Preclinical Models Give Early Indications of Effective Prevention, Management of CRS

With serious toxicities, such as cytokine release syndrome (CRS) and neurotoxicity, occurring in up to 1 in 3 patients receiving chimeric antigen receptor (CAR) T-cell therapy, researchers of a new paper outlined novel approaches being taken to prevent and manage the side effects.

Currently, how CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) are managed varies based on severity. For example, low-grade CRS and ICANS are managed with supportive care and antipyretics while moderate to severe CRS is managed with interleukin 6 receptor (IL-6R) blocking antibody tocilizumab with or without immunosuppression with corticosteroids and supportive care. Similarly, moderate-to-severe ICANS is typically treated with corticosteroids.

“A greater understanding of the molecular and cellular pathophysiologies of CRS and ICANS will facilitate the development of effective targeted therapies with reduced toxicities without compromising antitumour activity,” wrote the researchers. “Already, novel CAR constructs are being designed to minimize the risk of eliciting CRS and ICANS, while optimizing recognition of tumour antigen and effective T cell signalling.”

Preclinical models have indicated that ruxolitinib, itacitinib, and ibrutinib can reduce toxicity and cytokine secretion that occur with CRS. However, a mouse model showed that ibrutinib also reduces the levels of CAR T cell-derived cytokines, which could mean weakened CAR T-cell activation.

Other research has indicated that dasatinib, used in several blood cancers, showed potential for inhibiting CAR T cell-mediated cytotoxicity and cytokine production in both a “rapid and reversible manner.” It was also suggested in preclinical models that short-term dosing of the BCR-ABL-targeting kinase inhibitor reduced CRS-associated mortality.

“Cumulatively, these studies suggest that broad-spectrum cytokine inhibition through different mechanisms can reduce CRS pathology, an outcome that is expected given what we know about the pathophysiological mechanisms of CRS,” wrote the researchers. “Nonetheless, the long-term inhibition of cytokines may be detrimental to the anti-tumour efficacy of CAR T cells and, for this reason, targeted interventions aiming to selectively disrupt specific cytokine signalling pathways may be favoured.”

The researchers of the paper also highlighted a need for a better understanding of the biology and mechanisms of action of CAR T cells, including the effect of biophysical properties of the CAR.

Reference

Morris E, Neepalu S, Giavridis T, Sadelain M. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat Rev Immunol. Published online May 17, 2021. doi:10.1038/s41577-021-00547-6