CN112188895A - 通过强制表达CD8αβ和1类限制性T细胞受体将CD4 T细胞重编程为细胞毒性CD8细胞 - Google Patents
通过强制表达CD8αβ和1类限制性T细胞受体将CD4 T细胞重编程为细胞毒性CD8细胞 Download PDFInfo
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Abstract
本公开的实施方案包括与T细胞疗法的改善有关的方法和组合物。在特定的实施方案中,在CD8+T细胞中表达转基因CD8αβ共受体后,CD8+T细胞疗法得到增强。在某些实施方案中,在CD4+T细胞中表达转基因CD8αβ共受体后,CD4+T细胞具有了细胞毒性细胞功能用于过继转移。在特定的实施方案中,表达TCR和表达CD8αβ共受体的CD4+和CD8+T细胞用于过继转移。
Description
相关申请的交叉引用
本申请要求于2018年4月19日提交的美国临时专利申请系列号62/659,971的优先权,其全部内容通过引用并入本文。
技术领域
本公开的实施方案至少涉及免疫学,细胞生物学,生物学,分子生物学,细胞治疗和医学领域,至少包括癌症医学。
背景技术
T细胞受体(TCR)工程化的过继T细胞疗法对血液系统恶性肿瘤(例如多发性骨髓瘤)的治疗取得了令人鼓舞的结果1。然而,大多数靶向肿瘤相关自身抗原的TCR是从自体库中分离的,功能性亲和力(functional avidity)低。胸腺选择过程中消除了大多数具有高亲和力TCR的T细胞,幸存的克隆经过外周微调以避免自身免疫疾病2,3。这种微小的(modest)结合亲和力可能会限制TCR转基因T细胞识别在恶性细胞上的低水平的肿瘤相关抗原(TAA)的能力。克服这一局限性的策略包括从同种异体库中分离高亲和力TCR4或产生和选择高亲和力合成TCR5,6。虽然这种策略可能是成功的1,5,6,但它们可能导致严重的不希望的交叉反应,伴随可能致命的脱靶效应7-9。因此,发明人现已研究出了替代方法。大多数靶向衍生自肿瘤相关抗原的表位的TCR是HLA I类限制性的,在生理条件下,CD8αβ共受体可增加表达HLA I类限制性TCR的T细胞的功能性亲和力10,11。在CD8 T细胞中,由于引入的TCR和内源性CD8之间拷贝数的不平衡,有限的内源共受体可用性(endogenous co-receptoravailability)可能会阻碍它们的全面和持续的活化。经病毒载体进行工程化的T细胞表达所导入的转基因的超生理拷贝数12,而CD8共受体则以生理水平表达。本文显示,CD8αβ共受体与转基因TCR一起的强制表达增加了总体TCR+ T细胞与靶细胞的相互作用,产生增强的抗肿瘤功能。
CD8+和CD4+ T细胞之间的相互作用对于有效的免疫应答的协调至关重要13。因此,测定了在表达转基因HLA I类限制性TCR的CD4+ T细胞中强制表达CD8αβ共受体的结果。CD4+ T细胞从多方面促进了针对病毒感染的抗原特异性免疫力,在长期肿瘤控制的启动和维持中必不可少14。例如,在骨髓移植后输注巨细胞病毒特异的CD8+ T细胞克隆以治疗感染可控制病毒血症,但是只有在存在另外的CD4+辅助T细胞的情况下,这些转移的CD8+ T细胞才能持续存在15。当使用靶向肿瘤的T细胞疗法时,CD4+ T细胞的重要性也得到了类似的体现。例如,转移性胆管癌患者的新抗原反应性肿瘤浸润淋巴细胞大部分包含在CD4+ TH1区室中,这些细胞的过继转移导致肿瘤消退16。在Burkitt淋巴瘤异种移植小鼠模型中,已经报道了靶向CD19的嵌合抗原受体(CAR)T细胞的抗肿瘤活性协同增强,该模型使用特定的CD4:CD8比率的嵌合抗原受体T细胞17,而一项对淋巴瘤患者用1:1的CD4:CD8比率(在最终产物中)的CD19-CAR T细胞的临床试验产生高的肿瘤应答率,伴随着T细胞扩增以及CD4+和CD8+亚群的持续存在18,这表明CD4+和CD8+肿瘤特异性T细胞对恶性控制都是最佳的。
结果表明:(1)CD8共受体的可用性增加可增强TCR+ CD8+ T细胞功能,(2)强制表达CD8αβ和转基因MHC I类限制性TAA特异性TCR的CD4+ T细胞被重编程为多功能杂化细胞毒性效应细胞,同时保留CD4+ TH细胞的辅助功能。这些杂化细胞在体外和体内具有增强的抗肿瘤功能,伴随减少的功能耗竭和改善的扩增,与TCR-肽-MHC复合物的增加的稳定性和TCR信号传导传导相关联。
因此,本公开通过提供增强共受体依赖性TCR转基因CD8+ T细胞的功能以及使杂合CD4+ T细胞具有细胞毒性和辅助功能的方法来解决本领域过继转移(adoptivetransfer)的需要。
概述
本公开的实施方案包括与对需要其的哺乳动物个体的细胞疗法有关的方法和组合物。所述细胞疗法包括通过人工工程化而有效地用作诸如癌症的医学病症的疗法的细胞。细胞疗法包括免疫效应细胞,例如具有靶向抗原的受体的T细胞或NK细胞,并且该受体可能对于细胞而言是内源和天然的,或者可以是工程化的。在某些实施方案中,修饰细胞疗法的细胞以表达增强用于疗法的细胞的功效的蛋白质,特别是所述细胞还表达靶向特定抗原的受体(相对于细胞而言是天然的或不是天然的)。在特定实施方案中,受体靶向的抗原是癌症抗原。尽管在至少某些情况下,所述受体是T细胞受体(TCR),但在替代情况下,所述受体是嵌合抗原受体(CAR),或者所述细胞可以表达两者。
在特定的实施方案中,增强用于疗法的细胞的功效的蛋白质是包含CD8-α和/或CD8-β链的分化簇8(cluster of differentiation 8),CD8)。无论T细胞是CD4+ T细胞还是CD8+ T细胞,其都被修饰以表达CD8+。对于CD8+ T细胞,CD8+ T细胞中CD8αβ共受体表达水平的增加增强了细胞中天然TCR有效的能力,也增强了转基因CD8+ T细胞中工程化TCR有效的能力。在将CD4+ T细胞(其为天然辅助T细胞)修饰成表达CD8αβ的情况下,转基因表达使CD4+ T细胞也具有细胞毒活性。
本公开的实施方案包括增强对个体的免疫效应细胞疗法的方法,其包括以下步骤:向所述个体提供有效量的以下一项或两项:表达外源CD8αβ共受体、并任选地表达一种或多种外源工程化抗原受体的CD8+细胞;和表达外源CD8αβ共受体以及一种或多种外源工程化抗原受体的CD4+细胞。在特定情况下,所述工程化抗原受体是T细胞受体(TCR),嵌合抗原受体(CAR)或两者。所述CD8+细胞,CD4+细胞或两者对于所述个体可以是自体的或同种异体的。在一些情况下,所述外源工程化抗原受体和所述外源CD8αβ共受体在所述细胞中从同一载体表达,并且所述载体包含一种或多种表达构建体,其分别表达所述外源工程化抗原受体和所述外源CD8αβ共受体。在特定实施方案中,表达所述外源工程化抗原受体的表达构建体和表达所述外源CD8αβ共受体的表达构建体被2A元件或内部核糖体进入位点(IRES)元件隔开。在一些情况下,所述外源工程化抗原受体和所述外源CD8αβ共受体在所述细胞中从不同载体表达。在任何情况下,所述载体可以是病毒载体(腺病毒载体,腺相关病毒载体,逆转录病毒载体或慢病毒载体)或非病毒载体。
在所述方法的特定实施方案中,所述抗原是肿瘤抗原或病原体抗原。肿瘤抗原的示例包括选自下述的那些:生存素(survivin),PRAME,CD 19,CD20,CD22,κ或轻链,CD30,CD33,CD 123,CD38,ROR1,ErbB2,ErbB3/4,EGFR vIII,癌胚抗原,EGP2,EGP40,间皮素,TAG72,PSMA,NKG2D配体,B7-H6,IL-13受体cc2,IL-11受体R a,MUC1,MUC16,CA9,GD2,GD3,HMW-MAA,CD171,Lewis Y,G250/CAIX,HLA-AI MAGE Al,HLA-A2 NY-ESO-1,PSC1,叶酸受体a,CD44v7/8,8H9,NCAM,VEGF受体,5T4,胎儿AchR,NKG2配体,HER2,BCMA,CD44v6及其组合。
本公开的方法可以进一步包括向所述个体提供有效量的CD4+ T细胞,CD8+ T细胞或其混合物的步骤。在这种情况下,该方法可以进一步包括向所述个体提供额外的癌症治疗的步骤。
本公开的实施方案包括产生具有细胞毒性效应细胞功能和辅助功能的CD4+ T细胞的方法,该方法包括用外源CD8αβ共受体和外源工程化抗原受体转染CD4+ T细胞的步骤。所述工程化抗原受体可以是T细胞受体(TCR),嵌合抗原受体(CAR)或两者。所述外源工程化抗原受体和所述外源CD8αβ共受体在所述细胞中可以从相同载体或可以不从相同载体表达。特别是,所述载体包含一种或多种表达构建体,其分别表达所述外源工程化抗原受体和所述外源CD8αβ共受体。表达所述外源工程化抗原受体的表达构建体和表达所述外源CD8αβ共受体的表达构建体被2A元件或IRES元件隔开。载体包括病毒载体(腺病毒载体,腺相关病毒载体,逆转录病毒载体或慢病毒载体)或非病毒载体。
所述抗原可以是肿瘤抗原或病原体抗原。在一些情况下,所述肿瘤抗原选自下述:生存素,PRAME,CD 19,CD20,CD22,κ或轻链,CD30,CD33,CD 123,CD38,ROR1,ErbB2,ErbB3/4,EGFR vIII,癌胚抗原,EGP2,EGP40,间皮素,TAG72,PSMA,NKG2D配体,B7-H6,IL-13受体cc2,IL-11受体R a,MUC1,MUC16,CA9,GD2,GD3,HMW-MAA,CD171,Lewis Y,G250/CAIX,HLA-AI MAGE Al,HLA-A2 NY-ESO-1,PSC1,叶酸受体a,CD44v7/8,8H9,NCAM,VEGF受体,5T4,胎儿AchR,NKG2配体,HER2,BCMA,CD44v6及其组合。
本公开的方法包括向有此需要的个体(比如患有癌症的个体)提供有效量的所述CD4+ T细胞的步骤。可以向所述个体提供有效量的表达外源CD8αβ共受体、外源工程化抗原受体或两者的CD8+ T细胞,所述个体也可以正在接受额外的癌症治疗。
本公开的实施方案包括增强CD8+ T细胞的细胞毒性的方法,其包括用外源CD8αβ共受体转染所述CD8+ T细胞的步骤。所述CD8+ T细胞还可表达外源工程化抗原受体,比如T细胞受体(TCR)、嵌合抗原受体(CAR)或两者。所述外源工程化抗原受体和所述外源CD8αβ共受体在所述细胞中从相同载体表达。所述载体包含一种或多种表达构建体,其分别表达所述外源工程化抗原受体和所述外源CD8αβ共受体。在一些情况下,表达所述外源工程化抗原受体的表达构建体和表达所述外源CD8αβ共受体的表达构建体被2A元件或IRES元件分开。所述外源工程化抗原受体和所述外源CD8αβ共受体可以在所述细胞中从不同载体表达。可以使用病毒载体(腺病毒载体,腺相关病毒载体,逆转录病毒载体或慢病毒载体)或非病毒载体。
抗原包括肿瘤抗原或病原体抗原。肿瘤抗原包括选自下述的那些:CD 19,CD20,CD22,κ或轻链,CD30,CD33,CD 123,CD38,ROR1,ErbB2,ErbB3/4,EGFR vIII,癌胚抗原,EGP2,EGP40,间皮素,TAG72,PSMA,NKG2D配体,B7-H6,IL-13受体cc2,IL-11受体R a,MUC1,MUC16,CA9,GD2,GD3,HMW-MAA,CD171,Lewis Y,G250/CAIX,HLA-AI MAGE Al,HLA-A2 NY-ESO-1,PSC1,叶酸受体a,CD44v7/8,8H9,NCAM,VEGF受体,5T4,胎儿AchR,NKG2配体,HER2,BCMA,CD44v6及其组合。所述方法可以进一步包括向有此需要的个体提供有效量的所述CD8+ T细胞的步骤。所述方法可以进一步包括向有此需要的个体提供有效量的CD4+ T细胞的步骤。所述CD4+ T细胞可以经工程改造以表达外源CD8αβ共受体,外源工程化抗原受体或两者。所述个体可以患有癌症,并且所述方法可以进一步包括向所述个体提供额外的癌症治疗的步骤。
本公开的实施方案涉及包含转基因表达CD8αβ共受体的CD4+ T细胞的组合物。所述CD4+ T细胞还可以转基因表达一种或多种外源工程化抗原受体,比如TCR、CAR或两者。所述组合物可以进一步包含任何种类的CD8+ T细胞,包括转基因表达CD8αβ共受体、一种或多种外源工程化抗原受体或两者的CD8+ T细胞。
本公开的实施方案包括包含转基因表达CD8αβ共受体和任选地一种或多种外源工程化抗原受体的CD8+ T细胞的组合物。所述工程化抗原受体可以是TCR、CAR或两者。所述组合物可以进一步包含任何种类的CD4+ T细胞,包括转基因表达CD8αβ共受体、一种或多种外源工程化抗原受体或两者的CD4+ T细胞。
特别地考虑到,关于本发明的一个实施方案讨论的任何限制可以适用于本发明的任何其他实施方案。此外,本发明的任何组合物可用于本发明的任何方法中,并且本发明的任何方法可用于生产或利用本发明的任何组合物。在实施例中阐述的一个实施方案的方面是也可以在不同实施例中的其他地方或本申请的其他地方(例如发明概述,实施方案的详细描述,权利要求书和图例说明)讨论的实施方案的上下文中实施的实施方案。
前面已经相当广泛地概述了本公开的特征和技术优点,以便可以更好地理解以下的详细描述。在下文中将描述形成本文权利要求的主题的附加特征和优点。本领域技术人员应当理解,所公开的概念和特定实施方案可以容易地用作修饰或设计用于实现本设计的相同目的的其他结构的基础。本领域技术人员还应该意识到,这样的等同构造不脱离所附权利要求书中所阐述的精神和范围。当结合附图考虑时,从以下描述中将更好地理解被认为是本文公开的设计的特征的新颖特性(关于组织和操作方法二者而言)以及进一步的目的和优点。然而,应该清楚地理解,提供每个附图仅出于说明和描述的目的,不旨在作为对本公开的限制的定义。本发明的另外目的,特征,方面和优点将在下面的描述中部分地阐述,并且部分地从描述中将是显而易见的,或者可以通过实施本发明而获知。将足够详细地描述本公开的各种实施方案以使本领域技术人员能够实施本发明,并且应当理解,可以利用其他实施方案并且可以进行改变而不脱离本发明的范围。因此,以下详细描述不是限制性的,并且本发明的范围由所附权利要求书最好地限定。
附图说明
为了更完整地理解本公开,参考下述说明并结合附图,其中:
图1A-1E:CD4+ T细胞经I类TCR和CD8αβ传导后转变为杂合表型。(图1A)逆转录病毒载体的方案(scheme)。(图1B)与NT对照相比,具有TCR或T8载体的CD4+(红色方块)或CD8+(黑色圆圈)T细胞的传导效率,n=6。CD4+和CD8+ T细胞中(上图)CD8α表达(图1C)、CD8β表达(图1D)和生存素LML dextramer染色(图1E)的代表性直方图,和MFI总结(下图),n=5-7个供体。(图1C,1D,1E)NT:灰色,TCR+:蓝色,T8+:绿色线。平均值±SD,NS:不显著,*p≤0.05,**p≤0.01,***p≤0.001,****p≤0.0001。
图2:T8+ CD4+ T细胞显示出与TCR+或T8+ CD8+ T细胞相似的功能性亲和力。转基因生存素特异性(s24,左上;s16左下)或PRAME特异性(p28,右上;p11,右下)TCR+(空心柱)或T8+(实心柱)CD4+(红色柱)或CD8+(黑色柱)T细胞针对生存素LML或PRAME NLT肽的亲和力,通过IFN-γELISpots测定(SFU/105个转基因细胞)。显示了来自一名代表性供体的数据(每个TCR测试了3名供体)。检测极限:黑色虚线。
图3A-3F。CD8αβ与TCR的共表达赋予CD4+ T细胞以顺序杀伤能力,并改善CD8+ T细胞功能。(图3A)NT,TCR+或T8+ CD4+(红色柱)或CD8+(黑色柱)T细胞与BV173白血病细胞(HLA-A2*02:01+survivin+)的共培养物;E∶T为1∶5,在第3天定量剩余BV173细胞,n=7。(图3B)NT,TCR+或T8+ CD4+(左)或CD8+(右)T细胞与野生型(WT)BV173(实心柱)或β2-微球蛋白敲除(B2M-KO)BV173细胞的共培养物(空心柱);E∶T为1∶5,在第3天定量剩余BV173细胞,n=3。(图3C)顺序共培养物的实验装置。(图3D)CD4+(左)或CD8+(右)T细胞的顺序共培养物。随时间对肿瘤(上图)和T细胞(下图)进行定量,同时对肿瘤细胞进行再攻击(+),n=7。T细胞扩增:TCR+vs T8+ CD4:p<0.0001;TCR+vs T8+ CD8:p=NS;T8+ CD4 vs TCR+ CD8:p=0.002;T8+ CD4 vs CD8,p=0.015,对logAUC进行的t检验。(图3E)在第一次肿瘤攻击(D1)后24小时和在第三次肿瘤攻击(D10)后24小时,共培养物上清液中的细胞因子定量,n=6。(图3F)来自HLA-A*02+(上图)或HLA-A*02-(下图)供体的NT,TCR+或T8+ CD4+(红色)和CD8+(黑色)T细胞的T细胞扩增倍数,n=3-4。(图3A,3B,3E,3F)平均值±SD,NS:不显著,*p≤0.05,**p≤0.01,***p≤0.001,****p≤0.0001。
图4A-4B:TCR-CD8αβ共表达改善单个CD8+ T细胞的顺序杀伤能力,并将单个CD4+T细胞转化为细胞毒性CD8+ T细胞。(图4A)通过TIMING对T细胞与靶细胞之间相互作用的动力学进行单细胞定量。tSeek:效应子和靶细胞第一次相遇的时间,tContact:效应子和靶细胞之间结合的时间,tDeath:从第一次接触到靶细胞凋亡的时间。(图4B)单个效应细胞找到(tSeek)一个(左,E:T为1:1)或两个(右,E:T为1:2)靶细胞(顶行)、与靶标形成稳定突触(synapse)(tContact,中间行)或杀死靶标(tDeath)的累积发生率。TCR+ CD4+ T细胞(红色虚线),T8+ CD4+ T细胞(红色实线),TCR+ CD8+ T细胞(黑色虚线)和T8+ CD8+ T细胞(黑色实线)。NS:不显著,*p≤0.05,**p≤0.01,***p≤0.001,****p≤0.0001,对数秩检验。
图5A-5B:早期TCR信号传导事件的分析。(图5A)pLck Y394磷酸化NT(灰色)、TCR+(蓝色)和T8+(绿色)CD4+或CD8+ T细胞的代表性FACS直方图。(图5B)针对NT对照细胞中的MFI标准化了的pLCK MFI的总结。n=4个供体,平均值±SD,CD4 TCR+vs T8+:104±11 vs173±35%,CD8 TCR+vs T8+:106±7 vs 126±13%,T8+ CD8 vs CD4:126±13 vs 173±35%。NS:不显著,*p≤0.05,**p≤0.01,***p≤0.001,****p≤0.0001。
图6A-6E:转基因CD8αβ增强了TCR转基因CD8+和CD4+ T细胞的体内抗肿瘤功能。(图6A)实验设置。(图6B,6D)来自用(图6B)中CD8+ T细胞或(图6D)中CD4+ T细胞治疗的小鼠的BLI数据的总结。非传导(NT)对照T细胞(n=5,灰色),TCR+ T细胞(n=5,蓝色),T8+ T细胞(n=5,绿色)。(图6B)CD8:NT vs TCR+:p=0.0002,NT vs T8+:p<0.0001,TCR+vs T8+:p=0.01,对log AUC(第28天对比于第0天)进行t检验。(图6D)CD4:TCR+vs T8+:p=0.001,对log AUC(第35天对比于第0天)进行t检验。(图6C,6E),3只代表性小鼠/组随时间成像(通过BLI),颜色尺度(color scale)为5x103至5x104 p/sec/cm2/sr(对于(图6C)中CD8+ T细胞和(图6E)中CD4+ T细胞而言)。
详述
I.定义示例
为了与长期的专利法惯例保持一致,在本说明书中(包括权利要求书中),词语“一种”和“一个”与词语包含一起使用时,表示“一或多个(种)”。本公开的一些实施方案可以由本公开的一个或多个元素、方法步骤和/或方法组成或基本上由其组成。预期可以针对本文所述的任何其他方法或组合物实施本文所述的任何方法或组合物,在不脱离本公开的精神和范围的情况下,所公开的实施方案仍然获得相似或相似的结果。除非明确指出仅指代替代方案或替代方案是互斥的,否则权利要求中的术语“或”的使用是指“和/或”,尽管本公开支持仅提及其中之一和“和/或”的定义。如本文所用,“另一”可以表示至少第二或更多。
为了与长期的专利法惯例保持一致,在本说明书中(包括权利要求书中),词语“一种”和“一个”与词语包含一起使用时,表示“一或多个(种)”。本公开的一些实施方案可以由本公开的一个或多个元素、方法步骤和/或方法组成或基本上由其组成。预期可以针对本文所述的任何其他方法或组合物实施本文所述的任何方法或组合物,并且不同的实施方案可以联合。
在整个本申请中,术语“约”根据其在细胞和分子生物学领域中的简单和普通含义使用,以指示一个值包括用于确定该值的设备或方法的标准差。
在整个说明书中,除非上下文另外要求,否则词语“包括”、“包含”和“具有”将被理解为暗示包括陈述的步骤或元素或者步骤或元素的组,但不排除任何其他步骤或元素或者步骤或元素的组。“由……组成”是指包括且限于短语“由……组成”之后的任何内容。因此,短语“由……组成”表示所列出的元素是必需的或强制性的,并且不存在其他元素。“基本上由……组成”是指包括在短语之后列出的任何元素,并且限于不干扰或不影响本公开中针对所列元素所指明的活性(activity)或作用(action)的其他元素。因此,短语“基本上由……组成”表示所列出的元素是必需的或强制性的,但是没有其他元素是可选的,并且其他元素可能存在或不存在,这取决于它们是否影响所列举的元素的活性或作用。
在整个说明书中,提及“一个实施方案”,“实施方案”,“一个特定实施方案”,“一个相关实施方案”,“某实施方案”,“另外的实施方案”或“进一步的实施方案”或其组合是指就该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,在整个说明书中各个地方出现的前述短语不一定都指的是同一实施方案。此外,这些特定特征、结构或特性可以以任何合适的方式组合在一个或多个实施方案中。
如本文所用,术语“工程化抗原受体”是指与特定抗原结合并且由人工产生的合成细胞表面蛋白。
如本文所用,术语“外源的”相对于例如细胞使用时,指的是通过重组工程方法由人提供给细胞的分子。该术语不同于自然界中发现对于所述细胞而言天然的内源性分子。
“治疗”疾病或病症或者疾病或病症的治疗是指执行方案,该方案可包括向患者施用一种或多种药物或疗法(包括细胞),以减轻所述疾病的至少一种体征或症状。理想的治疗效果包括降低疾病进展速度,改善或减轻疾病状态,延迟至少一种症状的发作以及缓解或改善预后。缓解可以在疾病或病症的征兆或症状出现之前,以及在它们出现之后或两者兼而有之。因此,“治疗”可包括“预防”疾病或不良状况。另外,“治疗”不需要完全缓解一个或多个体征或症状,不需要治愈,并且特别包括仅对患者有轻微效果的方案。
在本申请全文中使用的术语“治疗益处”或“治疗上有效”是指就病症的医学治疗而言促进或增强受试者的健康的任何情形。这包括但不限于减少疾病的一种或多种体征或症状的频率或严重程度。例如,癌症的治疗可以涉及例如肿瘤尺寸的减小,肿瘤浸润性的减少,癌症生长速率降低和/或转移的预防。癌症的治疗还可以指延长患有癌症的受试者的生存。
“受试者”和“患者”以及“个体”是指人类或非人类,例如灵长类,哺乳动物和脊椎动物。在特定的实施方案中,受试者是人,狗,猫,马,牛等。
短语“药学上可接受的或药理学上可接受的”是指当适当地施用于动物(例如人)时不产生不利、过敏或其他不良反应的分子实体和组合物。根据本公开,包含抗体或另外的活性成分的药物组合物的制备对于本领域技术人员将是已知的。此外,对于动物(例如人)给药,应理解,制剂应符合FDA生物标准办公室(FDA Office of Biological Standards)要求的无菌性,热原性(pyrogenicity),一般安全性和纯度标准。
如本文所用,“药学上可接受的载体”包括任何和所有水性溶剂(例如,水,醇/水溶液,盐溶液,肠胃外媒介物,例如氯化钠,林格氏葡萄糖等),非水性溶剂(例如丙二醇,聚乙二醇,植物油和可注射的有机酯,例如油酸乙酯),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,像这样的本领域普通技术人员已知的材料及其组合。根据已广泛知晓的参数调节药物组合物中各种组分的pH和确切浓度。
II.一般实施方案
本公开的实施方案包括对受体工程化的过继T细胞疗法的改进。本公开的方法通过将治疗细胞修饰为能够用工程化受体靶向低亲和力抗原而无需使用可能导致有害作用的高亲和力受体,从而扩展了过继T细胞疗法的有效选项(effective option)。
A.CD4+ T细胞
本公开的方法包括在转基因表达CD8αβ链后产生兼具辅助功能和细胞毒性的CD4+T细胞用于过继转移。在特定情况下,存在产生具有表面表达CD8αβ链的CD4+ T细胞的方法,目的是产生具有识别和结合靶向pMHC I类复合物能力的CD4+ T细胞。
本文产生具有识别I类表位的活性的本公开的CD4+ T细胞。因此,由于转基因表达CD8αβ,本文包含的方法将CD4+细胞重定向至I类限制性表位。细胞除了能够识别I类表位之外,细胞还具有除表达TH2的天然活性外,表达TH1细胞因子(例如IFNγ,TNFα,穿孔素和/或粒酶B)的能力。
本公开的实施方案包括方法和组合物,其中CD4+ T细胞(和CD8+ T细胞)包含CD8αβ转基因表达,该表达使该细胞缺乏显著的杀伤活性,包括与不进行CD8αβ转基因表达而扩增的T细胞相比。
在特定的实施方案中,表达足够水平的CD8αβ的转基因CD4+ T细胞成为靶向I类pMHC的杂化细胞毒性和辅助T细胞,其在单细胞水平上有效地具有CD8+和CD4+ T细胞功能。因此,CD8αβ将具有低亲和力I类TCR的单个CD4+ T细胞重编程为具有增强的体内功能的杂化细胞毒性和辅助T细胞。
本公开的实施方案包括将CD4+ T细胞重编程使其具有CD4+和CD8+ T细胞的活性。在特定的实施方案中,CD4+ T细胞除细胞毒性活性外还包括辅助T细胞活性。因此,在特定情况下,CD4+ T细胞是杂化的和多功能的。在特定情况下,通过表达转基因的外源提供的CD8共受体,将CD4+ T细胞工程化,使其具有这些特征,并且此类细胞能够产生TH1和TH2细胞因子。该细胞还包含系列杀伤活性,并包含抗肿瘤功能。
表达CD8共受体的CD4+细胞包含细胞毒性的能力可以针对一种或多种外源工程化抗原受体(包括TCR和CAR)来利用。
B.CD8+ T细胞
在特定的实施方案中,方法和组合物涉及在CD8+ T细胞中利用外源CD8αβ共受体以增加细胞的效力。在特定情况下,CD8+ T细胞表达外源工程化抗原受体(例如HLA I类限制性TCR),并且CD8αβ共受体在细胞中的共表达可改善细胞的功能性亲和力。在其他情况下,修饰CD8+ T细胞以表达增强内源TCR活性的外源CD8αβ共受体。
所述方法和组合物至少通过增加CD8+ T细胞中CD8αβ共同受体的可用性,包括增加CD8αβ的细胞表面水平使其超过自然存在的水平,来改进CD8+ T细胞疗法。因此,在将CD8+ T细胞用于任何种类的细胞治疗时,在特定的实施方案中CD8+ T细胞表达外源CD8αβ共受体。
实施方案包括通过增加群体中至少一些细胞中CD8共受体的可用性来增强CD8+ T细胞群体的功能。本公开的方法克服了对于过继转移应用而言CD8+ T细胞中内源CD8共受体太少的限制因素。因此,在本公开的特定实施方案中,存在增加CD8+ T细胞中CD8共受体的可用性以增强CD8+ T细胞的功能的方法。
CD8共受体可以在CD8+ T细胞中使用,无论该细胞是否为人工抗原受体转基因的。在特定的实施方案中,本发明的方法和组合物增强了受体转基因(例如TCR和/或CAR)的CD8+ T细胞的功能。
C.CD4+和CD8+ T细胞
本公开的实施方案涵盖对个体用T细胞进行过继转移的改进。利用CD8+ T细胞作为细胞毒性T细胞进行过继转移的已知方法现已通过允许具有非天然的细胞毒性活性的CD4+ T细胞的利用而得到改进。本公开的实施方案包括利用CD8共受体功能与TCR转基因T细胞进行免疫疗法,所述TCR转基因T细胞包括低亲和力TCR转基因的T细胞,它们是CD4+或CD8+,或其功能性杂化形式)。
本公开的实施方案提供了对于CD8细胞中天然和/或外源提供的TCR或其他抗原受体的CD8 T细胞功能的增强。这种增强可以包括诸如与相应缺乏外源提供的CD8αβ表达的T细胞相比增加其连续肿瘤杀伤能力的优势。
在特定的实施方案中,在某些方法中使用表达足够水平的CD8αβ共受体和外源工程化抗原受体的CD4+ T细胞和表达足够水平的CD8αβ共受体和可选地外源工程化抗原受体的CD8+T细胞的混合物。混合物可使用CD4+ T细胞与CD8+ T细胞的特定比例,例如10:1、5:1、2:1、1:1、1:2、1:5、1:10、1:25,1:50、1:100、1:500、1:1000、1:10,000,等。
本文其他地方提供的实施例解决了对有效和安全的表达TCR的细胞的需求。由于宿主中的选择和耐受性,靶向过度表达的肿瘤相关自身抗原(TAA)的大多数天然存在的I类限制性TCR的亲和力较低,并且是CD8共受体依赖性的。因此,采用TCR工程化T细胞进行过继T细胞转移完全依赖CD8+ T细胞的功能,无法利用有利的CD4+ T细胞功能。因此,本公开涉及新颖的策略,其结合了TAA特异性低亲和力TCR与CD8αβ共受体的表达,并且分别表征了纯化的转基因CD8+和CD4+ T细胞的特性。已经确定,CD8αβ共转移通过增加其连续肿瘤杀伤能力而增强了TCR+ CD8+ T细胞功能,表明内源CD8共受体的有限可用性阻碍了其功能潜能的充分利用。工程化CD4+ T细胞在单细胞水平上被有效地重编程为杂化多功能细胞毒性和辅助T细胞:它们识别并杀死表达同源I类限制性肿瘤抗原的细胞,成为连续杀手(serialkiller),主要产生TH1,保留了一些TH2细胞因子,并显示在体内具有优异的抗肿瘤功能。因此,本公开的实施方案涉及至少(1)增强TCR-转基因CD8+ T细胞的功能和(2)制备可容易地在单细胞水平获得的、具有CD8+和CD4+ T细胞功能的靶向I类pMHC的杂化细胞毒性和辅助T细胞。
III.组合物示例
本公开涉及用于过继转移中的CD4+ T细胞和CD8+ T细胞。在自然界中未发现本发明的CD4+ T细胞和CD8+ T细胞,至少是因为它们分别表达至少一种外源提供的蛋白质:CD8αβ共受体。在特定情况下,CD8的α和β链都在同一细胞中表达。CD8αβ共受体可以在或可以不在细胞中瞬时表达。转基因表达CD8αβ共受体的CD8+细胞不是自然中具有CD8αβ共受体天然表达的CD8+细胞,至少是因为CD8αβ共受体分子的水平大于天然表达CD8αβ共受体的细胞,并且表达水平上的这种差异导致转基因CD8+ T细胞的效力高于天然CD8+ T细胞的功能差异。
在特定的实施方案中,除了表达CD8αβ共受体之外,CD4+ T细胞和CD8+ T细胞还表达一种或多种工程化抗原受体。所述一种或多种工程化抗原受体可以是任何种类,但在特定情况下,它们是HLA I类限制性TCR或嵌合抗原受体(CAR)。
A.T细胞受体(TCR)
在一些实施方案中,工程化抗原受体包括重组TCR和/或从天然存在的T细胞克隆的TCR。“T细胞受体”或“TCR”是指含有可变的α和β链(也被分别称为TCRα和TCRβ)或可变的γ和δ链(也被分别称为TCRγ和TCRδ),并且能够特异性结合与MHC受体结合的抗原肽的分子。在一些实施方案中,TCR为αβ形式。
通常,以αβ和γδ形式存在的TCR一般在结构上相似,但是表达它们的T细胞可能具有不同的解剖位置或功能。TCR可以在细胞表面或以可溶形式存在。通常,TCR在T细胞(或T淋巴细胞)的表面上被发现,其通常负责识别与主要组织相容性复合物(MHC)分子结合的抗原。在一些实施方案中,TCR还可以包含恒定结构域、跨膜结构域和/或短的胞质尾。例如,在一些方面,TCR的每条链可具有一个N末端免疫球蛋白可变结构域,一个免疫球蛋白恒定结构域,跨膜区域和在C末端的短胞质尾。在一些实施方案中,TCR与参与介导信号传导的CD3复合物不变蛋白(invariant proteins)相关联。除非另有说明,否则术语“TCR”应理解为包括其功能性TCR片段。该术语还涵盖完整的或全长的TCR,包括αβ形式或γδ形式的TCR。
因此,出于本文的目的,提及的TCR包括任何TCR或功能片段,例如结合与MHC分子(即MHC-肽复合物)结合的特定抗原肽的TCR的抗原结合部分。TCR的“抗原结合部分”或“抗原结合片段”可以互换使用,是指包含TCR的部分结构域但与抗原(例如MHC-肽复合物)结合的分子。在某些情况下,抗原结合部分包含TCR的可变结构域,例如TCR的可变α链和可变β链,其足以形成与特定MHC-肽复合物结合的结合位点,例如通常每条链包含三个互补决定区的情形。
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),其赋予抗原识别和决定肽特异性(通过形成TCR分子的结合位点并决定肽特异性)。通常,像免疫球蛋白一样,互补决定区被框架区(framework region,FR)隔开。在一些实施方案中,互补决定区3是负责识别加工的抗原的主要互补决定区,尽管也已显示α链的互补决定区1与抗原肽的N末端部分相互作用,而β链的互补决定区1与肽的C末端部分相互作用。互补决定区2被认为可以识别MHC分子。在一些实施方案中,β链的可变域可以包含又一个高变(HV4)区。
在一些实施方案中,TCR链包含恒定结构域。例如,像免疫球蛋白一样,TCR链的细胞外部分(例如α链,β链)可以包含两个免疫球蛋白结构域,一个可变结构域(例如Va或Vp;通常是氨基酸1至116(基于Kabat编号,Kabat等人,"Sequences of Proteins ofImmunological Interest,US Dept.Health and Human Services,Public HealthService National Institutes of Health,1991,5th ed.)位于N末端,一个恒定结构域(例如,α链恒定结构域或Ca,通常是氨基酸117至259(基于Kabat),β链恒定结构域或Cp,通常是氨基酸117至295(基于Kabat))与细胞膜相邻。例如,在某些情况下,由两条链形成的TCR的胞外部分包含两个膜近端(membrane-proximal)恒定结构域和两个包含CDR的膜远端(membrane-distal)可变结构域,TCR结构域的恒定结构域包含短连接序列,其中半胱氨酸残基形成二硫键,从而在两条链之间形成连接。在一些实施方案中,TCR可在α链和β链的每条中具有另外的半胱氨酸残基,使得TCR在恒定结构域中包含两个二硫键。
在一些实施方案中,TCR链可包含跨膜结构域。在一些实施方案中,跨膜结构域带正电。在某些情况下,TCR链包含胞质尾。在某些情况下,该结构允许TCR与其他分子(如CD3)缔合。例如,带有跨膜区的含有恒定结构域的TCR可以将蛋白质锚定在细胞膜中,并与CD3信号传导装置或复合物的不变亚基缔合。
通常,CD3是多蛋白复合物,在哺乳动物中可以具有三种不同的链(γ,δ和ε)和ζ链。例如,在哺乳动物中,该复合物可含有一条CD3γ链,一条CD3δ链,两条CD3ε链和CD3ζ链的同二聚体。CD3γ,CD3δ和CD3ε链是免疫球蛋白超家族的高度相关的细胞表面蛋白,其包含单个免疫球蛋白结构域。CD3γ,CD3δ和CD3ε链的跨膜区带负电荷,这个特性可使这些链与带正电荷的TCR链缔合。CD3γ,CD3δ和CD3ε链的胞内尾各自包含一个保守的基序,称为基于免疫受体酪氨酸的活化基序或ITAM(immunoreceptor tyrosine-based activationmotif),而每个CD3ζ链具有三个。通常,ITAM参与TCR复合体的信号传导能力。这些辅助分子具有带负电的跨膜区域,并在将信号从TCR传播到细胞中发挥作用。CD3和ζ链与TCR一起形成所称的TCR复合物。
在一些实施方案中,TCR可以是两条链α和β(或可选地γ和δ)的异二聚体,或者它可以是单链TCR构建体。在一些实施方案中,TCR是包含两个分开的链(α和β链或γ和δ链)的异二聚体,两个分开的链通过例如一个二硫键或多个二硫键连接。在一些实施方案中,鉴定了针对靶抗原(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的核酸可以从多种来源获得,例如通过聚合酶链式反应(PCR)扩增公开可获得的TCR DNA序列。在一些实施方案中,TCR获自生物学来源,诸如获自细胞,比如获自T细胞(例如细胞毒性T细胞),T细胞杂交瘤(T cell hybridomas)或其他可公开可获得的来源。在一些实施方案中,T细胞可以获自体内分离的细胞。在一些实施方案中,可以从患者中分离出高亲和力的T细胞克隆,并分离出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)工程化的转基因小鼠中产生了针对靶抗原的TCR克隆。在一些实施方案中,噬菌体展示用于分离针对靶抗原的TCR。在一些实施方案中,TCR或其抗原结合部分可以根据TCR序列的信息合成产生。
B.嵌合抗原受体
在一些实施方案中,工程化抗原受体包括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。CAR通常包括胞外抗原(或配体)结合结构域,其连接至一种或多种细胞内信号传导组分(在一些方面通过连接子(linker)和/或跨膜结构域连接)。这样的分子通常模拟或接近通过天然抗原受体的信号、通过这种受体与共刺激受体结合的信号和/或单独通过共刺激受体的信号。CAR可以是第一代,第二代或第三代或后续代。
在一些实施方案中,CAR由载体编码并且至少包含:a)细胞内信号传导结构域,b)跨膜结构域,和c)包含至少一个抗原结合区的细胞外结构域。
本公开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,包括已被人源化以降低免疫原性(hCAR)的CAR,其包含细胞内信号传导结构域,跨膜结构域,以及具有一个或多个信号传导基序的细胞外结构域。在某些实施方案中,CAR可以识别包含一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。在另一个实施方案中,该特异性源自与受体结合的肽(例如细胞因子)。
可以设想人CAR核酸可衍生自用于增强人类患者细胞免疫治疗的人类基因。在一个具体的实施方案中,本公开包括全长CAR cDNA或由载体编码的编码区。抗原结合区或结构域可包含衍生自特定人单克隆抗体(例如在美国专利7,109,304中描述的那些,该文献通过引用并入本文)的单链可变片段(scFv)的VH和VL链的片段。该片段也可以是任何数量的人抗原特异性抗体的不同抗原结合结构域。在一个更具体的实施方案中,该片段是由针对人密码子使用而优化以在人细胞中表达的序列编码的抗原特异性scFv。
该排布(arrangement)可以是多聚的,例如双体(diabody)或多聚体。多聚体最有可能通过将轻链和重链的可变部分交叉配对成双体而形成。构建体的铰链部分可以具有多种选择,从完全缺失到维持第一个半胱氨酸,到脯氨酸而非丝氨酸的取代,到被截短至第一个半胱氨酸。Fc部分可以被删除或可以不被删除。任何稳定和/或二聚的蛋白质都可以达到这个目的。可以仅使用所述Fc结构域中的一个,例如来自人免疫球蛋白的CH2或CH3结构域。还可以使用经过修饰以改善二聚化的人免疫球蛋白的铰链、CH2和CH3区。也可以只使用免疫球蛋白的铰链部分。也可以使用CD8α的部分。
在一些实施方案中,CAR核酸包含编码其他共刺激受体的序列,例如跨膜结构域和一个或多个细胞内信号传导结构域,例如CD28细胞内信号传导结构域。其他共刺激受体包括但不限于CD28,CD27,OX-40(CD134),DAP10,DAP12和4-1BB(CD137)中的一种或多种。除了由CD3引发的初级信号(primary signal)外,插入人CAR中的人共刺激受体提供的其他信号可用于NK细胞的完全活化,并可帮助改善体内持久性和过继免疫疗法的治疗成功。
在一些实施方案中,构建具有对特定抗原(或标志物或配体)的特异性的CAR,所述抗原例如在特定细胞类型中表达的、将被过继治疗靶向的抗原,例如癌症标志物,和/或旨在诱导减毒反应的抗原,例如在正常或未患病细胞类型上表达的抗原。因此,CAR通常在其细胞外部分中包含一个或多个抗原结合分子,例如一个或多个抗原结合片段、结构域或部分,或一个或多个抗体可变结构域,和/或抗体分子。在一些实施方案中,CAR包括抗体分子的一个或多个抗原结合部分,例如衍生自单克隆抗体(mAb)的可变重链(VH)和可变轻链(VL)的单链抗体片段(scFv)。
在CAR的某些实施方案中,受体的抗原特异性部分(其可以称为包含抗原结合区的细胞外结构域)包含肿瘤相关抗原结合结构域或病原体特异性抗原结合结构域。抗原包括被模式识别受体识别的糖类抗原。肿瘤相关抗原可以是任何种类的,只要它在肿瘤细胞的细胞表面上表达即可。
编码嵌合受体的开放阅读框的序列可获自基因组DNA来源、cDNA来源,或可合成(例如,经由PCR)或其组合。取决于基因组DNA的大小和内含子的数目,使用cDNA或其组合可能比较理想,因为发现内含子使mRNA稳定。同样,使用内源或外源非编码区来稳定mRNA可能是进一步有利的。
预期可以将嵌合构建体作为裸露的DNA或在合适的载体中引入免疫细胞。使用裸露的DNA通过电穿孔稳定转染细胞的方法是本领域已知的。参见,例如,美国专利号6,410,319。裸露的DNA通常是指编码嵌合受体的DNA,其包含在表达载体中并按合适的方向以便表达。本公开的多顺反子模块载体可以是病毒载体或可以不是病毒载体,例如质粒。尽管对于说明性实施方案,本文详述的载体是逆转录病毒载体,但是在其他情况下,该载体也是病毒载体,但是是例如腺病毒载体、腺相关病毒载体或慢病毒载体。
任何载体均可用于将嵌合构建体引入免疫细胞。根据本公开的方法使用的合适的载体可以是在免疫细胞中不复制的。已知许多基于病毒的载体,其中在细胞中维持的病毒的拷贝数低到足以维持细胞的生存力,例如基于HIV,SV40,EBV,HSV或BPV的载体。在特定情况下,所述载体基于莫洛尼鼠白血病病毒(Moloney Murine Leukemia Virus)。
在一些方面,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包括与CAR的细胞外结构域融合的跨膜结构域。在一个实施方案中,使用天然与CAR中的结构域之一相关联的跨膜结构域。在一些情况下,跨膜结构域经过选择或通过氨基酸取代被修饰,以避免此类结构域与相同或不同表面膜蛋白的跨膜结构域结合,以使与受体复合物的其他成员的相互作用最小化。
在一些实施方案中,跨膜结构域衍生自天然或合成来源。如果来源是天然的,则该结构域在某些方面源自任何膜结合蛋白或跨膜蛋白。跨膜区包括源自TCR的α,β或ζ链,CD28,CD3ζ,CD3ε,CD3γ,CD3δ,CD45,CD4,CD5,CD8,CD9,CD16,CD22,CD33,CD37,CD64,CD80,CD86,CD134,CD137,CD154,ICOS/CD278,GITR/CD357,NKG2D和DAP分子的那些(即至少包含其跨膜区)。可替代地,在一些实施方案中,跨膜结构域是合成的。在一些方面,合成的跨膜结构域主要包含疏水性残基,例如亮氨酸和缬氨酸。在一些方面,合成的跨膜结构域的每个末端将是苯丙氨酸、色氨酸和缬氨酸的三联体。
在某些实施方案中,本文公开的遗传修饰免疫细胞(例如T,NK,iNKT,B或MSC细胞)的平台技术包括(i)使用电穿孔装置(例如,核转染器(nucleofector))的非病毒基因转移,(ii)通过内结构域(例如CD28/CD3-ζ,CD137/CD3-ζ或其他组合)发出信号的CAR,(iii)具有可变长度的胞外结构域的CAR,这些胞外结构域将抗原识别结构域连接到细胞表面,并且在某些情况下,还包括(iv)源自K562的人工抗原呈递细胞(aAPC),以能够稳健地和在数量上(numerically)扩增CAR+免疫细胞。
单个载体可以编码两个分开的CAR分子,或者单个载体可以编码一个或多个CAR分子,其中至少一个对两种不同的抗原具有特异性,例如双特异性CAR、双特异性TCR、或双特异性CAR/TCR。由本公开的载体编码的抗原受体、载体本身以及带有该载体的细胞是由人工产生的,并且不存在于自然界中。
在一些实施方案中,CAR包含特异性结合抗原的细胞外抗原识别结构域。可以将CAR专门设计为靶向特定组织或细胞类型的抗原。在一些实施方案中,抗原是在细胞表面表达的蛋白质。在一些实施方案中,CAR是TCR样(TCR-like)CAR,并且抗原是加工的肽抗原,例如细胞内蛋白的肽抗原,其像TCR一样,在主要组织相容性复含物(MHC)分子的背景下在细胞表面被识别。
C.抗原
遗传工程化抗原受体靶向的抗原包括由过继细胞疗法靶向的疾病、病状或细胞类型的背景下表达的抗原。这些疾病和病症包括增殖性、赘生性和恶性疾病和病症,包括癌症和肿瘤,包括实体瘤,血液癌,免疫系统的癌症,例如淋巴瘤,白血病和/或骨髓瘤,例如B、T以及骨髓性白血病,淋巴瘤和多发性骨髓瘤以及自身免疫或同种免疫疾病。在一些实施方案中,与正常或非靶向的细胞或组织相比,抗原在疾病或病症的细胞(例如肿瘤或病原性细胞)上选择性表达或过表达。在其他实施方案中,抗原在正常细胞上表达和/或在工程化细胞上表达。在有些情况下,抗原与免疫相关紊乱(disorder)有关。在疾病是病原性疾病的情况下,抗原将是病原体的肿瘤,例如病毒,真菌,原生动物或细菌。
任何合适的抗原均可用于本发明的方法。示例性抗原包括但不限于来自传染原的抗原分子、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,抗原包括生存素,PRAME,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,对应于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是已知的,例如,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)。
肿瘤相关抗原可源自前列腺癌,乳腺癌,结肠直肠癌,肺癌,胰腺癌,肾癌,间皮瘤,卵巢癌,或黑色素瘤,或血液系统恶性肿瘤。示例性的肿瘤相关抗原或肿瘤细胞衍生的抗原包括MAGE 1,3和MAGE 4(或其他MAGE抗原,例如国际专利公开号WO99/40188中所公开的那些);PRAME;生存素,BAGE;RAGE,Lage(也称为NY ESO 1);SAGE;和HAGE或GAGE。这些非限制性的肿瘤抗原的示例在广泛的肿瘤类型中表达,例如黑素瘤,肺癌,肉瘤和膀胱癌或血液系统恶性肿瘤。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),前列腺酸磷酸盐,NKX3.1和前列腺六跨膜上皮抗原(six-transmembrane epithelial antigen of the prostate,STEAP)。
其他肿瘤相关抗原包括Plu-1,HASH-1,HasH-2,Cripto和Criptin。另外,肿瘤抗原可以是自身肽激素,例如全长促性腺激素释放激素(GnRH),此为一种短的10个氨基酸长的肽,可用于治疗许多癌症。
肿瘤抗原包括源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。目标肿瘤相关抗原包括谱系特异性肿瘤抗原,例如黑色素细胞-黑色素瘤(melanocyte-melanoma)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。示例性的肿瘤相关抗原包括但不限于源自或包含下述一种或多种的肿瘤抗原:p53,Ras,c-Myc,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(Phosphoinositide 3-kinases)(PI3Ks),TRK受体,PRAME,P15,RU1,RU2,SART-1,SART-3,Wilms肿瘤抗原(WT1),AFP,连环蛋白(-catenin/m),半胱天冬酶-8(Caspase-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,RAGE,SART-2,TRP-2/INT2,707-AP,膜联蛋白II(Annexin II),CDC27/m,TPI/mbcr-abl,BCR-ABL,干扰素调节因子4(IRF4),ETV6/AML,LDLR/FUT,Pml/RAR,肿瘤相关钙信号转导子1(TACSTD1)TACSTD2,受体酪氨酸激酶(例如,表皮生长因子受体(EGFR)(特别是,EGFRvIII),血小板衍生的生长因子受体(PDGFR),血管内皮生长因子受体(VEGFR)),胞质酪氨酸激酶(例如,src-家族,syk-ZAP70家族),整合素连接的激酶(ILK),转录信号转导子和激活子(signal transducers and activators of transcription)STAT3,STATS,和STATE,缺氧诱导因子(例如,HIF-1和HIF-2),核因子-κB(NF-B),Notch受体(例如,Notch1-4),c-Met,雷帕霉素的哺乳动物靶标(mTOR),WNT,细胞外信号调节激酶(ERKs),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)(也称为G250),STEAD,TEL/AML1,GD2,蛋白酶3,hTERT,肉瘤易位断点(sarcoma translocationbreakpoints),EphA2,ML-IAP,EpCAM,ERG(TMPRSS2ETS融合基因),NA17,PAX3,ALK,雄性激素受体,细胞周期蛋白B1,多唾液酸,MYCN,RhoC,GD3,岩藻糖GM1,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,legumain,TIE2,Page4,MAD-CT-1,FAP,MAD-CT-2,fos相关抗原1,CBX2,CLDN6,SPANX,TPTE,ACTL8,ANKRD30A,CDKN2A,MAD2L1,CTAG1B,SUNC1,LRRN1和独特型(idiotype)。
预期将其抗原用于本文所述方法的示例性病原生物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),爱泼斯坦-巴尔病毒(EBV),甲型、乙型和丙型流感(Influenza A,B,and C),疱疹性口炎病毒(VSV),疱疹性口炎病毒(VSV),多瘤病毒(例如BK病毒和JC病毒),腺病毒,葡萄球菌种(包括耐甲氧西林的金黄色葡萄球菌,MRSA)和链球菌种(包括肺炎链球菌)。如本领域技术人员将理解的那样,衍生自这些和其他病原微生物的如本文所述用作抗原的蛋白质和编码所述蛋白质的核苷酸序列可以在出版物和公共数据库中确定,如SWISS-和
源自人类免疫缺陷病毒(HIV)的抗原包括任何HIV病毒体结构蛋白(例如gp120,gp41,p17,p24),蛋白酶,逆转录酶或由tat,rev,nef,vif,vpr和vpu编码的HIV蛋白。
源自单纯疱疹病毒(例如,HSV 1和HSV2)的抗原包括但不限于从HSV晚期基因表达的蛋白质。晚期基因主要编码形成病毒粒子的蛋白质。这样的蛋白质包括形成病毒衣壳的五种蛋白质:UL6,UL18,UL35,UL38和主要衣壳蛋白UL19、UL45和UL27,它们中的每一种均可以用作本文所述的抗原。预期用作本文所述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,每个基因编码一种可能被用作抗原的蛋白质。
源自巨细胞病毒(CMV)的抗原包括CMV结构蛋白,在病毒复制的非常早期(immediate early)和早期阶段表达的病毒抗原,糖蛋白I和III,衣壳蛋白,外壳蛋白,下部基质蛋白(lower matrix protein)pp65(ppUL83),p52(ppUL44),IE1和1E2(UL123和UL122),来自UL128-UL150的基因簇的蛋白质产物(Rykman等人,2006),包膜糖蛋白B(gB),gH,gN和pp150。如本领域技术人员将理解的那样,可用作本文所述的抗原的CMV蛋白可在诸如SWISS-和的公共数据库中确定(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中的源自爱泼斯坦-巴尔病毒(EBV)的抗原包括EBV裂解蛋白gp350和gp110,在潜伏期感染期间产生的EBV蛋白,包括爱泼斯坦-巴尔核抗原(EBNA)-1,EBNA-2,EBNA-3A,EBNA-3B,EBNA-3C,EBNA前导蛋白(leader protein)(EBNA-LP)和潜伏膜蛋白(LMP)-1,LMP-2A和LMP-2B(参见例如Lockey等人,2008)。
预期用于本文的源自呼吸道合胞病毒(RSV)的抗原包括由RSV基因组编码的十一种蛋白质中的任何一种或其抗原片段:NS 1,NS2,N(核衣壳蛋白),M(基质蛋白)SH,G和F(病毒外壳蛋白),M2(第二基质蛋白),M2-1(延伸因子),M2-2(转录调节),RNA聚合酶和磷蛋白P.
预期使用的源自疱疹性口炎病毒(VSV)的抗原包括VSV基因组编码的五种主要蛋白质中的任何一种以及其抗原片段:大蛋白质(L),糖蛋白(G),核蛋白(N),磷蛋白(P)和基质蛋白(M)(参见例如Rieder等人,1999)。
预期在某些实施方案中使用的源自流感病毒的抗原包括血凝素(HA),神经氨酸酶(NA),核蛋白(NP),基质蛋白M1和M2,NS1,NS2(NEP),PA,PB1,PB1-F2和PB2。
示例性病毒抗原还包括但不限于腺病毒多肽,α病毒多肽,杯状病毒多肽(例如杯状病毒衣壳抗原),冠状病毒多肽,瘟热病毒多肽,埃博拉病毒多肽,肠病毒多肽,黄病毒多肽,肝炎病毒(AE)多肽(乙型肝炎核心或表面抗原,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),传染性腹膜炎病毒多肽,白血病病毒多肽,马尔堡病毒多肽,正粘病毒多肽,乳头瘤病毒多肽,副流感病毒多肽(例如血凝素和神经氨酸酶多肽),副粘病毒多肽,细小病毒多肽,瘟病毒多肽,小核糖核酸病毒多肽(例如脊髓灰质炎病毒衣壳多肽),痘病毒多肽(例如牛痘病毒多肽),狂犬病病毒多肽(例如狂犬病病毒糖蛋白G),呼肠孤病毒多肽,逆转录病毒多肽和轮状病毒多肽。
在某些实施方案中,抗原可以是细菌抗原。在某些实施方案中,目标细菌抗原可以是分泌的多肽。在其他某些实施方案中,细菌抗原包括多肽的一个或多个部分暴露于细菌的细胞外表面的抗原。
预期使用的源自葡萄球菌种(包括耐甲氧西林的金黄色葡萄球菌(MRSA))的抗原包括毒力调节子(virulence regulator),例如Agr系统,Sar和Sae,Arl系统,Sar同源物(Rot,MgrA,SarS,SarR,SarT,SarU,SarV,SarX,SarZ和TcaR),Srr系统和TRAP。其他可以用作抗原的葡萄球菌蛋白包括Clp蛋白,HtrA,MsrR,乌头酸酶,CcpA,SvrA,Msa,CfvA和CfvB(参见,例如,Staphylococcus:Molecular Genetics,2008Caister Academic Press,Ed.Jodi Lindsay)。已经对两种金黄色葡萄球菌(N315和Mu50)的基因组进行了测序,并已公开提供在例如PATRIC(PATRIC:The VBI PathoSystems Resource Integration Center,Snyder等人,2007)中。如本领域技术人员将理解的,用作抗原的葡萄球菌蛋白还可以在其他公共数据库(例如Swiss-和)中确定。
预期用于本文所述的某些实施方案中的源自肺炎链球菌的抗原包括肺炎球菌溶血素(pneumolysin),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在本领域中也是已知的,并且在一些实施方案中可以用作抗原(参见,例如,Zysk等人,2000)。已经对肺炎链球菌的毒株的完整基因组序列进行了测序,并且如本领域技术人员将理解的那样,用于本文的肺炎链球菌蛋白也可以在其他公共数据库如SWISS-和中确定。根据本公开的抗原的目标蛋白质包括毒力因子和预期在肺炎球菌表面暴露的蛋白质(参见,例如,Frolet等人,2010)。
可用作抗原的细菌抗原的示例包括但不限于放线菌多肽,芽孢杆菌多肽,拟杆菌多肽,博代氏杆菌(Bordetella)多肽,巴尔通体多肽,包柔氏螺旋体多肽(例如B.burgdorferi OspA),布鲁氏菌多肽,弯曲杆菌多肽,二氧化碳噬纤维菌(Capnocytophaga)多肽,衣原体多肽,棒状杆菌多肽,柯克斯氏体(Coxiella)多肽,嗜皮菌(Dermatophilus)多肽,肠球菌多肽,埃立克体(Ehrlichia)多肽,埃希氏杆菌多肽,弗朗西斯氏菌多肽,梭菌多肽,通氏体(Haemobartonella)多肽,嗜血杆菌(Haemophilus)多肽(例如流感嗜血杆菌b型外膜蛋白),幽门螺杆菌多肽,克雷伯菌多肽,L型细菌多肽,钩端螺旋体多肽,李斯特菌多肽,分枝杆菌多肽,支原体多肽,奈瑟菌多肽,新立克次体多肽,诺卡氏菌多肽,巴斯德氏菌多肽,消化球菌多肽,消化链球菌多肽,肺炎球菌多肽(即肺炎链球菌多肽)(参见本文的说明),变形杆菌多肽,假单胞菌多肽,立克次体多肽,罗沙利马体(Rochalimaea)多肽,沙门氏菌多肽,志贺氏菌多肽,葡萄球菌多肽,A组链球菌(group Astreptococcus)多肽(例如化脓性链球菌(S.pyogenes)M蛋白),B族链球菌(无乳链球菌)多肽,梅毒螺旋体(Treponema)多肽和耶尔森氏菌(Yersinia)多肽(例如,鼠疫耶尔森氏菌(Ypestis)F1和V抗原)。
真菌抗原的示例包括但不限于:犁头霉(Absidia)多肽,顶孢菌(Acremonium)多肽,链格孢菌(Alternaria)多肽,曲霉菌(Aspergillus)多肽,蛙粪霉属(Basidiobolus)多肽,离蠕孢菌(Bipolaris)多肽,芽生菌(Blastomyces)多肽,假丝酵母(Candida)多肽,球孢子菌多(Coccidioides)肽,Conidiobolus多肽,隐球菌(Cryptococcus)多肽,弯孢菌(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,Madurella多肽,马拉色氏霉菌(Malassezia)多肽,小孢子菌(Microsporum)多肽,丛梗孢(Moniliella)多肽,被孢霉多(Mortierella)肽,毛霉菌(Mucor)多肽,拟青霉(Paecilomyces)多肽,青霉菌(Penicillium)多肽,Phialemonium多肽,瓶霉菌(Phialophora)多肽,原壁菌(Prototheca)多肽,假霉样真菌(Pseudallescheria)多肽,Pseudomicrodochium多肽,腐霉(Pythium)多肽,鼻孢子虫(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示例包括但不限于巴贝西虫(Babesia)多肽,肠袋虫(Balantidium)多肽,贝诺孢子虫(Besnoitia)多肽,隐孢子虫(Cryptosporidium)多肽,艾美球虫(Eimeria)多肽,脑胞内原虫(Encephalitozoon)多肽,内变形虫(Entamoeba)多肽,贾第虫(Giardia)多肽,Hammondia多肽,肝簇虫(Hepatozoon)多肽,等孢子球虫(Isospora)多肽,利什曼虫(Leishmania)多肽,微孢子虫(Microsporidia)多肽,新孢子虫(Neospora)多肽,小孢子虫(Nosema)多肽,Pentatrichomonas多肽,疟原虫(Plasmodium)多肽。蠕虫寄生虫抗原的示例包括但不限于棘唇线虫(Acanthocheilonema)多肽,猫圆线虫(Aelurostrongylus)多肽,钩虫(Ancylostoma)多肽,管圆线虫(Angiostrongylus)多肽,蛔虫(Ascaris)多肽,布鲁格丝虫(Brugia)多肽,仰口线虫(Bunostomum)多肽,毛细线虫(Capillaria)多肽,夏柏特线虫(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,双瓣线虫(Dipetalonema)多肽,裂头绦虫(Diphyllobothrium)多肽,Diplydium多肽,恶丝虫(Dirofilaria)多肽,龙线虫(Dracunculus)多肽,蛲虫(Enterobius)多肽,类丝虫(Filaroides)多肽,血矛线虫(Haemonchus)多肽,兔唇蛔虫(Lagochilascaris)多肽,Loa多肽,曼森线虫(Mansonella)多肽,缪勒线虫(Muellerius)多肽,Nanophyetus多肽,板口线虫(Necator)多肽,细颈线虫(Nematodirus)多肽,结节线虫(Oesophagostomum)多肽,盘尾线虫(Onchocerca)多肽,后睾吸虫(Opisthorchis)多肽,奥斯特线虫(Ostertagia)多肽,副丝虫(Parafilaria)多肽,并殖吸虫(Paragonimus)多肽,副蛔虫(Parascaris)多肽,泡翼线虫(Physaloptera)多肽,原圆线虫(Protostrongylus)多肽,腹腔丝虫(Setaria)多肽,尾旋线虫(Spirocerca)多肽,迭宫绦虫(Spirometra)多肽,冠丝虫(Stephanofilaria)多肽,粪类圆线虫(Strongyloides)多肽,圆线虫(Strongylus)多肽,眼线虫(Thelazia)多肽,弓蛔虫(Toxascaris)多肽,弓蛔虫(Toxocara)多肽,旋毛虫(Trichinella)多肽,毛圆线虫(Trichostrongylus)多肽,鞭虫(Trichuris)多肽,钩虫(Uncinaria)多肽,和吴策线虫(Wuchereria)多肽(例如恶性疟原虫(P.falciparum)环子孢子(PfCSP)),孢子体表面蛋白2(PfSSP2),肝状态抗原1(liver state antigen 1)的羧基末端(PfLSA1 c-term)和输出蛋白1(exported protein 1)(PfExp-1),肺囊虫(Pneumocystis)多肽,肉孢子虫(Sarcocystis)多肽,血吸虫(Schistosoma)多肽,泰累尔氏梨浆虫(Theileria)多肽,弓形虫(Toxoplasma)多肽和锥体虫(Trypanosoma)多肽。
体表寄生虫抗的示例包括但不限于来自下述的多肽(包括抗原以及过敏原):跳蚤;壁虱,包括硬壁虱和软壁虱;蝇类,例如midge,蚊子,沙蝇,黑蝇,马蝇,角蝇,鹿蝇,采采蝇(tsetse fly),稳定(stable)蝇,引起蝇蛆病的蝇和叮咬的虫(biting gnat);蚂蚁;蜘蛛,虱子;螨;和半翅目(true bug),例如床虱和猎蝽(kissing bug)。
D.CD8αβ共受体
在特定的实施方案中,本发明的CD4+和CD8+细胞表达外源CD8αβ共受体。CD8αβ共受体来自哺乳动物来源,在特定的实施方案中,可以是人、大鼠、小鼠等。
E.用于生产的细胞
CD4+和CD8+细胞可以选自来自一个或多个个体的样本。样本可以来自被治疗的个体,因此对于被治疗的个体来说是自体的。在其他情况下,样品来自不同于用细胞治疗的个体的个体,因此相对于被治疗的个体来说是同种异体的。CD4+和CD8+细胞可以选自从受试者,特别是人类受试者(包括需要治疗的个体)中分离的免疫细胞。免疫细胞可从它们在受试者体内的任何位置收集,包括但不限于血液,脐带血,脾脏,胸腺,淋巴结和骨髓。分离的免疫细胞可以直接使用,或者可以保存一段时间,例如通过冷冻。
免疫细胞可以从它们所在的任何组织中富集/纯化,包括但不限于血液(包括通过血库或脐带血库收集的血液),脾脏,骨髓,在手术过程中除去和/或暴露的组织,以及通过活检程序获得的组织。可以从活体和非活体受试者中分离出组织/器官,从这些组织/器官中富集、分离和/或纯化免疫细胞,其中所述非活体受试者是器官供体。在特定的实施方案中,免疫细胞从血液中分离,例如外周血或脐带血。在一些方面,从脐带血分离的免疫细胞具有增强的免疫调节能力。在特定方面,为了增强的免疫调节能力,从汇集的血,特别是汇集的脐带血中分离出免疫细胞。汇集的血可以来自2个或更多来源,例如3、4、5、6、7、8、9、10个或更多来源(例如,供体受试者)。
CD4+和CD8+细胞从其中衍生的免疫细胞群体可以从需要治疗或患有疾病的受试者中获得。因此,细胞对于需要治疗的受试者将是自体的。或者,可以从供体,优选组织相容性匹配的供体获得免疫细胞群。可以从外周血,脐带血,骨髓,脾脏或任何其他免疫细胞在所述受试者或供体中所在的器官/组织中收获免疫细胞群。免疫细胞可以从受试者和/或供体群中分离,例如从汇集的脐带血中分离。
当从不同于受试者的供体中获得免疫细胞群时,该供体优选是同种异体的,条件是所获得的细胞与受试者相容,即它们可以被引入受试者中。同种异体供体细胞可能与人白细胞抗原(HLA)相容,也可能不相容。为了使其与受试者相容,可以处理同种异体细胞以降低免疫原性(Fast等人,2004)。
F.产生方法
通过标准重组技术(参见,例如,Sambrook等人,2001和Ausubel等人,1996,均通过引用并入本文),本领域技术人员能够构建载体,以表达本公开的转基因分子。可将转基因分子在载体中或载体上提供给受体细胞,所述载体包括病毒载体或非病毒载体。病毒载体的示例包括腺病毒,腺相关病毒,慢病毒或逆转录病毒。非病毒载体的示例包括质粒,脂质体,纳米颗粒等。在特定的实施方案中,载体是逆转录病毒。
1.调控元件
可用于本公开的载体中包括的表达盒特别地包含(沿5'至3'方向)可操作地连接至蛋白质编码序列的真核转录启动子,包括中间序列的剪接信号和转录终止/聚腺苷酸化(polyadenylation)序列。控制真核细胞中蛋白质编码基因转录的启动子和增强子可以由多种遗传元件组成。细胞机制能够收集和整合每个元件传达的调控信息,从而使不同的基因发展出独特的,通常是复杂的转录调控模式。在本公开的上下文中使用的启动子包括例如组成型、诱导型和组织特异性启动子。在将载体用于癌症治疗的情况下,启动子在缺氧条件下可以是有效的。
a.启动子/增强子
本文提供的表达构建体包含启动子,以驱动抗原受体和其他顺反子基因产物的表达。启动子通常包含用于定位RNA合成起始位点的序列。最有名的例子是TATA盒,但在一些启动子中缺少TATA盒,例如,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,覆盖起始位点的离散(discrete)元件本身有助于确定起始位置。另外的启动子元件调节转录起始的频率。通常,这些启动子位于起始位点上游的区域,尽管已显示许多启动子也包含起始位点下游的功能元件。为了使编码序列“处于启动子的控制之下”,将转录阅读框的转录起始位点的5′末端定位在所选择的启动子的“下游”(即3′端)。“上游”启动子刺激DNA的转录并促进编码的RNA的表达。
启动子元件之间的间隔经常是灵活的,从而当元件相对于彼此反转或移动时,启动子功能得以保留。例如,在tk启动子中,启动子元件之间的间隔可以增加到50bp,然后活性开始下降。取决于启动子,似乎各个元件可以协同或独立地起作用以激活转录。启动子可以与或可以不与“增强子”结合使用,“增强子”是指参与核酸序列转录激活的顺式作用调控序列。
启动子可以是与核酸序列天然关联的,如可以通过分离位于编码片段和/或外显子上游的5′非编码序列而获得。这样的启动子可以称为“内源的”。类似地,增强子可以是与核酸序列天然关联的,位于该序列的下游或上游。或者,将编码核酸片段置于重组或异源启动子的控制下将获得某些优势,其中重组或异源启动子是指在其天然环境中通常不与核酸序列相联的启动子。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相联的增强子。此类启动子或增强子可包括其他基因的启动子或增强子,以及从任何其他病毒或原核或真核细胞中分离的启动子或增强子,以及不是“天然存在”的启动子或增强子,即包含不同转录调控区的不同元件,和/或改变表达的突变。例如,重组DNA构建中最常用的启动子包括β-内酰胺酶(青霉素酶),乳糖和色氨酸(trp)启动子系统。除了合成产生启动子和增强子的核酸序列以外,还可以结合本文公开的组合物使用重组克隆和/或核酸扩增技术(包括PCRTM)来产生序列。此外,可以想到,也可以采用指导(direct)在非核细胞器(例如线粒体,叶绿体等)内转录和/或表达序列的控制序列。
自然地,使用有效地指导DNA片段在被选用于表达的细胞器、细胞类型、组织、器官或生物中的表达的启动子和/或增强子将是重要的。分子生物学领域的技术人员通常知晓使用启动子、增强子和细胞类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)。所用的启动子可以是组成型的,组织特异性的,可诱导的和/或在适当的条件下有用的,以指导导入的DNA片段的高水平表达,如在大规模生产重组蛋白和/或肽中是有利的。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(例如,通过网址为epd.isb-sib.ch/的真核启动子数据库(Eukaryotic Promoter Data Base)EPDB)也可用于驱动表达。T3、T7或SP6细胞质表达系统的使用是另一个可能的实施方案。如果提供合适的细菌聚合酶,则真核细胞可以支持从某些细菌启动子的胞质转录,无论是作为递送复合物的一部分还是作为额外的基因表达构建体。
启动子的非限制性示例包括早期或晚期病毒启动子,例如SV40早期或晚期启动子,巨细胞病毒(CMV)立即早期启动子,劳斯肉瘤病毒(RSV)早期启动子;真核细胞启动子,例如,β肌动蛋白启动子,GADPH启动子,金属硫蛋白(metallothionein)启动子;以及连环应答元件(concatenated response element)启动子,例如接近最小TATA盒的环AMP应答元件启动子(cre),血清应答元件启动子(sre),佛波酯启动子(TPA)和应答元件启动子(tre)。也可使用人生长激素启动子序列(例如,中描述的人生长激素最小启动子,登录号X05244,核苷酸283-341)或小鼠乳腺肿瘤启动子(可从ATCC获得,目录号ATCC 45007)。在某些实施方案中,启动子是CMV IE,dectin-1,dectin-2,人CD11c,F4/80,SM22,RSV,SV40,Ad MLP,β-肌动蛋白,MHC I类或MHC II类启动子,但是任何其他可用于驱动治疗性基因表达的启动子也适用于本公开的实施。
在某些方面,本发明的方法还涉及增强子序列,即,即使在相对长的距离(距靶启动子多至几千个碱基),并无论其方向如何,也可以增加启动子活性并具有顺式作用的核酸序列。然而,增强子功能不一定必须限于如此长的距离,因为它们也可以在非常接近给定启动子的情况下起作用。
b.起始信号和连锁表达
特异性起始信号也可用在本公开提供的表达构建体中以有效翻译编码序列。这些信号包括ATG起始密码子或相邻序列。可能需要提供外源翻译控制信号,包括ATG起始密码子。本领域普通技术人员将能够容易地确定这一点并提供必要的信号。众所周知,起始密码子必须在所需编码序列的阅读框“框内”(“in-frame”),以确保整个插入片段的翻译。外源翻译控制信号和起始密码子可以是天然的或合成的。可以通过包含适当的转录增强子元件来增强表达效率。
在某些实施方案中,使用内部核糖体进入位点(IRES)元件来产生多基因或多顺反子信息。IRES元件能够绕过5'甲基化帽依赖性翻译(5’methylated Cap dependenttranslation)的核糖体扫描模型,并在内部位点开始翻译。已描述了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使的IRES元件。IRES元件可以连接到异源开放阅读框。可以将多个开放阅读框一起转录,每个阅读框之间都被一个IRES隔开,从而产生多顺反子信使。借助于IRES元件,核糖体可接近每个开放阅读框以进行有效翻译。可使用单个启动子/增强子转录单个信使而有效表达多个基因。
某些2A序列元件可用于在本公开提供的构建体中产生基因的连锁表达或共表达。例如,通过连接开放阅读框以形成单个顺反子,切割序列(cleavage sequence)可用于共表达基因。一种示例性的切割序列是马甲型鼻炎病毒(equine rhinitis A virus)(E2A)或F2A(口蹄疫病毒2A)或“2A样”序列(例如,Thosea asigna病毒2A;T2A)或猪捷申病毒-1(porcine teschovirus-1)(P2A)。在特定实施方案中,在单个载体中,多个2A序列是不同的,尽管在替代实施方案中,相同载体利用两个或多个相同的2A序列。2A序列的示例在美国2011/0065779中提供,其通过引用整体并入本文。
在利用自切割2A肽的实施方案中,所述2A肽可以是18-22个氨基酸(aa)长的病毒寡肽,其在真核细胞的翻译过程中介导多肽的“切割”。名称“2A”指病毒基因组的特定区域,不同病毒2A通常以其源自的病毒来命名。最早发现的2A是F2A(口蹄疫病毒),其后还鉴定了E2A(马甲型鼻炎病毒),P2A(猪捷申病毒-1 2A)和T2A(Thosea asigna病毒2A)。发现2A介导的“自切割”的机制是核糖体跳过了在2A的C末端形成甘氨酰基-脯氨酰基肽键的过程。不同2A在C末端共享高度保守的序列GDVEXNPGP,其可用于创建位阻和核糖体跳过。成功跳过和重新开始翻译会产生两个“切割的”蛋白。2A序列的示例如下:
T2A:(GSG)E G R G S L L T C G D V E E N P G P(SEQ ID NO:6)
P2A:(GSG)A T N F S L L K Q A G D V E E N P G P(SEQ ID NO:7)
E2A:(GSG)Q C T N Y A L L K L A G D V E S N P G P(SEQ ID NO:8)
F2A:(GSG)V K Q T L N F D L L K L A G D V E S N P G P(SEQ ID NO:9)
c.复制起点
为了使载体在宿主细胞中增殖,其可以包含一个或多个复制位点的起点(通常称为“ori”),例如,与上述EBV的oriP或具有相似的或提高的编程功能的遗传工程化oriP相应的核酸序列,其为复制在此处起始的特定核酸序列。可替代地,可以使用如上所述的其他染色体外复制病毒的复制起点或自主复制序列(ARS)。
d.选择和筛选标记
在一些实施方案中,可以通过在表达载体中包含标记来在体外或体内鉴定含有本公开的构建体的细胞。这样的标记将赋予细胞可识别的改变,从而允许容易地鉴定含有表达载体的细胞。通常,选择标记是一种赋予允许选择的属性的标记。正选择标记是其中该标记的存在允许其选择的标记,而负选择标记是其中该标记的存在阻止其选择的标记。正选择标记的一个示例是抗药性标记。
通常,包含药物选择标记有助于克隆和转化子的鉴定,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(histidinol)的抗性的基因是有用的选择标记。除了赋予表型以允许基于条件的实施来区分转化体的标记之外,还考虑了其他类型的标记,包括筛选标记(例如GFP,其基础是比色分析(colorimetric analysis))。可替代地,可以使用可筛选的酶作为负选择标记,例如单纯疱疹病毒胸苷激酶(tk)或氯霉素乙酰转移酶(CAT)。本领域技术人员还将知晓如何使用免疫学标记(可能结合FACS分析)。所使用的标记不重要,只要其能够与编码基因产物的核酸同时表达。选择和筛选标记的其他示例是本领域技术人员众所周知的。
e.自杀基因
已被修饰以包含本公开涵盖的载体的本公开的细胞可以包含一个或多个自杀基因。如本文所用,术语“自杀基因”定义为这样的基因,其在施用前药或其他试剂后,实现基因产物向杀死其宿主细胞的化合物的转变。可以使用的自杀基因/前药组合的示例是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;以及脱氧胞苷激酶和胞嘧啶阿拉伯糖苷。
可以使用大肠杆菌嘌呤核苷磷酸化酶(所谓的自杀基因),其将前药6-甲基嘌呤脱氧核糖核苷转化为毒性的嘌呤6-甲基嘌呤。与前药疗法一起使用的自杀基因的其他示例是大肠杆菌胞嘧啶脱氨酶基因和HSV胸苷激酶基因。
示例性的自杀基因包括CD20,CD52,EGFRv3或诱导型半胱天冬酶9。在一个实施方案中,EGFR变体III(EGFRv3)的截短形式可以用作自杀抗原,其可以被西妥昔单抗(Cetuximab)消除。可以在本公开中使用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),羧基酯酶(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-裂合酶(Methionine-α,γ-lyase)(MET)和胸苷磷酸化酶(TP)。在特定的实施方案中,如在2018年11月19日提交的美国临时专利申请62/769,405和2018年11月30日提交的美国临时专利申请62/773,372以及2019年1月11日提交的美国临时专利申请62/791,464(所有这些通过引用整体并入本文)中所述,利用突变TNF-α自杀基因,其编码在细胞膜上表达的不可分泌的TNFα蛋白,使其可以被抑制剂如抗体靶向。
IV.治疗方法
在一些实施方案中,本公开提供了用于治疗的方法,包括免疫疗法,包括施用有效量的本发明所涵盖的免疫细胞,所述免疫细胞被工程化以表达CD8αβ共受体。在一些实施方案中,通过将细胞转移至受试者个体来治疗医学疾病或病症。在本公开的某些实施方案中,通过转移靶向抗原的细胞群体来治疗癌症。本文提供了用于治疗或延迟个体中癌症进展的方法,其包括向个体施用有效量的抗原特异性细胞疗法(对一种或多种抗原特异)。
在需要治疗的个体患有癌症的情况下,该癌症可以是血液癌或可以包括实体瘤。本发明治疗方法有用的肿瘤包括任何恶性细胞类型,例如在实体瘤或血液系统恶性肿瘤中发现的那些。示例性实体瘤可包括但不限于选自下述的器官或组织的肿瘤:胰腺,结肠,盲肠,胃,脑,头,颈,卵巢,肾,喉,肉瘤,肺,膀胱,黑色素瘤,前列腺,皮肤,甲状腺,胆囊,脾脏,肝脏,骨骼,子宫内膜,睾丸,子宫颈,食道,前列腺和乳房。血液肿瘤的示例包括骨髓肿瘤,T或B细胞恶性肿瘤,白血病,淋巴瘤,母细胞瘤,骨髓瘤等。可以使用本文提供的方法治疗的癌症的其他示例包括但不限于肺癌(包括小细胞肺癌,非小细胞肺癌,肺腺癌和肺鳞状癌),腹膜癌,胃(gastric)或胃(stomach)癌(包括胃肠道癌和胃肠道间质癌),胰腺癌,宫颈癌,卵巢癌,肝癌,膀胱癌,乳腺癌,结肠癌,结肠直肠癌,子宫内膜或子宫癌,唾腺癌(salivarygland carcinoma),肾脏癌或肾癌,前列腺癌,外阴癌,甲状腺癌,各种类型的头颈癌和黑素瘤。
癌症可以具体地是以下组织学类型,尽管不限于这些:肿瘤,恶性的;癌;癌,未分化的;巨细胞和梭形细胞癌;小细胞癌;乳头状癌;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛母质癌(pilomatrix carcinoma);移行细胞(transitional cell)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;合并肝细胞癌和胆管癌;小梁腺癌(trabecularadenocarcinoma);腺样囊性癌;腺瘤息肉中的腺癌;腺癌,家族性息肉病;实体癌;类癌瘤,恶性的;支气管肺泡腺癌;乳头状腺癌;嫌色细胞癌(chromophobe carcinoma);嗜酸癌(acidophil carcinoma);嗜氧细胞腺癌;嗜碱细胞癌;透明细胞腺癌;颗粒细胞癌;滤泡性腺癌;乳头状和滤泡性腺癌;非包膜硬化性癌;肾上腺皮质癌;子宫内膜样癌;皮肤附件癌;顶泌腺癌(apocrine adenocarcinoma);皮脂腺癌;耵聍腺癌(ceruminousadenocarcinoma);粘液表皮样癌;膀胱腺癌;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(paget's disease),乳腺的;腺泡细胞癌;腺鳞癌;有鳞状化生的腺癌(adenocarcinoma w/squamous metaplasia);胸腺瘤,恶性的;卵巢间质瘤,恶性的;泡膜细胞瘤,恶性的;颗粒细胞瘤,恶性的;母细胞瘤,恶性的;塞尔托利细胞癌;莱迪希细胞瘤(leydig cell tumor),恶性的;脂质细胞瘤,恶性的;副神经节瘤,恶性的;乳腺旁神经节瘤,恶性的;嗜铬细胞瘤;血管肉瘤;恶性黑色素瘤;无黑色素性黑素瘤(amelanotic melanoma);浅表黑色素瘤;雀斑痣样恶性黑色素瘤;急性肢端黑色素瘤;结节性黑色素瘤;色素沉着痣中的恶性黑色素瘤;上皮样细胞黑素瘤;蓝色痣,恶性的;肉瘤;纤维肉瘤;纤维组织细胞瘤,恶性的;黏液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎横纹肌肉瘤;肺泡横纹肌肉瘤;基质肉瘤;混合性肿瘤,恶性的;苗勒氏混合瘤;肾母细胞瘤;肝母细胞瘤;癌肉瘤;间皮肉瘤,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;肌营养不良症;胚胎癌;畸胎瘤,恶性的;卵巢间质,恶性的;绒毛膜癌;中肾瘤,恶性的;血管肉瘤;血管内皮瘤,恶性的;卡波西氏肉瘤;血管内皮细胞瘤,恶性的;淋巴管肉瘤;骨肉瘤;皮质骨肉瘤;软骨肉瘤;软骨母细胞瘤,恶性的;间质软骨肉瘤;骨巨细胞瘤;尤因氏肉瘤;牙源性肿瘤,恶性的;成釉细胞牙肉瘤;成釉细胞瘤,恶性的;釉质成纤维肉瘤;松果体瘤,恶性的;脊索瘤;胶质瘤,恶性的;室管膜瘤;星形细胞瘤;原生质星形细胞瘤;纤维性星形细胞瘤;星形母细胞瘤;胶质母细胞瘤;少突胶质细胞瘤;少突胶质母细胞瘤;原始神经外胚层;小脑肉瘤;神经节神经母细胞瘤;成神经细胞瘤;视网膜母细胞瘤;嗅觉神经源性肿瘤;脑膜瘤,恶性的;神经纤维肉瘤;神经瘤,恶性的;颗粒细胞瘤,恶性的;恶性淋巴瘤;霍奇金氏病;霍奇金氏肉芽肿;恶性淋巴瘤,小淋巴细胞;恶性淋巴瘤,大细胞,弥漫性;恶性淋巴瘤,滤泡;蕈样真菌病;其他指定的非霍奇金淋巴瘤;B细胞淋巴瘤;低级/滤泡性非霍奇金淋巴瘤(NHL);小淋巴细胞(SL)非霍奇金淋巴瘤;中级/滤泡性非霍奇金淋巴瘤;中级弥散性非霍奇金淋巴瘤;高级免疫原性非霍奇金淋巴瘤;高级淋巴母细胞非霍奇金淋巴瘤;高级小非裂细胞(small non-cleaved cell)非霍奇金淋巴瘤;大型疾病非霍奇金淋巴瘤(bulky disease NHL);套细胞淋巴瘤;艾滋病相关淋巴瘤;Waldenstrom巨球蛋白血症;恶性组织细胞增生症;多发性骨髓瘤;肥大细胞肉瘤;免疫增生性小肠疾病;白血病;淋巴性白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;骨髓性白血病;嗜碱细胞性白血病;嗜酸性粒细胞白血病;单核细胞性白血病;肥大细胞白血病;巨核细胞白血病;髓样肉瘤;毛细胞白血病;慢性淋巴细胞性白血病(CLL);急性淋巴细胞白血病(ALL);急性髓细胞性白血病(AML);和慢性髓性白血病。
具体的实施方案涉及治疗白血病的方法。白血病是血液或骨髓的癌症,其特征在于血细胞、通常是白血细胞(白细胞)的异常增殖(通过增殖产生)。它是被称为血液肿瘤的广泛疾病的一部分。白血病是一个涵盖广泛疾病的广义术语。白血病在临床和病理上分为急性和慢性形式。
在本公开的某些实施方案中,将转基因CD4+和/或CD8+细胞递送至有此需要的个体,例如患有癌症的个体。这些细胞随即增强个体的免疫系统,以攻击相应的癌症。在某些情况下,向个体提供一剂或多剂所述细胞。在为个体提供两剂或两剂所述细胞的情况下,两次施用之间的间隔应足有有时间使其在个体中增殖,在特定的实施方案中,剂量之间的间隔时间为1、2、3、4、5、6、7或更多天。
在某些实施方案中,将促进细胞生长和活化的生长因子与细胞一起或在其后向细胞施用。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示例包括白介素(IL)-2,IL-7,IL-15和IL-12,它们可以单独使用或以多种组合使用,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。
治疗有效量的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经修饰的CD4+和/或CD8+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,这可能是抑制癌症进展或导致癌症消退所必需的免疫细胞量。
可以按照与疾病相应的治疗方案来施用免疫细胞群,例如在一到几天内单剂或几剂以改善疾病状态或在长期的时间内定期剂量以抑制疾病进展并预防疾病复发。制剂中要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。细胞的治疗有效量将取决于接受治疗的受试者、患病的严重程度和类型以及给药方式。在一些实施方案中,可用于治疗人类受试者的剂量为至少3.8×104个,至少3.8×105个,至少3.8×106个,至少3.8×107个,至少3.8×108个,至少3.8×109个,或至少3.8×1010个免疫细胞/m2。在某些实施方案中,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从每千克体重约5×106个细胞到每千克体重约7.5×108个细胞,例如每千克体重约2×107个细胞至约5×108个细胞,或每千克体重约5×107个细胞到约2×108个细胞。免疫细胞的确切数量很容易由本领域技术人员根据受试者的年龄,体重,性别和生理状况来确定。可以从体外或动物模型测试系统得出的剂量反应曲线推断有效剂量。
V.药物组合物
本文还提供了包含修饰的CD4+和/或CD8+细胞(例如,T细胞或NK细胞)和药学上可接受的载体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(例如细胞)与一种或多种任选的药学上可接受的载体(Remington's Pharmaceutical Sciences 22ndEdition,2012)混合以冻干制剂或水溶液的形式来制备。药学上可接受的载体在所采用的剂量和浓度下通常对受体无毒,其包括但不限于:缓冲剂(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,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,如EDTA;糖,如蔗糖,甘露醇,海藻糖或山梨糖醇;成盐的抗衡离子,例如钠;金属复合物(例如Zn蛋白复合物);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体还包括间质药物分散(dispersion)剂,例如可溶性中性活性透明质酸酶糖蛋白(sHASEGP),例如人可溶PH-20透明质酸酶糖蛋白,例如rHuPH20(Baxter International,Inc.)。在美国专利公开号2005/0260186和2006/0104968中描述了某些示例性的sHASEGP和使用方法,包括rHuPH20。一方面,将sHASEGP与一种或多种另外的糖胺聚糖酶(如软骨素酶)组合。
VI.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修饰的CD4+和/或CD8+ T细胞群与至少一种附加疗法的组合。所述附加疗法可以是放射疗法,手术(例如,乳房肿瘤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。所述附加疗法可以采取辅助或新辅助疗法的形式。
在一些实施方案中,所述附加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,所述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/或严重性的试剂,例如抗恶心剂等)。在一些实施方案中,所述附加疗法是放射疗法。在一些实施方案中,所述附加疗法是手术。在一些实施例中,所述附加疗法是放射疗法和手术的组合。在一些实施方案中,所述附加疗法是伽马放射。在一些实施方案中,所述附加疗法是靶向PBK/AKT/mTOR途径,HSP90抑制剂,微管蛋白抑制剂,细胞凋亡抑制剂和/或化学预防剂的疗法。所述附加疗法可以是本领域已知的一种或多种化学治疗剂。
相对于附加癌症疗法,例如免疫检查点疗法,可以在其之前、期间、之后或以各种组合施用细胞疗法。施用可以是间隔的,从同时至数分钟至数天至数周。在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,通常将确保在每次递送的时间之间没有经过显著长的时间,使得两种化合物仍然能够在患者上发挥有利联合效果。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段显著延长,在各自施用之间间隔几天(2、3、4、5、6或7天)延长到几周(1、2、3、4、5、6、7或8周)。
考虑到试剂的毒性(如果有的话),将本实施方案的任何化合物或治疗施用于患者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。随后的具体实施例涉及其中个体患有癌症的实施方案。
A.化学疗法
根据本实施方案,可以使用多种化学治疗剂。术语“化学疗法”是指使用药物来治疗癌症。“化学治疗剂”用于表示在癌症的治疗中所施用的化合物或组合物。这些药剂或药物通过它们在细胞内的活性方式进行分类,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。或者,可以基于其直接交联DNA,嵌入DNA或通过影响核酸合成而诱导染色体和有丝分裂畸变的能力来表征药剂。
化学治疗剂的实例包括烷化剂,例如噻替派和环磷酰胺;烷基磺酸酯类,例如白消安、英丙舒凡和哌泊舒凡;氮丙啶类,例如苯佐替哌(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙撑亚胺类(ethylenimine)和甲基蜜胺类(methylamelamine),包括六甲蜜胺(altretamine)、三乙撑蜜胺(triethylenemelamine)、三乙撑磷酰胺(trietylenephosphoramide)、三乙撑硫代磷酰胺(triethylenethiophosphoramide)和三羟甲蜜胺(trimethylolomelamine);番荔枝内酯类(acetogenin)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱类(camptothecin)(包括合成类似物拓扑替康(topotecan));苔藓抑素(bryostatin);卡利抑素(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(cryptophycin)(特别是隐藻素1和隐藻素8);海兔毒素(dolastatin);倍癌霉素(duocarmycin)(包括合成类似物KW-2189和CBl-TM1);艾榴塞洛素(eleutherobin);水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑素(spongistatin);氮芥类(nitrogen mustard),例如氯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、胆磷酰胺(cholophosphamide)、雌氮芥(estramustine)、异磷酰胺(ifosfamide)、双氯乙基甲胺(mechlorethamine)、盐酸甲氧氮芥(mechlorethamine oxidehydrochloride)、美法仑、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);硝基脲类(nitrosurea),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(ranimustine);抗生素类,例如烯二炔类(enediyne)抗生素(例如,加利车霉素(calicheamicin),尤其是加利车霉素γ1和加利车霉素ω1;达内霉素(dynemicin),包括达内霉素A;二膦酸盐类(bisphosphonate),例如氯膦酸盐(clodronate);埃斯波霉素(esperamicin);以及新抑癌菌素(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(aclacinomysin)、放线菌素、氨茴霉素(authramycin)、氮丝氨酸(azaserine)、博来霉素、放线菌素C(cactinomycin)、卡柔比星(carabicin)、洋红霉素(carminomycin)、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)、6-二氮-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-吡咯代-多柔比星和脱氧多柔比星)、表柔比星、依索比星(esorubicin)、依达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(例如丝裂霉素C)、霉酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素(olivomycin)、培来霉素(peplomycin)、泊非霉素(potfiromycin)、嘌呤霉素、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链脲霉素(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,例如甲氨喋呤和5-氟尿嘧啶(5-FU);叶酸类似物,例如二甲叶酸(denopterin)、蝶罗呤(pteropterin)和三甲曲沙(trimetrexate);嘌呤类似物,例如氟达拉滨(fludarabine)、6-巯基嘌呤、硫咪嘌呤和硫鸟嘌呤;嘧啶类似物,例如安西他滨(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)、多西氟尿啶(doxifluridine)、依诺他滨(enocitabine)和氟尿苷(floxuridine);雄激素类,例如卡鲁睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、表硫雄醇(epitiostanol)、美雄烷(mepitiostane)和睾内酯(testolactone);抗肾上腺类,例如米托坦(mitotane)和曲洛司坦(trilostane);叶酸补充剂,例如亚叶酸;醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamideglycoside);氨基酮戊酸(aminolevulinic acid);恩尿嘧啶(eniluracil);氨苯吖啶(amsacrine);阿莫斯汀(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);依氟鸟氨酸(elformithine);醋酸羟吡咔唑(elliptinium acetate);埃博霉素类(epothilone);依托格鲁(etoglucid);硝酸镓;羟基脲;香菇多糖(lentinan);氯尼达明(lonidainine);美登木素生物碱类(maytansinoid),例如美登素(maytansine)和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidamol);二胺硝吖啶(nitraerine);喷司他丁(pentostatin);苯来美特(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基酰肼;丙卡巴肼(procarbazine);PSK多糖复合物;雷佐生(razoxane);根霉素(rhizoxin);西索菲兰(sizofiran);锗螺胺(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(trichothecene)(尤其是T-2毒素、疣孢菌素A(verracurinA)、杆孢菌素A(roridinA)和蛇形菌素(anguidine));聚氨酯;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);加西托星(gacytosine);阿糖胞苷(arabinoside)(“Ara-C”);环磷酰胺;紫杉烷类(taxoid),例如紫杉醇(paclitaxel)和多西他塞(docetaxel);吉西他滨;6-硫鸟嘌呤;巯基嘌呤;铂配位络合物,例如顺铂、奥沙利铂和卡铂;长春碱(vinblastine);铂类;依托泊苷(VP-16);异磷酰胺;米托蒽醌;长春新碱;长春瑞滨;诺安托(novantrone);替尼泊苷;依达曲沙;柔红霉素;氨基蝶呤;希罗达(xeloda);伊拜膦酸盐(ibandronate);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);类视黄醇,例如视黄酸;卡培他滨;卡铂、丙卡巴肼、普卡霉素(plicomycin)、吉西他滨、诺维本、法呢基蛋白转移酶抑制剂、反铂,以及以上任一种的可药用盐、酸或衍生物。
B.放射疗法
引起DNA损伤并已被广泛使用的其他因素包括众所周知的γ射线,X射线和/或放射性同位素向肿瘤细胞的直接递送。也可以考虑其他形式的DNA破坏因子,例如微波,质子束辐照(美国专利5,760,395和4,870,287)和UV辐照。所有这些因素非常可能对DNA、DNA前体、DNA复制和修复以及染色体装配和维持产生广泛损害。X射线的剂量范围从长时间(3-4周)内的日剂量50至200伦琴到单次剂量2000至6000伦琴。放射性同位素的剂量范围变化很大,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肿瘤细胞的吸收。
C.免疫疗法
本领域技术人员将理解,可以将额外的免疫疗法与所述实施方案的方法组合或结合使用。在癌症治疗的背景下,免疫疗法通常依靠使用免疫效应细胞和分子来靶向和破坏癌细胞。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治疗的效应子,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(化学疗法、放射性核素、蓖麻毒蛋白A链、霍乱毒素、百日咳毒素等)缀合,并用作靶向剂。或者,效应子可以是携带表面分子的淋巴细胞,该表面分子直接或间接与肿瘤细胞靶相互作用。各种效应细胞包括细胞毒性T细胞和NK细胞。
抗体-药物缀合物已经作为癌症治疗剂开发的突破性方法出现。癌症是世界上主要的死亡原因之一。抗体-药物偶联物(ADC)包含与杀细胞药物共价连接的单克隆抗体(MAb)。这种方法将单克隆抗体针对其抗原靶标的高特异性与高效的细胞毒性药物相结合,从而产生了“武装”单克隆抗体,可将有效载荷(药物)递送至具有丰富抗原水平的肿瘤细胞。药物的靶向递送还将其在正常组织中的接触降至最低,从而降低了毒性并提高了治疗指数。FDA批准了两种ADC药物,即于2011年批准了(布伦妥昔单抗维多汀(brentuximab vedotin))和于2013年批准了(曲妥珠单抗美坦新(trastuzumab emtansine)或T-DM1)证实了该方法。目前,在癌症治疗的临床试验的各个阶段中,有30多种ADC药物候选物。随着抗体工程和连接子载荷优化的日趋成熟,新ADC的发现和开发越来越依赖于对适用于该方法的新靶标的鉴定和验证以及靶向MAb的产生。ADC靶标的两个标准是肿瘤细胞内的上调/高水平表达和强健的内化(robust internalization)
在免疫疗法的一个方面,肿瘤细胞必须带有适合于靶向的某种标志物,即其在大多数其他细胞上不存在。存在许多肿瘤标志物,并且在本实施方案的背景下,这些肿瘤标志物中的任何一种都可能适于靶向。常见的肿瘤标志物包括CD20、癌胚抗原、酪氨酸酶(p97)、gp68、TAG-72、HMFG、唾液酸路易斯抗原、MucA、MucB、PLAP、层粘连蛋白受体、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结合起来。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。
目前正在研究或使用的免疫疗法的实例有免疫佐剂,例如牛分枝杆菌(Mycobacterium bovis)、恶性疟原虫(Plasmodium falciparum)、二硝基氯苯和芳香族化合物(美国专利5,801,005和5,739,169);细胞因子治疗,例如干扰素α、β和γ以及IL-1、GM-CSF和TNF;基因治疗,例如TNF、IL-1、IL-2和p53(美国专利5,830,880和5,846,945);单克隆抗体,例如抗CD20、抗神经节苷脂GM2和抗p185(美国专利5,824,311)。预期一种或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,免疫疗法可以是免疫检查点抑制剂。免疫检查点或者调高信号(例如共刺激分子)或调低信号。可能被免疫检查点封锁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淋巴细胞减毒剂(B and T lymphocyteattenuator,BTLA),细胞毒性T淋巴细胞相关蛋白4(cytotoxic T-lymphocyte-associatedprotein 4,CTLA-4,也称为CD152),吲哚胺2,3-二加氧酶(indoleamine 2,3-dioxygenase,IDO),杀伤细胞免疫球蛋白(killer-cell immunoglobulin,KIR),淋巴细胞激活基因3(lymphocyte activation gene-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(T-cell immunoglobulin domain and mucin domain 3,TIM-3)以及T细胞活化的V区Ig抑制剂(V-domain Ig suppressor of T cell activation,VISTA)。特别地,免疫检查点抑制剂靶向PD-1轴和/或CTLA-4。
D.手术
大约60%的癌症患者将接受某种类型的手术,包括预防、诊断或分期、根治性和姑息手术。根治性手术包括切除,其中全部或部分癌组织被物理取出、切除和/或破坏,并且可以与其他疗法结合使用,例如本实施方案的治疗、化学疗法、放射疗法、激素疗法、基因疗法、免疫疗法和/或替代疗法。肿瘤切除是指物理取出肿瘤的至少部分。除肿瘤切除术外,手术治疗还包括激光手术、冷冻手术、电外科手术和显微控制手术(莫氏手术)。
在切除部分或全部癌细胞、组织或肿瘤后,体内可能会形成空腔。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治疗来完成治疗。可以例如每1、2、3、4、5、6或7天,或者每1、2、3、4、5周或每1、2、3、4、5、6、7、8、9、10、11或12个月重复这种治疗。这些治疗也可以采用不同的剂量。
E.其他药剂
预期可以将其他药剂与本实施方案的某些方面组合使用以改善治疗的疗效。这些另外的药剂包括影响细胞表面受体和GAP连接的上调的药剂,细胞生长抑制和分化药剂,细胞粘附抑制剂,增加过度增殖细胞对凋亡诱导剂敏感性的药剂或其他生物药剂。通过增加GAP连接数来增加细胞间信号传导,将增加对邻近的过度增殖细胞群的抗过度增殖作用。在其他实施方案中,细胞抑制剂或分化剂可以与本实施方案的某些方面结合使用以改善治疗的抗过度增殖功效。预期细胞粘附抑制剂可改善本发明实施方案的功效。细胞粘附抑制剂的例子是粘着斑激酶(focal adhesion kinase,FAKs)抑制剂和洛伐他汀。进一步考虑可以将提高过度增殖细胞对凋亡的敏感性的其他药剂(例如抗体c225)与本实施方案的某些方面组合使用以改善治疗功效。
VII.制品或试剂盒
本文还提供了包含CD4+和/或CD8+细胞或者从中可以产生CD4+和/或CD8+细胞的细胞的制品或试剂盒。所述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所述细胞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书。本文所述的任何抗原特异性细胞或产生它们的试剂可包括在制品或试剂盒中。合适的容器包括例如瓶,小瓶,袋子和注射器。容器可以由多种材料形成,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)。在一些实施方案中,容器保持制剂,并且在容器上或与容器相关的标签可以指示使用指南。制品或试剂盒还可以包括从商业和用户角度出发期望的其他材料,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试剂(例如,化学治疗剂和抗肿瘤剂)。用于所述一种或多种试剂的合适容器包括例如瓶、小瓶、袋子和注射器。
实施例
包括以下实施例以说明本公开的具体实施方案。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方法的实施中发挥良好作用的技术,因此可以认为构成其实施的具体方式。然而,根据本公开,本领域技术人员应当理解,可以在所公开的特定实施例中进行许多改变,仍可获得类似或相似的结果,而不脱离本公开的精神和范围。
实施例1
结合CD8共受体功能与低亲和力TCR转基因T细胞进行免疫治疗
转基因TCR和CD8αβ的共转导修饰了CD8+和CD4+ T细胞表型。从自体TCR谱库中分离时,大多数靶向过度表达的肿瘤相关自身抗原的TCR的亲和力低,并且依赖于CD8共受体2,11。可以执行多种类型的测量来表征TCR-肽-MHC相互作用30。为测试转基因CD8α和CD8β链能否从掺有肿瘤靶向TCR的多顺反子载体中有效表达,构建了编码生存素特异性TCR(s24),CD8αβ和选择标记(ΔCD271)(T8,图1A)的逆转录病毒载体,以及只编码TCR(生存素s24和s16,PRAME p28和p11)或CD8αβ的载体。用s24-TCR或s24-T8转导选择的CD4+和CD8+T细胞,并分析转导效率。CD4+和CD8+细胞均能很好地转导(%TCR+ CD4 vs CD8:82±9 vs84±4,p=NS;%T8+ CD4 vs CD8:52±10 vs 45±8%,p=NS;n=6,平均值±SD,图1B)。但是与单独的TCR相比,多顺反子T8载体的转导效率显著较低(CD4 TCR+vs T8+:p<0.001,CD8 TCR+vs T8+:p<0.001,n=6,图1B)。在比较NT、TCR+和T8+细胞时,在CD8+ T细胞中,CD8α水平没有变化(图1C)。有趣的是,与TCR+ CD8+ T细胞相比,T8+中的CD8β水平显著更高(CD8βMFI:6.3±2.7x103 vs 1.9±0.6x103,n=7,平均值±SD,p=0.008,图1D)。在CD4+ T细胞中,与CD8αβ的共转导产生了杂化表型。T8+ CD4+ T细胞中的CD8α细胞表面水平与TCR+CD8+ T细胞相当(CD8αMFI:4.6±1.7x103 vs4.3±1.3x103,n=6,平均值±SD,p=NS)(图1C),但是与TCR+ CD8+ T细胞相比,T8+ CD4+ T细胞中CD8β细胞表面水平显著较低(CD8βMFI:1.0±0.6x103 vs 1.9±0.6x103,n=7,平均值±SD,p=0.002)。当CD8αβ与TCR共表达时,CD4+ T细胞仅识别被靶向的生存素表位(Dextramer MFI,CD4 TCR+vs T8+:0.1±0.08x103 vs 2.3±2.5x103,p=0.02;CD8 TCR+vs T8+:3.4±0.6x103 vs 4.2±2.6×103,p=NS;n=5,平均值±SD)(图1E)。Dextramer结合在TCR+和T8+ CD8+ T细胞中是相当的,并且在T8+ CD4+ T细胞和TCR+ CD8+ T细胞之间也相当(Dextramer MFI 2.3±2.5x103 vs3.4±0.6x103,p=NS)。因此,强制表达CD8αβ和I类限制性TCR产生了(1)CD8β细胞表面水平升高的CD8+ T细胞,和(2)具有CD8αβ链表面表达以及识别和结合靶向的pMHC I类复合物的新能力(与天然CD8+ T细胞相似)的杂化CD4+ T细胞。
T8+ CD4+ T细胞对于靶向的I类限制性表位具有与TCR+或T8+ CD8+ T细胞相似的亲和力。为了确定CD8αβ共表达在选定的CD8+和CD4+ T细胞中的效果,使用四种不同的TCR测量了转基因T细胞的亲和力;两个靶向生存素ELT/LML表位(s24和s16),两个靶向PRAMENLT表位(p28和p11)。所有TCR构建体均使用小鼠恒定区以最小化与内源TCR链的交叉配对(图1A),并调节了转导效率2。T细胞暴露于同源肽的连续稀释液中,并对所得的IFNγELIspots进行计数。CD8αβ的共转导不影响CD8+ T细胞的亲和力,但是,它重编程了CD4+ T细胞以识别被靶向的I类表位,与CD8+T细胞有相似的亲和力(图2)。在限制的肽浓度下,对于所有四个测试的TCR,与单独用TCR进行转导的CD8+ T细胞相比,在用T8进行转导的CD4+T细胞中IFN-γ斑点形成单位(spot forming units,SFU)的数量相似。因此,CD8共转移可以用作将CD4+ T细胞重定向至I类限制性表位的一般策略。
CD8αβ与TCR的共表达对CD8+和CD4+ T细胞赋予了顺序杀伤能力。将T细胞与生存素+HLA-A*02:01+BV173白血病细胞以低E:T比(1:5)共培养,并评估对HLA I类限制性靶细胞的杀伤力。正如预期的那样,TCR+和T8+ CD8+ T细胞很容易杀死其靶标。CD4+ T细胞仅在用T8转导时才杀伤,而在单独用TCR转导时不杀伤,而T8+ CD4+ T细胞的杀伤与TCR+或T8+CD8+ T细胞相当(CD4:T8+ vs TCR+,p=0.0004;T8+ CD4 vs TCR+ CD8或T8+ CD8,p=NS,n=7)(图3A)。这种细胞毒性是HLA I类限制性的,因为TCR+或T8+ CD8+ T细胞仅杀死野生型,而没有杀死表面HLA-A*02:01阴性的B2M-KO BV173细胞(图3B)。在T8+ CD4+ T细胞中观察到了相同的效果。为了评估高肿瘤负荷时抗肿瘤功能是否会迅速耗尽,发明人用新鲜生存素+HLA-A*02:01+BV173白血病细胞以低E:T比对用TCR、T8或NT对照转导的CD8+和CD4+ T细胞进行了多达四次攻击(图3C)。值得注意的是,与TCR+相比,T8+ CD8+ T细胞的连续肿瘤杀伤能力显著增加(杀伤数T8+ vs TCR+:2±1.4vs 1.3±1.1,p=0.04,n=7,图3D,右上图)。CD4+ T细胞仅在用T8转导时才杀伤,而单独用TCR则不杀伤(杀伤数T8+ vs TCR+:3.3±0.5vs 0±0,p<0.0001,n=7,图3D,左上图),而T8+ CD4+ T细胞在连续杀伤方面与T8+CD8+ T细胞一样有效(杀伤数T8+ CD4 vs CD8:3.3±0.5vs 2±1.4,p=NS,n=7)。最后,CD8αβ的强制表达还导致在多次肿瘤攻击中修饰的T细胞扩增(图3D,下图,虚线)。CD8αβ共转移后,CD8+ T细胞的扩增没有明显改变(CD8 TCR+vs T8+:p=NS,对logAUC进行的t检验)。然而,T8+ CD4+ T细胞扩增明显优于TCR+ CD4+ T细胞(p<0.0001)、TCR+ CD8+ T细胞(p<0.002)和T8+ CD8+ T细胞(p<0.02)。
为了进一步表征由CD8αβ共转移产生的细胞毒性表型,在初始接种(D1)和第三次肿瘤攻击(D10)之后,在24小时共培养上清液中检查了细胞因子的产生。TCR+与T8+ CD8+ T细胞相比,细胞因子的产生谱没有明显改变。但是,CD8αβ共转移至CD4+ T细胞产生了TH1为主的细胞毒性细胞因子模式。T8+ CD4+ T细胞分泌多种细胞毒性细胞因子,包括IFNγ、TNFα、穿孔素或粒酶B,其水平与TCR+或T8+ CD8+ T细胞相当(图3E)。另外,仅T8+ CD4+ T细胞产生一些TH2细胞因子,例如IL10(图3E)。因此,通过TCR和CD8αβ共转移增强了细胞毒性CD8+ T细胞的功能,而强制表达CD8αβ则给TCR+ CD4+ T细胞赋予了细胞毒功能并保留其天然的辅助功能。进一步地,HLA-A*02+和A*02-供体中的T细胞扩增与所有构建体相当(图3F),表明CD8共转移并没有通过低水平的内源性生存素表达而增加在激活的T细胞中产生TCR介导的靶点毒性(也称为fratricide)的可能性4。
TCR-CD8αβ表达改善了单个CD8+ T细胞的顺序杀伤能力,并将单个CD4+ T细胞转化为细胞毒性CD8+ T细胞。为了评估单细胞水平上转基因CD8αβ表达对TCR转基因CD8+和CD4+ T细胞杀伤动力学的影响,在纳米孔板(nanowell grid)中进行了高通量延时成像显微摄影(time-lapse imaging microscopy)(TIMING)22。建立与靶标的稳定结合所需的时间(tSeek),结合总持续时间(tContact)以及第一次接触与肿瘤细胞凋亡之间的时间(tDeath)在9小时内测量(图4A)。CD8+ T细胞可以有效地找到其靶标并建立稳定的结合。E:T为1:1时,在找到靶标方面,TCR+ CD8+ T细胞比T8+ CD8+ T细胞更有效(图4B上图,tSeek CD8 TCR+vsT8+,p=0.01),但它们建立了同样稳定的接触(图4B中间图,tContact p=NS)。它们的杀伤能力在E:T为1:1时是相当的(每孔单个T细胞和单个靶细胞,图4B左下,p=NS),但是,在E:T为1:2时,T8+ CD8+ T细胞中顺序杀伤能力显著增强(每个孔中单个T细胞和两个靶细胞,图4B右下,p=0.0002)。正如预期的那样,尽管TCR+ CD4+ T细胞积极寻找靶标并找到接触,但它们却无法形成稳定的结合并杀死靶细胞(图4B,tSeek和tContact,CD4:TCR+vs T8+;p<0.0001)。但是,T8+ CD4+T细胞可有效杀死其靶标。在E:T为1:1时,T8+ CD4+ T细胞与TCR+或T8+ CD8+ T细胞一样有效地发现、结合并杀死它们的靶标(图4B,p=NS)。在E:T为1:2时,T8+ CD4+T细胞与T8+ CD8+T细胞一样有效地杀死(图4B,右下,p=NS),并且比TCR+ CD8+ T细胞(图4B,右下,p<0.0001)更好地杀死。根据这些TIMING测试结果,可以确定(1)单个CD8+ T细胞中CD8αβ的共转移显著增强了连续杀伤能力,(2)T8+ CD4+ T细胞的单细胞靶标寻找、结合和杀伤动力学与TCR+或T8+ CD8+ T细胞相当。
转基因CD8αβ增强了早期TCR信号传导事件。为了评估转基因CD8αβ是否增强了早期TCR信号传导事件,发明人分析了用BV173白血病细胞短暂刺激T细胞后在活化Y394位点的Lck磷酸化。CD8αβ的共转移显著增加了T8+ CD8+ T细胞以及T8+ CD4+ T细胞中的活化pLCK Y394水平(图5A和5B),表明CD8共受体的转基因表达不仅对TCR-pMHC复合物提供了稳定性,还增强了CD8+和CD4+ T细胞亚群中的早期TCR信号传导事件。
转基因CD8αβ增强了TCR转基因CD8+和CD4+ T细胞的体内抗肿瘤功能。最后,在先前建立的白血病异种移植模型中,用植入了BV173.ffLuc白血病细胞的NSG小鼠测试了转基因T细胞的体内抗肿瘤功能2。简而言之,对亚致死剂量辐射的NSG小鼠经静脉注射BV173.ffLuc细胞,随后用NT、TCR或T8转基因CD8+或CD4+ T细胞进行三次T细胞输注(图6A)。通过体内BLI测量肿瘤的生长。与NT对照相比,TCR+ CD8+ T细胞治疗的小鼠有明显的白血病控制,而用T8+ CD8+ T细胞治疗的小鼠有进一步增强(图6B和6C,n=5/组,NT vsTCR:p=0.0002,NT vs T8:p<0.0001,TCR vs T8:p=0.01,对log AUC(第28天对比于第0天)进行t检验)。如预期的那样,NT对照T细胞和TCR+ CD4+ T细胞均不能控制白血病的生长。相反,T8+ CD4+ T细胞显著延迟了白血病进展直至第35天(图6D和6E,n=5/组,p=0.001,对log AUC(第35天对比于第0天)进行t检验)。因此,CD8αβ的转基因表达与靶向肿瘤的I类TCR一起增强了CD8+ T细胞的功能并对CD4+ T细胞赋予了抗肿瘤功能。
某些实施方案的意义
为了利用CD8共受体功能并增强采用靶向肿瘤的HLA-I类限制性TCR的过继T细胞疗法,发明人探索了经工程化以单独地或与CD8αβ共受体组合地表达TAA特异性TCR的纯化的CD8+和CD4+ T细胞群的特性。表征的两个主要问题是:(1)通过增加TCR和CD8αβ转导时共受体分子的可用性是否可以增强CD8+ T细胞功能,以及(2)TCR和CD8αβ的转基因共表达是否可以将CD4+ T细胞重定向至靶向的I类表位,同时保留其T辅助功能。已确定在体外和体内,CD8共转移增强了CD8+ T细胞的细胞毒性,包括其顺序杀伤能力。伴随CD4和CD8的共表达,转基因CD4+ T细胞表现出杂化表型,与天然CD8+ T细胞具有相似亲和力的同源抗原的识别,并以I类限制性方式杀死靶标。杂化CD4+ T细胞在连续杀伤试验中,在单细胞水平上很容易杀死白血病细胞,并产生了细胞毒性以及TH细胞因子。杂化CD4+ T细胞还能够在小鼠异种移植物中控制白血病生长。
强制表达I类限制性肿瘤相关抗原特异性TCR和过继T细胞转移是某些实体瘤和血液系统恶性肿瘤的成功治疗策略1,24,25。大多数自身TAA特异性TCR的亲和力低,并且依赖于CD8共受体的存在,而只有少数具有高亲和力的天然存在或离体工程化TAA特异性TCR是不依赖于CD8的11,26,27。因此,大多数过继转移方案都依赖CD8+ T细胞产生所需的体内抗肿瘤功能。从生理学上讲,异源二聚体形式(αβ)的CD8共受体在成熟外周T细胞中的I类限制性抗原识别和T细胞活化中起主要作用。这两个主要功能是使TCR-pMHC复合物稳定在免疫突触上,并通过脂筏中的Lck Y394磷酸化增强早期TCR信号传导事件28,29。转基因TCR因此依赖于细胞的内源CD8αβ共受体的可用性来发挥其功能。预期在本文特定实施方案中,CD8+ T细胞中可用的CD8分子的数目可能是TCR-转基因CD8+ T细胞的免疫突触形成和抗肿瘤功能的限制因素,因为转基因TCR的拷贝数是超生理学的12。在带有低亲和力TAA特异性TCR的CD8+ T细胞中评估了共受体过表达的功能后果,发现在校正TCR–CD8αβ分子不平衡后,TCR特异性细胞毒性、连续杀伤能力和体内抗肿瘤功能得到改善。
CD4+ T细胞在协调针对感染和癌症的有效免疫应答中发挥着多种功能,它们与CD8+ T细胞的相互作用至关重要13,14,如最近通过靶向肿瘤新抗原的CD4+ TH1肿瘤浸润性淋巴细胞的过继转移所证明的,或通过以特定比例的CD4:CD8 T细胞输注入CD19-CAR T细胞所证明的16,18。因此,应将功能性CD4+ T细胞掺入TCR转基因的T细胞产物中以进行过继转移,因为过继转移后,CD4+ T细胞可以极大地促进肿瘤控制和CD8+ T细胞的维持。先前显示,CD8非依赖性I类限制性TCR可以在CD4+ T细胞中有效过表达,这产生了多功能的CD4+ T细胞,其具有细胞毒性和辅助细胞功能,以及在异种移植模型中控制体内肿瘤生长能力26,27。因此,我们评估了转基因CD8共表达是否可以将表达低亲和力I类限制性TCR的不应答性CD4+ T细胞重编程为兼具细胞毒性和辅助功能的多功能杂化T细胞。实际上,CD4+ T细胞中CD8αβ共表达产生了多功能杂化细胞毒性和辅助细胞,其具有增强的过继转移特性,包括体外在单细胞水平上的连续杀伤能力和体内白血病的控制。
为过继T细胞疗法选择最佳TAA特异性TCR是一项艰巨的任务,因为在清除肿瘤细胞的最佳亲和力与产生脱靶毒性的潜力之间存在一条细线1,2,4,6-9。因为肿瘤相关自身抗原在癌症中过表达,但在某些正常健康组织中也以低水平存在,所以如果TCR亲和力太高且TCR识别细胞表面上呈递的非常低水平的pMHC,则可能会出现中靶脱肿瘤(on-target off-tumor)毒性。但是,通过CD8共受体的共表达来稳定TCR-pMHC与低亲和力TAA特异性TCR的相互作用的本公开的策略安全地增强了总体TCR+ T细胞与靶细胞的相互作用,因为在T细胞扩增培养中未见有姊妹杀伤(fratricide)证据。
总的来说,在体外和体内,CD8αβ共受体的转基因共表达对TCR转基因CD8+和CD4+T细胞的功能具有有益的作用。可以通过I类TCR和CD8将CD4+ T细胞重编程为多功能杂化T细胞,同时具有细胞毒性效应功能和保留的天然辅助功能。此类杂化细胞用于过继T细胞转移代表了一种新颖的策略,其中CD8和CD4功能都可以在单个细胞水平上容易地获得。
实施例2
材料和方法的实施例
细胞系。BV173细胞购自德国细胞培养物保藏中心(the German Cell CultureCollection)(DSMZ),K562,CEM-T2(TAP转运蛋白缺陷型),293T购自美国类型培养物保藏中心(American Type Culture Collection,ATCC)。将细胞维持在完全RPMI 1640或IMDM培养基(Hyclone;Thermo Scientific)中,其中补充了10或20%的胎牛血清(FBS,Hyclone),1%的青霉素-链霉素(Gibco)和1%的glutamax(Gibco)。如之前所述,使用CRISPR/Cas9技术产生了β-2微球蛋白敲除(B2M-KO)BV173细胞1。简而言之,B2M单链向导RNA(sgRNA,5'–GGCCACGGAGCGAGACAUCU–3'(SEQ ID NO:1),Synthego)和重组Cas9蛋白(CP01,PNA Bio)各自为1μg在室温下混合,用于电穿孔0.15x106个BV173细胞(3次1600V脉冲,10ms,NeonTransfection System,Invitrogen)。将电穿孔的细胞在不含抗生素的培养基中扩增,并用FACS分选至对于HLA-A2阴性细胞大于98%的纯度。对于体内异种移植实验,如前所述,使用经修饰以表达萤火虫荧光素酶(BV173.ffLuc)的BV173细胞2。
来自健康供体的血液样品。血沉棕黄层是从the Gulf Coast Regional BloodCenter(Houston,TX,USA)的身份不明的健康人类志愿者中获得的。
逆转录病毒载体和上清液的产生。先前已描述了表达HLA-A*02:01限制性生存素ELTLGEFLKL表位(SEQ ID NO:2)(s24或s16)和PRAME NLTHVLYPV表位(SEQ ID NO:3)(p11或p28)特异性TCR的逆转录病毒载体2。通过Geneart(Invitrogen)合成了2条以2A序列分隔的编码人CD8α(Uniprot P01732)和CD8β同种型1(βM1,Uniprot P10966-1)链的基因。将它们原样克隆到SFG逆转录病毒载体骨架中,或与s24生存素特异性TCR组合克隆,形成表达所有四个基因的多顺反子载体(被不同的2A序列隔开)(图1)(In-Fusion HD克隆试剂盒,Clontech)。如所述,通过转染293T制备瞬时逆转录病毒上清液3。
转基因T细胞的产生。使用Lymphoprep(Accurate Chemical and ScientificCorporation)进行密度梯度离心,从血沉棕黄层中分离出外周血单个核细胞(PBMC)。用微珠(Miltenyi Biotech或StemCell Technologies)从PBMC中正向选择多克隆CD4和CD8 T细胞,并在非组织培养处理的24孔板(Corning)(该板覆有OKT3(从杂交瘤CRL-8001中纯化;ATCC)和抗-CD28抗体(BD Biosciences)以及IL7和IL15(各自为10ng/mL,R&D Systems))中激活3天,并按所述进行转导3。在逆转录病毒转导后,将细胞在IL7和IL15中扩增7-10天,然后再用于实验。将T细胞在RPMI 1640和Click培养基(Hyclone)为1:1的混合培养基中培养,并加入10%FBS,1%青霉素/链霉素和1%Glutamax。
免疫表型确定。用FITC,藻红蛋白(PE-),别藻蓝蛋白(APC),V450或Krome Orange缀合的抗CD4,CD8,CD271,CD19抗体(Abs)(所有均为BD Biosciences),FITC或APC缀合的鼠TCRβ恒定区(ebiosciences,克隆号H57-597)或PE缀合的LML生存素特异性dextramer聚合物(Immudex)对细胞进行表面染色,在4℃下染色30分钟。使用7-AAD(BD Biosciences)排除死细胞。为了评估LCK磷酸化,在37℃下用BV173细胞刺激T细胞(1:1比例)或用金黄色葡萄球菌肠毒素B(0.1μg/ml,Millipore Sigma,作为阳性对照)刺激T细胞30分钟。根据制造商的建议,使用抗人磷酸化LCK(phospho-LCK)(Y394)(克隆#755103)和抗小鼠IgG-NL557抗体(R&D Systems)进行间接细胞内染色。在具有BD FACSDiva软件的FACSCanto上采集样品,并使用FlowJo软件(Tree Star Inc.)进行分析。
肽和IFN-γELISpot。从Genemed Synthesis获得生存素ELTLGEFLKL((SEQ ID NO:2),其特殊变体(heteroclitic variant)LMLGEFLKL(SEQ ID NO:4)和PRAME NLTHVLYPV(SEQ ID NO:5)肽。将T细胞(105)一式三份铺板,并用经肽脉冲的CEM-T2细胞(使用同源肽的连续稀释(10-4至10-10M))、BV173细胞或单独的培养基刺激T细胞(按1:1比例)。将板在37℃/5%CO2中孵育过夜并如前所述处理2。通过ZellNet计算斑点形成单位(SFU)。
顺序共培养测试。将T细胞和BV173细胞在四个重复孔中以1:5的E:T比率共培养,没有外源细胞因子。初次接种后24小时收获共培养上清液,并保存在-80℃以进行细胞因子分析。共培养每3-4天,通过FACS和CountBright Beads(Life Technologies)计数剩余的T细胞和BV173细胞。为了评估剩余T细胞的顺序杀伤能力,如果每孔剩余的肿瘤细胞少于1x105个,则将新鲜的BV173细胞(1x106个)加回到未接触的重复孔中。
细胞因子多重测试。使用MILLIPLEX人CD8+ T细胞磁珠板(MILLIPLEX Human CD8+T-cell Magnetic Bead Panel)(EMD Millipore)一式两份定量共培养上清液中的细胞因子浓度,并用Luminex 200仪器(Luminex)进行分析。
纳米孔板中的延时成像显微摄影(TIMING)。如先前所述进行纳米孔阵列的装配(fabrication)和单细胞细胞毒性测试5,6。简而言之,将纳米孔阵列固定在50毫米玻璃底Petri培养皿(Ted Pella)上。T细胞(效应子)和BV173细胞(靶标)分别用PKH67 Green和PKH26 Red染料(2μM,Sigma-Aldrich)标记。然后将效应子和靶标依次加载到纳米孔阵列(106个细胞/mL)上,并将该阵列在37℃/5%CO2中在含有Annexin V-Alexa Fluor 647(Invitrogen)的无酚红培养基中孵育。使用装有Hamamatsu数码科学CMOS相机的AxioObserver(Carl Zeiss)(使用20x 0.8NA物镜)以5分钟的间隔监控细胞,持续9h。图像是通过手动跟踪以及细胞跟踪与分割的内置(in-house)算法相结合来处理的7。
小鼠异种移植模型。从Jackson实验室购买雌性NOD-SCID-γc-/-(NSG)小鼠(6-8周龄),并安置在贝勒医学院动物中心(the Baylor College of Medicine AnimalFacility)中。在4-6小时后,将亚致死剂量辐射(120cGy)的小鼠静脉内(尾静脉)输注3x106个BV173.ffluc细胞/小鼠。使用Xenogen体内成像系统(IVIS)(Caliper Life Sciences)通过生物发光成像(BLI)(光子/秒/cm2/sr)监测白血病负荷。肿瘤注射后24小时开始静脉内(尾静脉或眼球后)施用三次T细胞输注(每2-3天,5×106个转基因细胞或对照/小鼠)。通过BLI每周监测白血病生长。
统计。使用描述性统计数据汇总数据。使用梯形法则(trapezoidal rule)计算曲线下面积(AUC),以了解T细胞频率和生物发光强度随时间的变化。对于连续变量,使用Wilcoxon秩和检验(Wilcoxon rank-sum test)或t检验(选用合适的那个)在各组之间进行比较。检验标准性(Normality)假设,并在必要时执行对数转换以达到标准性。使用Kaplan-Meier方法进行生存分析。Wilcoxon检验用于评估各组小鼠之间的统计学显著差异。对数秩检验用于分析TIMING测试结果。使用GraphPad Prism 5软件(GraphPad software,Inc.,LaJolla,CA),SAS 9.4和R 3.3.2进行统计分析。P值<0.05被认为是统计学上显著的。
研究批准。贝勒医学院的IACUC审查并批准了所有动物研究。
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尽管已经详细描述了本公开内容及其优点,但是应当理解,在不脱离由所附权利要求所限定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、替换和变更。而且,本申请的范围不旨在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。如本领域的普通技术人员将从本公开容易地理解的,本公开可以利用目前存在或将要开发的、执行与本文所述的相应实施方案基本相同的功能或实现如本文所述的相应实施方案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。由此,所附权利要求旨在将这样的过程、机器、制造、物质组成、手段、方法或步骤包括在其范围内。
Claims (53)
1.增强个体的免疫效应细胞治疗的方法,其包括以下步骤:
向所述个体提供有效量的以下一项或两项:
表达外源CD8αβ共受体、并任选地表达一种或多种外源工程化抗原受体的CD8+细胞;和
表达外源CD8αβ共受体以及一种或多种外源工程化抗原受体的CD4+细胞。
2.根据权利要求1所述的方法,其中所述工程化抗原受体是T细胞受体(TCR),嵌合抗原受体(CAR)或两者。
3.根据权利要求1或2所述的方法,其中所述CD8+细胞,CD4+细胞或两者对于所述个体是自体的。
4.根据权利要求1或2所述的方法,其中所述CD8+细胞,CD4+细胞或两者相对于所述个体是同种异体的。
5.根据权利要求2-4中任一项所述的方法,其中所述外源工程化抗原受体和所述外源CD8αβ共受体在所述细胞中从同一载体表达。
6.根据权利要求5所述的方法,其中所述载体包含一种或多种表达构建体,其分别表达所述外源工程化抗原受体和所述外源CD8αβ共受体。
7.根据权利要求6所述的方法,其中表达所述外源工程化抗原受体的表达构建体和表达所述外源CD8αβ共受体的表达构建体被2A元件或IRES元件分开。
8.根据权利要求2-4中任一项所述的方法,其中所述外源工程化抗原受体和所述外源CD8αβ共受体在所述细胞中从不同载体表达。
9.根据权利要求5至8中任一项所述的方法,其中所述载体是病毒载体或非病毒载体。
10.根据权利要求9所述的方法,其中所述病毒载体是腺病毒载体,腺相关病毒载体,逆转录病毒载体或慢病毒载体。
11.根据权利要求1-10中任一项所述的方法,其中所述抗原是肿瘤抗原。
12.根据权利要求11所述的方法,其中所述肿瘤抗原选自下述:survivin,PRAME,CD19,CD20,CD22,κ或轻链,CD30,CD33,CD 123,CD38,ROR1,ErbB2,ErbB3/4,EGFR vIII,癌胚抗原,EGP2,EGP40,间皮素,TAG72,PSMA,NKG2D配体,B7-H6,IL-13受体cc2,IL-11受体Ra,MUC1,MUC16,CA9,GD2,GD3,HMW-MAA,CD171,Lewis Y,G250/CAIX,HLA-AI MAGE Al,HLA-A2NY-ESO-1,PSC1,叶酸受体a,CD44v7/8,8H9,NCAM,VEGF受体,5T4,胎儿AchR,NKG2配体,HER2,BCMA,CD44v6,及其组合。
13.根据权利要求1至12中任一项所述的方法,其进一步包括以下步骤:向所述个体提供有效量的所述CD4+T细胞,所述CD8+T细胞或其混合物。
14.根据权利要求13所述的方法,其进一步包括以下步骤:向所述个体提供额外的癌症治疗。
15.产生具有细胞毒性效应细胞功能和辅助功能的CD4+T细胞的方法,该方法包括用外源CD8αβ共受体和外源工程化抗原受体转染CD4+T细胞的步骤。
16.根据权利要求15所述的方法,其中所述工程化抗原受体是T细胞受体(TCR),嵌合抗原受体(CAR)或两者。
17.根据权利要求15或16所述的方法,其中所述外源工程化抗原受体和所述外源CD8αβ共受体在所述细胞中从相同载体表达。
18.根据权利要求17所述的方法,其中所述载体包含一种或多种表达构建体,其分别表达所述外源工程化抗原受体和所述外源CD8αβ共受体。
19.根据权利要求18所述的方法,其中表达所述外源工程化抗原受体的表达构建体和表达所述外源CD8αβ共受体的表达构建体被2A元件或IRES元件分开。
20.根据权利要求15或16所述的方法,其中所述外源工程化抗原受体和所述外源CD8αβ共受体在所述细胞中从不同载体表达。
21.根据权利要求17-20中任一项所述的方法,其中所述载体是病毒载体或非病毒载体。
22.根据权利要求21所述的方法,其中所述病毒载体是腺病毒载体,腺相关病毒载体,逆转录病毒载体或慢病毒载体。
23.根据权利要求15至22中任一项所述的方法,其中所述抗原是肿瘤抗原。
24.根据权利要求23所述的方法,其中所述肿瘤抗原选自下述:survivin,PRAME,CD19,CD20,CD22,κ或轻链,CD30,CD33,CD 123,CD38,ROR1,ErbB2,ErbB3/4,EGFR vIII,癌胚抗原,EGP2,EGP40,间皮素,TAG72,PSMA,NKG2D配体,B7-H6,IL-13受体cc2,IL-11受体Ra,MUC1,MUC16,CA9,GD2,GD3,HMW-MAA,CD171,Lewis Y,G250/CAIX,HLA-AI MAGE Al,HLA-A2NY-ESO-1,PSC1,叶酸受体a,CD44v7/8,8H9,NCAM,VEGF受体,5T4,胎儿AchR,NKG2配体,HER2,BCMA,CD44v6,及其组合。
25.根据权利要求15至24中任一项所述的方法,其进一步包括以下步骤:向有此需要的个体提供有效量的所述CD4+T细胞。
26.根据权利要求25所述的方法,其中所述个体患有癌症。
27.根据权利要求25或26所述的方法,其中向所述个体提供有效量的表达外源CD8αβ共受体、外源工程化抗原受体或两者的CD8+T细胞。
28.根据权利要求25、26或27所述的方法,其进一步包括以下步骤:向所述个体提供额外的癌症治疗。
29.增强CD8+T细胞的细胞毒性的方法,包括用外源CD8αβ共受体转染所述CD8+T细胞的步骤。
30.根据权利要求29所述的方法,其中所述CD8+T细胞还表达外源工程化抗原受体。
31.根据权利要求30所述的方法,其中所述工程化抗原受体是T细胞受体(TCR),嵌合抗原受体(CAR)或两者。
32.根据权利要求30或31所述的方法,其中所述外源工程化抗原受体和所述外源CD8αβ共受体在所述细胞中从相同载体表达。
33.根据权利要求32所述的方法,其中所述载体包含一种或多种表达构建体,其分别表达所述外源工程化抗原受体和所述外源CD8αβ共受体。
34.根据权利要求33所述的方法,其中表达所述外源工程化抗原受体的表达构建体和表达所述外源CD8αβ共受体的表达构建体被2A元件或IRES元件分开。
35.根据权利要求30或31所述的方法,其中所述外源工程化抗原受体和所述外源CD8αβ共受体在所述细胞中从不同载体表达。
36.根据权利要求32-35中任一项所述的方法,其中所述载体是病毒载体或非病毒载体。
37.根据权利要求36所述的方法,其中所述病毒载体是腺病毒载体,腺相关病毒载体,逆转录病毒载体或慢病毒载体。
38.根据权利要求30-37中任一项所述的方法,其中所述抗原是肿瘤抗原。
39.根据权利要求38所述的方法,其中所述肿瘤抗原选自下述:CD19,CD20,CD22,κ或轻链,CD30,CD33,CD 123,CD38,ROR1,ErbB2,ErbB3/4,EGFR vIII,癌胚抗原,EGP2,EGP40,间皮素,TAG72,PSMA,NKG2D配体,B7-H6,IL-13受体cc2,IL-11受体Ra,MUC1,MUC16,CA9,GD2,GD3,HMW-MAA,CD171,Lewis Y,G250/CAIX,HLA-AI MAGE Al,HLA-A2 NY-ESO-1,PSC1,叶酸受体a,CD44v7/8,8H9,NCAM,VEGF受体,5T4,胎儿AchR,NKG2配体,HER2,BCMA,CD44v6,及其组合。
40.根据权利要求29-39中任一项所述的方法,其进一步包括以下步骤:向有此需要的个体提供有效量的所述CD8+T细胞。
41.根据权利要求29-40中任一项所述的方法,其进一步包括以下步骤:向有此需要的个体提供有效量的CD4+T细胞。
42.根据权利要求40所述的方法,其中所述CD4+T细胞经工程改造以表达外源CD8αβ共受体,外源工程化抗原受体或两者。
43.根据权利要求40-42中任一项所述的方法,其中所述个体患有癌症。
44.根据权利要求43所述的方法,其进一步包括以下步骤:向所述个体提供额外的癌症治疗。
45.一种组合物,其包含转基因表达CD8αβ共受体的CD4+T细胞。
46.根据权利要求45所述的组合物,其中所述CD4+T细胞还转基因表达一种或多种外源工程化抗原受体。
47.根据权利要求46所述的组合物,其中所述工程化抗原受体是TCR、CAR或两者。
48.根据权利要求45-47中任一项所述的组合物,其中所述组合物进一步包含CD8+T细胞。
49.根据权利要求48所述的组合物,其中所述CD8+T细胞转基因表达CD8αβ共受体、一种或多种外源工程化抗原受体或两者。
50.一种组合物,其包含转基因表达CD8αβ共受体和任选地一种或多种外源工程化抗原受体的CD8+T细胞。
51.根据权利要求50所述的组合物,其中所述工程化抗原受体是TCR、CAR或两者。
52.根据权利要求50或51所述的组合物,其中所述组合物进一步包含CD4+T细胞。
53.根据权利要求52所述的组合物,其中所述CD4+T细胞转基因表达CD8αβ共受体、一种或多种外源工程化抗原受体或两者。
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