A Systematic Review on the Dual Role of Interleukin-1 in CAR T-Cell Therapy: Enhancer and Mitigator

Abstract

Chimeric antigen receptor T-cell therapy is a groundbreaking approach for treating certain hematologic malignancies and solid tumors. However, its application is limited by severe toxicities, particularly CRS and ICANS, dramatically limit its broader application. IL-1 plays a crucial role in both enhancing CAR T-cell efficacy and driving these toxic effects. This review systematically examines the dual functions of IL-1, highlighting its role in promoting CAR T-cell activation and persistence while contributing to CRS and ICANS pathogenesis. Strategies to mitigate IL-1-driven toxicities, including IL-1 receptor antagonists, monoclonal antibodies, IL-1 trapping, and interference with IL-1 production, show promise in reducing adverse effects without compromising therapeutic efficacy. Understanding the complex role of IL-1 in CAR T-cell therapy may lead to optimized treatment strategies, improving safety and expanding clinical applicability. Further research is essential to refine IL-1-targeted interventions and enhance the therapeutic potential of CAR T-cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy is a groundbreaking approach for treating certain hematologic malignancies and solid tumors. However, its application is limited by severe toxicities, particularly cytokine release syndrome (CRS) and cell-associated neurotoxicity syndrome (ICANS), dramatically limit its broader application. IL-1 plays a crucial role in both enhancing CAR T-cell efficacy and driving these toxic effects. This review systematically examines the dual functions of IL-1, highlighting its role in promoting CAR T-cell activation and persistence while contributing to CRS and ICANS pathogenesis. Strategies to mitigate IL-1-driven toxicities, including IL-1 receptor antagonists, monoclonal antibodies, IL-1 trapping, and interference with IL-1 production, show promise in reducing adverse effects without compromising therapeutic efficacy. Understanding the complex role of IL-1 in CAR T-cell therapy may lead to optimized treatment strategies, improving safety and expanding clinical applicability. Further research is essential to refine IL-1-targeted interventions and enhance the therapeutic potential of CAR T-cell therapy.

Keywords: Interleukin-1; cytokine release syndrome; Chimeric antigen receptor T cells.

Fig. 1

Systematic review flowchart of this study.

Fig. 2

Role of IL-1 in the pathophysiology of CRS and ICANS associated with CAR T-cell therapy. Upon CAR T-cell activation, IL-1 is released by various immune cells, including macrophages and monocytes. This release initiates a cascade of pro-inflammatory cytokines, notably IL-6, which amplifies the systemic inflammatory response, characteristic of CRS. In the context of ICANS, IL-1 contributes to endothelial activation and blood-brain barrier disruption, facilitating neurotoxic effects. Understanding the signaling pathways of IL-1 and its downstream effects is crucial for developing targeted interventions to mitigate these toxicities without compromising the therapeutic efficacy of CAR T-cell treatments.

Fig. 3

Overview of IL-1 blockade strategy in CAR T-cell therapy. These strategies include IL-1Ra antagonists, anti-IL-1 mAbs, IL-1RAPs, and molecules interfering with IL-1 production.