Robust expansion of HIV CAR T cells following antigen boosting in ART-suppressed nonhuman primates.

Autor:	Rust BJ; Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA., Kean LS; Boston Children's Hospital/Dana-Farber Cancer Institute-Department of Pediatrics, Harvard Medical School, Boston, MA., Colonna L; Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA., Brandenstein KE; Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA., Poole NH; Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA., Obenza W; Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA., Enstrom MR; Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA., Maldini CR; Department of Microbiology and Center for Cellular Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Ellis GI; Department of Microbiology and Center for Cellular Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Fennessey CM; AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD., Huang ML; Department of Laboratory Medicine, University of Washington, Seattle, WA., Keele BF; AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD., Jerome KR; Department of Laboratory Medicine, University of Washington, Seattle, WA.; Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and., Riley JL; Department of Microbiology and Center for Cellular Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Kiem HP; Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA.; Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and.; Department of Medicine, University of Washington, Seattle, WA., Peterson CW; Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA.; Department of Medicine, University of Washington, Seattle, WA.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2020 Oct 08; Vol. 136 (15), pp. 1722-1734.
DOI:	10.1182/blood.2020006372
Abstrakt:	Chimeric antigen receptor (CAR) T cells targeting CD19+ hematologic malignancies have rapidly emerged as a promising, novel therapy. In contrast, results from the few CAR T-cell studies for infectious diseases such as HIV-1 have been less convincing. These challenges are likely due to the low level of antigen present in antiretroviral therapy (ART)-suppressed patients in contrast to those with hematologic malignancies. Using our well-established nonhuman primate model of ART-suppressed HIV-1 infection, we tested strategies to overcome these limitations and challenges. We first optimized CAR T-cell production to maintain central memory subsets, consistent with current clinical paradigms. We hypothesized that additional exogenous antigen might be required in an ART-suppressed setting to aid expansion and persistence of CAR T cells. Thus, we studied 4 simian/HIV-infected, ART-suppressed rhesus macaques infused with virus-specific CD4CAR T cells, followed by supplemental infusion of cell-associated HIV-1 envelope (Env). Env boosting led to significant and unprecedented expansion of virus-specific CAR+ T cells in vivo; after ART treatment interruption, viral rebound was significantly delayed compared with controls (P = .014). In 2 animals with declining CAR T cells, rhesusized anti-programmed cell death protein 1 (PD-1) antibody was administered to reverse PD-1-dependent immune exhaustion. Immune checkpoint blockade triggered expansion of exhausted CAR T cells and concordantly lowered viral loads to undetectable levels. These results show that supplemental cell-associated antigen enables robust expansion of CAR T cells in an antigen-sparse environment. To our knowledge, this is the first study to show expansion of virus-specific CAR T cells in infected, suppressed hosts, and delay/control of viral recrudescence. (© 2020 by The American Society of Hematology.)
Databáze:	MEDLINE
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