Self-regulating CAR-T cells modulate cytokine release syndrome in adoptive T-cell therapy

• DOI: 10.1084/jem.20221988
• Publication Date: 2024-04-12T13:40:19Z
• Authors: Meng-Yin Lin; Eunwoo Nam; Ryan M. Shih; Amanda Shafer; Amber Bouren; Melanie Ayala Ceja; Caitlin Harris; Mobina Khericha; Kenny H. Vo; Minsoo Kim; Chi-Hong Tseng; Yvonne Y. Chen
• Keywords: 0301 basic medicine; CD19; Antigens, CD19; Signal Transducing; Cell- and Tissue-Based Therapy; 610; Adaptor Proteins; Article; Mice; 03 medical and health sciences; 616; Animals; Cytokines; Antigens; Cytokine Release Syndrome; Adaptor Proteins, Signal Transducing

Cytokine release syndrome (CRS) is a frequently observed side effect of chimeric antigen receptor (CAR)-T cell therapy. Here, we report self-regulating T cells that reduce CRS severity by secreting inhibitors of cytokines associated with CRS. With a humanized NSG-SGM3 mouse model, we show reduced CRS-related toxicity in mice treated with CAR-T cells secreting tocilizumab-derived single-chain variable fragment (Toci), yielding a safety profile superior to that of single-dose systemic tocilizumab administration. Unexpectedly, Toci-secreting CD19 CAR-T cells exhibit superior in vivo antitumor efficacy compared with conventional CD19 CAR-T cells. scRNA-seq analysis of immune cells recovered from tumor-bearing humanized mice revealed treatment with Toci-secreting CD19 CAR-T cells enriches for cytotoxic T cells while retaining memory T-cell phenotype, suggesting Toci secretion not only reduces toxicity but also significantly alters the overall T-cell composition. This approach of engineering T cells to self-regulate inflammatory cytokine production is a clinically compatible strategy with the potential to simultaneously enhance safety and efficacy of CAR-T cell therapy for cancer.