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Review
. 2019 Mar 29;3(2):e186.
doi: 10.1097/HS9.0000000000000186. eCollection 2019 Apr.

CAR T Cell Toxicity: Current Management and Future Directions

Lucrecia Yáñez  1   2 , Miriam Sánchez-Escamilla  2   3 , Miguel-Angel Perales  3   4
Affiliations
Review

CAR T Cell Toxicity: Current Management and Future Directions

Lucrecia Yáñez et al. Hemasphere. .

Abstract

By late 2018, 2 chimeric antigen receptor T (CAR T) cell products have been approved by US and European regulatory authorities. Tisagenlecleucel (Kymriah, Novartis) is indicated in the treatment of patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse, or adult patients with large B-cell lymphoma relapsed or refractory (r/r) after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Axicabtagene ciloleucel (Yescarta, Kite) is indicated for the treatment of adult patients with large B-cell lymphoma relapsed or refractory after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (ZUMA-1 trial). This review will offer a practical guide for the recognition and management of the most important toxicities related to the use of the current commercial CAR T cells, and also highlight strategies to diminish these side effects in the future.

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Conflict of interest statement

Dr Perales reports personal fees from Abbvie, Bellicum, Incyte, Merck, Novartis, Nektar Therapeutics, and Takeda. He serves on DSMBs for Servier and Medigene, and the scientific advisory boards of MolMed and NexImmune. He has also received research support (clinical trials) from Incyte and Miltenyi Biotec. Dr Yanez reports personal fees from Janssen, Roche, Gilead, Merck and Pfizer. Dr Sanchez-Escamilla declares no conflicts of interest.

Figures

Figure 1
Figure 1
The most commonly used grading system for monitoring and treatment of CRS after CAR T cells. CRS = cytokine release syndrome, CAR T = chimeric antigen receptor T.
Figure 2
Figure 2
Management of CRS and neurotoxicity based on prescribing information of tisagenlecleucel and axicabtagene ciloleucel. CRS = cytokine release syndrome.
Figure 3
Figure 3
Model of neurotoxicity secondary to CAR T cell therapy adapted from Gust et aland Santomasso et al. A) Components of the blood-brain-barrier. B) CAR T cell activation and expansion produces the release of TNF-α and IFN-γ. TNF-α together with other molecules that can be present even before the CAR T cell infusion, such as ANG2, are able to activate the endothelial cells and disrupt the joints between them. In addition, pericytes exposed to IFN-γ contribute to endothelial cells activation and increase BBB permeability. After the disruption of the blood-brain-barrier IFN-γ and TNF-α can activate the microglia. C) The cytokines released upon the activation of the microglia induces an inflammatory state and brain damage. CAR T = chimeric antigen receptor T.
Figure 4
Figure 4
Future strategies to decrease side effects related with CAR T cell therapy. CAR T = chimeric antigen receptor T.
See this image and copyright information in PMC

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