Riding the storm: managing cytokine-related toxicities in CAR-T cell therapy

Abstract

The advent of chimeric antigen receptor T cells (CAR-T) has been a paradigm shift in cancer immunotherapeutics, with remarkable outcomes reported for a growing catalog of malignancies. While CAR-T are highly effective in multiple diseases, salvaging patients who were considered incurable, they have unique toxicities which can be life-threatening. Understanding the biology and risk factors for these toxicities has led to targeted treatment approaches which can mitigate them successfully. The three toxicities of particular interest are cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and immune effector cell-associated hemophagocytic lymphohistiocytosis (HLH)-like syndrome (IEC-HS). Each of these is characterized by cytokine storm and hyperinflammation; however, they differ mechanistically with regard to the cytokines and immune cells that drive the pathophysiology. We summarize the current state of the field of CAR-T-associated toxicities, focusing on underlying biology and how this informs toxicity management and prevention. We also highlight several emerging agents showing promise in preclinical models and the clinic. Many of these established and emerging agents do not appear to impact the anti-tumor function of CAR-T, opening the door to additional and wider CAR-T applications.

Keywords: CAR-T toxicity; Chimeric antigen receptor T cells (CAR-T); cytokine release syndrome (CRS); immune effector cell-assocaited HLH-like syndrome (IEC-HS); immune effector cell-associated neurotoxicity (ICANS).

Fig. 1

Schematic detailing the current understanding of the pathophysiology of CRS and ICANS caused by cross-talk between CAR-T cells and macrophages. Several of the current and emerging therapies for CRS and ICANS are shown in their mechanism of action. Created with biorender.com

Fig. 2

IEC-HS timing is disctinct from that of CRS in that it occurs as CRS is resolving or later, after CRS has resolved (A). Schematic detailing the current understanding of the pathophysiology of IEC-HS, inferred from lines of evidence in sHLH as well. The general concept is that CAR-T activation creates feed-forward loops with macrophages and endogenous T cells, activated by and resulting in cytokine secretion and tissue damage. The mechanisms of action of several proposed therapies for IEC-HS are incorporated into the schematic to illustrate how they may work to ameliorate this pathology (B). Created with biorender.com