Abstract

Adoptive cell therapy (ACT) using T cells expressing chimeric antigen receptors (CARs) is an area of intense investigation in the treatment of malignancies and chronic viral infections. One of the limitations of ACT-based CAR therapy is the lack of in vivo persistence and maintenance of optimal cell function. Therefore, alternative strategies that increase the function and maintenance of CAR-expressing T cells are needed. In our studies using the humanized bone marrow/liver/thymus (BLT) mouse model and nonhuman primate model (NHP) of HIV infection, we evaluated two CAR-based gene therapy approaches. In ACT approach, we utilized cytokine enhancement and preconditioning to generate greater persistence of anti-HIV CAR+ T cells. We observed limited persistence and expansion of anti-HIV CAR T cells which led to minimal control of the virus. In our stem-cell based approach, we modified hematopoietic stem/progenitor cells (HSPCs) with anti-HIV CAR to generate anti-HIV CAR T cells in vivo. We observed CAR-expressing T cell expansion which led to better plasma viral load suppression. HSPC-derived CAR cells in infected NHPs showed superior trafficking and persistence in multiple tissues. Our results suggest a stem cell-based CAR T cell approach may be superior to generate long-term persistence and functional antiviral responses against HIV infection.

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