Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome

ABSTRACT

Introduction: Cancer-directed immunotherapies are transforming the landscape in oncology as new and exciting therapies move from the laboratory to the bedside. Chimeric antigen receptor T (CAR-T) cells are one of these novel therapies, demonstrating impressive efficacy against B-cell malignancies. With the development of new therapies, it is not uncommon to identify new and unanticipated toxicities. CAR-T cells cause unique toxicities not typically found with traditional cytotoxic chemotherapy or small molecule inhibitors.

Areas covered: CAR-T cell associated toxicities include cytokine release syndrome (CRS) and CAR-T cell-related encephalopathy syndrome (CRES), alternatively known as immune effector cell-associated neurotoxicity syndrome (ICANS). Prompt identification and management of CRS and CRES are imperative for the prevention of life-threatening complications of these innovative therapies. This literature review describes the seminal trials of CD19-directed immunotherapy and the pathophysiology and management of the toxicities found with CAR-T cells. In addition, the use of the interleukin-6 receptor antibody tocilizumab for CRS is reviewed.

Expert opinion: This review describes the recommended management of CRS and CRES and examines the current limitations in management. Alternative therapies for the treatment of CAR-T cell related toxicities are also explored. Furthermore, the review proposes future directions for research.

KEYWORDS:

• Chimeric antigen receptor T cells (CAR T)
• chimeric antigen receptor T cell related encephalopathy syndrome (CRES)
• cytokine release syndrome (CRS)
• hemophagocytic lymphohistiocytosis (HLH)
• immune effector cell-associated neurotoxicity syndrome (ICANS)
• interleukin 6 (IL-6)
• neurotoxicity (NT)
• tisagenlecleucel
• tocilizumab

Article Highlights

• Tocilizumab is a humanized monoclonal antibody against both the soluble and membrane-bound interleukin 6 receptor and was approved by the FDA in 2017 for the treatment of cytokine release syndrome.

• Tocilizumab demonstrates impressive efficacy in the management of chimeric antigen receptor T cell related cytokine release syndrome.

• Tocilizumab does not attenuate symptoms of neurotoxicity and is currently not FDA approved for the treatment of CAR T cell related encephalopathy syndrome.

• High dose corticosteroids should be reserved for those with life-threatening cytokine release syndrome and CAR T cell related encephalopathy syndrome that is unresponsive to interleukin 6 targeted therapy.

• Future steps in the management of cytokine release syndrome are prospective trials comparing anti-interleukin-6 targeted therapies to tocilizumab in the management of both cytokine release syndrome and CAR T cell related encephalopathy syndrome.

Declaration of interest

D Teachey has been on advisory boards for La Roche and Amgen. D Barrett has received research funding from Novartis. 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 or other relationships to disclose.

Additional information

Funding

The manuscript was funded by the Leukemia and Lymphoma Society (DTT and DMB) the National Institutes of Health (R01CA193776, DTT) and Stand Up 2 Cancer - St. Baldricks’ Pediatric Dream Team translational research grant (SU2C-AACR-DT1113, DTT and DMB), and Cookies for Kids’ Cancer (DTT and DMB). The funding sources had no role in data collection, analysis, or interpretation of the data, the writing of the report, or the decision to submit for publication.