Neurotoxicity and Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy: Insights Into Mechanisms and Novel Therapies

Abstract

Chimeric antigen receptor T (CART) cell immunotherapy has been remarkably successful in treating certain relapsed/refractory hematological cancers. However, CART cell therapy is also associated with toxicities which present an obstacle to its wider adoption as a mainstay for cancer treatment. The primary toxicities following CART cell administration are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). New insights into the mechanisms of these toxicities have spurred novel treatment options. In this review, we summarize the available literature on the clinical manifestations, mechanisms, and treatments of CART-associated CRS and ICANS.

Keywords: CART; CRS; chimeric antigen receptor; immunotherapy; neurotoxicity.

FIGURE 1

Schematic of key cells and cytokines involved in CRS and ICANS. Cancer cells expressing the target antigen stimulate CART cells to secrete inflammatory cytokines including IFNγ and TNFα. These cytokines activate myeloid cells, which produce CRS-linked cytokines such as IL-1 and IL-6. In ICANS, activated endothelial cells produce von Willebrand factor and Ang-2 and contribute to blood-brain barrier dysfunction.