Enhancing Chimeric Antigen Receptor T cell therapy in Mouse EGFRvIII Heterogeneous Glioblastoma

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2023

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Abstract

Chimeric antigen receptor (CAR) T cell therapy for glioblastoma remains challenging due to insufficient CAR T cell abundance and antigen-negative tumor cells evading targeting. Unfortunately, most preclinical studies evaluating CAR T cells in glioblastoma use tumors expressing a single antigen, xenografts, and/or lymphodepletion. While lymphodepletion enhances CAR T cell efficacy, it diminishes the endogenous immune system, which has the potential for tumor eradication. Here, we orthotopically delivered IL7 and/or Flt3L expressing CAR T cells in 50% EGFRvIII-positive and -negative tumors pre-conditioned with non-lymphodepleting irradiation. IL7 and IL7 Flt3L CAR T cells increased intratumoral CD8 CAR T cell populations seven days after treatment. IL7 co-expression with Flt3L increased conventional dendritic cells (cDCs) as well as the CD103+XCR1+ population known for migration and antigen cross-presentation. Treatment with IL7 or IL7 Flt3L CAR T cells improved overall survival to 67% and 50%, respectively, compared to 9% in vCAR and vFL and no survivors in PBS treated. However, there was no significant difference in survival between IL7 and IL7 Flt3L CAR T cells. We conclude that CAR T cells modified to express IL7 demonstrate therapeutic potential in glioblastoma treated with non-lymphodepleting irradiation and co-expression with Flt3L modestly improved intratumoral dendritic cell populations.

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Swan, Sheridan Leigh-Carroll (2023). Enhancing Chimeric Antigen Receptor T cell therapy in Mouse EGFRvIII Heterogeneous Glioblastoma. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/27581.

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