Combination antigen sensing engineered T cell for precise recognition and enhanced elimination of solid tumors

摘要： 这项提议的目标是开发一种有可能转化为人类的工程化T细胞疗法 测试。我们将开发一种临床优化的组合抗原传感起杀电路T细胞，用于精确 间皮瘤是一种罕见的疾病，预后差。这项工作是建立在 我们在T细胞工程和新发现的肿瘤抗原方面的最新进展：(1)一种启动和杀死双重抗原 与门电路，含全人类成分(称为SNIPR)，用于合成膜内蛋白分解 受体)，以促进临床翻译。(2)一种新的肿瘤特异性细胞表面抗原ALPPL2(又名ALPG) 它在间皮瘤中表达，但在除胎盘外的任何正常人体组织中都不表达。与之配对 获得认证的间皮瘤抗原Mesothelin，ALPPL2SNIPR→CAR环路T细胞能够使精确的 对肿瘤部位T细胞激活的时间和空间控制，将靶点上的肿瘤外毒性降至最低， 减少紧张性信号和T细胞耗竭，维持多功能T细胞状态。电路设计是 模块化和灵活性，并可被诱导在本地提供额外的免疫调节有效载荷，如 进一步提高疗效的细胞因子。此外，我们的研究表明，SNIPR→CAR电路T细胞 能够有效地靶向在肿瘤中异质表达的抗原，这是 治疗效果。我们建议进行翻译使能研究：(目标1)优化SNIPR抗体 T细胞构建，并开发用于患者分层的生物标志物。(目标2)设计和评估人性化 体内外临床分级→和LOGIC T细胞。(目标3)评估SNIPR工程素数和- 靶抗原异质性表达的肿瘤杀伤回路T细胞的杀伤作用圆满完成 项目将使我们能够将SNIPR→CAR电路T细胞转移到翻译开发并通过 生物标志物适合间皮瘤患者的临床检测。

Abstract: The goal of this proposal is to develop an engineered T cell therapy with potential of translation into human testing. We will develop a clinically optimized combination antigen sensing prime-and-kill circuit T cell for precise recognition and enhanced elimination of mesothelioma, a rare disease with poor prognosis. The work is built on our recent progress in T cell engineering and novel tumor antigen discovery: (1) a prime-and-kill dual antigen AND-gated circuit with fully human components (dubbed as SNIPR for SyNthetic Intramembrane Proteolysis Receptors) that facilitate clinical translation. (2) A novel tumor specific cell surface antigen ALPPL2 (aka ALPG) that is expressed in mesothelioma but not any of the normal human tissues except for the placenta. Paired with the credentialed mesothelioma antigen mesothelin, the ALPPL2 SNIPR → CAR circuit T cell enables precise temporal and spatial control of T cell activation at the site of the tumor, minimizes on-target off-tumor toxicity, reduces tonic signaling and T cell exhaustion, and maintains multifunctional T cell states. The circuit design is modular and flexible and can be induced to locally deliver additional immune modulatory payloads such as cytokines to further improve efficacy. In addition, our research has shown that SNIPR → CAR circuit T cells are capable of effectively targeting antigens that are heterogeneously expressed in tumors, a common pitfall for therapeutic efficacy. We propose to perform translation-enabling studies: (Aim 1) Optimize antibodies for SNIPR T cell construction, and develop biomarker for patient stratification. (Aim 2) Engineer and evaluate humanized clinical grade SNIPR → AND logic T cells in vitro and in vivo. (Aim 3) Evaluate SNIPR-engineered prime-and- kill circuit T cells in killing tumor with heterogeneous target antigen expression. Successful completion of the project will enable us to move the SNIPR → CAR circuit T cell to translational development and identify via the biomarker appropriate mesothelioma patients for clinical testing.