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

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Abstract

Chimeric antigen receptor (CAR) T cells targeting CD191 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 CAR1 T cells in vivo; after ART treatment interruption, viral rebound was significantly delayed compared with controls (P 5.014). 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.

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Rust, B. J., Kean, L. S., Colonna, L., Brandenstein, K. E., Poole, N. H., Obenza, W., … Peterson, C. W. (2020). Robust expansion of HIV CAR T cells following antigen boosting in ART-suppressed nonhuman primates. Blood, 136(15), 1722–1734. https://doi.org/10.1182/blood.2020006372

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