Multivalent CAR T cell therapy demonstrated potent and durable control of HIV escape and replication in BLT humanized mice 4622

Abstract Description Chimeric antigen receptor (CAR) T cell therapy, utilizing broadly neutralizing antibody (bNAb) shows promise to enhance the immune response against HIV, offering a potent strategy to target a wide range of HIV strains. We generated 19 bNAb-based CAR T cells targeting 6 conserved HIV envelope (Env) epitopes. CARs were evaluated for potency in vitro through killing and suppression assays. Notably, CARs targeting distal epitopes (V1/V2 apex, V3 glycan, CD4 binding site) showed greater killing potency suggesting that epitope accessibility dictates hierarchy between epitopes. NPs-based avidity assay showed how differences within an epitope were dictated by avidity. HIV-infected humanized mice treated with CAR monotherapy showed escape at well-described bNAb contact site. However, mice treated with a combination of CAR T cells with orthogonal escape patterns restricted the kinetics of HIV escape and durably reduced plasma viremia. We next developed a tri-valent CAR product, which demonstrated greater expansion magnitude and showed promising durable viral control in humanized mice. In summary, we identified bNAb CAR classes with superior potency and described mechanisms underlying their effectiveness. Limiting HIV escape kinetics, through combining CARs targeting distinct epitopes, is essential for durable control of viremia in vivo. Tri-specific CAR products simultaneously expressing the most potent bNAb CARs may represent a promising cellular therapy advancing HIV cure efforts. Funding Sources NIH RO1 AI86810 Topic Categories Vaccines and Immunotherapy (VAC)