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

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
Source :
Molecular Therapy: Methods & Clinical Development, Vol 25, Iss , Pp 344-359 (2022)
Publication Year :
2022
Publisher :
Elsevier, 2022.

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.

Details

Language :
English
ISSN :
23290501
Volume :
25
Issue :
344-359
Database :
Directory of Open Access Journals
Journal :
Molecular Therapy: Methods & Clinical Development
Publication Type :
Academic Journal
Accession number :
edsdoj.35d7761f02247f9aa1379d906dc6325
Document Type :
article
Full Text :
https://doi.org/10.1016/j.omtm.2022.04.007