Toxicity and management in CAR T-cell therapy

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Toxicity and management in CAR T-cell therapy Challice L Bonifant, Hollie J Jackson, Renier J Brentjens, Kevin J Curran Molecular Therapy - Oncolytics Volume 3, (January 2016) DOI: 10.1038/mto.2016.11 Copyright © 2016 Official journal of the American Society of Gene & Cell Therapy Terms and Conditions

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. Molecular Therapy - Oncolytics 2016 3, DOI: (10.1038/mto.2016.11) Copyright © 2016 Official journal of the American Society of Gene & Cell Therapy Terms and Conditions

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. Molecular Therapy - Oncolytics 2016 3, DOI: (10.1038/mto.2016.11) Copyright © 2016 Official journal of the American Society of Gene & Cell Therapy Terms and Conditions