Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS.

Autor: Zhen A; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America., Peterson CW; Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.; Departments of Medicine, University of Washington, Seattle, Washington, United States of America., Carrillo MA; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America., Reddy SS; Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America., Youn CS; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America., Lam BB; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America., Chang NY; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America., Martin HA; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America., Rick JW; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America., Kim J; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America., Neel NC; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America., Rezek VK; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America., Kamata M; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America., Chen ISY; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America.; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at University of California, Los Angeles, California, United States of America., Zack JA; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America.; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at University of California, Los Angeles, California, United States of America., Kiem HP; Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.; Departments of Medicine, University of Washington, Seattle, Washington, United States of America.; Department of Pathology, University of Washington, Seattle, Washington, United States of America., Kitchen SG; Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2017 Dec 28; Vol. 13 (12), pp. e1006753. Date of Electronic Publication: 2017 Dec 28 (Print Publication: 2017).
DOI: 10.1371/journal.ppat.1006753
Abstrakt: Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer and show promise in treating HIV-1 infection. However, significant limitations are persistence and whether peripheral T cell-based products can respond to malignant or infected cells that may reappear months or years after treatment remains unclear. Hematopoietic Stem/Progenitor Cells (HSPCs) are capable of long-term engraftment and have the potential to overcome these limitations. Here, we report the use of a protective CD4 chimeric antigen receptor (C46CD4CAR) to redirect HSPC-derived T-cells against simian/human immunodeficiency virus (SHIV) infection in pigtail macaques. CAR-containing cells persisted for more than 2 years without any measurable toxicity and were capable of multilineage engraftment. Combination antiretroviral therapy (cART) treatment followed by cART withdrawal resulted in lower viral rebound in CAR animals relative to controls, and demonstrated an immune memory-like response. We found CAR-expressing cells in multiple lymphoid tissues, decreased tissue-associated SHIV RNA levels, and substantially higher CD4/CD8 ratios in the gut as compared to controls. These results show that HSPC-derived CAR T-cells are capable of long-term engraftment and immune surveillance. This study demonstrates for the first time the safety and feasibility of HSPC-based CAR therapy in a large animal preclinical model.
Databáze: MEDLINE