CN112088012A - 诱导免疫应答的组合物和方法 - Google Patents
诱导免疫应答的组合物和方法 Download PDFInfo
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- CN112088012A CN112088012A CN201980030633.8A CN201980030633A CN112088012A CN 112088012 A CN112088012 A CN 112088012A CN 201980030633 A CN201980030633 A CN 201980030633A CN 112088012 A CN112088012 A CN 112088012A
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Abstract
本发明涉及一种诱导T细胞介导的免疫应答的组合物,其用于治疗或预防前列腺癌,所述组合物包括修饰的痘苗病毒安卡拉(MVA)载体,所述载体在痘病毒F11启动子的控制下表达5T4抗原多肽。适当地,所述痘病毒F11启动子是内源性MVA F11启动子。更适当地,所述载体表达具有SEQ ID NO:1所示的氨基酸序列的多肽或所述载体表达由具有SEQ ID NO:2所示的核酸序列的多核苷酸编码的多肽。本发明还涉及用途和方法。
Description
技术领域
本发明涉及诱导对前列腺癌相关的肿瘤抗原的免疫应答,适当地是保护性免疫应答。
背景技术
前列腺癌是最常见的非皮肤癌,也是男性癌症死亡的第二大主要原因。2012年,全球约有110万人被诊断出患有该疾病,占男性所有癌症诊断的15%。超过70%的前列腺癌病例发生在发达国家。例如,仅在2014年,在美国估计有233,000名男性被诊断出患有该疾病,并预测约有30,000例死亡(Siegel et al(2014).CA Cancer J Clin 64:9–29)。尽管前列腺癌治疗已取得显著进展,但很少有可用于该疾病晚期的治疗,且这些方法已证明有效性不理想。因此,开发有效的疗法仍然是治疗该疾病的高度优先事项。
已加紧努力开发针对癌症(包括前列腺癌)的主动免疫疗法(疫苗)。传统疫苗已基于对外来“非自身”抗原的识别,有效诱导对病原体的保护性免疫。然而,迄今为止表征的绝大多数癌症抗原是由肿瘤和正常细胞表达的未改变的“自身”抗原。这对开发有效的癌症主动免疫疗法提出了挑战。尽管在免疫监视和清除癌症方面存在局限性,但临床上已观察到多种肿瘤形式的癌症免疫性(Challis&Stam(1990).ActaOncol.29:545–550)。此外,肿瘤切片的组织病理学发现肿瘤床周围有淋巴细胞浸润,并且最近的研究表明,与未伴淋巴细胞浸润的相似分期患者相比,伴肿瘤周围有该浸润的卵巢癌患者的预后有所改善(Zhang etal(2003).N Engl J Med.348:203–213)。因此,免疫组库包含自身反应性免疫细胞,当适当活化时,可排斥肿瘤。这些自身反应性细胞在识别正常细胞上的靶分子后,也具有诱导组织破坏的潜力,从而导致毒性自身免疫。因此,开发旨在使用适当的免疫学靶标活化宿主抗肿瘤免疫力的疗法仍然是成功治疗癌症(包括前列腺癌)的有希望途径。
已知T细胞在癌症的免疫控制中很重要,并且在过去的二十年中累积的大量证据表明,在几种动物模型和临床试验中,涉及序贯施用编码相同抗原的不同载体的初免-加强方案可产生明显更高的免疫应答,并具有保护能力。事实上,在临床试验中,基于猿猴腺病毒初免和MVA加强的疫苗接种策略被证明是诱导对某些人病原体的多功能保护性T细胞应答的最有效方法(Ewer et al(2013).Nat Commun.4:2836;Antrobus et al(2014).J AmSoc Gene Therapy.22:668-674;Borthwick et al.(2014).MolTher.22:464-475;Swadling et al(2014).Science translational medicine.6:261ra153;Hodgson et al(2015).J Inf Dis.211:1076-1086;and Ewer et al(2016).New Engl J Med.374:1635-1646)。
尽管有希望,但是在癌症中使用治疗性疫苗接种存在许多挑战,肿瘤对自身抗原的耐受性和主动免疫抑制机制是阻碍疗效的两个主要因素。两种最先进的前列腺癌免疫疗法Sipuleucel-T和ProstVac分别靶向两种明确定义的前列腺癌抗原,即前列腺酸磷酸酶(PAP)和前列腺特异性抗原(PSA)。5T4,属于共享肿瘤抗原家族的一种癌胚糖蛋白,是前列腺癌疫苗的另一种有希望的抗原候选物。它是在1990年通过寻找人滋养层细胞和癌细胞的表面共享分子而被鉴定出,其基本原理是它们可能以半同种异体移植物的形式在胎儿的存活中发挥作用(Southall et al(1990).Br J Cancer.61:89-95)。5T4因其在多种人实体恶性肿瘤中的高表达而成为癌症免疫治疗的潜在靶标,已成为深入研究的主题(Southall etal.(1990).Br J Cancer.61:89-95;Starzynska et al(1994).Br J Cancer.69:899-902;and Amato&Stepankiw(2012).Future Oncol.8:231–237),并且其表达与疾病进展之间存在明显的相关性(Stern et al(2014).Seminars in Cancer Biology.29:13–20;andStern&Harrop(2016).Cancer Immunology,Immunotherapy.2016:1–12)。
靶向5T4的疫苗的临床试验始于十多年前,其修饰的痘苗病毒安卡拉病毒(MVA)表达5T4蛋白。该疫苗以商品名TroVax作为同源的初免加强疫苗的形式施用于晚期结肠直肠癌患者,迄今为止,在I–III期临床试验过程中已向超过500名患有结肠直肠癌、乳腺癌、肾癌、前列腺癌和间皮瘤的患者接种(Kim et al(2010).Human Vaccines.6:784-791;andAl-Taei et al(2012).Lung Cancer.77:312-318)。TroVax具有良好的安全性特征,在5T4特异性抗体滴度最高的患者中耐受性良好,并具有改善无进展生存期的趋势(Harrop etal(2010);however,vaccine-specific cellular immune responses and clinicalefficacy were modest,J immunotherapy.33:999-1005;and Harrop et al(2012).Cancer Immunology,Immunotherapy.61:2283-2294)。
Harrop等人(Cancer Immunology,Immunotherapy 2014,62(9);1511-1520)披露了一种在mH5(修饰的H5)早期启动子控制下表达5T4抗原的MVA,与多西他赛联合用于去势抵抗性前列腺癌患者的临床施用的结果。该研究表明,与单独接受多西他赛的患者相比,所有患者均具有疫苗耐受性,并且接受联合多西他赛的患者的中位无进展生存期更长。然而,测量的疗效增加适度。
Cappuccini等人(Oncotarget 2017,8(29);47474-47489)比较了作为前列腺癌小鼠模型中异源初免-加强疗法的一部分,表达未修饰的5T4抗原的MVA和与MHC 2类相关恒定链(Ii)融合的相同抗原在p7.5启动子的控制下施用的情况。这项研究表明,抗体对未修饰的5T4产生应答,但除修饰的抗原外,没有可测量的T细胞应答的报告。对未修饰的“自身”抗原缺乏T细胞免疫应答,表明在p7.5启动子控制下表达未修饰的5T4的MVA不太可能是有效的抗肿瘤疫苗。
因此,现有技术中尚无疫苗被证明单独使用或与任何其他治疗剂联合使用可提供有效的前列腺癌治疗和预防。
本发明试图克服与现有技术相关的问题。
发明内容
我们描述了一种组合,其包括在内源性病毒F11启动子的控制下表达5T4蛋白抗原的修饰的痘苗病毒安卡拉(MVA)载体。本发明基于发明人的出人意料的发现,即当用作表达5T4的腺病毒构建体初始免疫后的初免-加强方案的一部分时,来自MVA的内源性F11启动子的5T4表达足以破坏耐受性并诱导5T4特异性T细胞免疫应答。因此,本发明的组合物可用于破坏耐受性以诱导抗原特异性免疫应答从而治疗前列腺癌。下图和实例提供了证明这些优势的数据。
第一方面,本发明提供了诱导T细胞介导的免疫应答的组合物,其用于治疗或预防前列腺癌,所述组合物包括修饰的痘苗病毒安卡拉(MVA)载体,所述载体在痘病毒F11启动子的控制下表达5T4抗原多肽。
第一方面的组合物可以有利地用于破坏对5T4抗原的免疫耐受性并诱导对5T4抗原的T细胞介导的免疫应答,并且这可以实现有效治疗或预防前列腺癌。
由第一方面的组合物表达的5T4多肽可以具有SEQ ID NO:1所示的氨基酸序列,或者可以具有由SEQ ID NO:2所示的核酸序列编码的氨基酸序列。
有利地,所述组合物进一步包括佐剂,并且所述组合物可以用于诱导受试者体内对5T4抗原多肽的T细胞介导的免疫应答并用于治疗或预防前列腺癌。
附图说明
现将参考附图以示例的方式对本发明进行描述,其中:
图1显示了5T4抗原的氨基酸序列(SEQ ID NO:1)。
图2显示了编码全长5T4抗原的核酸序列(SEQ ID NO:2)。
图3说明了与mH5启动子驱动的表达相比,在F11启动子的控制下用表达5T4的MVA.5T4加强免疫后,血液中5T4特异性T细胞应答的幅度明显更高。以1010VP的表达h5T4抗原的ChAdOx1载体肌内接种C57BL/6小鼠,间隔三周,然后在p7.5、F11和mH5启动子的控制下用107pfu的表达h5T4的MVA载体进行免疫,或者以107pfu表达由F11启动子驱动的抗原进行同源MVA.h5T4初免-加强。图显示了初免加强免疫后进行的离体血液(A)和脾脏(B)ELISPOT的代表性数据。X轴:第1-4组的给药方案。Y轴:每106个PBMC的斑点形成细胞(SFC)数。条形代表中位数。(C=ChAdOx1,M=MVA)。显示显著的p值。
图4说明了用ChAdOx1.5T4初免并用MVA.5T4_F11加强的小鼠血液和脾脏中5T4特异性T细胞的流式细胞仪分析,表明生成分泌多种细胞因子的多功能CD4+和CD8+T细胞。在用表达由F11启动子驱动的抗原进行MVA.5T4加强后,对用ChAdOx1.5T4免疫的小鼠分离的PBMC和脾细胞进行细胞内细胞因子染色(ICS)。这些图显示了对体外h5T4肽池过夜刺激应答而分泌IFN-γ(A)、TNF-α(B)和IL-2(C)的CD4+和CD8+T细胞的百分比。X轴:血液和脾脏中的CD4+和CD8+T细胞应答。Y轴:5T4特异性细胞因子分泌性T细胞的百分比。通过从T细胞暴露于h5T4肽池后分泌细胞因子的百分比减去背景(即T细胞无特异性刺激而自发分泌细胞因子的百分比)计算Δ值。条形代表中位值。
具体实施方式
第一方面,本发明提供了一种诱导T细胞介导的免疫应答的组合物,其用于治疗或预防前列腺癌,所述组合物包括修饰的痘苗病毒安卡拉(MVA)载体,所述载体在痘病毒F11启动子的控制下表达5T4抗原多肽。先前尚未公开表达在痘病毒F11启动子的控制下表达的5T4抗原多肽的MVA,因此具有新颖性。这种组合物可以有利地用于破坏对5T4抗原的免疫耐受性并诱导对5T4抗原的T细胞介导的免疫应答,并且这可以实现有效治疗或预防前列腺癌。
现有技术提出了对未修饰的5T4抗原在疫苗中用于治疗或预防前列腺癌的用途的偏见。Cappuccini 2017(同上)证实,通过MVA表达未修饰的5T4抗原可作为同源或异源初免方案的一部分,从而实现对5T4的抗体应答。然而,在异源初免-加强方案中,对由MVA表达的5T4抗原的体外T细胞介导的免疫应答的产生,需要抗原与MHC 2类相关的恒定链(Ii)融合。本发明的优点在于在内源性F11启动子的控制下,由MVA表达的未修饰的5T4抗原诱导强细胞免疫应答。
使用基于MVA的疫苗候选产品的初免-加强现有技术在多种适应症中对大量不同的“非自身”抗原产生强T细胞免疫应答。本发明的优点在于破坏了免疫耐受性,并类似地产生对“自身”抗原的稳健的T细胞介导的免疫应答。这种应答是非预期的,并提供许多益处,包括更有效的治疗以及更简单的开发和生产方案,因为不需要抗原修饰或融合。
优选地,MVA载体在MVA的内源性F11启动子的控制下表达5T4抗原多肽。在内源性F11启动子的控制下,在MVA的F11基因座中插入编码抗原的多核苷酸已经在国际公开WO2011/128704中描述。这种在内源性F11启动子控制下表达5T4抗原多肽的载体先前尚未公开,因此具有新颖性。有利地,该构象简化了MVA载体的制备。另外,F11侧翼序列中的Kozac样序列被认为有助于真核细胞中的翻译起始,并因此通过MVA促进5T4抗原的表达。
本发明人提供了一种用于治疗或预防前列腺癌的疫苗,其包括MVA病毒载体,所述MVA病毒载体包含编码具有SEQ ID NO:1所示的氨基酸序列的全长未修饰的人5T4抗原多肽的核酸序列。制备MVA构建体,使得重组病毒中不存在标记基因。
在小鼠模型中,将本发明的MVA疫苗构建体((F11)5T4)与在修饰的H5早期启动子((mH5)5T4)的控制下或在p7.5早期/晚期启动子((p7.5)5T4)的控制下表达5T4抗原的MVA构建体进行比较,以测量T细胞介导的免疫应答。当作为异源初免-加强方案的一部分施用时,MVA(F11)5T4构建体可诱导强5T4特异性T细胞应答,如在外周血单核细胞(PBMC)和脾细胞中使用IFNγELISPOT分析所测量的(图3)。PBMC中的这种应答比MVA(p7.5)5T4诱导的应答高3倍以上,而使用MVA(mH5)5T4诱导的PBMC中没有可检出的应答(图3A)。当在同源初免-加强方案中单独施用时,相同的MVA(F11)5T4构建体无法诱导相同的5T4特异性应答。有利地,MVA(F11)5T4在破坏耐受性方面有效,以诱导对5T4的稳健T细胞应答,因此预期在治疗或预防前列腺癌中有效。
在某些实施方式中,痘病毒F11启动子是内源性MVA F11启动子。MVA F11启动子区域中的内源性增强子序列和Kozac样序列可增强人细胞中5T4抗原的转录。
在具体实施方式中,5T4抗原多肽具有SEQ ID NO:1提供的氨基酸序列。
在另一具体实施方式中,5T4抗原多肽具有由SEQ ID NO:2提供的核酸序列编码的氨基酸序列。施用组合物后,使用这种编码5T4抗原多肽的密码子优化的序列改善了抗原多肽在受试者体内的表达。
在某些实施方式中,所述组合物进一步包括佐剂。包含佐剂可以改善在将组合物施用于受试者时产生免疫应答。
本发明还提供了如上所定义的组合物在诱导对5T4抗原多肽的T细胞介导的免疫应答中的用途。发明人发现,该组合物的施用可有效诱导对“自身”抗原5T4的免疫应答。该组合物优选用于诱导CD8+T细胞应答。
有力地,该组合物可有效地用于治疗或预防受试者的前列腺癌。
另一方面,本发明提供了一种诱导对5T4抗原多肽的T细胞介导的免疫应答以及诱导用于治疗或预防前列腺癌的T细胞介导的免疫应答的方法,所述方法包括向需要这种T细胞介导的免疫应答的受试者施用第一方面的组合物。
在优选的实施方式中,在该方法中,本发明的组合物以1×106至5×108空斑形成单位(pfu)的剂量施用。在最优选的实施方式中,在该方法中,组合物以1×107pfu的剂量施用。这种剂量提供了稳健的免疫应答,同时使不必要的施用和组合物的浪费最小化。
在某些实施方式中,通过该方法诱导的T细胞介导的免疫应答包括CD8+T细胞应答。这样的溶细胞性T细胞应答适合于受试者有效去除表达5T4抗原的细胞。
在优选的实施方式中,该方法是初免-加强方法,其中向受试者施用第一方面的组合物以诱导初始T细胞介导的免疫应答或加强现有的T细胞介导的免疫应答。在特别优选的实施方式中,第一方面的组合物作为对先前施用的初免疫苗接种的加强而施用。已经显示这种施用方案有利地破坏耐受性并实现诱导强抗5T4T细胞应答。
通过施用表达5T4抗原多肽的腺病毒提供该方法的优选初免疫苗接种,并且在最优选的实施方式中,所使用的腺病毒是ChAdOx1。
在优选的实施方式中,在该方法中,表达5T4抗原抗原多肽的腺病毒以1×108至1×1012病毒颗粒(VP)的剂量施用,并且更优选地,其以1×109至1×1011VP的剂量施用。在最优选的实施方式中,在该方法中,该腺病毒以1×1010VP的剂量施用。这种剂量提供了稳健的免疫应答,同时使不必要的施用和组合物的浪费最小化。
在另外的实施方式中,本发明的方法进一步包括本发明的第一方面的组合物与免疫检查点抑制剂化合物联合施用。在优选的这种实施方式中,该免疫检查点抑制剂化合物是抗PD1单克隆抗体。
在整个说明书和所附的权利要求书中,词语“包括(comprise)”和“包含(include)”以及诸如“包括(comprises)”、“包括(comprising)”、“包含(includes)”和“包含(including)”的变体将被理解为包括在内。也就是说,在上下文允许的情况下,这些词意在传达可能包含的其他未明确叙述的元素或整数。
实例
MVA构建
通过GeneArt Gene Synthesis(Thermo Fisher Scientific)合成编码5T4抗原多肽(NCBI参考序列:NM_006670.4)的密码子优化的多核苷酸。然后将5T4转基因克隆到穿梭质粒载体中,该载体设计为具有F11L ORF的上游和下游(侧翼)作为同源序列臂。在这些臂中插入5T4转基因使得能够利用内源性F11启动子(它是右同源臂的一部分),同时删除天然F11L ORF。这产生用于产生MVA.(F11)5T4的穿梭载体(F11穿梭载体)。
MVA.(mH5)5T4和MVA.(p7.5)5T4的构建分别如先前在Harrop等人(2010)和Cappuccini等人(2017)中所述。
制备MVA构建体,使得重组病毒中不存在标记基因。
5T4免疫原性
每组6只雄性C57BL/6小鼠(Harlan,UK)在第0天接受初免,包括肌内(i.m.)施用1×1010VP ChAdOx1.5T4(第1至3组)或1×107pfu MVA.(F11)5T4(第4组)。
相同的动物在第21天接受加强免疫,由i.m.使用1×107pfu MVA.(p7.5)5T4(第1组)、1×107pfu MVA.(F11)5T4(第2组)、1×107pfu MVA.(mH5)5T4(第3组)或1×107pfuMVA.(F11)5T4(第4组)组成。
加强免疫后3周(第42天)收集每只小鼠的血液和脾脏,并通过IFNg ELISPOT检测PBMC和脾细胞中是否存在5T4特异性T细胞。ELISPOT分析的结果如图3所示。
还对来自初免ChAdOx1.5T4并用MVA.(F11)5T4加强的小鼠的PBMC和脾细胞进行5T4特异性T细胞的流式细胞术分析。图4提供了流式细胞仪分析的结果。
所有动物程序均按照英国动物(科学程序)法(ASPA)的项目许可证30/2947的条款执行,并获得牛津大学动物保健和道德审查委员会的批准。在无特定病原体(SPF)条件下,在英国牛津大学动物设施中进行任何程序之前,将所有小鼠饲养至少7天以使其适应。
MVA-(F11)5T4在人受试者中的安全性和免疫原性
MVA-(F11)5T4已在临床试验中施用于人受试者,用于治疗晚期转移性前列腺癌。
这些前列腺癌患者在第0周接受初免,由以2×1010vp的剂量肌内注射(i.m.)编码5T4的猿猴腺病毒载体ChAdOx1组成,并在第4周肌内注射MVA-(F11)5T4的加强剂量,联合检查点抑制剂抗PD1的静脉内给药。相同的患者在第12周和第16周接受第二轮免疫接种,并在第8周和第12周进一步接受抗PD1的标准i.v.给药。在第0、2、5、9、13、17、24和36周收集血液样本以测量免疫应答,并且任何不良事件(AE)均已记录并进行研究。
11名患者施用MVA-(F11)5T4,并且安全性特征非常良好。接种后第二天,有50%的患者在注射部位出现疼痛或压痛。已发生三(3)例严重不良事件(SAE),但研究得出结论,它们均不是由MVA-(F11)5T4引起。
序列表
<110> 牛津大学创新有限公司
<120> 诱导免疫应答的组合物和方法
<130> BMOUI001WO
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Claims (32)
1.一种诱导T细胞介导的免疫应答的组合物,其用于治疗或预防前列腺癌,所述组合物包括修饰的痘苗病毒安卡拉(MVA)载体,所述载体在痘病毒F11启动子的控制下表达5T4抗原多肽。
2.根据权利要求1所述的组合物,其中,所述痘病毒F11启动子是内源性MVA F11启动子。
3.根据权利要求1或权利要求2所述的组合物,其中,所述载体表达具有SEQ ID NO:1所示的氨基酸序列的多肽。
4.根据权利要求1或权利要求2所述的组合物,其中,所述载体表达由具有SEQ ID NO:2所示的核酸序列的多核苷酸编码的多肽。
5.根据前述权利要求中任一项所述的组合物,所述组合物进一步包括佐剂。
6.根据前述权利要求中任一项所述的组合物在诱导对5T4抗原多肽的T细胞介导的免疫应答中的用途。
7.用于根据权利要求6所述的用途的组合物,其中,所述T细胞介导的免疫应答包括CD8+T细胞应答。
8.根据权利要求1至6中任一项所述的组合物在治疗或预防前列腺癌中的用途。
9.一种诱导受试者体内对5T4抗原多肽的T细胞介导的免疫应答的方法,所述方法包括向所述受试者施用根据权利要求1至6中任一项所述的组合物。
10.根据权利要求9所述的方法,其中,所述组合物以1×106至5×108空斑形成单位(pfu)的剂量施用。
11.根据权利要求10所述的方法,其中,所述组合物以1×107pfu的剂量施用。
12.根据权利要求9至11中任一项所述的方法,其中,所述T细胞介导的免疫应答包括CD8+T细胞应答。
13.根据权利要求9至12中任一项所述的方法,其中,所述施用作为初免-加强疫苗接种方案的一部分进行。
14.根据权利要求13所述的方法,其中,所述施用作为对先前的初免疫苗接种的加强提供。
15.根据权利要求14所述的方法,其中,所述先前的初免疫苗接种通过施用表达5T4抗原多肽的腺病毒提供。
16.根据权利要求15所述的方法,其中,所述腺病毒是ChAdOx1。
17.根据权利要求15或权利要求16所述的方法,其中,所述腺病毒以1×108至1×1012病毒颗粒(VP)的剂量施用。
18.根据权利要求17所述的方法,其中,所述腺病毒以1×109至1×1011VP的剂量施用。
19.根据权利要求17所述的方法,其中,所述腺病毒以1×1010VP的剂量施用。
20.一种诱导T细胞介导的免疫应答的方法,其用于治疗或预防受试者的前列腺癌,所述方法包括向所述受试者施用根据权利要求1至6中任一项所述的组合物。
21.根据权利要求20所述的方法,其中,所述组合物以1×106至5×108空斑形成单位(pfu)的剂量施用。
22.根据权利要求21所述的方法,其中,所述组合物以1×107pfu的剂量施用。
23.根据权利要求20至22中任一项所述的方法,其中,所述T细胞介导的免疫应答包括CD8+T细胞应答。
24.根据权利要求20至23中任一项所述的方法,其中,所述施用作为初免-加强疫苗接种方案的一部分进行。
25.根据权利要求24所述的方法,其中,所述施用作为对先前的初免疫苗接种的加强提供。
26.根据权利要求25所述的方法,其中,所述先前的初免疫苗接种通过施用表达5T4抗原多肽的腺病毒提供。
27.根据权利要求26所述的方法,其中,所述腺病毒是ChAdOx1。
28.根据权利要求26或权利要求27所述的方法,其中,所述腺病毒以1×108至1×1012VP的剂量施用。
29.根据权利要求28所述的方法,其中,所述腺病毒以1×109至1×1011VP的剂量施用。
30.根据权利要求29所述的方法,其中,所述腺病毒以1×1010VP的剂量施用。
31.根据权利要求20至30中任一项所述的方法,所述方法进一步包括施用免疫检查点抑制剂化合物的步骤。
32.根据权利要求31所述的方法,其中,所述免疫检查点抑制剂化合物是抗PD1单克隆抗体。
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