Leveraging TCR signaling for the design of sensitive bispecific receptors for cancer therapy

Abstract

Immune-based therapies have revolutionized the treatment of cancer by improving the immune system’s capacity to target and kill cancer cells. These advances were built on foundational research in immunology, underscoring that continued immunology research is critical to the improvement of human health. Adoptive T cell therapies, particularly chimeric antigen receptors (CAR) T cell therapies exemplify the direct impact of fundamental immunology on treatment innovations. Chimeric Antigen Receptors (CARs) are engineered by combining and extracellular binding domain with signaling molecules essential T cell activation into one molecule, enabling specific activation of T cells to target tumor cells expressing the ligand for the extracellular binder. Research in T cell biology, particularly the T cell receptor (TCR) enabled the design of CARs by identifying essential TCR activation signals that were incorporated in the CAR architecture. Thousands of patients have been treated with CAR T cell therapies, with remarkable success, particularly in therapy of B cell malignancies and multiple myeloma. However, further advances are required to overcome the escape of tumor cells that express low levels or lack the target antigen improve the durability of responses and expand the application T cell therapies. This thesis presents the development a novel class of receptors for adoptive T cell therapy, termed chimeric T cell receptors (ChTCRs)that provide improved sensitivity and specificity over traditional CAR T cell therapies. Our receptor design leverages an understanding of TCR signaling to more closely mimic native TCR signaling, and improves receptor sensitivity. This approach led to the development of two novel receptors: the monospecific ‘Full ChTCR,’ which has superior antigen sensitivity and tumor control in pre-clinical mouse models relative to existing CARs and other ChTCR variants, and the dual-antigen targeting ‘Bi-ChTCR,’ which has enhanced sensitivity and efficacy in to targeting heterogenous tumors compared to monospecific and bispecific CARs. Additionally, I developed a mass cytometry tool to determine similarities and differences in proximal receptor signaling in engineered T cells and understand how improved signaling may impact cell differentiation and function. Collectively this work demonstrates the value of TCR signaling research in guiding novel receptor design for adoptive T cell therapies. It introduces a tool to study signaling dynamics and reports an adaptable receptor architecture for sensitive targeting of tumor antigen.