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

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

Molecular Therapy: Methods & Clinical Development (Jun 2022)

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

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

Affiliations

Min Guan: T Cell Therapeutics Research Laboratory, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA
Laura Lim: T Cell Therapeutics Research Laboratory, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA
Leo Holguin: Center for Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
Tianxu Han: Center for Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
Vibhuti Vyas: T Cell Therapeutics Research Laboratory, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA
Ryan Urak: Center for Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
Aaron Miller: Department of Molecular Imaging and Therapy, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
Diana L. Browning: Center for Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
Liliana Echavarria: Center for Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
Shasha Li: Center for Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
Shirley Li: Center for Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
Wen-Chung Chang: T Cell Therapeutics Research Laboratory, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA
Tristan Scott: Center for Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
Paul Yazaki: Department of Molecular Imaging and Therapy, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
Kevin V. Morris: Center for Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
Angelo A. Cardoso: Center for Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
M. Suzette Blanchard: Division of Biostatistics, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
Virginia Le Verche: Center for Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
Stephen J. Forman: T Cell Therapeutics Research Laboratory, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA
John A. Zaia: Center for Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
John C. Burnett: Center for Gene Therapy, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
Xiuli Wang: T Cell Therapeutics Research Laboratory, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA; Corresponding author Xiuli Wang, T Cell Therapeutics Research Laboratory, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010-3000, USA.

Journal volume & issue: Vol. 25
pp. 344 – 359

Abstract

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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.

Published in Molecular Therapy: Methods & Clinical Development

ISSN: 2329-0501 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Science: Biology (General): Cytology
Website: http://www.cell.com/molecular-therapy-family/methods/latest-content

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