Research ArticleCancer

A chimeric antigen receptor with antigen-independent OX40 signaling mediates potent antitumor activity

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Science Translational Medicine  27 Jan 2021:
Vol. 13, Issue 578, eaba7308
DOI: 10.1126/scitranslmed.aba7308

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Optimizing with OX40

Chimeric antigen receptor (CAR)–T cells have transformed treatment of B cell malignancies. However, existing CAR-T cell constructs have not been as successful in treating solid tumors. To improve CAR-T cell function in solid tumors, Zhang et al. incorporated a full-length costimulatory signaling molecule, OX40, into CAR-T cells. The combination of CAR signaling and OX40 signaling improved the antitumor cytolytic capacity of CAR-T cells in vitro and in mouse models of B cell lymphoma. Further, in a phase 1 clinical trial, the authors showed that CAR-T cells expressing OX40 persist in patients with metastatic lymphoma, are well tolerated, and reduce tumor burden. These findings suggest that CAR-T cells with independent OX40 signaling may be a useful therapeutic approach to treat solid tumors.

Abstract

Although chimeric antigen receptor (CAR)–modified T cells have shown great success in the treatment of B cell malignancies, this approach has limited efficacy in patients with solid tumors. Various modifications in CAR structure have been explored to improve this efficacy, including the incorporation of two costimulatory domains. Because costimulatory signals are transduced together with T cell receptor signals during T cell activation, we engineered a type of CAR-T cells with a costimulatory signal that was activated independently from the tumor antigen to recapitulate physiological stimulation. We screened 12 costimulatory receptors to identify OX40 as the most effective CAR-T function enhancer. Our data indicated that these new CAR-T cells showed superior proliferation capability compared to current second-generation CAR-T cells. OX40 signaling reduced CAR-T cell apoptosis through up-regulation of genes encoding Bcl-2 family members and enhanced proliferation through increased activation of the NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase), and PI3K-AKT (phosphoinositide 3-kinase to the kinase AKT) pathways. OX40 signaling not only enhanced the cytotoxicity of CAR-T cells but also reduced exhaustion markers, thereby maintaining their function in immunosuppressive tumor microenvironments. In mouse tumor models and in patients with metastatic lymphoma, these CAR-T cells exhibited robust amplification and antitumor activity. Our findings provide an alternative option for CAR-T optimization with the potential to overcome the challenge of treating solid tumors.

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