A Phase 1 Study to Evaluate Chimeric Antigen Receptor (CAR) T cells Targeting TAG72 in Patients with Recurrent Epithelial Ovarian Cancer

项目摘要 复发性上皮性卵巢癌（EOC）患者的预后较差，复发后中位数 生存期约为30个月，治疗选择有限，因此， 医疗需求。在广泛的肿瘤类型中的免疫治疗的进展提供了希望， 免疫方法可能改善EOC患者的预后。特别是一种免疫疗法 称为嵌合抗原受体（CAR）T细胞疗法重新训练免疫系统靶向癌症， 识别特定的癌症标志物。EOC对有效的CAR T细胞免疫疗法提出了几个挑战， 包括这些T细胞在肿瘤内的不良肿瘤部位浸润、活化、功能不足和持久性。 恶劣的腹膜肿瘤微环境。此外，在细胞表面缺乏有效的CAR T细胞靶点。 晚期EOC肿瘤细胞的表面。我们的目标是开发针对转移性EOC的有效疗法， 特别关注区域递送CAR T细胞疗法以治疗腹膜转移。TAG 72是一个非常... 在EOC和其他实体瘤中表达，在正常组织中很少或不表达，使其成为理想的靶点 用于CAR T细胞疗法。我们在City of Hope的团队已经开发并完成了TAG 72的实验室测试- 靶向CAR T细胞疗法。我们的临床前数据也支持TAG 72 CAR T具有上级抗肿瘤活性， 细胞通过腹膜内递送局部施用，而不是通过静脉内递送全身施用， 这是由于抗原CAR T细胞直接和立即接近肿瘤细胞。假设是区域性的- 施用的TAG 72-CAR T细胞将是安全的并介导抗肿瘤作用，这将在研究中评估。 1）评估TAG 72-CAR T的区域性腹膜内递送的安全性和可行性 1期临床试验中晚期EOC患者的CAR T细胞; 2）评估CAR T细胞介导的免疫景观 可能指示治疗反应或抗性的变化;和3）研究肿瘤抗性的途径 和CAR T细胞诱导的肿瘤演变。我们的计划已经纳入了一个创新的使用预处理 我们的实体瘤CAR T细胞疗法的方案，CAR T细胞给药的区域途径，以及完全- 优化的TAG 72-CAR构建体。这些特征旨在提高靶向TAG 72+的效力和选择性。 肿瘤，同时潜在地最小化限制TAG 72-CAR T的持久性和/或功能的免疫应答。 细胞这种方法具有重要意义，因为它将扩大我们对EOC和其他实体瘤的治疗组合。

PROJECT SUMMARY Patients with recurrent epithelial ovarian cancer (EOC) have a poor prognosis with a post-relapse median survival of approximately 30 months and limited therapeutic options, thus presenting a fundamental unmet medical need. Progress in immunotherapy across a broad range of tumor types provides hope that immunological approaches may improve outcomes for patients with EOC. Particularly, a type of immunotherapy called chimeric antigen receptor (CAR) T cell therapy retrains the immune system to target cancers by recognizing specific cancer markers. EOC presents several challenges to effective CAR T cell immunotherapy, including poor tumor site infiltration, activation, inadequate function and persistence of these T cells within the harsh peritoneal tumor microenvironment. Additionally, there are a lack of effective CAR T cell targets on the surface of advanced EOC tumor cells. Our goal is to develop effective therapies against metastatic EOC, with a specific focus on regional delivery of CAR T cell therapies to treat peritoneal metastasis. TAG72 is highly over- expressed in EOC and other solid tumors with little or no expression in normal tissues, making it an ideal target for CAR T cell therapy. Our team at City of Hope has developed and completed laboratory testing of a TAG72- targeting CAR T cell therapy. Our preclinical data also supports superior anti-tumor activity when TAG72 CAR T cells are administered regionally by intraperitoneal delivery versus systemically by intravenous delivery, likely due to direct and immediate antigen CAR T cell access to tumor cells. The hypothesis is that regionally- administered TAG72-CAR T cells will be safe and mediate anti-tumor effects, which will be assessed in the following specific aims: 1) Evaluate safety and feasibility of regional intraperitoneal delivery of TAG72-CAR T cells in patients with advanced EOC in a phase 1 clinical trial; 2) Assess CAR T cell-mediated immune landscape changes that may indicate therapeutic response or resistance; and 3) investigate pathways of tumor resistance and CAR T cell-induced tumor evolution. Our program has incorporated an innovative use of pre-conditioning regimens to our solid tumor CAR T cell therapies, regional routes of CAR T cell administration, and a fully- optimized TAG72-CAR construct. These features aim to improve the potency and selectivity of targeting TAG72+ tumors while potentially minimizing immune responses that limit persistence and/or function of TAG72-CAR T cells. This approach is significant in that it will expand our therapeutic portfolio for EOC and other solid tumors.