PE+)SRC-3基因靶向细胞。
图6:过继性SRC-3KO-Treg小鼠肿瘤模型的实验设计。
图7A-7B:SRC-3KO Treg细胞的过继性转移消除了E0771肿瘤。图7A:将萤光素酶标记的乳腺癌E0771肿瘤细胞植入野生型C57BL/6小鼠的清洁脂肪垫中。随后,给动物(每个实验组2只)注射SRC-3KO Treg、对照(Cont)Treg或无Treg(无ACT,对应于野生型细胞),并通过萤光素酶肿瘤成像来监测肿瘤生长。在接受SRC-3KO Treg的动物中肿瘤的消除用箭头标记。肿瘤萤光素酶成像定量显示在图7B中。
具体实施方式
I.定义示例
根据长期以来的专利法惯例,当在本说明书中(包括权利要求在内)与词语“包含”一起使用时,词语“一个”和“一种”表示“一个(种)或多个(种)”。在说明书和权利要求中使用的单数形式“一个”、“一种”和“该”包括复数引用,除非上下文另有明确规定。例如,术语“核酸”包括多种核酸,包括其混合物。本公开的一些实施方案可以由本公开的一个或多个要素、方法步骤和/或方法组成,或者基本上由其组成。可以设想,本文所述的任何方法或组合物可以相对于本文所述任何其他方法或组合物来实施,并且可以组合不同的实施方案。
在本说明书中,除非上下文另有要求,否则词语“包括”、“包含”和“含有”应理解为暗示包括所述步骤或要素或者步骤或要素的组,但不排除任何其他步骤或要素或者步骤或要素的组。“由…组成”的意思是包括并限于“由…构成”之间的任何内容。因此,“由…组成”表示所列要素是必需的或强制性的,并且不存在其他要素。“基本上由…组成”是指包括在短语中列出的任何要素,并限于不干扰或有助于在公开中为列出的要素指定的活性或作用的其他要素。因此,短语“基本上由…组成”表示所列要素是必需的或强制性的,但没有其他要素是可选的,并且可能存在也可能不存在,这取决于它们是否影响所列要素的活性或作用。
如本文所用,术语“或”和“和/或”用于描述相互组合或排除的多个组分。例如,“x、y和/或z”可以指单独的“x”,单独的“y”,单独的“z”,“x,y和z”,“(x和y)或z”,“x或(y和z)”,或“x或y或z”。特别地设想x、y或z可以从实施方案中特别地排除。
在本申请中,术语“约”根据其在细胞和分子生物学领域的普通含义使用,以表明一个值包括用于确定该值的方法的误差标准差。
在本说明书中,对“一个实施方案”、“实施方案”、“具体实施方案”、“相关实施方案”、“特定实施方案”、“附加实施方案”或“进一步的实施方案”的引用或其组合意味着结合实施方案描述的特定特征、结构或特性包括在本发明的至少一个实施方案中。因此,在本说明书的各个地方出现的前述短语不一定都指同一实施方案。此外,在一个或多个实施方案中,可以以任何合适的方式组合特定特征、结构或特性。
如本文所用,基因的“破坏”或“改变”是指与没有改变时基因产物的表达水平相比,在细胞中受试基因编码的一种或多种基因产物的表达的消除或减少。示例性的基因产物包括由该基因编码的mRNA和蛋白质产物。在某些情况下,变化是瞬时的或可逆的,而在其他情况下则是永久的。在某些情况下,改变是在功能性或全长蛋白质或mRNA中,尽管可能产生截短或非功能性产物。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。基因破坏或改变通常通过人工方法进行诱导,即通过添加或引入化合物、分子、复合物或组合物,和/或通过改变基因的核酸或与基因相关的核酸,例如在DNA水平上。基因改变的示例性方法包括基因沉默、敲低、敲除和/或基因改变技术,例如基因编辑。实例包括反义技术,如RNAi、siRNA、shRNA和/或核酶,其通常导致表达的瞬时减少,以及导致靶向基因失活或改变的基因编辑技术,例如通过诱导断裂和/或同源重组。实例包括插入、突变和/或缺失。破坏或改变通常导致由基因编码的正常或“野生型”产物的抑制和/或完全不表达。这种基因破坏或改变的实例是基因或部分基因的插入、移码和错义突变、缺失、敲入和敲除,包括整个基因的缺失。这种改变可以发生在编码区,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,例如通过插入终止密码子。这种改变也可能通过启动子或增强子或其他影响转录激活的区域中的改变而发生,从而阻止基因的转录。基因破坏或改变包括基因靶向,包括通过同源重组的靶向基因失活。
如本文所用,“药学上可接受的运载体”包括任何和所有的水性溶剂(例如,水、酒精/水溶液、盐水溶液、胃肠外媒介物,如氯化钠、林格右旋糖等)、非水溶剂(例如丙二醇、聚乙二醇、植物油和可注射有机酯,如油酸乙酯)、分散介质、涂层,表面活性剂、抗氧化剂、防腐剂(例如,抗细菌或抗真菌剂、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、增甜剂、调味剂、染料、液体和营养补充剂,例如材料及其组合,如本领域普通技术人员所知。药物组合物中各种组分的pH和确切浓度根据众所周知的参数进行调节。
本文中使用的术语“受试者”通常指需要治疗的个体。受试者可以是作为方法或材料的对象的任何动物受试者,包括哺乳动物,例如人类、实验动物(例如灵长类动物、大鼠、小鼠、兔子)、牲畜(例如牛、绵羊、山羊、猪、火鸡和鸡)、家养宠物(例如狗、猫和啮齿动物)、马和转基因非人动物。受试者可以是患者,例如,患有或怀疑患有疾病(可称为医疗状况),例如一种或多种癌症。受试者可能正在或已经接受癌症治疗。在至少一些实施方案中,术语“个体”可以互换使用。本文中使用的“受试者”或“个体”可以或可以不被安置在医疗机构,并可以以医疗机构的门诊患者进行治疗。个体可以通过互联网接收一种或多种医疗组合物。个体可以包括任何年龄的人类或非人类动物,并因此包括成人和青少年(例如儿童)以及婴儿,并包括子宫内个体。个体可以是任何性别、种族或民族。
“治疗”或治疗疾病或状况是指执行一项方案,其可以包括向患者施用一种或多种药物,以缓解疾病的症状或体征,所述疾病包括癌症。治疗的理想效果包括降低疾病进展率,缓解或减轻疾病状态,以及减缓或改善预后。缓解可以发生在疾病或病况的体征或症状出现之前,也可以发生在出现之后。因此,“进行治疗”或“治疗”可以包括对疾病或不良病况的“进行预防”或“预防”。此外,“进行治疗”或“治疗”不需要完全减轻体征或症状,不需要治愈,并且特别包括对患者只有轻微作用的方案。
本申请中使用的术语“治疗益处”或“治疗有效”是指在该病况的医疗处理方面促进或增强受试者健康的任何东西。这包括但不限于减少疾病的体征或症状的频率或严重程度。例如,癌症的治疗可以包括缩小肿瘤的大小、降低肿瘤的侵袭性、降低癌症的生长速度、防止转移或延迟转移的发生。癌症的治疗也可能指延长癌症患者的生存期。
II.本公开的实施方案
本公开涉及用于有效癌症疗法的方法和组合物,包括避免对治疗个体产生严重影响的癌症疗法。在特定实施方案中,疗法包括以离体方式修饰免疫细胞,以及向患有癌症的个体施用经修饰的免疫细胞。在特定实施方案中,免疫细胞属于特定类型的T细胞,例如Treg,并且它们的修饰使得Treg的标准功能不受有害影响。
本公开的特定实施方案包括SRC-3作为免疫细胞中的关键靶标,所述免疫细胞至少包括Treg。就Treg而言,特异性隔室特异性破坏至少在乳腺癌症同基因肿瘤模型中导致肿瘤根除,如本文所示。将目前破坏Treg中SRC-3的策略与其他免疫检查点抑制剂区分开的一个关键区别是SRC3是一种核蛋白,并且本公开中的修饰调节Treg的功能而不失去Treg的所有活性,这在其他情况下可能导致严重的副作用。此外,本公开建立了一种使用基于CRISPR的基因靶向离体特异性消融T细胞中的SRC3的方法。在应用于人CD4+淋巴细胞的特定实施方案中,例如,本公开提供了用于治疗癌症的基于过继性T细胞/Treg治疗剂的方法。
III.免疫细胞
在本公开中,对免疫细胞进行修饰,以破坏内源性SRC-3的表达,从而使细胞能够有效治疗细胞的受体个体的癌症。尽管免疫细胞可以是任何种类,但在特定实施方案中,它们是任何种类的T细胞,包括至少Treg和B细胞。
本公开的实施方案包括T细胞的修饰,包括Treg,其中该修饰仍然允许T细胞执行其所需的功能(对于Treg,控制对自身和外来颗粒(抗原)的免疫应答)。因此,本文包含的方法和组合物提供的癌症疗法与使用经修饰的T细胞(包括经修饰的T调节细胞)的其他疗法相比具有降低的毒性风险。
任何类型的T细胞都可以用于本公开的方法和组合物中。术语“T细胞”是指T淋巴细胞,包括但不限于CD4+T细胞、CD8+T细胞,γ:δ+T细胞或NK T细胞。CD4+T细胞包括TH0、TH1和TH2细胞,以及T调节细胞(Treg)。至少有三种类型的T调节细胞:CD4+CD25+Treg、CD25TH3 Treg和CD25 TR1 Treg。“细胞毒性T细胞”是指可以杀死另一个细胞的T细胞。大多数细胞毒性T细胞是CD8+MHC I类限制性T细胞,然而一些细胞毒性T淋巴细胞是CD4+。在特定的实施方案中,本公开的T细胞是CD4+。
可以选择本文所用的任何T细胞用于一种或多种特异性标志物和/或针对一种或多种特异性标志物进行选择。任何选择步骤都可以通过正选择或负选择,或者两者而发生。在特定实施方案中,Treg是CD4+、CD25+和/或FOXP3+。在特定情况下,Treg是CD4+、CD25+和FOXP3+。在一些实施方案中,Treg是CTL相关蛋白4(CTLA4)+、C-C趋化因子受体7型(CCR7)+和/或CD62抗原配体(CD62L)+。本文还包括通过SRC-3基因的破坏随后停止表达FOXP3、CD25和/或CD4+的Treg。
在一些实施方案中,用本公开的方法和组合物靶向CD4+免疫细胞,包括CD4+T细胞,以破坏SRC-3的表达,并且在至少一些情况下,可以从中进一步选择Treg用作治疗性细胞。在备选的情况下,修饰各种CD4+细胞并将其共同用作治疗性细胞,而无需进一步分离Treg的步骤。
在使用T细胞的情况下,T细胞的来源可以属于任何合适的来源,包括脾脏、骨髓、血液、血浆或其组合。在某些情况下,T细胞是商业上获得的。在任何情况下,T细胞可以相对于受体个体是自体的,或者相对于受体个体可以是同种异体的或同基因的。可以在工程化细胞以具有SRC-3破坏的步骤之前操作T细胞。在某些情况下,从来源处理细胞,例如去除不需要的成分。细胞可以在使用前暴露于一种或多种增强其在个体中的活性的组合物,例如一种或多种靶向SRC-3的试剂,或其他组合物,例如一种或多种细胞因子和/或一种或多种生长因子。细胞可以在修饰步骤之前、期间和/或之后暴露于一种或多种靶向SRC-3的试剂以破坏SRC-3的表达。
IV.基因表达的修饰
在特定的实施方案中,本公开的免疫细胞被修饰以具有改变的SRC-3表达,并且对这种细胞的工程化可以通过任何合适的方法进行。对工程化的细胞进行遗传修饰以在细胞中缺乏内源性SRC-3的表达或具有减少的表达。表达的减少可以达到本领域的标准方法无法检测到的水平。
在一些实施方案中,改变的基因表达是通过对基因进行破坏来进行的,例如敲除、插入、错义或移码突变,例如双等位基因移码突变,基因的全部或部分(例如一个或多个外显子或其部分)的缺失,和/或敲入。例如,改变的基因表达可以通过序列特异性或靶向的核酸酶来实现,包括DNA结合靶向的核酸酶,如锌指核酸酶(ZFN)和转录激活子样效应核酸酶(TALEN),以及RNA指导的核酸酶,例如CRISPR相关的核酸酶(Cas),特别设计为靶向SRC-3基因的序列或其一部分。
在一些实施方案中,通过破坏基因来改变基因的表达、活性和/或功能。在一些方面,对基因进行修饰,使得其表达与不存在基因修饰或不存在引入以实现修饰的组分时的表达相比减少至少或约20%、30%或40%,通常至少或约50%、60%、70%、80%、90%、95%、96%、97%、98%、99%或更多。
在一些实施方案中,改变是瞬时的或可逆的,使得基因的表达在以后恢复。在其他实施方案中,改变是不可逆的或瞬时的,例如,是永久的。
在一些实施方案中,通常以靶向方式,通过诱导SRC-3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基因改变。在一些实施方案中,双链或单链断裂是通过核酸酶,例如核酸内切酶,例如基因靶向核酸酶进行的。在一些方面,断裂是在基因的编码区中,例如在SRC-3外显子中诱导的。例如,在一些实施方案中,诱导发生在SRC-3编码区的N-末端部分附近,例如在第一外显子、第二外显子或随后的外显子中。
在一些方面,双链或单链断裂通过细胞修复过程进行修复,例如通过非同源末端连接(NHEJ)或同源定向修复(HDR)进行。在一些方面,修复过程是容易出错的,并导致基因的破坏,例如移码突变,例如双等位基因移码突变,这可以导致SRC-3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/或过早终止密码子的存在导致基因的表达、活性和/或功能的破坏。
任何用于破坏SRC-3表达的试剂都可以以任何合适的方式递送到受体细胞,例如包括任何类型的T细胞(包括Treg)的免疫细胞。在特定的实施方案中,试剂可以通过任何种类的核感染、脂转染、任何种类的电穿孔、阳离子聚合物、非病毒载体(如质粒)、病毒载体(包括腺病毒载体、逆转录病毒载体、慢病毒载体或腺相关病毒载体)、基于环状直链淀粉的载体、任何种类的纳米颗粒(包括使用PLGA/PLA或基于DODAP而生产的金属或无机或聚合物纳米颗粒)、脂聚物等来递送。
在一些实施方案中,使用反义技术实现基因改变,例如通过RNA干扰(RNAi)、短干扰RNA(siRNA)、短发夹(shRNA)和/或用于选择性抑制或阻抑基因表达的核酶。siRNA技术是使用具有与从基因转录的mRNA的核苷酸序列同源的序列和与该核苷酸序列互补的序列的双链RNA分子的RNAi。siRNA通常与从基因转录的mRNA的一个区域同源/互补,或者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包含在多顺反子构建体中。
将细胞修饰为具有SRC-3表达的破坏的实例如下:
A.ZFP和ZFN
在一些实施方案中,靶向SRC-3的DNA靶向分子包括与效应蛋白如核酸内切酶融合的DNA结合蛋白,如一种或多种锌指蛋白(ZFP)或转录激活因子样蛋白(TAL)。实例包括ZFN、TALE和TALEN。
在一些实施方案中,DNA靶向分子包含一种或多种锌指蛋白(ZFP)或其结构域,其以序列特异性方式结合DNA。ZFP或其结构域是通过一个或多个锌指以序列特异性方式结合DNA的较大蛋白质内的蛋白质或结构域,锌指是结合结构域内的氨基酸序列的区域,其结构通过锌离子的配位而稳定。术语“锌指DNA结合蛋白”通常缩写为锌指蛋白或ZFP。ZFP中有靶向特定DNA序列(通常9-18个核苷酸长)的人工ZFP结构域,由单个手指的组装产生。
ZFP包括其中单个指结构域长度为约30个氨基酸并且包含α螺旋的ZFP,所述α螺旋包含两个通过锌与单个β转角的两个半胱氨酸配位的不变组氨酸残基,并且具有两个、三个、四个、五个或六个指。通常,ZFP的序列特异性可以通过在锌指识别螺旋上的四个螺旋位置(-1、2、3和6)进行氨基酸取代来改变。因此,在一些实施方案中,ZFP或含ZFP的分子是非天然存在的,例如,经工程化为与所选择的靶位点结合。
在一些实施方案中,DNA靶向分子是或包含与DNA切割结构域融合以形成锌指核酸酶(ZFN)的锌指DNA结合结构域。在一些实施方案中,融合蛋白包含来自至少一种liS型限制性酶的切割结构域(或切割半结构域)和一个或多个锌指结合结构域,其可以或可以不被工程化。在一些实施方案中,切割结构域来自liS型限制性内切核酸酶Fok I。Fok I通常催化DNA的双链切割,在一条链上距其识别位点9个核苷酸处,在另一条链距其识别位点13个核苷酸处。
许多基因特异性工程化的锌指可在商业上获得。例如,Sangamo Biosciences(Richmond,CA,USA)与Sigma-Aldrich(St.Louis,MO,USA)合作开发了一种用于锌指构建的平台(CompoZr),使研究人员能够完全绕过锌指构建和验证,并为数千种蛋白质提供特异性靶向的锌指(Gaj等人,Trends in Biotechnology,2013,31(7),397-405)。在一些实施方案中,使用市售的锌指或者是定制设计的。(例如,参见Sigma-Aldrich目录编号CSTZFND、CSTZFN、CTil lKT和PZD0020)。
B.TAL、TALE和TALEN
在一些实施方案中,用于SRC-3的DNA靶向分子包含天然存在的或工程化的(非天然存在的)转录激活因子样蛋白(TAL)DNA结合结构域,例如在转录激活因子样蛋白效应(TALE)蛋白中,参见例如美国专利公开号2011/0301073,通过引用将其全部并入本文。
TALE DNA结合结构域或TALE是包含一个或多个TALE重复结构域/单元的多肽。重复结构域参与TALE与其同源靶DNA序列的结合。单个“重复单元”(也称为“重复”)的长度通常为33-35个氨基酸,并且与天然存在的TALE蛋白中的其他TALE重复序列显示出至少一些序列同源性。每个TALE重复单元包括1或2个DNA结合残基,构成重复可变双残基(RVD),通常在重复的位置12和/或13处。已经确定了用于这些TALE的DNA识别的天然(经典)编码,使得位置12和13处的HD序列导致与胞嘧啶(C)结合,NG与T结合,NI与A结合,NN与G或A结合,NO与T结合以及非经典(非典型)RVD也是已知的。在一些实施方案中,TALE可以通过设计对靶DNA序列具有特异性的TAL阵列而靶向任何基因。靶序列通常以胸苷开始。
在一些实施方案中,该分子是DNA结合核酸内切酶,例如TALE核酸酶(TALEN)。在一些方面,TALEN是包含衍生自TALE的DNA结合结构域和用于切割核酸靶序列的核酸酶催化结构域的融合蛋白。
在一些实施方案中,TALEN识别并切割基因中的靶序列。在某些方面,DNA的切割导致双链断裂。在某些方面,断裂刺激同源重组或非同源末端连接(NHEJ)的速率。一般来说,NHEJ是一种不完美的修复过程,通常会导致在切割位点处DNA序列的变化。在某些方面,修复机制包括通过直接重新连接或经由所谓的微同源介导的末端连接,使两个DNA末端的剩余部分重新连接。在一些实施方案中,经由NHEJ的修复导致小的插入或缺失,并且可以用于破坏并由此抑制基因。在一些实施方案中,修饰可以是至少一个核苷酸的取代、缺失或添加。在一些方面,可以通过本领域公知的方法鉴定和/或选择其中发生了切割诱导的诱变事件(即与NHEJ事件连续的诱变事件)的细胞。
在一些实施方案中,组装TALE重复以特异性靶向基因。(Gaj等人,2013)。已经构建了一个靶向18,740个人类蛋白质编码基因的TALEN文库(Kim等人,2013)。定制设计的TALE阵列可通过Cellectis Bioresearch(Paris,France)、Transposagen Biopharmaceuticals(Lexington,KY,USA)和Life Technologies(Grand Island,NY,USA)商购得到。具体而言,靶向CD38的TALEN是可商购的(参见Gencopoeia,目录号HTN222870-1、HTN222870-2和HTN222870-3)。示例性分子描述于例如美国专利公开号US 2014/0120622和2013/0315884中。
在一些实施方案中,TALEN作为由一种或多种质粒载体编码的反式基因引入。在一些方面,质粒载体可以包含选择标志物,其提供对接收所述载体的细胞的鉴定和/或选择。
C.RGEN(CRISPR/Cas系统)
在一些实施方案中,SRC-3基因的改变是使用一种或多种DNA结合核酸进行的,例如通过RNA指导的核酸内切酶(RGEN)的改变。例如,可以使用成簇的规则间隔短回文重复序列(CRISPR)和CRISPR相关(Cas)蛋白进行改变。通常,“CRISPR系统”统称为转录物和其他参与CRISPR相关(“Cas”)基因表达或指导其活性的元件,包括编码Cas基因的序列、tracr(反式激活CRISPR)序列(例如tracrRNA或活性部分tracrRNA),tracr配偶序列(在内源性CRISPR系统中包括“直接重复”和tracrRNA处理的部分直接重复)、引导序列(在内源性CRISPR系统的上下文中也称为“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序列特异性结合DNA的非编码RNA分子(指导)RNA和具有核酸酶功能性(例如,两个核酸酶结构域)的Cas蛋白(例如,Cas9)。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,例如衍生自包括内源性CRISPR系统的特定生物体,例如酿脓链球菌(Streptococcus pyogenes)。
在一些方面,将Cas核酸酶和gRNA(包括对靶序列具有特异性的crRNA和固定的tracrRNA的融合)引入细胞中。通常,使用互补碱基配对,在gRNA的5’端的靶位点将Cas核酸酶靶向靶位点,例如基因。靶位点可以基于其在原间隔区相邻基序(PAM)序列的紧邻5’的位置来选择,例如典型的NGG或NAG。在这方面,gRNA通过修饰指导RNA的前20、19、18、17、16、15、14、14、12、11或10个核苷酸以对应于靶DNA序列而靶向所需序列。通常,CRISPR系统的特征在于促进在靶序列位点处形成CRISPR复合物的元件。通常,“靶序列”通常是指指导序列被设计为对其具有互补性的序列,其中靶序列和引导序列之间的杂交促进CRISPR复合物的形成。只要有足够的互补性来引起杂交并促进CRISPR复合物的形成,就不一定需要完全的互补性。
CRISPR系统可以在SRC-3靶位点诱导双链断裂(DSB),随后如本文所述发生破坏或改变。在其他实施方案中,被认为是“缺口酶”的Cas9变体用于在靶位点切割单链。例如,可以使用成对的缺口酶来提高特异性,每个缺口酶由一对不同的gRNA靶向序列指导,使得在引入缺口的同时引入5’突出端。在其他实施方案中,将催化失活的Cas9与异源效应结构域例如转录阻遏因子或激活因子融合,以影响基因表达。
SRC-3的靶序列可以包含任何多核苷酸,例如DNA或RNA多核苷酸。靶序列可以位于细胞的细胞核或细胞质中,例如位于细胞的细胞器内。通常,可用于重组到包含靶序列的靶基因座中的序列或模板被称为“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被称为编辑模板。在某些方面,重组是同源重组。
通常,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蛋白复合的引导序列)的形成导致靶序列中或附近(例如在1、2、3、4、5、6、7、8、9、10、20、50或更多碱基对内)的一条或两条链被切割。tracr序列可以包含或由野生型tracr序列的全部或一部分组成(例如野生型tratr序列的约或超过约20个、26个、32个、45个、48个、54个、63个、67个、85个或更多个核苷酸),也可以形成CRISPR复合物的部分,例如通过沿着tracr序列的至少一部分与可操作地连接到指导序列的tracr配偶序列的全部或一部分杂交而形成。tracr序列与tracr配偶序列具有足够的互补性,以杂交并参与CRISPR复合物的形成,例如当最佳比对时,沿着tracr配偶体序列的长度具有至少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表达的一种或多种载体引入细胞中,使得CRISPR系统元件的表达指导在一个或多个靶位点处形成CRISPR复合物。组分也可以作为蛋白质和/或RNA递送到细胞中。例如,Cas酶、连接到tracr配偶序列的指导序列和tracr序列可以各自可操作地连接到单独载体上的单独调节元件。备选地,由相同或不同的调控元件表达的两种或更多种元件可以组合在单个载体中,一种或多种附加的载体提供CRISPR系统的不包括在第一载体中的任何成分。载体可以包括一个或多个插入位点,例如限制性内切核酸酶识别序列(也称为“克隆位点”)。在一些实施方案中,一个或多个插入位点位于一种或多种载体的一个或多种序列元件的上游和/或下游。当使用多个不同的指导序列时,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、对应的靶序列。
载体可以包括可操作地连接到编码CRISPR酶的酶编码序列的调控元件,例如Cas蛋白。Cas蛋白的非限制性实例包括Cas1、Cas1B、Cas2、Cas3、Cas4、Cas5、Cas6、Cas7、Cas8、Cas9(也称为Csn1和Csx2)、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及其同源物,或其修改版本。这些酶是已知的;例如,酿脓链球菌Cas9蛋白的氨基酸序列可以在SwissProt数据库中以登录号Q99ZW2找到。
CRISPR酶可以是Cas9(例如,来自酿脓链球菌或肺炎链球菌(S.pneumonia))。CRISPR酶可以在靶序列的位置,例如在靶序列内和/或在靶序列互补序列内,引导一条或两条链的切割。载体可以编码相对于相应的野生型酶突变的CRISPR酶,使得突变的CRISPR酶缺乏切割含有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-丙氨酸取代(D10A)将Cas9从切割两条链的核酸酶转化为缺口酶(切割单链)。在一些实施方案中,Cas9缺口酶可以与一个或多个指导序列(例如两个指导序列)组合使用,所述指导序列分别靶向DNA靶标的有义链和反义链。这种组合允许两条链都被切割并用于诱导NHEJ或HDR。
在一些实施方案中,编码CRISPR酶的酶编码序列是密码子优化的,用于在特定细胞(如真核细胞)中表达。真核细胞可以是特定生物体的细胞或来源于特定生物体,例如哺乳动物,包括但不限于人、小鼠、大鼠、兔、狗或非人灵长类动物。通常,密码子优化是指通过用在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维持天然氨基酸序列来修饰核酸序列以在目的宿主细胞中增强表达的过程。各种物种对特定氨基酸的某些密码子表现出特定的偏好。密码子偏好(生物体之间密码子使用的差异)通常与信使RNA(mRNA)的翻译效率相关,而信使RNA的翻译效率又被认为取决于被翻译的密码子的性质和特定转运RNA(tRNA)分子的可用性。细胞中所选tRNA的优势通常反映了肽合成中最常用的密码子。因此,基于密码子优化,可以针对给定生物体中的最佳基因表达来定制基因。
通常,指导序列是与靶多核苷酸序列具有足够互补性以与靶序列杂交并指导CRISPR复合物与靶序列的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进行最佳比对时,指导序列与其对应的靶序列之间的互补程度为约或大于约50%、60%、75%、80%、85%、90%、95%、97.5%、99%或更高。
最佳比对可以通过使用任何合适的用于比对序列的算法来确定,其非限制性示例包括Smith-Waterman算法、Needleman-Wunsch算法、基于Burrows-Wheeler变换的算法(例如Burrows Wheeler Aligner)、Clustal W、Clustar X、BLAT、Novoalign(NovocraftTechnologies)、ELAND(Illumina,San Diego,CA)、SOAP(可在soap.genomics.org.cn上获得)和Maq(可在maq.sourceforge.net上获得)。
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酶融合蛋白可以包括任何附加的蛋白质序列,以及任选地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以下一种或多种活性的蛋白质结构区:甲基化酶活性、去甲基化酶活性、转录激活活性、转录抑制活性、转录释放因子活性、组蛋白修饰活性,RNA切割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-葡萄糖醛酸酶、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)以及包括蓝色荧光蛋白(BFP)的自发荧光蛋白。CRISPR酶可以与编码结合DNA分子或结合其他细胞分子的蛋白质或蛋白质片段的基因序列融合,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酶的融合蛋白的部分的附加结构域描述于US20110059502中,其通过引用并入本文。
V.使用方法
在一些实施方案中,本公开提供了采用免疫疗法用于癌症治疗的方法,包括施用有效量的本公开的SRC-3被破坏的免疫细胞。在一个实施方案中,本文涵盖通过向个体施用有效量的SRC-3被破坏的细胞疗法对个体的癌症进行治疗、延迟其进展、延迟其发病或降低其患癌症风险的方法。本发明的方法可以应用于治疗实体癌或血液学癌症。在特定实施方案中,癌症是SRC-3阳性的。癌症可能是原发性、转移性、难治性等。癌症可以属于任何类型和任何阶段。个体可能有患癌症的风险,包括高于普通人群,个体有患癌症的风险可能是因为个体或家族史,因为该个体是烟草使用者,肥胖,饮酒过量,患有某些类型的病毒感染,如人乳头瘤病毒(HPV),暴露于一种或多种致癌物,或过度暴露于辐射,包括来自太阳的紫外线辐射。当量大于群体的平均个体时,该量可能被认为是过量的。
所公开的治疗方法可用于的肿瘤包括任何恶性细胞类型,例如在实体瘤或血液肿瘤中发现的那些。示例性实体瘤可以包括但不限于选自由乳腺、卵巢、胰腺、结肠、盲肠、胃、脑、头、颈、肾、喉、肉瘤、肺、膀胱、黑色素瘤、前列腺、胃组织和子宫内膜组成的组的器官的肿瘤。示例性血液肿瘤包括骨髓肿瘤、T或B细胞恶性肿瘤、白血病、淋巴瘤、母细胞瘤、骨髓瘤等。可使用本文提供的方法治疗的癌症的特定实例包括但不限于肺癌(包括小细胞肺癌、非小细胞肺癌、肺腺癌和肺鳞癌)、腹膜的癌症、胃癌或胃部癌症(包括胃肠道癌症和胃肠道间质癌症),胰腺癌、宫颈癌、卵巢癌、肝癌、膀胱癌、乳腺癌、结肠癌、结直肠癌、子宫内膜癌或子宫癌、涎腺癌、肾脏癌或肾癌、前列腺癌、外阴癌、甲状腺癌、各种类型的头颈部癌和黑色素瘤。
虽然癌症不限于以下组织学类型,但其具体组织学类型如下:赘生物,恶性;癌症;癌症,未分化的;巨细胞癌和梭形细胞癌;小细胞癌;乳头状癌;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛母质癌;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;合并肝细胞癌和胆管癌;小梁腺癌;腺样囊性癌;腺瘤性息肉中的腺癌;腺癌,家族性大肠息肉病;实体癌;类癌肿瘤,恶性;鳃泡腺癌(branchiolo-alveolar adenocarcinoma);乳头状腺癌;嫌色癌;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;卵泡腺癌;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;皮肤附属物癌;顶泌腺癌;皮脂腺癌;盯聍腺癌;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;佩吉特病,乳腺;腺泡细胞癌;腺鳞状细胞癌;伴有鳞状化生的腺癌;胸腺瘤,恶性;卵巢间质瘤,恶性;卵泡膜瘤,恶性;颗粒细胞瘤,恶性;睾丸母细胞瘤,恶性;塞托利细胞癌;间质细胞瘤,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;血管肉瘤;恶性黑色素瘤;无色素黑色素瘤;浅表扩散性黑色素瘤;雀斑痣性恶性黑色素瘤;肢端雀斑痣性黑色素瘤;结节性黑色素瘤;巨大色素痣中的恶性黑色素瘤;上皮样细胞黑色素瘤;蓝色痣,恶性;肉瘤;纤维肉瘤;纤维组织细胞瘤,恶性;黏液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎性横纹肌肉瘤;肺泡横纹肌肉瘤;间质肉瘤;混合瘤,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;布伦纳肿瘤,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;卵巢甲状腺肿,恶性;绒毛膜癌;中肾瘤,恶性;血管肉瘤;血管内皮瘤,恶性;卡波西肉瘤;血管外皮细胞瘤,恶性;淋巴管肉瘤;骨肉瘤;癌旁骨肉瘤;软骨肉瘤;软骨母细胞瘤,恶性;间充质软骨肉瘤;骨巨细胞瘤;尤文氏肉瘤;牙源性肿瘤,恶性;成釉细胞性牙肉瘤;成釉细胞瘤,恶性;成釉细胞纤维肉瘤;松果体瘤,恶性;脊索瘤;胶质瘤,恶性;室管膜瘤;星形细胞瘤;原生质体星形细胞瘤;原纤维星形细胞瘤;星形母细胞瘤;胶质母细胞瘤;少突胶质瘤;少突胶质母细胞瘤;原始神经外胚层;小脑肉瘤;神经节细胞神经母细胞瘤;神经母细胞瘤;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;霍奇金病;霍奇金的;副神经节瘤;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;其他特定的非霍奇金淋巴瘤;B细胞淋巴瘤;低级别/滤泡性非霍奇金淋巴瘤(NHL);小淋巴细胞(SL)NHL;中级别/滤泡性NHL;中级别弥漫性NHL;高级别免疫母细胞NHL;高级别淋巴细胞性NHL;高级别小型非切割细胞NHL;大型疾病NHL;套细胞淋巴瘤;艾滋病相关淋巴瘤;Waldenstrom巨球蛋白血症;恶性组织细胞增多症;多发性骨髓瘤;肥大细胞肉瘤;免疫增殖性小肠疾病;白血病;淋巴白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;髓细胞白血病;嗜碱性白血病;嗜酸性白血病;单核细胞白血病;肥大细胞白血病;巨核细胞白血病;髓细胞肉瘤;毛细胞白血病;慢性淋巴细胞白血病(CLL);急性成淋巴细胞白血病(ALL);急性髓细胞白血病(AML);和慢性粒细胞白血病。
在本发明的某些实施方案中,将免疫细胞递送给有此需要的个体,例如患有癌症或怀疑患有癌症的个体。然后,这些细胞增强个体的免疫系统来攻击各自的癌症。在某些情况下,向个体提供一个或多个剂量的免疫细胞。在向个体提供两个或更多个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,并且在特定实施方案中,剂量之间的持续时间为1、2、3、4、5、6、7或更多天。在某些情况下,施用之间的持续时间为1-24小时、1-7天、1-4周、1-12个月或更长,或其间的任何范围。
在一些实施方案中,可以在免疫细胞疗法之前对受试者施用非清髓性淋巴细胞清除性化疗。非清髓性淋巴细胞清除性化疗可以是任何合适的此类疗法,可以通过任何合适的途径进行施用。例如,非清髓性淋巴细胞清除性化疗可以包括环磷酰胺和氟达拉滨的施用,特别是如果癌症是可以转移的黑色素瘤的情形。施用环磷酰胺和氟达拉滨的一种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,之后施用约25mg/m2的氟达拉滨五天。
在某些实施方案中,将促进免疫细胞生长和活化的一种或多种生长因子和/或一种或多种细胞因子与免疫细胞同时或在免疫细胞之后施用给受试者。免疫细胞生长因子可以是促进免疫细胞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细胞介素(IL)-2、IL-7、IL-15和IL-12,其可以单独使用或以各种组合使用,例如IL-2和IL-7、IL-2和IL-15、IL-7和IL-15,IL-2、IL-7与IL-15、IL-12和IL-7,IL-12和IL-15或IL-12和IL2。
治疗有效量的免疫细胞可以通过多种途径进行施用,包括胃肠外施用,例如静脉内、腹腔内、肌肉内、胸骨内或关节内注射、鼻内、动脉内或通过输注。
用于过继性细胞疗法的免疫细胞的治疗有效量是在被治疗的受试者中达到所需效果的量。例如,这可能是抑制生长、导致癌症消退或改善至少一种癌症症状所需的免疫细胞的量。
免疫细胞群体可以以与疾病一致的治疗方案进行施用,例如在一到几天内单次或几次剂量以缓解疾病状态,或在延长时间内的定期剂量以抑制疾病进展和防止疾病复发。制剂中使用的确切剂量也将取决于施用途径、疾病或病症的严重程度,并应根据医生的判断和每个患者的情况来决定。免疫细胞的治疗有效量将取决于被治疗的受试者、痛苦的严重程度和类型以及施用方式。在一些实施方案中,可用于治疗人类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个免疫细胞/m2。在特定的实施方案中,用于治疗人类受试者的剂量范围为约3.8×109至约3.8×1010个免疫细胞/m2。在另外的实施方案中,免疫细胞的治疗有效量可以在约5×106个细胞/kg体重至约7.5×108个细胞/kg重量变化,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。免疫细胞的确切量很容易由本领域技术人员基于受试者的年龄、体重、性别和生理状况来确定。有效剂量可以从体外或动物模型测试系统得出的剂量-应答曲线中推断出来。
免疫细胞可与一种或多种其他治疗剂组合施用,以治疗癌症。组合疗法可以包括但不限于一种或多种抗肿瘤剂或疫苗。在特定情况下,在免疫细胞之外可以施用化疗药物(如甲氨蝶呤、曲奥舒凡、白消安);放射;或趋化因子、白细胞介素或其抑制剂(例如BAFF、IL-2、抗IL-2R、IL-4、JAK激酶抑制剂)。可以在施用免疫细胞之前、期间或之后施用这样的附加药物试剂,取决于所需效果。可以通过相同途径或通过不同途径,并且在相同位置或不同位置进行细胞和一种或多种附加抗癌试剂的这种施用。
VI.药物组合物
本文提供了包含免疫细胞(例如SRC-3被破坏的免疫细胞,包括T细胞如Treg细胞)和药学上可接受的运载体的药物组合物和制剂。在一些实施方案中,提供了组合物,其包含:(a)本文所涵盖的任何免疫细胞;和(b)一种或多种靶向SRC-3的试剂。在这种情况下,(a)和(b)可以是或可以不是在相同的制剂中,并且可以或可以不被配置为通过相同的施用途径进行递送。
本文所述的药物组合物和制剂可以通过将具有所需纯度的活性成分(如抗体或多肽)与一种或多种任选的药学上可接受的运载体(Remington’s Pharmaceutical Sciences第22版,2012)以冻干制剂或水溶液的形式混合来制备。药学上可接受的运载体在所用的剂量和浓度下通常对受者无毒,包括但不限于:缓冲剂如磷酸盐、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(如十八烷基二甲基苄基氯化铵;氯化六甲铵;苯扎氯铵;苯索氯铵;苯酚、丁醇或苄醇;对羟基苯甲酸烷基酯,如对羟基苯甲酯或对羟基苯丙酯;邻苯二酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(小于约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、双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、海藻糖或山梨醇;形成盐的反离子,例如钠;金属络合物(例如Zn-蛋白质络合物);和/或非离子表面活性剂,例如聚乙二醇(PEG)。本文的示例性药学可接受运载体还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),例如人类可溶性PH-20透明质酸糖蛋白,例如rHuPH20(Baxter International,Inc.)。某些示例性sHASEGP和使用方法,包括rHuPH20,在美国专利公开号2005/0260186和2006/0104968中进行了描述。在一个方面,将sHASEGP与一种或多种额外的糖胺聚糖酶如软骨素酶组合。
VII.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免疫细胞群与至少一种附加疗法的组合。附加疗法可以是放疗、手术、化疗、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、蛋白质疗法或上述的组合。附加治疗可以是辅助或新辅助疗法的形式。附加疗法可以是一种或多种靶向SRC-3的试剂,例如任何种类的抗体、小分子抑制剂、核酸、蛋白质或其组合。
在一些实施方案中,附加疗法是施用SRC-3的小分子抑制剂或抗转移剂。在一些实施方案中,附加疗法是施用副作用限制剂(例如,旨在减轻治疗副作用的发生和/或严重程度的试剂,如抗恶心试剂等)。在一些实施方案中,附加疗法是放疗。在一些实施方案中,附加疗法是手术。在一些实施方案中,附加治疗是放疗和手术的组合。在一些实施方案中,附加疗法是γ辐射。在一些实施方案中,附加疗法是靶向PBK/AKT/mTOR途径的疗法、HSP90抑制剂、微管蛋白抑制剂、凋亡抑制剂和/或化学预防剂。附加疗法可以是本领域已知的一种或多种化疗剂。
免疫细胞疗法可以相对于附加癌症疗法在之前、期间、之后或以各种组合进行施用。施用的时间间隔从同时到几分钟到几小时,到几天,到几周不等。在将免疫细胞疗法与附加治疗剂分开提供给患者的实施方案中,通常可以确保在每次递送之间没有经过显著的时间段,使得这两种化合物仍然能够对患者施加有利的组合作用。
对患者施用本实施方案的任何化合物或疗法将遵循施用此类化合物的一般方案,同时考虑到试剂的毒性(如果有的话)。因此,在一些实施方案中,存在可归因于组合疗法的监测毒性的步骤。
A.化疗
根据本实施方案,可以使用多种化疗剂。术语“化疗”是指使用药物治疗癌症。“化疗剂”是指在治疗癌症中施用的化合物或组合物。这些试剂或药物根据其在细胞内的活性模式进行分类,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。备选地,可以基于试剂直接交联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表征试剂。
化学治疗剂的实例包括烷基化剂,如噻替哌(thiotepa)和环磷酰胺(cyclosphosphamide);烷基磺酸盐类(alkyl sulfonates),例如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶类(aziridines),例如苯佐替派(benzodopa)、卡波醌(carboquone)、美妥替派(meturedopa)和乌瑞替派(uredopa);乙撑亚胺类(ethylenimines)和甲基蜜胺类(methylamelamines),包括六甲蜜胺(altretamine)、三乙撑蜜胺(triethylenemelamine)、三乙撑磷酰胺(triethylenephosphoramide)、三乙撑硫代磷酰胺(triethiylenethiophosphoramide)和三羟甲蜜胺(trimethylolomelamine);番荔枝内酯类(acetogenins)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱(camptothecin)(包括合成类似物拓扑替康(topotecan));苔藓抑素(bryostatin);callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);隐藻素类(cryptophycins)(特别是隐藻素1和隐藻素8);多拉司他汀(dolastatin);倍癌霉素(duocarmycin)(包括合成类似物,KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);pancratistatin;sarcodictyin;海绵抑素(spongistatin);氮芥类(nitrogen mustards),例如苯丁酸氮芥(chlorambucil)、萘氮芥(chlomaphazine)、胆磷酰胺(chlorophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、双氯乙基甲胺(mechlorethamine)、盐酸氧氮芥(mechlorethamine oxidehydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)和尿嘧啶氮芥(uracil mustard);亚硝脲类(nitrosoureas),例如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimnustine);抗生素类,诸如烯二炔类抗生素(例如加利车霉素(calicheamicin),尤其是加利车霉素γ1I和加利车霉素ωI1;达内霉素(dynemicin),包括达内霉素A;二膦酸盐类(bisphosphonates),诸如氯膦酸盐(clodronate);埃斯培拉霉素(esperamicin);以及新制癌素(neocarzinostatin)生色团和相关色蛋白烯二炔类抗生素生色团、阿克拉霉素(aclacinomysins)、放线菌素(actinomycin)、氨曲霉素(authramycin)、偶氮丝氨酸(azaserine)、博来霉素(bleomycin)、放线菌素C(cactinomycin)、carabicin、洋红霉素(caminomycin)、嗜癌霉素(carzinophilin)、色霉素(chromomycinis)、放线菌素D(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-吡咯代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(mitomycin)例如丝裂霉素C、霉酚酸(mycophenolic acid)、诺拉霉素(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、泊非霉素(porfiromycin)、嘌呤霉素(puromycin)、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);抗代谢物类,诸如甲氨蝶呤(methotrexate)和5-氟尿嘧啶(fluorouracil)(5-FU);叶酸类似物,诸如二甲叶酸(denopterin)、蝶酰三谷氨酸(pteropterin)和三甲曲沙(trimetrexate);嘌呤类似物,诸如氟达拉滨(fludarabine)、6-巯基嘌呤(6-mercaptopurine)、硫咪嘌呤(thiamiprine)和硫鸟嘌呤(thioguanine);嘧啶类似物,诸如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)和氟尿苷(floxuridine);雄激素类,诸如卡鲁睾酮(calusterone)、丙酸屈他雄酮(dromostanolonepropionate)、表硫雄醇(epitiostanol)、美雄烷(mepitiostane)和睾内酯(testolactone);抗肾上腺类,诸如米托坦(mitotane)和曲洛司坦(trilostane);叶酸补充剂,例如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);bestrabucil;比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);elfomithine;依利醋铵(elliptinium acetate);埃博霉素(epothilone);依托格鲁(etoglucid);硝酸镓;羟脲(hydroxyurea);香菇多糖(lentinan);氯尼达明(lonidainine);美登木素生物碱类(maytansinoids),诸如美登素(maytansine)和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidanmol);二胺硝吖啶(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(2-ethylhydrazide);丙卡巴肼(procarbazine);PSK多糖复合物(PSKpolysaccharide complex);雷佐生(razoxane);根霉素(rhizoxin);西索菲兰(sizofiran);螺旋锗(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2’,2”-三氯三乙胺;单端孢菌素类(trichothecenes)(尤其是T-2毒素、疣孢菌素(verracurin)A、杆孢菌素(roridin)A和蛇形菌素(anguidine));乌拉坦(urethan);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);gacytosine;阿糖胞苷(arabinoside,“Ara-C”);环磷酰胺(cyclophosphamide);类紫烷醇(taxoids),例如紫杉醇(paclitaxel)和多西他赛吉西他滨(docetaxel gemcitabine);6-硫鸟嘌呤(6-thioguanine);巯基嘌呤(mercaptopurine);铂配位复合物,诸如顺铂(cisplatin)、奥沙利铂(oxaliplatin)和卡铂(carboplatin);长春碱(vinblastine);铂;依托泊苷(etoposide,VP-16);异环磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);长春新碱(vincristine);长春瑞滨(vinorelbine);诺消灵(novantrone);替尼泊苷(teniposide);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基蝶呤(aminopterin);希罗达(xeloda);伊本膦酸盐(ibandronate);伊立替康(irinotecan)(例如,CPT-11);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视黄酸(retinoids),例如视黄酸(retinoic acid);卡培他滨(capecitabine);卡铂(carboplatin)、丙卡巴肼(procarbazine)、普卡霉素(plicomycin)、吉西他滨(gemcitabien)、诺维本(navelbine)、法呢基蛋白转移酶抑制剂、反式铂(transplatinum)和上述任一种的可药用盐、酸或衍生物。
B.放疗
引起DNA损伤并已被广泛使用的其他因素包括通常已知的γ射线、X射线和/或将放射性同位素直接递送至肿瘤细胞。还可以考虑其他形式的DNA损伤因子,例如微波、质子束辐照(美国专利5,760,395和4,870,287)和UV辐射。所有这些因素最有可能引起对DNA、对DNA的前体、对DNA的复制和修复以及染色体的组装和维持的广泛损害。X射线的剂量范围从50至200伦琴的每日剂量持续延长的时间(3至4wk)到单次剂量的2000至6000伦琴。放射性同位素的剂量范围差异很大,并且取决于同位素的半衰期、所发射辐射的强度和类型以及赘生细胞的吸收。
C.免疫疗法
本领域技术人员将理解对于本文所涵盖的方法的附加免疫疗法可以与实施方案的方法组合或结合使用。在癌症治疗的情况下,免疫治疗剂通常依靠使用免疫效应细胞和分子来靶向和破坏免疫细胞。利妥昔单抗就是这样的例子。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。单独的抗体可以充当疗法的效应物,或者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,并且仅用作靶向试剂。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。多种效应细胞包括细胞毒性T细胞和NK细胞。
抗体药物缀合物已成为开发癌症治疗剂的突破性方法。癌症是世界上导致死亡的主要原因之一。抗体-药物缀合物(ADC)包含与细胞杀伤药物共价连接的单克隆抗体(MAb)。这种方法将MAb对其抗原靶标的高特异性与高效细胞毒性药物相组合,产生“武装的”MAb,其将有效载荷(药物)递送到具有富集水平的抗原的肿瘤细胞。药物的靶向递送也最大限度地减少了其在正常组织中的暴露,产生降低的毒性并改善的治疗指数。FDA批准了两种ADC药物,即在2011年批准的(本妥昔单抗(brentuximab vedotin))和在2013年批准的/>(恩美曲妥珠单抗(trastuzumab emtansine)或T-DM1),这两种药物仅作为例子验证了该方法。
在免疫疗法的一方面,肿瘤细胞必须携带一些适合于靶向的标志物,即,其在大多数其他细胞上不存在。存在许多肿瘤标志物,并且在本发明实施方案的情况下,这些肿瘤标志物中的任一种都可适于靶向。常见的肿瘤标志物包括CD20、癌胚抗原、酪氨酸酶(p97)、gp68、TAG-72、HMFG、唾液酸路易斯抗原、MucA、MucB、PLAP、层黏连蛋白受体、erb B和p155。免疫疗法的另一个方面是将抗癌作用与免疫刺激作用组合起来。还存在免疫刺激分子,包括:细胞因子,例如IL-2、IL-4、IL-12、GM-CSF、γ-IFN,趋化因子,例如MIP-1、MCP-1、IL-8,以及生长因子,例如FLT3配体。
在一些实施方案中,免疫疗法可以是免疫检查点抑制剂。免疫检查点要么调高信号(例如,共刺激分子),要么调低信号。可以被免疫检查点阻断所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淋巴细胞弱化剂(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)以及T细胞活化的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。在本文提供的方法中可以靶向的另一个免疫检查点是细胞毒性T淋巴细胞相关蛋白4(CTLA-4),也称为CD152。在一些实施方案中,免疫检查点抑制剂是抗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。
D.手术
大约60%的患有癌症的人将接受某种类型的手术,其包括预防、诊断或分期、治愈和姑息手术。治愈手术包括切除术,其中物理地去除、切除和/或破坏癌组织的全部或一部分,并且可与其他疗法例如本发明实施方案的治疗、化疗、放疗、激素疗法、基因疗法、免疫疗法和/或替代疗法结合使用。肿瘤切除术是物理去除肿瘤的至少一部分。除肿瘤切除术外,通过手术的治疗还包括激光手术、冷冻手术、电手术和显微控制手术(莫氏手术)。
在切除癌细胞、组织或肿瘤的一部分或全部之后,可在体内形成腔。可以通过对该区域进行灌注、直接注射或局部应用其他抗癌疗法来完成治疗。这样的治疗可以重复,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的用药量。
VIII.工程化的B细胞及其使用方法
在特定的实施方案中,经工程化为具有SRC-3的破坏的免疫细胞包括B细胞。在特定实施方案中,SRC-3被破坏的B细胞用于B细胞对其有效的任何医疗病况,但在特定实施方案中,经修饰的B细胞被用于治疗一种或多种炎症疾病或治疗任何种类的癌症,例如,包括至少B细胞淋巴瘤和本文别处列出的癌症。
在某些实施方案中,B细胞是从商业上或从需要治疗的个体获得的。B细胞可以从健康个体获得用于同种异体目的。可以通过标准方法离体工程化B细胞,以破坏B细胞中内源性SRC-3的表达。在某些情况下,工程化的B细胞暴露于一种或多种试剂,包括TGF-□或肿瘤特异性抗原,其一旦施用给有需要的个体就促进B细胞的功效。
在特定的实施方案中,将与非工程化的B细胞相比缺乏SRC-3表达或具有降低的SRC-3表达的工程化的B细胞以有效量施用给患有或有患一种或多种炎性疾病风险的个体。尽管炎性疾病可以是任何种类的,但在具体实施方案中,疾病是过敏、哮喘、自身免疫性疾病、腹腔疾病、肾小球肾炎、肝炎、炎性肠病、灌流前损伤、移植排斥、强直性脊柱炎(AS)、痛风;肌炎、类风湿性关节炎、硬皮病、干燥综合征、系统性红斑狼疮(SLE、狼疮)、盆腔炎性疾病或血管炎,仅作为例子。B细胞治疗可以降低或延迟疾病的严重程度,延迟疾病的发作,改善疾病的一种或多种症状,等等。
IX.制品或试剂盒
本文还提供了包含免疫细胞的制品或试剂盒。免疫细胞可以是T细胞,例如Treg细胞。试剂盒可包含不具有SRC-3破坏的细胞、产生SRC-3破坏的一种或多种试剂(包括,例如,促进特异性敲低或敲除SRC-3的核酸和蛋白质)、具有SRC-3破坏的细胞、一种或多种靶向SRC-3的试剂、缓冲剂、盐、使用说明书或其组合。在具体实施方案中,试剂盒包括用于靶向SRC-3的CRISPR试剂、T调节细胞或两者。
制品或试剂盒还可以包括包装插页,其包含使用免疫细胞来治疗或延迟个体癌症进展的说明。本文所述的任何免疫细胞都可以包括在制品或试剂盒中。合适的容器包括例如瓶子、小瓶、袋和注射器。容器可以由多种材料例如玻璃或塑料(如聚氯乙烯或聚烯烃)或金属合金(如不锈钢或镍钼合金)形成。在一些实施方案中,容器容纳制剂和在容器上或与容器相关联的标签,可以指示使用的说明。制品或试剂盒可以进一步包括从商业和用户的角度来看所需的其他材料,包括其他缓冲剂、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另一种试剂(例如,化疗剂和抗肿瘤剂)。用于一种或多种试剂的合适容器包括,例如,瓶子、小瓶、袋和注射器。
实施例
包括以下实施例以说明本发明的一些优选实施方案。本领域技术人员应该理解,以下实施例中公开的技术代表发明人发现的在本公开的方法和组合物的实践中发挥良好作用的技术,因此可以认为构成其实践的具定方式。然而,根据本公开内容,本领域技术人员应当理解,可以在不脱离本公开的精神和范围的情况下对所公开的特定实施方案进行许多改变,并且仍可获得相同或相似的结果。
实施例1
SRC-3控制免疫细胞群体
尽管SRC-3(基因名:NCOA3)在乳腺癌细胞中的细胞自主致癌功能已得到很好的证实(1-9),但在免疫细胞中表达的SRC-3的作用很大程度上尚不清楚。小鼠中Src-3基因的遗传缺失导致淋巴谱系的扩增,导致CD4+和CD8+T细胞以及B淋巴细胞的数量增加(首次在(11)中报道,最近的数据概括了这一观察结果,如图1所示)。在Src-3 KO小鼠的外周血中,几种细胞因子水平升高,包括CXCL2、IL2、IL1α和β、CCL2和GCSF(数据未显示)。这些发现揭示了SRC-3的免疫抑制功能,强调了它是一种新型的转录免疫检查点调节因子,并强烈表明对免疫细胞中的SRC-3进行药物抑制可以增强其攻击癌症细胞的能力。然而,SRC-3发挥这种作用的确切免疫细胞群体仍有待确定。公共数据集的基因表达分析显示在Treg细胞中的SRC-3表达非常高,并且与Foxp3的表达相关(图2)。在核受体信号传导图谱(NURSA)中的296个精选共调节因子中,NCOA3(Src-3)是Treg中对于Foxp3表达的第二最相关的共激活因子(图3)。
实施例2
遗传破坏TREG中的SRC-3促进乳腺癌肿瘤的稳健清除
鉴于先前报道的数据显示SRC-3-/-小鼠具有淋巴增殖表型,并且破坏Treg中的SRC-3表达导致该细胞类型中免疫抑制蛋白的表达减少,本发明人使用小鼠遗传模型系统将SRC-3表征为在“Treg隔室”中特异性的免疫检查点调节蛋白。本发明人将SRC-3flox/flox小鼠回交10代到纯C57BL/6J背景中,然后将该小鼠与已经在C57BL/6J背景下的Foxp3:EGFP-Cre-ERT2小鼠杂交以产生Treg:SRC-3KO小鼠。
他莫昔芬处理将激活Cre,特异性导致对Treg中SRC-3基因的破坏。使用这种遗传工程化的小鼠模型系统,在与C57BL/6J背景兼容的广泛的免疫活性的、同基因肿瘤细胞系(包括下面显示的E0771小鼠乳腺肿瘤系)中,测试SRC-3基因破坏的效果。E0771肿瘤特别具有侵袭性,并且众所周知,在该模型系统中很难控制肿瘤生长。然而,在Treg中的SRC-3被特异性破坏的宿主小鼠中,肿瘤基本上被根除,而在野生型宿主动物中,肿瘤迅速生长到大尺寸(图4)。
这项研究的结果有力地证明了SRC-3是一个新发现的关键免疫检查点调节靶点。这项动物模型实验的另一个预料不到的重要结果是,这些动物看起来是健康的,脾脏大小正常,体重或活动没有任何显著变化。这与Foxp3突变的scurfy小鼠形成对比,后者具有严重的自身免疫表型,并在幼年时死亡。在一个特定的实施方案中,Treg:SRC-3KO小鼠不同于scurfy小鼠,因为Foxp3细胞中SRC-3的遗传破坏仅破坏Treg的免疫抑制活性的一个子集。临床上现有的免疫检查点调节剂药物具有强烈的、剂量限制的和危及生命的副作用。因此,在特定的实施方案中,SRC-3SMI仅对Treg生物学的某些方面的抑制使得可以仅靶向其肿瘤相关的免疫抑制,而不会通常过度刺激其他组织中不想要的免疫系统事件。
实施例3
针对TREG中的SRC-3的基于CRISPR的靶向作用
遗传工程化的小鼠模型表明,特异性靶向Treg中的SRC-3导致对侵袭性乳腺癌的根除。为了将这一发现转化为临床上可转化的治疗,本发明人已经开发了一种使用下述基于CRISPR的方法来靶向小鼠免疫细胞中的SRC-3基因的方法。在特定的实施方案中,遗传改变的细胞被用作T细胞/Treg的来源,用于过继疗法以消除同基因小鼠模型系统中的乳腺肿瘤。该过程适用于人类CD4+细胞(例如),这些细胞可用于治疗患有乳腺癌或其他癌症的人类患者。
从一只12周龄的雄性C57BL/6小鼠身上采集脾。通过使用注射器的柱塞端通过40μm细胞过滤器将脾脏捣碎,制备脾细胞的单细胞悬浮液。将脾细胞悬浮液置于锥形管中,离心(1500rpm,5min),并使用RBC去除缓冲液(Sigma R 7757)对红细胞团块进行RBC去除,得到米色淋巴细胞团块。使用补充有CD28/IL2/MeSH的全RPMI培养基(L-glu、FBS、抗生素)将淋巴细胞铺板在CD3包被的板中。培养三天后,评估细胞活力(80%),并使用Miltenyi CD4富集试剂盒(130-104-545)对大量淋巴细胞进行CD4富集。将富集的CD4细胞(40M)在上述条件下再铺板两天,导致细胞群体扩增至超过1亿个细胞。
核感染:使用Lonza 4D核感染仪和原代细胞核感染试剂盒(Lonza V4XP-3024),用Cas9-NCoA3指导RNA(gRNA)核糖核蛋白(RNP)对富集的和扩增的CD4细胞群体进行核感染。通过将荧光标记的trcrRNA(IDT#1075928)与crRNA(IDT)以1:1的比例混合(11.25μlTrcrRNA-ATTO 550与三种不同的crRNA,每个3.75μl)来制备RNP。gRNA(由trcrRNA+crRNA构成)在37℃孵育15min。然后将gRNA(浓度50μM)与Cas9蛋白(IDT#1081059,浓度60μM)以3:1的比例混合,得到含有过量gRNA组分的15μM RNP。将RNP在37℃孵育15min,然后以1:5的比例与核感染缓冲剂混合。制备了13个核感染反应——每个反应包含800万至1000万个CD4细胞和130μl RNP核感染缓冲剂混合物(RNP的最终浓度为3.5μM,具有3倍过量的gRNA组分)。通过对每个nucleocuvvete进行制造商的EN138脉冲程序,在4D核转染器中进行核转染。
核转染后,向细胞提供培养基,并将其转移到覆盖有CD3的培养皿中。在过夜复苏后,通过流式细胞术对细胞进行分选,以分离受核感染的群体(通过追踪荧光标记的gRNA)。
将分选的群体(阳性和阴性)培养五天,用于遗传编辑,以进行蛋白质周转和细胞扩增。随后,从这些细胞中分离总RNA,然后进行两步RT-qPCR以测试SRC-3(基因符号Ncoa3)表达的破坏。
这些结果表明,对T淋巴细胞中SRC-3的基于CRISPR的破坏是稳健的,并产生高产量的活的、可扩增的细胞,用于进一步的下游应用,如过继性T细胞转移。
数据强烈暗示SRC-3是Treg中的关键靶点,其在该细胞室中的特异性破坏导致乳腺癌症同基因肿瘤模型中的肿瘤根除。目前破坏Treg中的SRC-3的策略与其他免疫检查点抑制剂不同,因为SRC-3是一种调节Treg功能的核蛋白,以这种方式促进肿瘤根除而不会完全破坏Treg功能,Treg功能的破坏与潜在的严重副作用有关。本公开提供了一种使用基于CRISPR的基因靶向在从小鼠获得的T细胞中离体特异性消融SRC-3的方法。当使用人类CD4+淋巴细胞应用时,该方法具有明确的、可转化的潜力,作为用于治疗人类癌症的基于过继性T细胞/Treg的治疗剂。
实施例4
过继性SRC-3KO-TREG细胞转移至乳腺肿瘤小鼠
鉴于先前报道的数据显示SRC-3-/-小鼠具有淋巴增殖表型,并且Treg中SRC-3表达的破坏导致该细胞类型中免疫抑制蛋白的表达减少,本发明人使用小鼠遗传模型系统将SRC-3表征为在“Treg隔室”中特异性的免疫检查点调节蛋白。本发明人将SRC-3flox/flox小鼠回交10代到纯C57BL/6J背景中,然后将该小鼠与已经在C57BL/6J背景下的Foxp3:EGFP-Cre-ERT2小鼠杂交以产生Treg:SRC-3KO C57BL/6J小鼠。
他莫昔芬处理激活Cre,导致Treg细胞中SRC-3基因的特异性破坏。使用这种遗传工程化的小鼠模型系统以产生SRC-3敲除(KO)Treg细胞,该细胞从SRC-3KO Treg动物取出的脾脏中分离。从脾脏中分离出约160万个SRC-3KO Treg细胞,并且分离的SRC-3KO-Treg细胞具有92%的存活率。作为对照,还从SRC-3flox/flox(SRC-3F/F)小鼠取出的脾脏中分离出Treg细胞(约190万),并且分离的对照细胞具有93%的存活率。
在携带来源于E0771细胞的肿瘤的C57BL/6J小鼠中测试分离的SRC-3KO Treg细胞的作用,该肿瘤细胞来源于最初从C57BL-6小鼠中自发肿瘤分离的小鼠乳腺癌症细胞系(图6)。E0771肿瘤特别具有侵袭性,并且在免疫完整的C57BL/6J小鼠中难以抑制E0771瘤的生长。然而,与没有过继性Treg细胞转移(无AT)的C57BL/6J小鼠中E0771肿瘤的生长相比,在用分离的SRC-3KO Treg细胞(90万个细胞)处理的小鼠中,E0771瘤基本上被根除。相反,与没有过继性Treg细胞转移的C57BL/6J小鼠中E0771肿瘤的生长相比,来自SRC-3F/F对照小鼠的90万个Treg细胞的转移(Cont Treg,对照SRC-3+Treg)没有抑制E0771细胞的生长(图7)。此外,过继性SRC-3KO-Treg细胞转移没有引起明显的毒性,并且接受SRC-3KO-Treg细胞的动物仍然具有繁殖能力(数据未显示)。
本研究的结果表明,SRC-3KO Treg细胞的过继性转移对癌症治疗有用,并且在特定实施方案中,SRC-3KO Treg细胞用于控制和/或消除肿瘤生长。
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尽管已经详细描述了本公开及其优点,但应该理解,在不脱离所附权利要求所定义的设计的精神和范围的情况下,可以在本文中进行各种改变、替换和更改。此外,本申请的范围并不旨在局限于说明书中描述的过程、机器、制造、物质组成、手段、方法和步骤的特定实施方案。如本领域普通技术人员将从本公开中容易理解的那样,根据本公开,可以利用当前存在的或以后要开发的执行与本文所描述的对应实施方案基本相同的功能或实现基本相同的结果的过程、机器、制造、物质组成、手段、方法或步骤。因此,所附权利要求旨在在其范围内包括这样的过程、机器、制造、物质组成、手段、方法或步骤。
Claims (60)
1.一种工程化的免疫细胞,其包含对类固醇受体共激活因子-3(SRC-3)的破坏。
2.权利要求1所述的免疫细胞,其中所述免疫细胞是T细胞。
3.权利要求2所述的免疫细胞,其中所述T细胞是T调节细胞。
4.权利要求2或3所述的免疫细胞,其中所述T细胞是CD4+。
5.权利要求2-4中任一项所述的免疫细胞,其中所述T细胞是CD25+细胞。
6.权利要求2-4中任一项所述的免疫细胞,其中所述T细胞是FOXP3+细胞。
7.权利要求1-6中任一项所述的免疫细胞,其中所述破坏进一步限定为免疫细胞经遗传修饰以具有降低的SRC-3表达水平或基本上不具有SRC-3表达。
8.权利要求1-7中任一项所述的免疫细胞,其中所述免疫细胞是使用一种或多种引导RNA和Cas9酶工程化的。
9.权利要求1-8中任一项所述的免疫细胞,其中所述免疫细胞相对于个体是自体的。
10.权利要求1-8中任一项所述的免疫细胞,其中所述免疫细胞相对于个体是同种异体的。
11.一种组合物,包含:
(a)权利要求1-10中任一项所述的免疫细胞;和
(b)一种或多种靶向SRC-3的试剂。
12.权利要求11所述的组合物,其中(a)和(b)在不同的制剂中。
13.权利要求11所述的组合物,其中(a)和(b)在相同的制剂中。
14.权利要求11-13中任一项所述的组合物,其中靶向SRC-3的试剂是小分子抑制剂、抗体、蛋白质、核酸或其组合。
15.权利要求14所述的组合物,其中SRC-3的小分子抑制剂是蟾毒灵、棉酚、疣孢菌素A、SI-2、SI-10、SI-12、其功能衍生物或其组合。
16.权利要求14或15所述的组合物,其中所述抗体是单克隆抗体或多克隆抗体。
17.权利要求14-16中任一项所述的组合物,其中所述抗体是5E11、LS-C801929、PA1-845、AX15.3、PA5-29854、EPR4374(3)或其组合。
18.一种治疗个体的癌症的方法,包括向个体施用治疗有效量的权利要求1-10中任一项所述的细胞的步骤。
19.权利要求18所述的方法,其中所述癌症是SRC-3+癌症。
20.权利要求18或19所述的方法,其中所述癌症是乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、胃癌、多发性骨髓瘤、甲状腺癌症或胰腺癌。
21.权利要求18-20中任一项所述的方法,其中在施用步骤之前,将细胞离体暴露于有效量的一种或多种靶向SRC-3的试剂。
22.权利要求21所述的方法,其中靶向SRC-3的试剂是小分子抑制剂、抗体、蛋白质、核酸或其组合。
23.权利要求22所述的方法,其中SRC-3的小分子抑制剂是蟾毒灵、棉酚、疣孢菌素A、SI-2、SI-10、SI-12、其功能衍生物、其组合。
24.权利要求22或23所述的方法,其中所述抗体是单克隆抗体或多克隆抗体。
25.权利要求22-24中任一项所述的方法,其中所述抗体是5E11、LS-C801929、PA1-845、AX15.3、PA5-29854、EPR4374(3)或其组合。
26.权利要求18-25中任一项所述的方法,其中向个体施用治疗有效量的附加癌症疗法。
27.权利要求26所述的方法,其中所述附加癌症疗法包括手术、放疗、化疗、激素疗法、药物疗法、蛋白质疗法、免疫疗法或其组合。
28.权利要求26或27所述的方法,其中所述附加癌症疗法包括一种或多种靶向SRC-3的试剂。
29.权利要求28所述的方法,其中所述靶向SRC-3的试剂是小分子抑制剂、抗体、蛋白质、核酸或其组合。
30.权利要求29所述的方法,其中SRC-3的小分子抑制剂是蟾毒灵、棉酚、疣孢菌素A、SI-2、SI-10、SI-12、其功能衍生物或其组合。
31.权利要求29或30所述的方法,其中所述抗体是单克隆抗体或多克隆抗体。
32.权利要求29-31中任一项所述的方法,其中所述抗体是5E11、LS-C801929、PA1-845、AX15.3、PA5-29854、EPR4374(3)或其组合。
33.权利要求26-32中任一项所述的方法,其中基本上同时将细胞和附加癌症疗法施用给个体。
34.权利要求26-32中任一项所述的方法,其中在不同时间将细胞和附加癌症疗法施用给个体。
35.权利要求26-34中任一项所述的方法,其中细胞和附加癌症疗法在相同的制剂中。
36.权利要求26-34中任一项所述的方法,其中细胞和附加癌症疗法在不同的制剂中。
37.权利要求18-36中任一项所述的方法,其中静脉内、腹膜内、动脉内、局部、通过吸入、肌肉内、胸骨内、通过关节内注射或通过输注施用细胞。
38.权利要求18-37中任一项所述的方法,其中施用细胞一次或多次。
39.权利要求38所述的方法,其中当将细胞多次施用给个体时,施用之间的持续时间在1-24小时、1-7天、1-4周或1-12个月内。
40.一种治疗个体的癌症的方法,包括向个体施用治疗有效量的权利要求11-17中任一项所述的组合物的步骤。
41.权利要求40所述的方法,其中(a)和(b)在不同的制剂中施用给个体。
42.权利要求40所述的方法,其中(a)和(b)在相同的制剂中施用给个体。
43.权利要求41所述的方法,其中基本上同时将(a)和(b)施用给个体。
44.权利要求41所述的方法,其中在不同时间将(a)和(b)施用给个体。
45.权利要求44所述的方法,其中当在不同时间将(a)和(b)施用给个体时,(a)与(b)施用之间的持续时间在1-24小时、1-7天、1-4周或1-12个月内。
46.权利要求40-45中任一项所述的方法,其中将组合物施用给个体一次或不同次数。
47.权利要求46所述的方法,其中当在不同时间将组合物施用给个体时,施用之间的持续时间在1-24小时、1-7天、1-4周或1-12个月内。
48.权利要求40-47中任一项所述的方法,其中所述癌症是SRC-3+癌症。
49.权利要求40-48中任一项所述的方法,其中所述癌症是乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、胃癌、多发性骨髓瘤、甲状腺癌或胰腺癌。
50.权利要求40-49中任一项所述的方法,其中在施用步骤之前,将(a)中的细胞离体暴露于有效量的一种或多种靶向SRC-3的试剂。
51.一种产生权利要求1-10中任一项所述的免疫细胞的方法,包括破坏在免疫细胞中的SRC-3表达的步骤。
52.权利要求51所述的方法,其中所述免疫细胞是T细胞。
53.权利要求51或52所述的方法,其中所述免疫细胞是Treg。
54.权利要求52或53所述的方法,其中所述方法进一步限定为:
(a)分别获得CD4+T细胞或CD4+Treg;和
(b)将CD4+T细胞或CD4+Treg分别暴露于一种或多种分别破坏T细胞或Treg中内源性SRC-3表达的试剂。
55.权利要求54所述的方法,其中从脾脏、骨髓、血液、血浆或其组合获得T细胞或Treg。
56.权利要求54或55所述的方法,进一步包括从CD4+T细胞获得T调节细胞的步骤。
57.权利要求56所述的方法,其中T调节细胞是CD25+和/或Fox3p+。
58.权利要求54-57中任一项所述的方法,其中一种或多种破坏T细胞中内源性SRC-3表达的试剂包括核酸。
59.权利要求58所述的方法,其中一种或多种破坏T细胞中内源性SRC-3表达的试剂包括CRISPR试剂。
60.权利要求51-59中任一项所述的方法,还包括将免疫细胞离体暴露于有效量的一种或多种靶向SRC-3的试剂的步骤。
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US7097993B2 (en) | 2003-06-25 | 2006-08-29 | Wisconsin Alumni Research Foundation | Method for identifying an agent that modulates type 1 phosphatidylinositol phosphate kinase isoform β661 activity |
US8080534B2 (en) | 2005-10-14 | 2011-12-20 | Phigenix, Inc | Targeting PAX2 for the treatment of breast cancer |
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US20130259925A1 (en) | 2012-03-28 | 2013-10-03 | Baylor College Of Medicine | METHODS AND COMPOSITIONS TO TREAT CANCER USING BIFUNCTIONAL SRC 3 shRNA |
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