Toward development of senolytic CAR T cells

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SUMMARY Senescence is a stress response program that provides a potent barrier to cancer progression, and restoration of this program in advanced cancers can produce potent anti-tumor effects. Conversely, the aberrant accumulation of senescent cells in tissues contributes to pathologies associated with aged and damaged tissue, such that elimination of senescent cells from these tissues can ameliorate disease symptoms in mice. Consequently, strategies to trigger senescence in cancer, or eliminate senescent cells in aged or damaged tissues, are of potential clinical significance. Superficially, cellular senescence involves a two component process: on one hand, the p53 and RB tumor suppressors control a gene repression program that leads to stable cell cycle arrest; on the other hand, transcriptional activators such as NF-kB execute a gene activation program, leading to the production of a range of secreted or cell surface proteins collectively known as the senescence associated secretory phenotype (SASP). The molecular composition and biological roles of the SASP are diverse, but SASP factors include growth factors, immune modulators and matrix metalloproteinases, and thus the process can contribute to both the anti-tumor effects but also to the deleterious consequences of senescence in aged or damaged tissues. Our team combines the extensive expertise of the Lowe laboratory in senescence mechanisms and biology with the innovation of the Sadelain group in developing chimeric antigen receptor T (CAR T) cells capable of targeting cell surface proteins for therapeutic purposes. Our goals are to identify novel cell surface markers that are selectively expressed in senescent cells for the purpose of better identifying and characterizing senescent cells in tissues and as biomarkers for senescence related diseases. In parallel, we exploit the selective features of these molecules with the aim of producing senolytic CAR T cells, which we then characterize in preclinical senescence models and, if successful, apply as tools to interrogate senescence biology in vivo. Preliminary data strongly supports the feasibility of the proposed work: we have already identified one cell surface molecule that is predominantly expressed on senescent cells, and produced CAR T cells targeting it. We further provide preliminary data to demonstrate that these CAR T cells behave as bona fide senolytics, capable of eliminating senescent cells in culture and in mice. In our application, we continue to validate the protein and CAR T cells as useful tools and in preclinical models, and work towards the development of enhanced versions of the CAR T that, with further validation, could be developed clinically. We expect our studies to better define the senescent state, produce new insights into senescence biology, and produce a new therapeutic modality for treating senescence associated pathologies.