A phase I/II combination immunotherapy clinical trial: mesothelin-targeted chimeric antigen receptor T cells and checkpoint blockade agent in pleural mesothelioma

项目摘要/摘要 恶性胸膜间皮瘤(MPM)是一种罕见的癌症，预后不良。没有食品和药物管理局- 自2003年以来批准用于MPM患者的治疗。出现高水平细胞毒的MPM患者 肿瘤浸润性淋巴细胞(TIL)具有较好的存活率。为了在MPM中推广TIL，我们开发了一种采用 使用嵌合抗原受体(CARS)的T细胞治疗。我们已经开发并翻译了间皮脂素 (MSLN)-针对CAR T细胞的I期临床试验(NCT02414269和NCT02792114)。MSLN是一个细胞- 表面抗原在MPM中高表达，在正常组织中低表达。在我们的两个临床试验中， 到目前为止，在接受治疗的28名患者中，没有发现靶点上和肿瘤外的毒性。CAR T细胞是 根据我们发表的数据(Sci Transl Med 2014)，在NCT02414269中胸腔内注射 已建立的区域管理的CAR T细胞通过增加CD4T细胞辅助分子来增强抗肿瘤效果 功能。除了安全性外，在我们的胸腔内I期试验中观察到了良好的抗肿瘤效果。 CAR T细胞。在给予低剂量CAR T细胞后，肿瘤细胞上调PD-L1/L2和 通过与PD-1结合抑制T细胞。我们已经证明，给予抗PD-1药物可以克服 肿瘤介导的适应性抵抗和促进CAR T细胞功能持续(J Clin Inv 2016)。 在这些数据的支持下，我们用抗PD-1药物pembrolizumab治疗了18名MPM患者中的11名，并 注意到没有不良反应，CAR T细胞的持久性和抗肿瘤疗效增强。 基于这些强有力的数据，我们建议一项由研究人员发起的I/II期临床试验 使用培溴利珠单抗进行CAR T细胞治疗。我们假设癌症抗原靶向的CAR T细胞可以 促进TIL和抗PD-1药物可通过逆转两种细胞衰竭来对抗适应性抵抗 和内源性T细胞。我们将确定转基因、自体、 MSLN靶向T细胞进入MPM患者胸腔(既往给药 (环磷酰胺)，然后用培溴利珠单抗治疗，直到肿瘤根除或出现毒性(目标1)。这个 主要终点是确定MSLN导向的CAR T细胞的安全性和最大耐受量(MTD 联合培溴利珠单抗(I期)，并评估联合治疗的有效率 (第二阶段)。我们将分析连续采集的胸液、肿瘤活检标本和外周血，以 评估PD-1阻断逆转CAR T细胞衰竭和激活抗肿瘤作用的能力(目标2) 内源性免疫(目标3)，与单独使用培溴利珠单抗治疗相比。调查区域 与抗PD-1试剂激活后的系统内源性和CAR T细胞免疫的比较 单独使用抗PD1试剂，是机械性的、创新性的和转化性的。随之而来的结果是 适用于15万名胸膜转移肿瘤患者(来自MSLN+VE肺癌和乳腺癌)和 仅在美国，每年就可扩展到200多万名表达MSLN的实体肿瘤患者。

PROJECT SUMMARY/ABSTRACT Malignant pleural mesothelioma (MPM) is a rare cancer with poor prognosis. There have been no FDA- approved therapies for MPM patients since 2003. Patients with MPM who present with high levels of cytotoxic tumor infiltrating lymphocytes (TILs) have better survival. To promote TILs in MPM, we developed an adoptive T-cell therapy using chimeric antigen receptors (CARs). We have developed and translated mesothelin (MSLN)–targeted CAR T cells to phase I clinical trials (NCT02414269 and NCT02792114). MSLN is a cell- surface antigen highly expressed in MPM, with very low expression in normal tissues. In our two clinical trials, no on-target, off-tumor toxicities were noted among 28 patients treated so far. CAR T cells are administered intrapleurally in NCT02414269, on the basis of our published data (Sci Transl Med 2014) that established regionally administered CAR T cells potentiate antitumor efficacy by augmenting CD4 T-cell helper function. Beyond safety, promising antitumor efficacy has been observed in our phase I trial of intrapleural CAR T cells. Following administration of a low dose of CAR T cells, tumor cells upregulate PD-L1/L2 and inhibit T cells via binding to PD-1. We have shown that administration of anti-PD-1 agents can overcome tumor-mediated adaptive resistance and promote CAR T-cell functional persistence (J Clin Inv 2016). Supported by these data, we treated 11 of 18 MPM patients with pembrolizumab, an anti-PD-1 agent, and noted no adverse events, and enhanced persistence of CAR T cells and antitumor efficacy. Building on these strong data, we propose an investigator-initiated phase I/II clinical trial combining CAR T-cell therapy with pembrolizumab. We hypothesize that cancer antigen-targeted CAR T cells can promote TILs and that anti-PD-1 agent can combat adaptive resistance by reversing exhaustion of both CAR and endogenous T cells. We will determine the safety of adoptive transfer of genetically modified, autologous, MSLN-targeted T cells into the pleural cavity of MPM patients (with previous administration of cyclophosphamide), followed by treatment with pembrolizumab until tumor eradication or toxicity (Aim 1). The primary endpoint is to determine the safety and maximum tolerated dose (MTD) of MSLN-directed CAR T cells in combination with pembrolizumab (phase I) and to estimate the response rate of the combination therapy (phase II). We will analyze serially collected pleural fluid, tumor biopsy specimens, and peripheral blood to assess the ability of PD-1 blockade to reverse CAR T-cell exhaustion (Aim 2) and activate antitumor endogenous immunity (Aim 3), compared with treatment with pembrolizumab alone. Investigating regional versus systemic endogenous and CAR T-cell immunity following activation with anti-PD-1 agent, compared with anti-PD1 agent alone, is mechanistic, innovative, and translational. The ensuing results are directly applicable to 150,000 patients with pleural metastatic tumors (from MSLN+ve lung and breast cancers) and extendable to more than 2 million patients with MSLN-expressing solid tumors per year in the U.S. alone.