Project 1 - Clinical Trial

项目1.临床试验 摘要 非小细胞肺癌和恶性胸膜间皮瘤具有很高的致命性 治疗效果不佳的癌症。在这个项目中使用的治疗策略是通过基因产生 表达嵌合抗原受体(CARS)的工程化T细胞将T细胞靶向肿瘤。CAR T细胞 在治疗血液系统恶性肿瘤方面显示出令人印象深刻的早期临床效果。我们是第一批 世界上通过靶向肿瘤相关抗原启动CAR T细胞试验专注于实体瘤 间苯妥英林。尽管显示出安全性和可行性，但疗效有限，这是实体肿瘤的常见主题。在……里面 这个项目，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，在我们之前的试验中有两个关键问题是次优的抗肿瘤药物 由于单链的小鼠起源，CAR T细胞的活性和快速免疫排斥反应 车上的抗体。因此，在目标1中，我们将完成对非小细胞肺癌患者和 MPM使用一种新设计的抗间皮质素-CAR结构，称为huCART-Meso，它包含一个完整的 人单链抗体，在临床前模型中的活性比以前使用的SS1高得多 小汽车。我们还将评估以下可能的好处：1)治疗前淋巴滤过术 环磷酰胺和2)恶性胸腔积液患者CAR T细胞的局部传递。其他 实体瘤CAR治疗成功的障碍可能是肿瘤的异质性，从而不是所有的肿瘤细胞 表达靶向抗原，T细胞转运不良，局部免疫抑制。一种解决这些问题的方法 问题是要攻击肿瘤间质。我们小组和其他人之前的研究支持这样的假设 针对一种名为成纤维细胞激活蛋白(FAP)的蛋白质的CAR T细胞可以降低癌症的数量-- 联合成纤维细胞，缩小肿瘤体积，激发抗肿瘤免疫。在目标2中，我们将测试这一点 通过进行一期临床试验来评估潜在的安全性和临床活性 一辆以人类FAP为目标的汽车。在这两个目标中，我们还将通过以下方式解决肿瘤异质性的问题 向项目3提供样本，在该项目中，我们将研究CAR T细胞诱导表位扩散的能力，a CAR T细胞以免疫原性方式杀伤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。根据这两个试验的结果以及项目2和项目2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 检查点封锁，2)结合huCART-Meso和FAPCAR T细胞，以及3)使用更高的 活跃的汽车。PO1和项目1具有很高的意义：使用CAR T细胞在 与白血病相似的实体肿瘤将是实体肿瘤治疗的范式转变。 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