Robust expansion of HIV CAR T cells following antigen boosting in ART-suppressed nonhuman primates
| Autor: | Mark Enstrom, Katherine E. Brandenstein, Hans-Peter Kiem, Meei-Li Huang, Gavin I. Ellis, James L. Riley, Christine M. Fennessey, Blake J. Rust, Keith R. Jerome, Willimark M. Obenza, Christopher W. Peterson, Colby R. Maldini, Brandon F. Keele, Leslie S. Kean, Lucrezia Colonna, Nikhita Hegde Poole |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Primates T-Lymphocytes Immunology Receptors Antigen T-Cell HIV Infections Biochemistry CD19 03 medical and health sciences Immunocompromised Host 0302 clinical medicine Immune system Antigen Antiretroviral Therapy Highly Active Animals Antigens Viral Immune Checkpoint Inhibitors Receptors Chimeric Antigen biology Cell Biology Hematology Gene Therapy Immune Checkpoint Proteins Macaca mulatta Chimeric antigen receptor Immune checkpoint Blockade Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis biology.protein HIV-1 Simian Immunodeficiency Virus Antibody Viral load human activities BLOOD Commentary |
| Zdroj: | Blood |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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