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

项目总结/摘要 恶性胸膜间皮瘤是一种罕见的癌症，预后差。没有FDA- 自2003年以来，已批准用于MPM患者的治疗。存在高水平细胞毒性的MPM患者 肿瘤浸润淋巴细胞（TIL）具有更好的存活。为了在MPM中促进TILs，我们开发了一种采用 使用嵌合抗原受体（汽车）的T细胞疗法。我们开发并翻译了间皮素 在第一阶段临床试验（NCT 02414269和NCT 02792114）中，使用靶向MSLN的CAR T细胞。MSLN是一个细胞- 表面抗原在MPM中高表达，在正常组织中极低表达。在我们的两个临床试验中， 迄今为止，在28名接受治疗的患者中未观察到靶向、肿瘤外毒性。CAR T细胞 在NCT 02414269中，根据我们发表的数据（Sci Transl Med 2014）， 建立的区域施用的CAR T细胞通过增强CD 4 T细胞辅助物来增强抗肿瘤功效 功能除了安全性外，在我们的I期胸膜内给药试验中观察到了有希望的抗肿瘤疗效。 CAR T细胞。在施用低剂量的CAR T细胞后，肿瘤细胞上调PD-L1/L2和PD-L3。 通过结合PD-1抑制T细胞。我们已经证明，施用抗PD-1药物可以克服 肿瘤介导的适应性抗性并促进CAR T细胞功能持久性（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例MPM患者中的11例， 没有发现不良事件，CAR T细胞的持久性和抗肿瘤功效增强。 在这些强有力的数据的基础上，我们提出了一项由研究者发起的I/II期临床试验，结合 使用pembrolizumab的CAR T细胞疗法。我们假设靶向癌症抗原的CAR T细胞可以 而抗PD-1剂可通过逆转两种CAR耗竭来对抗适应性抗性 和内源性T细胞。我们将确定过继转移转基因，自体， 将靶向MSLN的T细胞注入MPM患者的胸膜腔中（先前施用MSLN）。 环磷酰胺），然后用派姆单抗治疗直至肿瘤根除或毒性（目的1）。的 主要终点是确定MSLN导向的CAR T细胞的安全性和最大耐受剂量（MTD 与帕博利珠单抗联合治疗（I期），并估计联合治疗的缓解率 （第二阶段）。我们将分析连续收集的胸腔积液、肿瘤活检标本和外周血， 评估PD-1阻断逆转CAR T细胞耗竭（Aim 2）并激活抗肿瘤活性的能力 内源性免疫（目的3），与单独使用派姆单抗治疗相比。调查区域 与用抗PD-1剂活化后的全身内源性和CAR T细胞免疫相比， 与单独的抗PD 1剂，是机械的，创新的，和翻译。结果直接导致 适用于150，000例胸膜转移性肿瘤患者（来自MSLN+ve肺癌和乳腺癌）， 仅在美国，每年就可扩展至超过200万名表达MSLN的实体瘤患者。

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.