Engineering Hybrid SynNotch CAR Receptors to Enhance Cell Therapies for Cancer

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Chimeric Antigen T Cell (CAR-T) therapies, which redirect a patient’s own T cells towards their cancer, are very promising therapies for difficult to treat and refractory cancers. While CAR T cell therapies have been very successful in treating refractory B cell cancers,1,2 they have encountered many challenges when directed towards more complex solid and liquid tumors, such as multiple myeloma. CAR T cells face challenges such as an immunosuppressive tumor microenvironment, in which inhibitory ligands are often expressed, nutrients and oxygen are lacking, and cytokines or soluble factors are secreted to support malignant cell growth.3 This hostile environment, as well as cell intrinsic defects, can lead to reduced CAR T cell proliferation, inhibition of function and loss of CAR T cell persistence. Previously developed synthetic Notch (synNotch) receptors allow for control and customization of therapeutic immune cells.4,5,6 SynNotch T cells can deliver user defined cell intrinsic or extrinsic payloads, such as transcription factors, cytokines, or antibodies in an antigen specific, spatially controlled manner. While these receptor circuits could be used to address the many challenges of complex tumors, these receptors lack the ability to initiate cytotoxicity like CARs or TCRs. Therefore, successful and persistent engineered T cells require both the ability to recognize, activate and kill tumor cells, as well as the ability to produce payloads to counteract a wide range of challenges encountered in challenging tumor microenvironments. Recently, I have engineered a novel “Hybrid SynNotch CAR” receptor, whose architecture incorporates signaling domains (e.g. co-stimulation, CD3z, etc.) that can initiate activation of T cells concomitant with custom transcriptional regulation typical of a SynNotch receptor. These Hybrid synNotch CAR receptors are functional and represent a new class of synthetic receptors that activate short timescale signaling and long term custom transcriptional responses in a single receptor architecture. This proposal seeks to expand upon these initial proof-of-concept Hybrid SynNotch CAR receptors, understanding their full range of function and effect on engineered T cells, and demonstrating their ability to address therapeutic challenges in multiple myeloma. The University of California, San Francisco (UCSF) is a leading institution in immunology and is regarded as one of the top doctoral programs in Biomedical Sciences graduate education. As a graduate student in the Roybal lab, I receive regular guidance and mentorship from renowned investigators and have access to resources provided by the Parker Institute for Cancer Immunotherapy, and the Chan Zuckerberg Biohub. This training plan also includes commitment to professional development programs, such as the UCSF TRAIN UP Mentorship program, and courses in manuscript and thesis writing. This proposal seeks to develop and apply a novel synthetic receptor circuit, which simultaneously targets cancer cells and addresses diverse challenges in tumors and tumor microenvironments. Completion of the proposed work will move the field of engineered cancer immunotherapy forward and prepare me for a future career as an independent investigator.