Pre-clinical data supporting immunotherapy for HIV using CMV-HIV-specific CAR T cells with CMV vaccine

• Main Authors: Blanchard, M.S (Author), Browning, D.L (Author), Burnett, J.C (Author), Cardoso, A.A (Author), Chang, W.-C (Author), Echavarria, L. (Author), Forman, S.J (Author), Guan, M. (Author), Han, T. (Author), Holguin, L. (Author), Le Verche, V. (Author), Li, S. (Author), Lim, L. (Author), Miller, A. (Author), Morris, K.V (Author), Scott, T. (Author), Urak, R. (Author), Vyas, V. (Author), Wang, X. (Author), Yazaki, P. (Author), Zaia, J.A (Author)
• Format: Article
• Language: English
• Published: Cell Press 2022
• Subjects: broadly neutralizing antibody (bNAb); chimeric antigen receptor T cell (CAR T); cytomegalovirus (CMV) vaccine; HIV/AIDS; immunotherapy; N6
• Online Access: View Fulltext in Publisher

 T cells engineered to express HIV-specific chimeric antigen receptors (CARs) represent a promising strategy to clear HIV-infected cells, but to date have not achieved clinical benefits. A likely hurdle is the limited T cell activation and persistence when HIV antigenemia is low, particularly during antiretroviral therapy (ART). To overcome this issue, we propose to use a cytomegalovirus (CMV) vaccine to stimulate CMV-specific T cells that express CARs directed against the HIV-1 envelope protein gp120. In this study, we use a GMP-compliant platform to engineer CMV-specific T cells to express a second-generation CAR derived from the N6 broadly neutralizing antibody, one of the broadest anti-gp120 neutralizing antibodies. These CMV-HIV CAR T cells exhibit dual effector functions upon in vitro stimulation through their endogenous CMV-specific T cell receptors or the introduced CARs. Using a humanized HIV mouse model, we show that CMV vaccination during ART accelerates CMV-HIV CAR T cell expansion in the peripheral blood and that higher numbers of CMV-HIV CAR T cells were associated with a better control of HIV viral load and fewer HIV antigen p24+ cells in the bone marrow upon ART interruption. Collectively, these data support the clinical development of CMV-HIV CAR T cells in combination with a CMV vaccine in HIV-infected individuals. © 2022