Mechanisms and Management of Chimeric Antigen Receptor T-Cell Therapy-Related Toxicities
Chimeric antigen receptor T-cell (CAR-T) therapy has proven to be a very effective cancer immunotherapy. Axicabtagene ciloleucel and tisagenlecleucel are the first-in-class anti-CD19 CAR-T currently available for relapsed/refractory adult large B-cell lymphoma. Tisagenlecleucel is also available for pediatric and young adult (up to age 25 years) patients with relapsed/refractory B-acute lymphoblastic leukemia. Cytokine release syndrome (CRS) and CAR-T-associated encephalopathy syndrome (neurotoxicity) are the most common adverse effects associated with CAR-T therapy. They can lead to significant morbidity and preclude widespread use of this treatment modality. Treatment-related deaths from severe CRS and cerebral edema have been reported. There is a significant heterogeneity in the side-effect profile of different CAR-T products under investigation and there is a need to develop standardized guidelines for toxicity grading and management. Here, we summarize the current literature on pathogenesis, clinical presentation, and management of CRS and neurotoxicity. The different grading systems of CRS and management protocols used in different trials have made it difficult to compare the outcomes of different CAR-T therapies. Several prevention strategies such as predictive biomarkers of CRS and neurotoxicity and modified CAR-T with ‘built-in’ safety mechanisms are being studied, with the potential to greatly expand the safety and applicability of CAR-T treatment across various malignancies.
Compliance with Ethical Standards
This work was supported by an NCI K23 award (PI- Locke, F; CA201594, NIH/NCI) and an NCI Cancer Center support grant P30 (CA076292-18S4, NIH/NCI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Conflict of interest
Frederick Locke declares being a scientific advisor to Kite (a Gilead subsidiary) and Novartis; and a consultant for Cellular BioMedicine Group. Bhagirathbhai R. Dholaria and Christina Bachmeier declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.
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