CAR-T therapy toxicities: the importance of macrophages in their development and possible targets for their management

Abstract

CAR-T cell therapies have risen to prominence over the last decade, and their indications are increasing with several products approved as early as second line in Large B Cell non-Hodgkin Lymphomas. Their major toxicities are the cytokine release syndrome (CRS) and the Immune-effector Cell Associated Neurotoxicity Syndrome (ICANS). These entities involve a hyperinflammatory cascade which is amplified through the mononuclear phagocytic system (MPS). Herein, we review the immune mediated adverse events related to CAR therapy, including their pathophysiologies, and current therapies. In particular, we discuss the emerging role of the MPS in both the toxicity and efficacy of CAR-T therapy, and possible avenues for the modulation of the MPS to optimize efficacy while minimizing toxicity.

Fig. 1

CRS Pathophysiology. Here CAR-T and the antigen connect causing target B-cell lysis. The resulting cytokines from both the CAR-T and target cell activate the macrophage. The macrophage and remaining MPS, here shown as a monocyte, create a positive feedback loop increasing the inflammatory cascade, and activate the endothelium increasing the lining’s permeability

Fig. 2.

ICANS Pathophysiology. CAR-T cell and target B-cell signal the macrophage as in Fig. 1, but in ICANS the activation of endothelium causes weakening of the BBB, shown here with degenerating astrocyte foot processes, allowing for the entrance of Monocytes, and CAR-T into the CSF. This results in a localized positive feedback loop in the CNS