Assessment and management of cytokine release syndrome and neurotoxicity following CD19 CAR-T cell therapy

ABSTRACT

Introduction: The success of CD19 chimeric antigen receptor (CAR)-T cell therapy for treatment of CD19 positive malignancies has led to the FDA approval of two CD19 CAR-T cell products, tisagenlecleucel and axicabtagene ciloleucel, and ongoing clinical trials of new products. Cytokine release syndrome (CRS) and neurotoxicity are common toxicities associated with CD19 CAR-T cell therapies.

Areas covered: This review will discuss CRS and neurotoxicity associated with CD19 CAR-T cell therapies, including clinical presentation, risk factors, pathophysiology, and therapeutic or prophylactic interventions.

Expert opinion: In conjunction with improved understanding of the pathophysiology of CRS and neurotoxicity, we expect that the recent development of consensus guidelines for the evaluation of these toxicities will enhance management of patients undergoing CD19 CAR-T cell therapies.

KEYWORDS:

• CAR-T cell
• CD19 malignancies
• chimeric antigen receptor
• cytokine release syndrome
• immunotherapy
• leukemia
• lymphoma
• neurotoxicity

Article Highlights

• Cytokine release syndrome and neurotoxicity are common toxicities associated with CD19 chimeric antigen receptor-modified T cell therapy.

• Cytokine release syndrome and neurotoxicity are often self-limited but can be life-threatening or fatal.

• Severe cytokine release syndrome and neurotoxicity are associated with factors that contribute to more robust CAR-T cell activation.

• Management of cytokine release syndrome and neurotoxicity involves supportive care with or without corticosteroids and/or cytokine-directed therapies in selected patients.

• Standardized management strategies have been difficult to establish, in part due to differences between grading systems employed in clinical trials of different CAR-T cell products.

This box summarizes key points contained in the article.

Declaration of interest

CJ Turtle has received research funding from Juno/BMS, Nektar Therapeutics; is on scientific advisory boards for Precision Biosciences, T-CURX, Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, Arsenal Bio; has equity in Precision Biosciences, Eureka Therapeutics, Caribou Bioscience, Myeloid Therapeutics, Arsenal Bio; acted ad hoc on advisory boards (last 12 months) for Kite/Gilead, Allogene, PACT Pharma, Nektar Therapeutics, Astra Zeneca; and has patents pending to cover technology related to cellular therapies with Juno/BMS. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

Funding for this work was provided by the National Institutes of Health 1R01HL132350-03A1 (CJ Turtle), 5R01CA136551-07 (CJ Turtle) and T32CA009351 (CK Chou).