Extending Chimeric Antigen (CAR) T cell therapy to thoracic cancers

总体摘要 该计划项目的目标是开发复制采用T细胞转移的成功的方法 利用嵌合抗原受体(CAR)转导的T细胞治疗恶性血液病到实体瘤 重点关注胸部恶性肿瘤(非小细胞肺癌和恶性胸膜间皮瘤) [MPM]。所有项目中的一个重要科学主题是探索CAR T细胞 诱导表位扩散，即它们刺激内源性B和T细胞对 肿瘤--实体肿瘤治疗成功的关键因素。此PO1将有3个项目，将由 3核。项目1将使用CAR T细胞进行临床试验。在目标1中，我们将继续在 非小细胞肺癌和MPM患者使用新设计和改进的抗间皮蛋白-CAR结构。在AIM 2、我们将进行第一阶段临床试验，以评估靶向CAR的潜在安全性和临床活性 通过结合成纤维细胞激活蛋白(FAP)对肿瘤间质(肿瘤相关成纤维细胞)进行诱导。在未来 研究，我们将根据这两个试验的结果和来自 项目2和项目3。项目2将研究如何克服实体瘤CAR T细胞治疗中的异质性 临床前研究将与我们计划的临床试验紧密结合。在目标1中，我们会进行研究，以 靶向抗人成纤维细胞的CARS靶向肿瘤间质的安全性和有效性评价 激活蛋白(FAP)。在目标2中，我们将探讨Mesothelin和FAP CARS能够 引发旁观者效应和表位扩散。在目标3中，我们将研究加强这一点的方法。项目3 将进行人体生物相关研究。在目标1中，我们将研究持续、贩运和功能 肿瘤中的CAR T细胞。在目标2中，我们将评估临床试验中使用的CAR T细胞的假设 可以激活内源性抗肿瘤CD8 T细胞反应(类似于项目2中的研究)。在《目标3》中，我们将 Car T细胞输注后表位扩散所致T细胞应答的多克隆性特征 外周血和肿瘤。我们将从新成立的独特环境中受益匪浅 由卡尔·琼博士领导的宾夕法尼亚大学细胞免疫疗法中心(CCI)。这些项目将由一个 行政核心(有内部和外部咨询委员会)、病理学/样本采集核心、 和一个生物统计/生物信息学/数据管理核心。将举行每月计划项目会议。 PO1有非常丰富的领导经验，项目负责人和核心负责人有长期的记录 成功的合作和出版物。每个项目都高度依赖于其他项目，需要 成功的计划项目格式。PO1具有很高的意义：使用CAR T实现成功率 实体瘤中的细胞类似于白血病中的细胞，这将是实体瘤治疗中的重大范式转变 肿瘤。 1

Overall Summary The goal of this Program Project is to develop approaches to reproduce the success of adoptive T cell transfer using chimeric antigen receptor (CAR) transduced T cells for hematologic malignancies to solid tumors, with a focus on thoracic malignancies (non-small cell lung cancer [NSCLC] and malignant pleural mesothelioma [MPM]. An important scientific theme in all of the projects is an exploration of the ability of CAR T cells to induce epitope spreading, that is, their ability to stimulate endogenous B and T cell responses against the tumor- a key component for success in solid tumors. This PO1 will have 3 projects which will be supported by 3 Cores. Project 1 will conduct clinical trials using CAR T cells. In Aim 1, we will continue a clinical trial in patients with NSCLC and MPM using a newly designed and improved anti-mesothelin-CAR construct. In Aim 2, we will conduct a Phase 1 clinical trial to evaluate the potential safety and clinical activity of a CAR targeted to tumor stroma (cancer associated fibroblasts) by engaging fibroblast activation protein (FAP). In future studies, we will design a third CAR T cell trial based on the results of these two trials and on new data from Projects 2 and 3. Project 2 will study ways to overcome heterogeneity in solid tumor CAR T cell therapy using preclinical studies that will integrate closely with our planned clinical trials. In Aim 1, we will conduct studies to evaluate the safety and efficacy of targeting tumor stroma using CARs targeted against anti-human fibroblast activation protein (FAP). In Aim 2, we will explore the key issue of mesothelin and FAP CARs being able to induce bystander effects and epitope spreading. In Aim 3, we will examine ways to augment this. Project 3 will conduct human biocorrelative studies. In Aim 1, we will study the persistence,trafficking, and function of CAR T cells in tumors. In Aim 2, we will evaluate the hypothesis that the CAR T cells used in our clinical trials can activate endogenous anti-tumor CD8 T cell responses (similar to the studies in Project 2). In Aim 3, we will characterize the polyclonality of T cell responses generated by epitope spreading after CAR T cell infusion in peripheral blood and tumors. We will benefit greatly from the unique environment of the newly established Penn Center for Cellular Immunotherapies (CCI) led by Dr. Carl June. These projects will be supported by an Administrative Core (with an internal and external advisory board), a Pathology/Sample Acquisition Core, and a Biostatistics/Bioinformatics/Data Management Core. Monthly Program Project meetings will be held. The PO1 has highly experienced leadership and the Project leaders and Core leaders have long track records of successful collaborations and publications. Each project is highly dependent on the other projects, requiring the Program Project format for success. The PO1 has high significance: achieving success rates with CAR T cells in solid tumors similar to that seen in leukemia would be a major paradigm shift in the treatment of solid tumors. 1