Project 1 - Clinical Trial

项目1。临床试验 摘要 非小细胞肺癌（NSCLC）和恶性胸膜间皮瘤（MPM）是高致死性的 治疗欠佳的癌症。在这个项目中使用的治疗策略是通过基因工程 表达嵌合抗原受体（汽车）的工程化T细胞，其将T细胞靶向肿瘤。CAR T细胞 已经在血液恶性肿瘤中显示出令人印象深刻的早期临床结果。我们是第一批 全球启动CAR T细胞试验，通过靶向肿瘤相关抗原，专注于实体瘤 间皮素尽管显示出安全性和可行性，但疗效有限，这是实体瘤的常见主题。在 在这个项目中，我们的目标是利用我们以前的临床试验和正在进行的研究中的信息， 项目2和3在肺癌和MPM患者中进行新的CAR T细胞临床试验。 我们最近的数据表明，我们以前的试验中存在两个关键问题， 活性和由于单链的鼠源性导致的CAR T细胞的快速免疫排斥 CAR上的抗体。因此，在目标1中，我们将在NSCLC患者中完成一项临床试验， MPM使用一种新设计的抗间皮素-CAR构建体，称为huCART-meso，其包含一个完整的 人单链抗体，在临床前模型中具有比先前使用的SS 1高得多的活性 车我们还将评估以下可能的益处：1）治疗前淋巴细胞清除， 环磷酰胺和2）在恶性胸腔积液患者中局部递送CAR T细胞。其他 实体瘤CAR治疗成功的障碍可能是肿瘤异质性， 表达靶抗原、T细胞运输不良和局部免疫抑制。对这些问题的处理方法 问题是攻击肿瘤间质。我们小组和其他人以前的研究支持这一假设， CAR T细胞靶向一种称为成纤维细胞活化蛋白（FAP）的蛋白质，可以降低癌症的数量。 相关的成纤维细胞，减少肿瘤大小和刺激抗肿瘤免疫。在目标2中，我们将测试这一点 通过进行I期临床试验在患者中评估潜在安全性和临床活性 针对人类FAP的CAR。在这两个目标中，我们还将通过以下方式解决肿瘤异质性问题： 为项目3提供样本，我们将研究CAR T细胞诱导表位扩散的能力， CAR T细胞以免疫原性方式杀死肿瘤细胞并诱导内源性抗肿瘤细胞的过程。 肿瘤T细胞或B细胞活性。根据这两项试验的结果和项目2和项目3的新数据， 在未来的研究中，我们将设计第三个CAR T细胞试验。我们将考虑的试验包括：1）添加 检查点阻断，2）将huCART-meso和FAPCAR T细胞组合，和3）使用甚至更高水平的 活跃的汽车PO 1和项目1具有很高的意义：在治疗中使用CAR T细胞实现成功率 类似于在白血病中观察到的实体瘤将是实体瘤治疗的范例转变。 1

Project 1. Clinical Trials Abstract Non-small cell lung cancer (NSCLC) and Malignant Pleural mesothelioma (MPM) are highly lethal cancers with suboptimal treatment. The treatment strategy to be used in this project is to produce genetically engineered T cells expressing chimeric antigen receptors (CARs) that target T cells to tumors. CAR T cells have shown impressive early clinical results in hematologic malignancies. We were among the first groups in the world to inititate CAR T cell trials focused on solid tumors by targeting the tumor-associated antigen mesothelin. Despite showing safety and feasibility, efficacy was limited, a common theme in solid tumors. In this Project, our goal is to use information from our previous clinical trials and ongoing studies in Projects 2 and 3 to conduct new CAR T cell clinical trials in patients with lung cancer and MPM. Our recent data suggest that two key problems in our previous trials were suboptimal anti-tumor activity and a rapid immune-based rejection of the CAR T cells due to the murine origin of the single chain antibody on the CAR. Accordingly, in Aim 1, we will complete a clinical trial in patients with NSCLC and MPM using a newly designed anti-mesothelin-CAR construct, called huCART-meso, that contains a fully human single chain antibody and has much higher activity in preclinical models than the previously used SS1 CAR. We will also evaluate the possible benefits of: 1) pre-treatment lymphodepletion using cyclophosphamide and 2) local delivery of CAR T cells in patients with malignant pleural effusions. Other barriers to solid tumor CAR therapy success are likely to be tumor heterogeneity, whereby not all tumor cells express the targeted antigen, poor trafficking of T cells, and local immunosuppression. An approach to these issues is to attack the tumor stroma. Previous studies from our group and others support the hypothesis that CAR T cells targeting a protein called Fibroblast Activation Protein (FAP) can lower the number of cancer- associated fibroblasts, reduce tumor size and stimulate anti-tumor immunity. In Aim 2, we will test this approach in patients by conducting a Phase 1 clinical trial to evaluate the potential safety and clinical activity of a CAR targeted to human FAP. In both Aims, we will also address the issue of tumor heterogeneity by providing samples to Project 3 where we will study the ability of CAR T cells to induce epitope spreading, a process by which the CAR T cells kill tumor cells in an immunogenic fashion and induce endogenous anti- tumor T cell or B cell activity. Based on the results of these two trials and on new data from Projects 2 and 3, in future studies, we will design a third CAR T cell trial. Trials we will consider include: 1) adding checkpoint blockade, 2) combining huCART-meso and FAPCAR T cells, and 3) using even more highly active CARs. The PO1 and Project 1 have high significance: achieving success rates with CAR T cells in solid tumors similar to that observed in leukemia would be a paradigm shift in the treatment of solid tumors. 1