Low-Strength Type I Interferon Signaling Promotes CAR T-Cell Treatment Efficacy

CD19-directed chimeric antigen receptor (CAR) T-cell therapy has significantly advanced the treatment landscape for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). However, up to 60% of patients do not achieve a complete response. In this study, we analyzed the infusion products of eight r/r DLBCL patients with distinct clinical responses to axicabtagene ciloleucel using single-cell transcriptomics. Compared to patients with progressive disease, infusion products of complete responders demonstrated stronger signatures of type I interferon (IFN-I) signaling and cytotoxicity. Based on these findings, we developed a novel strategy to improve CD19-directed CAR T-cell treatment efficacy by incorporating IFN-I during the ex vivo manufacturing process. While high-strength IFN-I signaling increases both CAR T-cell cytotoxicity and apoptosis, low-strength IFN-I signaling selectively enhances CAR T-cell cytotoxicity without compromising viability. Our manufacturing method leverages an existing FDA-approved pharmacophore to improve CAR T-cell efficacy without altering CAR expression or current manufacturing protocols. This study demonstrates proof-of-principle for IFN-I as a modulator to enhance CAR T-cell treatment efficacy in vivo, showcasing its translational potential for improving CAR T-cell therapy.