A Comprehensive analysis and the impact of promemory gene incorporation on CAR T cell memory differentiation in the context of solid tumors

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Project summary/abstract CAR T cell immunotherapy has shown increasing success in the early control of liquid tumors including B-cell Acute Lymphoblastic Leukemia (B-ALL), B cell lymphomas, and multiple myeloma. However, establishing CAR T cell-mediated long-term protection has proven challenging, and tumor relapse occurs in approximately 30-50% of patients who showed initial responses to CAR T cell therapy. In many clinical trials, the tumor antigen(+) recurrence has accounted for the majority of total relapse cases, suggesting that the CAR T cells in these patients failed to instill long-term tumor control and protection from tumor relapse. Consistent with the trends observed in CAR T cell therapy clinical trials, preliminary data in our lab from a solid tumor model, has revealed a striking negative-correlation between tumor relapse and the number of CAR T cells detected at the time of relapse. Thus, we hypothesize that effective CAR T cell memory is critical for long-term protection against tumor antigen(+) relapse. Despite the widespread consensus for this hypothesis, limitations in relevant preclinical models have left the field of CAR T cell research lacking in comprehensive studies that directly address CAR T cell memory. To pursue our long-term goal of developing methods to enhance CAR T cell function and memory generation, we have developed a solid tumor model involving murine third-generation CAR T cells, fully immunocompetent mice, and distinct synergistic tumor cell lines. Using this established model, we propose experiments to conduct a comprehensive study on CAR T cell memory that will investigate CAR T cell differentiation into distinct subsets and protection from tumor relapse. CAR T cell memory will be studied in the context of immunologically distinct solid tumors and will concurrently assess the impacts of some clinical strategies to enhance CAR T cell immunotherapy on CD8 CAR T cell memory generation. In the second aim of this proposal, we will test our hypothesis that ectopic expression of a gene that promotes both CD8 T cell memory differentiation and effector T cell survival will enhance the overall outcome of CAR T cell therapy. By incorporating this gene into our existing CAR, we will test this hypothesis using a 4th generation CAR and investigate the impacts of constitutive expression of a pro-memory gene in CAR T cell function and memory. The research and training in this proposal will be conducted at Seattle Children’s Research Institute (SCRI) which is among the top ranked centers for pediatric cancer research, and a member of the Seattle Cancer Care Alliance. Training will be performed under the close mentorship of top experts in the field of T cell immunology Drs. Vandana Kalia and Surojit Sarkar, with additional support from leaders in the field of cancer immunotherapy: Drs. Mac Cheever, Mike Jensen, and Cam Turtle. Additional postdoctoral training will be provided through seminars, presentations, workshops, and classes dedicated to postdoctoral training provided by SCRI, The University of Washington, and Fred Hutchinson Cancer Research Center.