Clinical management strategies for cytokine release syndrome and their impact on CAR T-cell efficacy in lymphoma.

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy has significantly advanced the treatment of relapsed/refractory (R/R) lymphoma. However, its broader clinical application is often limited by cytokine release syndrome (CRS), a major immune-mediated complication. Because the in vivo expansion of CAR-T cells drives both tumor clearance and CRS, addressing this toxicity without impairing anti-tumor efficacy remains a critical clinical necessity. This review comprehensively evaluates current and emerging CRS management strategies across the entire treatment process. First, we explore proactive pre-infusion measures, such as bridging therapies and lymphodepletion regimens, which help mitigate baseline inflammatory risks. Next, we outline standard-of-care treatments for established CRS, focusing on the optimized dosing of corticosteroids and cytokine-blocking agents. We then discuss novel investigational approaches, including targeted kinase inhibitors and emerging cytokine-directed antibodies, that show potential to decouple inflammatory signaling from CAR-T cytotoxicity. Overall, our findings highlight that effective CRS management relies on a comprehensive strategy that optimizes established treatments and integrates novel targeted therapies. When adapted to individual clinical profiles, these customized approaches can effectively control systemic inflammation while potentially preserving anti-tumor efficacy, though more prospective trials are needed to confirm these findings.