Programming T Cells for Successful Adoptive Cell Therapy

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DESCRIPTION (provided by applicant): The long term goal of this career development award is to establish the candidate, Dr. C. Marcela Diaz-Montero, as an independent translational scientist. To achieve this goal, the candidate, concurrently with her mentors, has designed a comprehensive training plan that includes research and extramural funding mentoring, as well as an educational component on the design, implementation and conduct of clinical trials. The candidate's research interests focus on enhancing the activity of T lymphocytes for adoptive cell therapy. She has made the novel observation that antigen-dependent activation of CD8+ T cells in the presence of IL-12 results in the accumulation of a subpopulation of T cells with an early-activated phenotype (TEA). In vivo, TEA show augmented survival and increased anti-tumor activity. Based on these observations, it is hypothesized that TEA have an enhanced ability to reach secondary lymphoid organs; and that their immature phenotype allows them to progress through the activation process under optimal stimulatory conditions resulting in effector cells with stronger anti-tumor capabilities and superior immunologic memory. To test this hypothesis the following specific aims are being proposed: 1) Define the contribution of homing to the lymph node to the survival and maturation of transferred TEA; 2) Ascertain if enhanced survival of TEA is due to their plasticity conferring a competitive advantage for cytokine sinks; 3) Determine the impact of enhanced TEA on the generation of T cell memory; 4) Test the impact of activation in the presence of IL-12 on the phenotypic and functional characteristics of human TCR transduced T cells. A better understanding of the programming and differentiation of CD8+ T cells will allow us to identify the subset best fitted for ACT therapy for cancer and to design effective strategies that enhance the generation and survival of this subset. In addition, these studies represent the foundation for the candidate's research program that through close mentorship will develop into a state of the art, extramurally funded program in cancer immunotherapy. The mentors, Dr. Joseph Rosenblatt and Dr. Eli Gilboa, are experts in the field of cancer immunology and adoptive cell therapy with extensive mentorship experience. In addition, the University of Miami has made a significant investment in the candidate, which reflects on her potential to achieve her proposed goals. Dr. Diaz-Montero was recruited as part of the Dodson Interdisciplinary Immunotherapy Institute initiative to develop high-impact and broadly useful immune-based treatments. Her recruitment package included start up funds and laboratory space. In summary, this award will provide the candidate protective time to conduct her proposed studies and to fully exploit the outstanding institutional environment available at the University of Miami with the ultimate goal of becoming a successful translational scientist in cancer immunotherapy.