Abstract
Chimeric antigen receptor (CAR) T cell therapies are being investigated as potential HIV cures and designed to target HIV reservoirs. Monoclonal antibodies (mAbs) targeting the simian immunodeficiency virus (SIV) envelope allowed us to investigate the potency of single-chain variable fragment (scFv)-based anti-SIV CAR T cells. In vitro, CAR T cells expressing the scFv to both the variable loop 1 (V1) or V3 of the SIV envelope were highly potent at eliminating SIV-infected T cells. However, in preclinical studies, in vivo infusion of these CAR T cells in rhesus macaques (RMs) resulted in lack of expansion and no detectable in vivo antiviral activity. Injection of envelope-expressing antigen-presenting cells (APCs) 1 week post-CAR T cell infusion also failed to stimulate CAR T cell expansion in vivo. To investigate this in vitro versus in vivo discrepancy, we examined host immune responses directed at CAR T cells. A humoral immune response against the CAR scFv was detected post-infusion of the anti-SIV CAR T cells; anti-SIV IgG antibodies present in plasma of SIV-infected animals were associated with inhibited CAR T cell effector functions. These data indicate that lack of in vivo expansion and efficacy of CAR T cells might be due to antibodies blocking the interaction between the CAR scFv and its epitope.
Highlights
The technologies to characterize and manufacture broadly neutralizing antibodies to HIV have broadened the potential for using immunological approaches to treat and prevent HIV infection
We developed a proof-of-concept preclinical program to evaluate if chimeric antigen receptor (CAR) T cells constructed with the scFv of rhesus macaque (RM) bnAbs could exert in vivo immunological control of simian immunodeficiency virus (SIV)-infected T cells
As a first step in designing anti-SIV CAR lentiviral vectors, we investigated whether the configuration of the VH and VL domains of the scFv or the length of the spacers linking the scFv to the transmembrane domain have an effect on the overall potency of the CAR T cells
Summary
The technologies to characterize and manufacture broadly neutralizing antibodies (bnAbs) to HIV have broadened the potential for using immunological approaches to treat and prevent HIV infection. Clinical development of bnAbs for both their antiviral function and prevention of HIV is underway, and several successes have been seen with such antibodies. Several clinic trials with autologous T cells from patients that had been engineered to express a CAR have demonstrated the potential of CAR T cell therapy against cancer, especially for hematologic malignancies.[3,4,5] Adoptive cell therapy has been investigated as a strategy to eliminate HIV-infected cells.[6,7] The therapeutic potential of such an approach has been primarily studied with CD4CAR constructed with the extracellular domain of the human CD4 receptor that binds to the HIV envelope (Env).[8,9,10,11] Other HIV-specific CARs were engineered with the single-chain variable fragment (scFv) of bnAbs recognizing a conserved epitope of the HIV Env.[12] some success was obtained with CD4CAR in controlling viremia to lower levels, eradication of the HIV reservoirs using CAR T cells has not yet been accomplished.[13,14]
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