Toxicity and management in CAR T-cell therapy

Abstract

T cells can be genetically modified to target tumors through the expression of a chimeric antigen receptor (CAR). Most notably, CAR T cells have demonstrated clinical efficacy in hematologic malignancies with more modest responses when targeting solid tumors. However, CAR T cells also have the capacity to elicit expected and unexpected toxicities including: cytokine release syndrome, neurologic toxicity, "on target/off tumor" recognition, and anaphylaxis. Theoretical toxicities including clonal expansion secondary to insertional oncogenesis, graft versus host disease, and off-target antigen recognition have not been clinically evident. Abrogating toxicity has become a critical step in the successful application of this emerging technology. To this end, we review the reported and theoretical toxicities of CAR T cells and their management.

Figure 1

Toxicities of chimeric antigen receptor (CAR) T-cell therapy. Depiction of reported/potential toxicities following the use of CAR T cells: insertional oncogenesis (theoretical); neurological toxicity; “on-target, off-tumor” toxicity (engagement of target antigen on nonpathogenic tissues); anaphylaxis/allergy (host reaction to foreign antigen expressed by the CAR T cell); cytokine release syndrome (systemic inflammatory response following activation of CAR T cells). CRP, C-reactive protein.

Figure 2

Management of chimeric antigen receptor (CAR) T-cell toxicity. (a) CAR T cells can be further engineered to express “suicide genes” or “elimination genes” such as herpes simplex virus thymidine kinase (HSV-tk) which converts the prodrug ganciclovir (GCV) into GCV-triphosphate resulting in cell death by incorporation into replicating DNA; inducible caspase 9 (iCasp9) a chimeric protein that binds the small molecule AP1903, leading to caspase 9 dimerization and ultimate apoptosis; truncated endothelial growth factor receptor (tEGFR) which is a targetable antigen which allows for elimination of modified cells following infusion of associated anti-EGFR MAb (cetuximab). (b) Pharmacological immunosuppression will ameliorate toxicity from CAR T including blockade of IL-6R and/or treatment with systemic corticosteroid. ADCC, antibody-dependent cellular cytotoxicity.