Format

Send to

Choose Destination
Blood Rev. 2019 Mar;34:45-55. doi: 10.1016/j.blre.2018.11.002. Epub 2018 Nov 14.

Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management.

Author information

1
Experimental Transplantation and Immunology Branch, National Cancer Institute, Building 10, Suite 3-3330, Bethesda, MD 20892, United States. Electronic address: Jennifer.brudno@nih.gov.
2
Experimental Transplantation and Immunology Branch, National Cancer Institute, Building 10, Suite 3-3330, Bethesda, MD 20892, United States. Electronic address: kochendj@mail.nih.gov.

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is an effective new treatment for hematologic malignancies. Two CAR T-cell products are now approved for clinical use by the U.S. FDA: tisagenlecleucel for pediatric acute lymphoblastic leukemia (ALL) and adult diffuse large B-cell lymphoma subtypes (DLBCL), and axicabtagene ciloleucel for DLBCL. CAR T-cell therapies are being developed for multiple myeloma, and clear evidence of clinical activity has been generated. A barrier to widespread use of CAR T-cell therapy is toxicity, primarily cytokine release syndrome (CRS) and neurologic toxicity. Manifestations of CRS include fevers, hypotension, hypoxia, end organ dysfunction, cytopenias, coagulopathy, and hemophagocytic lymphohistiocytosis. Neurologic toxicities are diverse and include encephalopathy, cognitive defects, dysphasias, seizures, and cerebral edema. Our understanding of the pathophysiology of CRS and neurotoxicity is continually improving. Early and peak levels of certain cytokines, peak blood CAR T-cell levels, patient disease burden, conditioning chemotherapy, CAR T-cell dose, endothelial activation, and CAR design are all factors that may influence toxicity. Multiple grading systems for CAR T-cell toxicity are in use; a universal grading system is needed so that CAR T-cell products can be compared across studies. Guidelines for toxicity management vary among centers, but typically include supportive care, plus immunosuppression with tocilizumab or corticosteroids administered for severe toxicity. Gaining a better understanding of CAR T-cell toxicities and developing new therapies for these toxicities are active areas of laboratory research. Further clinical investigation of CAR T-cell toxicity is also needed. In this review, we present guidelines for management of CRS and CAR neurotoxicity.

KEYWORDS:

Chimeric antigen receptor (CAR) T cells; Hematologic malignancies; Toxicity

PMID:
30528964
PMCID:
PMC6628697
DOI:
10.1016/j.blre.2018.11.002
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center