CN112118853A - 新辅助癌症疗法 - Google Patents
新辅助癌症疗法 Download PDFInfo
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- CN112118853A CN112118853A CN201980032645.4A CN201980032645A CN112118853A CN 112118853 A CN112118853 A CN 112118853A CN 201980032645 A CN201980032645 A CN 201980032645A CN 112118853 A CN112118853 A CN 112118853A
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Abstract
提供了通过新辅助疗法治疗个体中的肿瘤的方法,其中该个体先前未经历过有效减轻肿瘤负荷的治疗,该方法包括施用溶瘤性嵌合脊髓灰质炎病毒构建体或溶瘤性嵌合脊髓灰质炎病毒构建体和免疫检查点抑制剂,然后减少肿瘤。该方法可以进一步包括在减少肿瘤后施用免疫检查点抑制剂或溶瘤性嵌合脊髓灰质炎病毒构建体。还提供了用于实施该方法的试剂盒。
Description
对相关申请的交叉引用
本专利申请要求2018年4月2日提交的美国临时专利申请第62/651,470号和2019年3月25日提交的美国临时专利申请第62/823,277号的优先权权益,在此通过引用将两个申请的全部内容并入本文。
关于联邦资助研究的声明
本发明是在NCI/NIH授予的R35-CA197264联邦资助金和国防部乳腺癌研究计划3级突破奖(the Department of Defense Breast Cancer Research Program Level 3Breakthrough Award)授予的BC151083联邦资助金的政府资助下完成的。联邦政府对本发明享有某些权利。
技术领域
本发明涉及抗肿瘤疗法领域。特别是,它涉及新辅助疗法中的溶瘤病毒抗肿瘤治疗。
背景技术
PVSRIPO是重组溶瘤脊髓灰质炎病毒。它由1型PV(Sabin)活减毒疫苗组成,该疫苗含有2型人鼻病毒(HRV2)的外源内部核糖体进入位点(IRES)。参见Gromeier et al.,PNAS93:2370-2375(1996)和美国专利第6,264,940号。IRES是位于脊髓灰质炎病毒基因组5'非翻译区的顺式作用遗传元件,介导病毒的m7G-帽非依赖性翻译。PVSRIPO的抗肿瘤作用包括直接的病毒介导的肿瘤细胞杀伤;和由宿主介导的针对肿瘤的继发性免疫应答。参见Brownet al.,Sci Transl Med(:4220(2017)。该病毒已在人类中表现出令人兴奋和出乎意料的功效。然而,本领域仍需要鉴定和开发为人类,尤其是为患有难治性癌症的个体提供一种或多种改善的治疗益处的抗癌疗法。
发明内容
根据本发明的一个方面,提供了通过新辅助疗法治疗个体的肿瘤的方法。在该方法中,个体先前未经历过减轻肿瘤负荷的疗法(例如,未进行减轻肿瘤负荷的手术疗法或放射疗法)。与溶瘤性嵌合脊髓灰质炎病毒构建体同时或与之相关顺序地(施用之前或之后),还向个体施用免疫检查点抑制剂。用治疗有效量的溶瘤性嵌合脊髓灰质炎病毒构建体和治疗有效量的免疫检查点抑制剂治疗后,然后对该个体进行治疗以减轻肿瘤负荷。一方面,施用于个体的溶瘤性嵌合脊髓灰质炎病毒构建体包含脊髓灰质炎I型Sabin毒株,该毒株在脊髓灰质炎病毒的三叶草结构与所述脊髓灰质炎病毒的开放阅读读框之间的脊髓灰质炎病毒5'非翻译区中具有人鼻病毒2(HRV2)内部核糖体进入位点(IRES)。
根据本发明的另一方面,提供了通过新辅助疗法治疗个体的肿瘤的方法。在这种方法中,该个体先前未经历过治疗肿瘤的切除术(例如,未进行减轻肿瘤负荷的手术疗法)。对个体施用免疫检查点抑制剂。还向个体施用溶瘤性嵌合脊髓灰质炎病毒构建体,其中溶瘤性嵌合脊髓灰质炎病毒构建体包含脊髓灰质炎病I型Sabin毒株,该毒株在所述脊髓灰质炎病毒的三叶草结构与所述脊髓灰质炎病毒的开放阅读框(PVSRIPO)之间的所述脊髓灰质炎病毒5'非翻译区中具有人鼻病毒2(HRV2)内部核糖体进入位点(IRES)。在施用包含免疫检查点抑制剂和溶瘤性嵌合脊髓灰质炎病毒的新辅助疗法之后,对该个体进行治疗以减轻肿瘤负荷,包括手术切除肿瘤。在施用免疫检查点抑制剂和溶瘤性嵌合脊髓灰质炎病毒后的1周至一个月的时间范围内,可以进行这种肿瘤切除术。
根据本发明的另一方面,本文所述新辅助疗法方法中的任何一个都还可以包括在施用溶瘤性嵌合脊髓灰质炎病毒构建体之前6个月至1周之间,施用脊髓灰质炎病毒免疫增强剂(例如,来自Sanofi-Pasteur的三价灭活的IPOL)。
根据本发明的另一方面,本文所述方法中的任何一个都还可以包括在切除肿瘤后的辅助疗法,其中这类疗法包括向肿瘤负荷减轻的个体施用溶瘤性嵌合脊髓灰质炎病毒构建体或免疫检查点抑制剂中的一种或多种。例如,在肿瘤切除术或肿瘤放射治疗之后,可以根据维持疗法的需要,将免疫检查点抑制剂施用于个体。在另一个实例中,如果肿瘤在切除或放射治疗后复发,则可以将溶瘤性嵌合脊髓灰质炎病毒施用于个体。
根据本发明的另一个方面,提供了个体的肿瘤的新辅助疗法,和溶瘤性嵌合脊髓灰质炎病毒构建体本身或与免疫检查点抑制剂组合作为药物或组合物在肿瘤的新辅助疗法中的用途,其中个体先前未经历过治疗肿瘤的切除术,其中溶瘤性嵌合脊髓灰质炎病毒构建体包含脊髓灰质炎病I型Sabin毒株,该毒株在所述脊髓灰质炎病毒的三叶草结构与所述脊髓灰质炎病毒的开放阅读框之间的所述脊髓灰质炎病毒5'非翻译区中具有人鼻病毒2(HRV2)内部核糖体进入位点(IRES);并且其中在用治疗有效量的溶瘤性嵌合脊髓灰质炎病毒构建体或包含溶瘤性嵌合脊髓灰质炎病毒构建体和治疗有效量的免疫检查点抑制剂的组合治疗肿瘤之后,减轻了肿瘤负荷。在肿瘤负荷减轻之后,新辅助疗法还可以包括一种或多种疗法,包括施用治疗有效量的溶瘤性嵌合脊髓灰质炎病毒构建体,或治疗有效量的免疫检查点抑制剂,或其组合。
还提供了用于癌症的新辅助免疫疗法的方法,包括:
a)向患有肿瘤的个体施用治疗有效量的一种或多种免疫治疗剂,其中所述一种或多种免疫治疗剂包含溶瘤性嵌合脊髓灰质炎病毒构建体,或在组合疗法中顺序施用的溶瘤性嵌合脊髓灰质炎病毒构建体和免疫检查点抑制剂;b)在接受一种或多种免疫治疗剂后,用选自由有效减轻个体的肿瘤负荷(例如,肿瘤量)的手术、放射疗法及其组合组成的组的抗癌疗法治疗个体(即在抗癌疗法之前施用一种或多种免疫治疗剂)。溶瘤性嵌合脊髓灰质炎病毒构建体或免疫检查点抑制剂或其组合还可以进一步包括添加药学上可接受的载体。一方面,溶瘤性嵌合脊髓灰质炎病毒构建体是PVSRIPO。
本发明提供了个体的肿瘤的新辅助疗法,包括向先前未经历过切除术或放射疗法而减轻肿瘤的个体施用免疫检查点抑制剂和溶瘤性嵌合脊髓灰质炎病毒构建体,各自都以治疗有效量施用,其中溶瘤性嵌合脊髓灰质炎病毒构建体包含脊髓灰质炎病毒I型Sabin毒株,该毒株在所述脊髓灰质炎病毒的三叶草结构与所述脊髓灰质炎病毒的开放阅读框之间的所述脊髓灰质炎病毒5'非翻译区中具有人鼻病毒2(HRV2)内部核糖体进入位点;其中在用溶瘤性嵌合脊髓灰质炎病毒构建体和免疫检查点抑制剂治疗肿瘤之后,然后治疗肿瘤以减轻肿瘤负荷;并且其中,与使用溶瘤性嵌合脊髓灰质炎病毒构建体和免疫检查点抑制剂的组合的辅助疗法相比,新辅助疗法提供了改善的治疗益处。利用本领域技术人员已知的适当反应评估标准并根据治疗的癌症类型(例如,对于淋巴瘤,参见Cheson et al.,2014,J.Clin.Oncology32(27):3059-3067;对于实体非淋巴瘤,则参见Response EvaluationCriteria In Solid Tumors(RECIST)),治疗益处可包括以下中的一项或多项:肿瘤部位周围的炎症减轻(切除之前和/或之后);改善总生存率;改善无病生存率;复发的可能性降低(在原发器官复发和/或远处复发);转移性疾病的发生率降低;和增强抗肿瘤免疫应答;或改善总体客观有效率(overall objective response rate)。对于炎症减轻,发现患有肿瘤,尤其是患有脑肿瘤的患者,该患者用溶瘤性嵌合脊髓灰质炎病毒构建体进行了治疗并经历最小或易于控制的炎症,与用溶瘤性嵌合脊髓灰质炎病毒构建体治疗并经历了广泛或难以控制的炎症的个体相比,表现出更好(更有效和/或更持久)的抗肿瘤反应。
通过阅读说明书,这些和其他方面对于本领域技术人员而言应是显而易见的,并且为本领域提供了用于治疗癌症的新治疗方案。
附图说明
图1是描述溶瘤性嵌合脊髓灰质炎病毒构建体PVSRIPO的遗传结构的图。脊髓灰质炎病毒5'非翻译区(UTR)含有来自人类鼻病毒B的内部核糖体进入位点(IRES),代替脊髓灰质炎病毒5'末端的三叶草结构与脊髓灰质炎病毒的开放阅读框之间的天然脊髓灰质炎病毒序列。
图2是与用各种剂量的PVSRIPO(蓝线;“PVSRIPO”)治疗的个体相比,历史对照(红线)的总生存率的Kaplan-Meier曲线,y轴为总生存率(“生存概率”),x轴为月数。
图3显示了使用代表乳腺癌(SUM149和MDA-MB231)、黑素瘤(DM6)和前列腺癌(LNCaP)的四种不同肿瘤细胞系的结果。将树突状细胞(DC)接种在培养皿中。将来自溶瘤裂解物(onco-lysate)的上清液添加到DC培养物中并孵育。然后除去上清液,并洗涤DC。将经DNase I处理的外周血单核细胞(PBMC)在37℃下孵育。收获非贴壁细胞,并将其在CTL刺激培养基中存在IL-7的情况下,在响应细胞与刺激物DC之比为10:1的条件下,用负载脊髓灰质炎病毒诱导的肿瘤裂解产物的DC进行刺激。在第12-14天收获T细胞,计数,并在铕释放CTL测定中用作效应T细胞。用编码相关和不相关的肿瘤抗原的mRNA转染的自体DC被用作对照靶标。对于DC对照靶标,收获mRNA电穿孔的靶细胞,洗涤以除去所有痕量培养基,并用铕(Eu)标记。或者,用Eu标记最初的靶细胞(Sum149、MDAMB231、LNCaP或DM6)。将一万个铕标记的靶标(T)和以不同E:T比连续稀释的效应细胞(E)孵育在96孔V型底平板中。将平板离心3分钟,并在37℃下孵育。收获50μl上清液,并将其添加到96孔平底平板中的150μl增强溶液中,并使用VICTOR3 Multilabel Counter(Perkin-Elmer)通过时间分辨荧光测量铕释放。使用下式确定比细胞毒性活性:%特异性释放=[((实验性释放-自发性释放)/(总释放性-自发性释放)]×100。靶细胞的自发性释放小于洗涤剂总释放的25%。通过在没有T细胞的培养基中孵育靶细胞来确定靶细胞的自发释放。所有测定均一式三份进行,条形棒表示平均裂解%,误差棒表示平均值的标准误差。
图4A-图4D显示了使用了多种疗法,包括类似于本发明的脊髓灰质炎病毒和检查点抑制剂的组合疗法,在C57B16小鼠中,在使用CT2A神经胶质瘤的小鼠肿瘤模型中进行体内测试的结果;小鼠和CT2A细胞均表达人脊髓灰质炎病毒受体CD155。在顶部图中显示了以下实验处理的结果(随时间变化的肿瘤体积):图4A,组I:DMEM(病毒的载体对照)+IgG(抗PD1的对照);图4B,组II:肿瘤内单次注射PVSRIPO+IgG;图4C,组III:肿瘤内单次注射DMEM+抗PD1;图4D,IV组:肿瘤内单次注射PVSRIPO(“mRIPO”)+抗PD1。通过腹膜内注射分三次(第3、6、9天)给予抗PD1。较下方的三个图显示了治疗组II-IV中每只小鼠(每条线为不同的小鼠)的肿瘤反应(随时间变化的肿瘤体积)。
图5A-图5B显示了用PVSRIPO(mRIPO)与抗PD1或抗PDL1检查点抑制剂抗体组合治疗小鼠的结果,限制了在E0771原位免疫活性鼠乳腺癌模型中的生长。将106个E0771-CD155肿瘤细胞植入小鼠的乳腺脂肪垫中。当肿瘤达到约100mm3时,将PBS或mRIPO(5x107pfu)注射到肿瘤中。在mRIPO注射当天腹膜内注射抗PD1(图5A)/抗PDL1(图5B)(在200μL PBS中250μg),然后每2-3天注射4次。随着时间的推移监测肿瘤的生长。如图5A所示,与PBS相比,mRIPO和抗PD1抗体都能控制肿瘤体积,但是mRIPO和抗PD1的组合明显更好。如图5B所示,使用抗PDL-1获得了相似的结果,其中单独的mRIPO或抗PDL1都能够比PBS对照更好地控制肿瘤生长,但是mRIPO和抗PDL1的组合导致肿瘤生长降低。
图6A-图6B显示了原位植入5x105个E0771-CD155细胞的C57BL/6-CD155转基因小鼠的各种治疗结果。图6A是随小鼠肿瘤植入后的天数变化的肿瘤体积的图形,该小鼠接受(i)新辅助疗法(mRIPO,接着进行手术(-★-),(ii)接受PBS治疗,接着进行手术(-◆-),(iii)不接受手术但接受治疗mRIPO(-■-),以及(iv)不接受手术,但接受PBS治疗(-●-)。显著性由p值表示:★,P≤0.05;★★,P≤0.01;★★★,P≤0.001。图6B是与用PBS治疗随后进行手术的小鼠(-◆-)相比,随用mRIPO治疗、随后进行手术的小鼠(-★-)的肿瘤再攻击后的天数变化的肿瘤体积的图形。
具体实施方式
尽管癌症的新辅助化学疗法已经应用了多年,但是癌症的新辅助免疫疗法仍是发展中的医疗应用。本发明人开发了新辅助免疫疗法(在本文中也称为新辅助疗法),其中将一种或多种免疫治疗剂施用于患有肿瘤的人,所述免疫治疗剂包含溶瘤性嵌合脊髓灰质炎病毒构建体或包含溶瘤性嵌合脊髓灰质炎病毒构建体和免疫检查点抑制剂的组合。在施用一种或多种免疫治疗剂后,然后减小用一种或多种免疫治疗剂治疗的肿瘤(例如,通过手术切除,或通过放射疗法减小尺寸和/或量)。任选地,个体然后可以接受包含一种或多种免疫治疗剂的维持疗法。出乎意料的是,对于用新辅助免疫疗法治疗的个体观察到一种或多种治疗益处,所述新辅助免疫疗法包含溶瘤性嵌合脊髓灰质炎病毒构建体(例如,美国专利第6,264,940号所述的PVSRIPO,该专利的全部内容通过引用并入本文)或溶瘤性嵌合脊髓灰质炎病毒构建体和免疫检查点抑制剂的组合。在本发明时这些治疗益处尚不明显。例如,在本发明时,已知使用新辅助疗法后观察到的病理学完全缓解率并不总是转化为改善的生存率,正如在新辅助疗法后的一些乳腺癌患者中观察到的那样。另外,具有低突变负荷的肿瘤对溶瘤性嵌合脊髓灰质炎病毒构建体PVSRIPO的治疗反应最强;然而(和相比之下),对来自免疫突变检查点抑制剂治疗的免疫检查点阻断的响应主要是由突变负荷高的肿瘤引起的。此外,PVSRIPO已在辅助环境下用于临床试验;即用PVSRIPO治疗后不切除肿瘤的情况。在辅助环境中,肿瘤细胞被PVSRIPO感染,产生更多的感染性病毒,感染的肿瘤细胞被病毒溶解,释放出新产生的感染性病毒,然后所述病毒可以感染肿瘤的其他肿瘤细胞,并重复该循环。新产生的病毒还可以在诱导抗肿瘤免疫应答中进一步刺激树突状细胞。在新辅助疗法中,这种反复的肿瘤感染和溶解以及进一步免疫应答刺激受到了限制,因为在施用PVSRIPO和免疫检查点抑制剂后,肿瘤负荷得以减轻。因此,利用这种新辅助免疫疗法,如通过提高的存活率所观察到的抗肿瘤作用的持久性,或其他观察到的治疗益处,将是出乎意料的。
在本发明的方法中,可以使用将溶瘤性嵌合脊髓灰质炎病毒构建体直接施用于肿瘤的任何技术。直接施用不依赖于进入肿瘤的血管系统。可以将制剂涂在肿瘤的表面上,注射到肿瘤中,在手术过程中滴注在肿瘤部位中或肿瘤部位处,通过导管注入肿瘤中,等等。可以使用的一种治疗脑癌的具体技术是对流增强递送(convection enhanced delivery)。溶瘤性嵌合脊髓灰质炎病毒构建体是重组或基因工程脊髓灰质炎病毒,其中天然脊髓灰质炎病毒IRES至少部分与其他小核糖核酸病毒例如人鼻病毒2的IRES交换。脊髓灰质炎病毒通常是Sabin脊髓灰质炎病毒,合适的是脊髓灰质炎病I型Sabin毒株。因此,在本文所述的工程溶瘤性嵌合脊髓灰质炎病毒构建体的5'非翻译区(UTR)中包括天然脊髓灰质炎病毒的5'三叶草结构,并且脊髓灰质炎病毒的天然IRES至少部分地被人鼻病毒2的IRES替代,并且天然或野生型脊髓灰质炎病毒开放阅读框的其余部分保持完整。
根据本发明可以使用的免疫检查点抑制剂是任何破坏细胞毒性T细胞和肿瘤细胞的抑制性相互作用的抑制剂。这些包括但不限于抗PD-1抗体、抗PD-L1抗体、抗CTLA4抗体、抗LAG-3抗体和/或抗TIM-3抗体。在美国,批准的检查点抑制剂包括阿特珠单抗、易普米单抗(ipimilumab)、利妥昔单抗和纳武单抗(nivolumab)以及替雷利珠单抗(tislelizumab)。抑制剂不必是抗体,而可以是小分子或其他聚合物。如果抑制剂是抗体,则其可以是多克隆、单克隆、片段、单链或其他抗体变体构建体。抑制剂可以靶向本领域已知的任何免疫检查点,包括但不限于CTLA-4、PDL1、PDL2、PD1、B7-H3、B7-H4、BTLA、HVEM、TIM3、GAL9、LAG3、VISTA、KIR、2B4、CD160、CGEN-15049、CHK 1、CHK2、A2aR和B-7配体家族。可以使用针对单个靶标免疫检查点的抑制剂的组合或针对不同免疫检查点的不同抑制剂。另外,CSF-1R阻断剂可与免疫检查点抑制剂组合使用或用作其替代选项,以确保产生有效消除远处转移和复发性肿瘤的有效而持久的免疫。对CSF-1R具有特异性的抗体或者抑制或阻断CSF-1R的药物可用于此目的,包括但不限于伊马珠单抗(imactuzumab)和AMG820。
在新辅助疗法方法中,在个体经历减少个体的肿瘤量的手术治疗或放射治疗之前,施用一种或多种免疫治疗剂(治疗有效量的溶瘤性嵌合脊髓灰质炎病毒构建体,或免疫检查点抑制剂和溶瘤性嵌合脊髓灰质炎病毒构建体)。通常,其中,新辅助疗法包含两种免疫治疗剂,将在彼此的几天之内施用这两种治疗剂。例如,施用免疫检查点抑制剂,然后在施用免疫检查点抑制剂后第30、28、21、14、10、9、8、7、6、5、4、3、2或1天施用溶瘤性嵌合脊髓灰质炎病毒构建体。或者,在施用免疫检查点抑制剂之前施用溶瘤性嵌合脊髓灰质炎病毒构建体可能是有利的,其中然后在施用溶瘤性嵌合脊髓灰质炎病毒构建体后几天或几周内(例如第30、28、21、14、10、9、8、7、6、5、4、3、2或1天)向个体施用免疫检查点抑制剂。溶瘤性嵌合脊髓灰质炎病毒构建体引发细胞毒性T淋巴细胞反应可能需要约5天至约14天来发生。可以有利地在所述引发期之前、之中或之后开始免疫检查点抑制剂的施用。例如,一方面,在施用溶瘤性嵌合脊髓灰质炎病毒构建体后14天后施用免疫检查点抑制剂,并且在施用免疫检查点抑制剂后约1周至约3周后,然后对个体进行治疗以减轻肿瘤负荷(例如,通过手术或放射疗法)。通常,其中新辅助疗法包括施用溶瘤性嵌合脊髓灰质炎病毒,在接受溶瘤性嵌合脊髓灰质炎病毒构建体后约1周至约3周后,然后对个体进行治疗以减轻肿瘤负荷(例如,通过手术或放射疗法)。任选地,在肿瘤负荷减轻之后,个体可以接受免疫检查点抑制剂的维持疗法,所述维持疗法包括定期(例如,约每1周至3周)施用治疗有效量的免疫检查点抑制剂,和/或如果肿瘤复发,则可以与溶瘤性嵌合脊髓灰质炎病毒构建体组合施用。
包含溶瘤性嵌合脊髓灰质炎病毒构建体或免疫检查点抑制剂的免疫治疗剂的治疗有效量是对接受该免疫治疗剂的个体有效引起治疗益处的量。该有效量可以根据个体的特征而变化,包括健康状况、性别、大小(例如体重)、年龄、癌症类型、癌症阶段、给药途径、对治疗的耐受性、毒性或副作用和建立适当的治疗剂量和方案时熟练的医师应考虑的其他因素。例如,溶瘤性嵌合脊髓灰质炎病毒构建体的治疗有效量可以为约1×108组织培养物感染剂量(tissue culture infectious dose,TCID)至约5×106TCID。免疫检查点抑制剂的治疗有效量可以为约0.5mg/kg体重至约5mg/kg体重,约1mg/kg体重到约5mg/kg体重,约1mg/kg体重至约3mg/kg体重,约500mg至约1500mg,或医师确定的更少或更多的量。
免疫检查点抑制剂可以通过本领域已知的用于具体抑制剂的任何适当方式来施用。这些方式包括静脉内、口服、腹膜内、舌下、鞘内、腔内、肌内、肿瘤内和皮下。任选地,可以将免疫检查点抑制剂与溶瘤性嵌合脊髓灰质炎病毒构建体组合施用。
可以通过这种新辅助疗法来治疗任何人类肿瘤,包括小儿和成人肿瘤。肿瘤可以在任何器官中,例如脑、前列腺、乳房、肺、结肠和皮肤。可以治疗各种类型的肿瘤,包括例如胶质母细胞瘤、髓母细胞瘤、癌、腺癌等。肿瘤的其他实例包括肾上腺皮质癌、肛门癌、阑尾癌、I级(间变性)星形细胞瘤、II级星形细胞瘤、III级星形细胞瘤、IV级星形细胞瘤、中枢神经系统非典型畸胎瘤/横纹样瘤、基底细胞癌、膀胱癌、乳腺肉瘤、支气管癌、支气管肺泡癌、宫颈癌、颅咽管瘤、子宫内膜癌、子宫内膜子宫癌、室管膜母细胞瘤、室管膜瘤、食管癌、鼻腔神经胶质瘤、尤因氏肉瘤、颅外生殖细胞瘤、性腺外生殖细胞瘤、肝外胆管癌、纤维组织细胞瘤、胆囊癌、胃癌、胃肠道类癌瘤、胃肠道间质瘤、妊娠滋养细胞瘤、妊娠滋养细胞瘤、神经胶质瘤、头颈癌、肝细胞癌、肝门部胆管癌、下咽癌、眼内黑素瘤、胰岛细胞瘤、卡波西肉瘤、朗格汉斯细胞组织细胞增生症、大细胞未分化肺癌、喉癌、唇癌、肺腺癌、恶性纤维组织细胞瘤、髓上皮瘤、黑素瘤、Merker细胞癌、间皮瘤、内分泌腺瘤、鼻腔癌、鼻咽癌、成神经细胞瘤、口腔癌、口咽癌、骨肉瘤、卵巢透明细胞癌、卵巢上皮癌、卵巢生殖细胞瘤、胰腺癌、乳头瘤病、副鼻窦癌、甲状旁腺癌、阴茎癌、咽喉癌、松果体实质肿瘤、松果体母细胞瘤、垂体瘤、胸膜肺母细胞瘤、肾细胞癌、具有15号染色体变化的呼吸道癌、视网膜母细胞瘤、横纹肌肉瘤、唾腺癌、小细胞肺癌、小肠癌、软组织肉瘤、鳞状细胞癌、鳞状非小细胞肺癌、鳞颈癌(squamous neck cancer)、幕上原始神经外胚层肿瘤、幕上原始神经外胚层肿瘤、睾丸癌、喉癌、胸腺癌、胸腺瘤、甲状腺癌、肾盂癌、尿道癌、子宫肉瘤、阴道癌、外阴癌和Wilms肿瘤。
任选地,在根据本文所述的方法进行治疗之前,可以基于个体肿瘤NECL5(CD155,脊髓灰质炎病毒受体)的表达对患有肿瘤的个体进行分级。例如,这可以使用探针、引物或抗体在RNA或蛋白质水平上进行测定。NECL5表达可以指导是否决定用溶瘤性嵌合脊髓灰质炎病毒构建体治疗。NECL5表达还可用于指导治疗的积极性,包括治疗的剂量、频率和持续时间。NECL5(CD155)的抗体可商购获得并可以使用。还可以使用本领域已知的方法测定NECL5 RNA的表达。
除了新辅助疗法之外,所述新辅助疗法包括施用溶瘤性嵌合脊髓灰质炎病毒构建体和一种或多种免疫检查点抑制剂,然后手术切除肿瘤或手术减少肿瘤,个体的治疗还可以包括化学疗法、生物疗法和放射疗法中的一种或多种。这些方式可能是当前治疗某些人类肿瘤的护理标准。新辅助疗法可以在治疗肿瘤的护理标准之前、期间或之后施用。例如,可以在护理标准失败后施用包含新辅助疗法的PVSRIPO和免疫检查点抑制剂组合。当指定了免疫治疗剂的组合时,每种治疗剂都可以作为单独组合方案中的两种单独的治疗剂及时单独施用。或者,可以将两种(或多种)治疗剂混合施用。
试剂盒可在单个分开或未分开的容器中包含溶瘤性嵌合脊髓灰质炎病毒构建体,例如PVSRIPO,以及免疫检查点抑制剂。两种药剂可以在分开的容器中,或以混合的形式位于单个容器中。可以包括使用说明。任选地,可以包括用于检测个体肿瘤NECL5表达的抗体和试剂或PCR引物,作为试剂盒的组成。
申请人已经开发了产生溶瘤性嵌合脊髓灰质炎病毒构建体的方法和测试遗传稳定性和同质性的方法。可以使用任何合适的用于产生和测试遗传稳定性的方法。例如,评估稳定性的方法包括测试无法在39.5摄氏度下生长,批量测序以确定是否存在突变,以及测试灵长类神经毒性。
多种机制可能有助于溶瘤性嵌合脊髓灰质炎病毒构建体即PVSRIPO诱导抗肿瘤免疫应答的功效,包括癌细胞的感染和溶解,抗原呈递细胞的感染和激活,以及靶向癌细胞的免疫细胞的募集和激活。因此,除了病毒直接杀伤肿瘤以外,用PVSRIPO治疗肿瘤还包括免疫疗法。
虽然据信,肿瘤学和医学领域的普通技术人员会充分理解本发明的描述中使用的术语,但是本文中提供的定义是为了方便本发明的描述而阐述的,并且为该术语的使用提供了说明性实例。
本文所用术语“一(a/an)”和“该/所述”表示“一个/种或多个/种”,除非明确指定单数(例如,在短语“单个药剂”中明确指定单数)。
本文所用术语“药学上可接受的载体”是指可用于本文所述组合物或组合的给药、递送、储存、稳定性中的任何一种或多种的任何化合物或组合物或载体介质。本领域已知,这些载体包括但不限于制药领域众所周知的稀释剂、水、盐水、合适的载剂(例如脂质体、微粒、纳米颗粒、乳剂、胶囊)、缓冲剂、示踪剂、医药肠胃外载剂、赋形剂、水溶液、悬浮液、溶剂、乳液、洗涤剂、螯合剂、增溶剂、盐、着色剂、聚合物、水凝胶、表面活性剂、乳化剂、佐剂、填充剂、防腐剂、稳定剂、油、粘合剂、崩解剂、吸收剂、调味剂等。
治疗癌症或治疗患有肿瘤的个体包括但不限于减少个体的癌细胞数量或肿瘤大小,减少癌症向更具侵袭性的形式发展,降低癌细胞的增殖或降低肿瘤生长的速度,杀伤癌细胞,减少癌细胞转移或降低个体的癌症复发的可能性。本文所用的治疗个体是指赋予受疾病折磨或处于发展疾病风险的个体益处的任何类型的治疗,包括改善个体状况(例如,一种或多种症状),延迟疾病的进展,延迟症状的发作或减缓症状的进展等。
本文所用“治疗有效量”或有效量是指,当施用于个体以治疗肿瘤时,组合物的量足以实现治疗(如上所定义)。取决于制剂或组成、肿瘤类型及其严重性以及待治疗个体的年龄、体重、身体状况和反应性,治疗有效量会变化。
在本文中“新辅助疗法”用来表示,在患有肿瘤的个体经历肿瘤负荷减轻之前,例如在手术以切除或减少肿瘤量,或放射疗法以减少肿瘤量之前,给予该个体的疗法。手术可以包括肿瘤的全部切除或部分切除。新辅助疗法可以减轻肿瘤负荷,从而有助于后续切除。
在本文中“辅助疗法”用来表示肿瘤切除手术后给予的疗法。
在本文中“维持疗法”用来表示,为了降低疾病进展或复发的可能性而给予的治疗方案。可以根据评估对疗法的反应的临床参数的评估,提供任何时间长度的维持疗法。
在本文中“生存率”用来表示治疗后仍存活的个体,包括总体生存率和无病生存率。生存率通常通过Kaplan-Meier方法进行衡量。无病生存率是指在没有癌症复发迹象的情况下仍然存活的治疗个体。总体生存率是指在规定的时间内存活的个体。
以上公开内容总体上描述了本发明。通过参考以下具体实施例可以获得更完整的理解,本文提供的这些具体实施例仅出于说明的目的,而无意限制本发明的范围。
实施例1
仅使用PVSRIPO对患有肿瘤的个体进行了I期临床试验。肿瘤为复发性胶质母细胞瘤(GBM),在肿瘤切除后施用PVSRIPO(辅助疗法)。测试了许多剂量,包括1x108组织培养物感染剂量(TCID)、5x107TCID和1x107TCID。将PVSRIPO(“PVSRIPO DL 1-5”,图2,表1)直接递送到肿瘤中。对流增强递送用于肿瘤内注入PVSRIPO。使用植入的导管以500μL/hr的递送速度注入PVSRIPO,其中3mL是递送给个体的接种物总量。I期试验的结果总结在表1和图2中(追踪至2018年3月20日),其中将用PVSRIPO治疗的个体与历史对照进行比较。如表1和图2所示,与历史对照相比,用PVSRIPOP治疗的个体的总体生存率得以显著改善,尤其是在2年以后。
表1.患者PVSRIPO剂量增加与历史对照:总体生存率
实施例2
免疫检查点抑制剂的机制是从阻断其效应器功能的肿瘤引发的事件中释放细胞毒性T细胞功能。肿瘤参与控制细胞毒性T细胞的天然存在的“刹车器”系统。对于肿瘤而言,这具有下述优点,即限制免疫系统攻击表达突变蛋白并因此代表外来特征的肿瘤的潜力。免疫检查点抑制剂逆转这种肿瘤机制并释放免疫功能。PVSRIPO引发诱导细胞毒性T细胞(CTL)攻击肿瘤的免疫应答。因此,PVSRIPO与免疫检查点抑制剂的组合增强了治疗效果。如下文所示,PVSRIPO确实通过诱导CTL应答来治疗肿瘤。
使黑素瘤细胞、乳腺癌细胞、脑肿瘤细胞、前列腺癌细胞与培养物中的PVSRIPO接触并感染,并收集培养物中垂死/死亡细胞的上清液。来自感染的肿瘤细胞的上清液用于暴露自人个体分离的树突状细胞(负责与CTL通讯并协调其激活的免疫细胞群)。结果,树突状细胞显示出强烈的促炎性激活迹象(即,肿瘤细胞的病毒感染产生了促进树突状细胞CTL激活功能的可溶性因子;并且从感染的肿瘤细胞释放的病毒激活了树突状细胞)。然后将激活的树突状细胞与来自捐赠树突状细胞的同一个人的T细胞(包括CTL)共培养。然后将共培养的T细胞(包括CTL)与来自用于感染步骤的相同品系的未感染的肿瘤细胞共培养。如图3所示,观察到激活的CTL对肿瘤细胞具有高水平的细胞毒性。
本实验体外例证了据信发生在用PVSRIPO治疗的患有肿瘤的个体中的情况:病毒感染引发了一系列最终导致产生针对肿瘤的CTL应答。这一系列事件可以用免疫检查点抑制剂来协同增强。PD1-PD-L1连接体是T细胞功能的天然存在的“刹车器”之一(免疫检查点)。肿瘤中的树突状细胞通常被诱导表达PD-L1,PD-L1然后与T细胞上的PD1结合以抑制T细胞的激活。证实了暴露于PVSRIPO/PVSRIPO-肿瘤裂解产物的树突状细胞增加PD-L1表达。PD-1或PD-L1抑制剂,即范式检查点抑制剂,可防止此作用,并通过PVSRIPO溶瘤作用增加CTL激活。
在本实验中,在AIMV培养基中,用模拟(DMEM)或PVSRIPO(MOI0.1)以48小时感染融合的10cm培养皿的Sum149、MDAMB231、LNCaP或DM6细胞。收集上清液,并通过离心除去细胞碎片。将冷冻的PBMC解冻,在PBS中洗涤,并以2x108个细胞重悬浮于T-150组织培养瓶中的30ml AIM-V培养基中。将细胞在37℃下孵育1小时。非贴壁细胞通过左右摇动瓶子以使其移动加以收获。用补充有800U/ml人GM-CSF和500U/ml人IL-4的30ml AIM-V补充贴壁细胞,然后在37℃下孵育。在第6天,通过收集所有非贴壁细胞,然后进行冷PBS洗涤,收获DC。用细胞解离缓冲液解离仍贴壁的细胞。在AIMV培养基中洗涤DC,计数,并以每培养皿1×106个细胞接种在35mm培养皿中。将来自溶瘤裂解物的上清液添加到DC培养物中,并孵育24小时。然后除去上清液,并在AIMV培养基中洗涤DC。将PBMC解冻并重悬浮于PBS中,并在37℃下用200U/ml的DNase I处理20分钟。将经DNase I处理的PBMC在37℃下孵育1小时。收获非贴壁细胞,并在25ng/ml IL-7存在的情况下,用载有脊髓灰质炎病毒诱导的肿瘤裂解产物的DC以响应细胞与刺激物DC之比为10:1进行刺激。所有刺激均在RPMI 1640中进行,RPMI 1640具有10%FCS、2mM L-谷氨酰胺、20mM HEPES、1mM丙酮酸钠、0.1mM MEM非必需氨基酸、100IU/ml青霉素、100μg/ml链霉素和5x 10-5Mβ-巯基乙醇(CTL刺激培养基)。响应T细胞浓度为2×106个细胞/ml。在第3天,并且每4-5天,添加100U/ml的IL-2,持续12-14天。在CTL刺激培养基中,将T细胞维持在1-2x106个细胞/ml。在第12-14天收获T细胞,计数,并在铕释放CTL测定中用作效应T细胞。用肿瘤抗原编码mRNA转染的自体DC用作靶标对照。对于DC靶标对照,收获mRNA电穿孔的靶细胞(如图2所示),洗涤以除去所有痕量培养基,并用铕(Eu)标记。或者,用Eu标记最初的靶细胞(Sum149、MDAMB231、LNCaP或DM6)。Eu标记缓冲液(每个靶标1ml)含有1ml HEPES缓冲液(50mM HEPES,93mM NaCl,5mM KCl,2mM MgCl2,pH 7.4)、10μl Eu(在0.01N HCl中的10mM EuCl3.6H2O)、5μl DTPA(HEPES缓冲液中的100mM二亚乙基三胺五乙酸酯)和4μl DS(1%葡聚糖硫酸酯)。将5x106个靶细胞非常温和地重悬浮于1ml铕标记缓冲液中,并在冰上孵育20分钟。然后将30μl CaCl2溶液(100mM)添加到标记的细胞中,混合,并将细胞在冰上再孵育5分钟。将30ml修复缓冲液(含10mM葡萄糖、2mM CaCl2的HEPES缓冲液)添加到细胞中,并将细胞以1000rpm离心10分钟。计数细胞,并用修复缓冲液将5×106个细胞洗涤4次。最后洗涤后,将细胞以105个细胞/ml重悬浮于不含青霉素-链霉素的CTL刺激培养基中。将一万个铕标记的靶标(T)和效应细胞的不同E:T比例的连续稀释液(E)孵育在96孔V底平板中的200μl无青霉素-链霉素的CTL刺激培养基中。将平板以500xg离心3分钟,并在37℃下孵育4小时。收获50μl上清液,并将其添加到96孔平底平板中的150μl增强溶液中,并使用VICTOR3 Multilabel Counter(Perkin-Elmer)通过时间分辨荧光测量铕释放。使用下式确定比细胞毒性活性:%特异性释放=[((实验性释放-自发性释放)/(总释放-自发性释放)]×100。靶细胞的自发性释放小于洗涤剂总释放的25%。通过在没有T细胞的培养基中孵育靶细胞来确定靶细胞的自发性释放。所有测定均一式三份进行,条形棒表示平均裂解%,误差棒表示SEM。
实施例3
病毒在感染的肿瘤细胞和感染的抗原呈递细胞(树突状细胞、巨噬细胞、小胶质细胞)中引发强烈的免疫原性1型干扰素(IFN)应答的能力可能有助于PVSRIPO抗肿瘤功效。然而,尽管非常需要1型IFN应答作为免疫疗法的介质,但是它们也参与可以抑制PVSRIPO引发的抗肿瘤免疫应答的已知免疫检查点,例如PD-L1。因此,可以研究尝试通过与免疫检查点阻断组合来最大化PVSRIPO免疫疗法。
在本实验中,将CT2A神经胶质瘤皮下植入对脊髓灰质炎病毒受体CD155是转基因的C57B16小鼠中。先前已用CD155转导了用于引发肿瘤的CT2A细胞(以实现类似于人细胞的PVSRIPO感染)。按如下处理四组荷瘤动物(n=10):组I:DMEM(病毒的载剂对照)+IgG(抗PD1的对照);组II:肿瘤内单次注射PVSRIPO+IgG;组III:肿瘤内单次注射DMEM+抗PD1;组IV:肿瘤内单次注射PVSRIPO+抗PD1。通过腹膜内注射分三批(第3、6、9天)给予抗PD1。结果显示在图4A-4D中。
PVSRIPO和抗PD1两者分别具有显著抗肿瘤作用(图4B;图4C)。两种试剂的组合增加了治疗效果,表明机制协同作用(图4D)。重要的是,仅组合治疗实现了持久的肿瘤缓解(由在非常低的肿瘤体积下呈平线的肿瘤反应曲线表明)。
实施例4
本实施例提供了溶瘤病毒、溶瘤性嵌合脊髓灰质炎病毒PVSRIPO与免疫检查点抑制剂的组合介导显著抗肿瘤作用的另一说明。在这些研究中,E0771原位乳腺肿瘤模型用作乳腺癌的标准实验模型。该模型代表了三阴性乳腺癌(TNBC)。用人CD155即脊髓灰质炎病毒受体转染小鼠肿瘤细胞系E0771,使细胞(“E0771-CD155”)易于被溶瘤性脊髓灰质炎病毒PVSRIPO感染。为了确保在小鼠肿瘤细胞系中复制,使PVSRIPO在小鼠肿瘤细胞系中传代以产生小鼠PVSRIPO(mRIPO)。所有研究均在C57BL/6-CD155转基因小鼠中进行。将106个E0771-CD155肿瘤细胞植入小鼠的乳腺脂肪垫中。当肿瘤达到70-100mm3时,将PBS或mRIPO(5x107pfu)注射到肿瘤中。在mRIPO注射当天,然后每2-3天,腹膜内注射免疫检查点抑制剂抗PDL1抗体或抗PD1抗体(在200μL PBS中250μg),总计注射四次免疫检查点抑制剂。然后随时间监测肿瘤的生长。
测试与各自作为单一疗法(单独的mRIPO、单独的抗PD1抗体或单独的抗PDL1抗体)相比,使用靶向PD1或PDL1的抗体与mRIPO的组合阻断PD1/PDL1途径在控制肿瘤生长方面是否更好。如图5A和5B所示,与PBS对照相比,单独的溶瘤脊髓灰质炎病毒(mRIPO,■)、单独的抗PD1抗体(抗PD1,图5A-◆)或抗PDL1抗体(抗PDL1,图5B-◆)和组合疗法即mRIPO加抗PD1/PDL1显著抑制了肿瘤生长。在整个研究中,mRIPO和抗PD1(图5A)或抗PDL1(图5B)单一疗法在肿瘤生长抑制方面无明显差异。在研究结束时,mRIPO与抗PD1或抗PDL1的组合比单独的每种单一疗法在控制肿瘤生长方面更有效(无统计学意义)。该初步实验表明,PVSRIPO与抗PD1/PDL1疗法的组合在小鼠原位免疫活性乳腺癌模型中趋于协同改善肿瘤生长抑制作用。
实施例5
提供了使用一种或多种免疫治疗剂的新辅助疗法。在本实施例中,将5x105个E0771-CD155细胞原位植入C57BL/6-CD155转基因小鼠。肿瘤植入后第15天,用mRIPO或PBS(一旦肿瘤大小达到约50mm3,则各自进行肿瘤内注射)治疗小鼠,然后在肿瘤植入后第22天进行手术或不进行手术。如图6A所示,与5/10只接受PBS治疗然后进行手术的小鼠相比,在接受新辅助疗法(mRIPO然后进行手术;图6A,-★-)的组中,9只小鼠中的9只都没有肿瘤(图6A,-★-)。相比之下,非手术组(无论是接受PBS还是接受mRIPO)中的所有小鼠均发生肿瘤,其中与用PBS治疗(图6A,-●-)相比,用mRIPO治疗(图6A,-■-)在控制肿瘤生长方面更有效。在肿瘤植入后第80天,用亲本E0771细胞再次攻击用PBS治疗然后进行手术的组中的五只小鼠和用mRIPO治疗然后进行手术的五只小鼠。如图6B所示,在肿瘤植入后第130天,与PBS治疗组中5只小鼠中有1只没有肿瘤相比(图6B;-◆-),5只接受新辅助疗法(小鼠用mRIPO治疗,随后进行手术;图6B;-★-)的小鼠中有3只没有肿瘤。
实施例6
提供了治疗患有肿瘤的个体的方法,包括在手术切除肿瘤之前,向该个体施用治疗有效量的免疫检查点抑制剂和治疗有效量的溶瘤性嵌合脊髓灰质炎病毒构建体,进行手术切除肿瘤,其中在肿瘤切除后,向该个体施用的是免疫检查点抑制剂。为了说明这种新辅助疗法,在施用PVSRIPO前约1周,未切除肿瘤的个体接受市售脊髓灰质炎免疫增强剂,并通过向该个体施用PVSRIPO来开始治疗。例如,可以肿瘤内施用PVSRIPO。在本实施例中,用PVSRIPO治疗后数天(约7天至约14天),然后将抗PD-1抗体施用于该个体。可以静脉内施用抗PD1抗体。施用抗PD1抗体后一周到三周,对该个体进行治疗以减轻肿瘤负荷(例如,通过手术切除肿瘤)。任选地,在肿瘤负荷减轻之后,该个体可以接受维持疗法,包括根据医学需要施用免疫检查点抑制剂,抗PD-1抗体可以每2周施用一次,持续4个月,然后每4周施用一次,长达2年。
Claims (28)
1.治疗患有肿瘤的个体的方法,所述方法包括:
a)在手术切除肿瘤之前,向所述个体施用治疗有效量的免疫检查点抑制剂和治疗有效量的溶瘤性嵌合脊髓灰质炎病毒构建体,
b)随后进行手术切除所述肿瘤,
c)切除所述肿瘤后,向所述个体施用治疗有效量的免疫检查点抑制剂;其中所述溶瘤性嵌合脊髓灰质炎病毒构建体任选地包含脊髓灰质炎病毒I型Sabin毒株,所述毒株在所述脊髓灰质炎病毒的三叶草结构与所述脊髓灰质炎病毒的开放阅读框之间的所述脊髓灰质炎病毒5'非翻译区中具有人鼻病毒2(HRV2)内部核糖体进入位点(IRES)。
2.用于癌症的新辅助免疫疗法的方法,包括:
a)向患有肿瘤的个体施用一种或多种治疗有效量的免疫治疗剂,其中所述一种或多种免疫治疗剂包含溶瘤性嵌合脊髓灰质炎病毒构建体或溶瘤性嵌合脊髓灰质炎病毒构建体和免疫检查点抑制剂;
b)在接受所述一种或多种免疫治疗剂之后,用有效减轻所述个体的肿瘤负荷的抗癌疗法治疗所述个体。
3.根据权利要求2所述的方法,其中所述抗癌疗法选自由手术、放射疗法或其组合组成的组。
4.根据权利要求2或3中任一项所述的方法,其中所述溶瘤性嵌合脊髓灰质炎病毒构建体包含脊髓灰质炎病毒I型Sabin毒株,所述毒株在所述脊髓灰质炎病毒的三叶草结构与所述脊髓灰质炎病毒的开放阅读框之间的所述脊髓灰质炎病毒5'非翻译区中具有人鼻病毒2(HRV2)内部核糖体进入位点(IRES)。
5.根据权利要求2所述的方法,其中在所述个体接受减轻肿瘤负荷的抗癌疗法之前,仅将一种免疫治疗剂施用于所述患有肿瘤的个体,并且其中所述免疫治疗剂包含脊髓灰质炎病毒I型Sabin毒株,所述毒株在所述脊髓灰质炎病毒的三叶草结构与所述脊髓灰质炎病毒的开放阅读框之间的所述脊髓灰质炎病毒5'非翻译区中具有人鼻病毒2(HRV2)内部核糖体进入位点(IRES)。
6.根据权利要求2所述的方法,其中在接受减轻肿瘤负荷的抗癌疗法之后,所述方法进一步包括所述个体接受维持疗法,所述维持疗法包括所述溶瘤性嵌合脊髓灰质炎病毒构建体或所述免疫检查点抑制剂中的一种或多种。
7.根据权利要求1-6中任一项所述的方法,其中所述溶瘤性嵌合脊髓灰质炎病毒构建体进一步包含药学上可接受的载体。
8.根据权利要求1-7中任一项所述的方法,其中所述免疫检查点抑制剂进一步包含药学上可接受的载体。
9.根据权利要求1-8中任一项所述的方法,其中所述肿瘤选自由以下组成的组:脑瘤,肾细胞癌、前列腺肿瘤、膀胱肿瘤、食道肿瘤、胃肿瘤、胰腺肿瘤、结肠直肠肿瘤、肝肿瘤、胆囊肿瘤、乳腺肿瘤、肺肿瘤、头颈肿瘤、皮肤肿瘤、黑色素瘤和肉瘤。
10.根据权利要求1或2所述的方法,其中所述肿瘤表达NECL5(粘连蛋白样蛋白5)。
11.根据权利要求1-9中任一项所述的方法,其中所述肿瘤表达NECL5(粘连蛋白样蛋白5)。
12.根据权利要求1-11中任一项所述的方法,其中将所述溶瘤性嵌合脊髓灰质炎病毒构建体直接施用于所述肿瘤。
13.根据权利要求1或2所述的方法,其中在向所述个体施用所述溶瘤性嵌合脊髓灰质炎病毒构建体之前,所述方法包括测试所述个体的肿瘤以确定NECL5表达的步骤。
14.根据权利要求1-12中任一项所述的方法,其中在向所述个体施用所述溶瘤性嵌合脊髓灰质炎病毒构建体之前,所述方法包括测试所述个体的肿瘤以确定NECL5表达的步骤。
15.根据权利要求1或2所述的方法,其中所述免疫检查点抑制剂选自由以下组成的组:抗PD-1抗体、抗PDL-1抗体、抗CTLA4抗体、抗LAG-3抗体和抗TIM-3抗体。
16.根据权利要求1-14中任一项所述的方法,其中所述免疫检查点抑制剂选自由以下组成的组:抗PD-1抗体、抗PDL-1抗体、抗CTLA4抗体、抗LAG-3抗体和抗TIM-3抗体。
17.根据权利要求2所述的方法,其中将溶瘤性嵌合脊髓灰质炎病毒构建体和免疫检查点抑制剂施用于所述患有肿瘤的个体。
18.根据权利要求2-16中任一项所述的方法,其中将所述溶瘤性嵌合脊髓灰质炎病毒构建体和所述免疫检查点抑制剂两者施用于所述患有肿瘤的个体。
19.根据权利要求1、17或18中任一项所述的方法,其中在所述个体接受免疫检查点抑制剂之前,将所述溶瘤性嵌合脊髓灰质炎病毒构建体施用于所述个体。
20.根据权利要求1、17或18中任一项所述的方法,其中在所述个体接受所述溶瘤性嵌合脊髓灰质炎病毒构建体之前,将所述免疫检查点抑制剂施用于所述个体。
21.根据权利要求1或2所述的方法,进一步包括在施用所述溶瘤性嵌合脊髓灰质炎病毒构建体之前的数天前向所述个体施用脊髓灰质炎病毒免疫增强剂。
22.根据权利要求1-20中任一项所述的方法,进一步包括在施用所述溶瘤性嵌合脊髓灰质炎病毒构建体之前的数天前向所述个体施用脊髓灰质炎病毒免疫增强剂。
23.根据权利要求1或权利要求2所述的方法,进一步包括在切除或减少所述肿瘤之后,向所述个体施用多剂量的免疫检查点抑制剂,其中所述剂量间隔数天或数周。
24.根据权利要求1-22中任一项所述的方法,进一步包括在切除或减少所述肿瘤之后,向所述个体施用多剂量的免疫检查点抑制剂,其中所述剂量间隔数天或数周。
25.试剂盒,包含溶瘤性嵌合脊髓灰质炎病毒构建体和免疫检查点抑制剂。
26.根据权利要求25所述的试剂盒,其中所述溶瘤性嵌合脊髓灰质炎病毒构建体在第一容器中,并且所述免疫检查点抑制剂在第二容器中。
27.根据权利要求25或26所述的试剂盒,进一步包含用于测试肿瘤细胞样品上NECL5表达的试剂。
28.根据权利要求27所述的试剂盒,其中所述试剂包括对NECL-5具有特异性的抗体或对NECL-5具有特异性的PCR引物。
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