Development of senolytic CAR T cells as new therapeutic agents

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PROJECT SUMMARY/ABSTRACT Senescence is a cellular program that leads to irreversible cell cycle arrest in response to stress. Although in the short term it promotes restoration of tissue homeostasis, the lack of immune clearance of senescent cells and thus their chronic accumulation leads to a chronic pro-inflammatory environment that has been shown to promote tumor development and to contribute to a variety of pathologies associated with chronic tissue damage such as lung or liver fibrosis, diabetes and atherosclerosis among others. Previous senolytic approaches have relied on the use of non-selective chemical inhibitors that have off-target toxicities and, owing to heterogeneity between senescent cells, are inefficient. The long term objective of my thesis project is to develop, for the first time, Chimeric Antigen Receptor (CAR) T cells as living senolytic agents. As a first step towards developing senolytic CAR T we will identify senescence-specific surface molecules to better identify, characterize and target senescent cells. In parallel, we will exploit the selective features of these molecules with the aim of producing senolytic CAR T cells, which we then characterize their efficacy and safety profile in preclinical senescence models. Preliminary data from the initial years of my graduate studies strongly supports the feasibility of the proposed work: we have already identified one cell surface molecule predominantly expressed on senescent cells and developed CAR T cells targeting it. We further provide preliminary data showing that these CAR T cells are bona fide senolytics capable of eliminating senescent cells in culture and in mice. For the rest of my doctoral work we continue to validate the protein and senolytic CAR T cells and gain better understanding of their mechanism of action and safety profile and use our findings to develop enhanced versions as well as combinatorial targeting strategies with newly identified factors. Completion of the proposed work will lead to the development of effective senolytic CAR T cells and provide further data for their clinical development as novel therapeutic options in cancer as well as for a wide range of other senescence- associated diseases. My postdoctoral research will continue to study senescence and CAR T cells but with a slight change of focus in order to try to understand how the Senescence Associated Secretory Phenotype (SASP) influences the activity of CAR T cells. The proposal aims to elucidate the exact mechanism(s) whereby senescence stimulates CAR T activity: through modulation of microenvironment and/or CAR T activity itself and exploit this knowledge to develop enhanced CAR T constructs of combinatorial approaches to improve CAR T efficacy in solid tumors. Overall these two projects will shed light for the first time into the possibility of combining the fields of senescence and cellular therapy and will lead to the development of highly effective senolytic agents as well as new strategies to improve the efficacy of CAR T cells in solid tumors.