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

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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.