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

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Publication Year:
2022
Authors:
Min Guan, Laura Lim, Leo Holguin, Tianxu Han, Vibhuti Vyas, Ryan Urak, Aaron Miller, Diana L Browning, Liliana Echavarria, Shasha Li, Shirley Li, Wen-Chung Chang, Tristan Scott, Paul Yazaki, Kevin V Morris, Angelo A Cardoso, M Suzette Blanchard, Virginia Le Verche, Stephen J Forman, John A Zaia, John C Burnett, Xiuli Wang
PubMed ID:
35573050
Funding Grants:
Public Summary:
In these late stage pre-clinical studies, we successfully armed immune T cells with a molecule called chimeric antigen receptors (CAR) derived from an anti-HIV antibody. We demonstrated that engineered CAR T cells are able to target and kill HIV-infected cells and control the infection in a mouse model of HIV. These CAR T cells were also designed to respond to a virus vaccine and multiply on demand to efficiently battle any residual HIV. These results are leading to a submission to the Food and Drug Administration (FDA) for permission to start a clinical trial in HIV-infected individuals. This therapy has the potential to provide individuals living with HIV a life-long viral suppression in the absence of anti-HIV drugs.
Scientific Abstract:
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.