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Generation and Functional Verification of Hypoxia-Sensitive Chimeric Antigen Receptor-T Cells

Extensive studies have proven the promise of chimeric antigen receptor T (CAR-T) cell therapy in treating hematological malignancies. However, treating ...

Fudan University

Despite the success of antiretroviral therapy in suppressing HIV to an undetectable level in the blood and improving patients' quality of life, HIV persists in antiretroviral therapy-treated patients and threatens their lives. Anti-HIV chimeric antigen receptor (CAR) T cells could offer a cure by recognizing and killing virus-producing cells in an Env-specific manner. In this review, the authors summarize several important aspects of the development of anti-HIV CAR T cells, with a special focus on the evolution of CAR design for enhanced potency and targeting specificity, and also outline the challenges that still need to be addressed to take anti-HIV CAR T cells from a hopeful approach to a real HIV cure.

Current status and future development of anti-HIV chimeric antigen receptor T-cell therapy.

Chimeric antigen receptor-modified T cells (CAR-T cells) have shown good effects in the treatment of hematologic cancers; however, they may cause on-target off-tumor toxicity because of minimal expression of tumor-associated antigens (TAAs) on normal tissues, particularly in the context of treating solid tumors. Hypoxia is a common hallmark of solid tumors because of the Warburg effect. To minimize side effects, we designed a hypoxia-inducible CAR (HiCAR), which is driven by a hypoxia response element (HRE), and consists of a conventional CAR and an oxygen-dependent degradation domain (ODD) that is actively degraded under normoxia but stabilized under hypoxia. HiCAR-T cells showed enhanced cytotoxicity against tumor cells under hypoxia compared to normoxia in vitro and antitumor efficacy comparable to that of conventional CAR-T cells in vivo. Overall, our study demonstrates the potential of the HiCAR for improving the safety of CAR-T cells to promote the clinical application of CAR-T immunotherapy.

Engineering T cells with hypoxia-inducible chimeric antigen receptor (HiCAR) for selective tumor killing.

On-target off-tumor toxicity impedes the clinical application of chimeric antigen receptor-modified T cells (CAR-T cells) in the treatment of solid tumors. Previous reports proved that the combinatorial antigen recognition strategy could improve the safety profile of CAR-T cells by targeting two different tumor-associated antigens (TAAs), one as a CAR-T targeted antigen and the other as a chimeric costimulatory receptor (CCR) ligand. The programmed death-ligand 1 (PD-L1, also known as B7-H1) is preferentially overexpressed on multiple tumors, it will be highly interesting to explore the potential of PD-L1 as a universal target for designing CCR.

PD-L1 chimeric costimulatory receptor improves the efficacy of CAR-T cells for PD-L1-positive solid tumors and reduces toxicity in vivo.

Chimeric antigen receptor T (CAR-T) cells have been proposed for HIV-1 treatment but have not yet demonstrated desirable therapeutic efficacy. Here, we report newly developed anti-HIV-1 CAR-T cells armed with endogenic broadly neutralizing antibodies (bNAbs) and the follicle-homing receptor CXCR5, termed M10 cells. M10 cells were designed to exercise three-fold biological functions, including broad cytotoxic effects on HIV-infected cells, neutralization of cell-free viruses produced after latency reversal, and B-cell follicle homing. After demonstrating the three-fold biological activities, M10 cells were administered to treat 18 HIV-1 patients via a regimen of two allogenic M10 cell infusions with an interval of 30 days, with each M10 cell infusion followed by two chidamide stimulations for HIV-1 reservoir activation. Consequently, 74.3% of M10 cell infusions resulted in significant suppression of viral rebound, with viral loads declining by an average of 67.1%, and 10 patients showed persistently reduced cell-associated HIV-1 RNA levels (average decrease of 1.15 log10) over the 150-day observation period. M10 cells were also found to impose selective pressure on the latent viral reservoir. No significant treatment-related adverse effects were observed. Overall, our study supported the potential of M10 CAR-T cells as a novel, safe, and effective therapeutic option for the functional cure of HIV-1/AIDS.

Yunyu Mao

Clinical Center of Biotherapy at Zhongshan Hospital

Fudan University

Generation and Functional Verification of Hypoxia-Sensitive Chimeric Antigen Receptor-T Cells

Yunyu Mao

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Clinical Center of Biotherapy at Zhongshan Hospital

Fudan University

Generation and Functional Verification of Hypoxia-Sensitive Chimeric Antigen Receptor-T Cells

Clinical Center of Biotherapy at Zhongshan Hospital