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

<p>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.</p>

Author dc:creator

• Swan, Sheridan Leigh-Carroll

Advisor dc:contributor.advisor

• Bellamkonda, Ravi

• Immunology
• Biomedical engineering
• CAR T cells
• dendritic cells
• Flt3L
• glioblastoma
• IL7
• T cell abundance

Handle dc:identifier.uri

https://hdl.handle.net/10161/27581

OAI identifier oai:identifier

oai:dukespace.lib.duke.edu:10161/27581