Cytokine release syndrome: grading, modeling, and new therapy

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Chimeric antigen receptor (CAR) T cell therapy represents a significant advancement in cancer immunotherapy, with ongoing clinical trials for various malignancies.
• Cytokine release syndrome (CRS) and CAR-related encephalopathy syndrome (CRES) are dose-limiting toxicities associated with CAR T cell treatments.

Purpose of the Study:

• To review current understanding of the pathogenesis and etiology of CRS and CRES.
• To explore advancements in grading, modeling, and therapeutic strategies for managing CAR T cell-related toxicities.

Main Methods:

• Utilized established mouse models to investigate the mechanisms underlying CAR T cell-induced toxicities.
• Analyzed the roles of specific cytokines (IL-1, IL-6) and cell types (myeloid cells) in mediating CRS and CRES.

Main Results:

• Myeloid cells, particularly macrophages and monocytes, were identified as the primary mediators of CRS and CRES through cytokine release (IL-1, IL-6).
• Blocking IL-1 or depleting monocytes effectively abolished both CRS and CRES.
• IL-6 blockade ameliorated CRS but did not resolve CRES, highlighting IL-1's critical role in neurotoxicity.
• Therapeutic interventions targeting CRS did not impair CAR T cell anti-tumor efficacy in preclinical models.

Conclusions:

• IL-1 and IL-6 are key cytokines in CRS, with IL-1 being particularly crucial for CRES.
• Targeting myeloid cell-derived cytokines, especially IL-1, presents a viable strategy for mitigating CAR T cell toxicities without compromising anti-tumor activity.