Immune inactivation of anti-simian immunodeficiency virus chimeric antigen receptor T cells in rhesus macaques

• Published in: Molecular therapy. Methods & clinical development Vol. 22; pp. 304 - 319
• Main Authors: Haeseleer, Françoise, Fukazawa, Yoshinori, Park, Haesun, Varco-Merth, Benjamin, Rust, Blake J., Smedley, Jeremy V., Eichholz, Karsten, Peterson, Christopher W., Mason, Rosemarie, Kiem, Hans-Peter, Roederer, Mario, Picker, Louis J., Okoye, Afam A., Corey, Lawrence
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.09.2021; American Society of Gene & Cell Therapy; Elsevier
• Subjects: autologous cell therapy; CAR T cells; HIV; humoral immune response; infectious diseases; Original; SIV; SIV; humoral immune response; HIV; autologous cell therapy; CAR T cells; infectious diseases
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2021.06.008

Chimeric antigen receptor (CAR) T cell therapies are being investigated as potential HIV cures and designed to target HIV reservoirs. Monoclonal antibodies (mAbs) targeting the simian immunodeficiency virus (SIV) envelope allowed us to investigate the potency of single-chain variable fragment (scFv)-based anti-SIV CAR T cells. In vitro, CAR T cells expressing the scFv to both the variable loop 1 (V1) or V3 of the SIV envelope were highly potent at eliminating SIV-infected T cells. However, in preclinical studies, in vivo infusion of these CAR T cells in rhesus macaques (RMs) resulted in lack of expansion and no detectable in vivo antiviral activity. Injection of envelope-expressing antigen-presenting cells (APCs) 1 week post-CAR T cell infusion also failed to stimulate CAR T cell expansion in vivo. To investigate this in vitro versus in vivo discrepancy, we examined host immune responses directed at CAR T cells. A humoral immune response against the CAR scFv was detected post-infusion of the anti-SIV CAR T cells; anti-SIV IgG antibodies present in plasma of SIV-infected animals were associated with inhibited CAR T cell effector functions. These data indicate that lack of in vivo expansion and efficacy of CAR T cells might be due to antibodies blocking the interaction between the CAR scFv and its epitope. [Display omitted] Corey and colleagues evaluated CAR T cells targeting the envelope of simian immunodeficiency virus. They show that antibodies blocking the interaction between the CAR and its epitope might be responsible for the lack of in vivo proliferation of anti-SIV CAR T cells and killing of SIV-infected cells after infusion in rhesus macaques.