Management of cytokine release syndrome and neurotoxicity in chimeric antigen receptor (CAR) T cell therapy

ABSTRACT

Introduction: Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated remarkable anti-tumor activity in B-cell malignancies and is under investigation in other hematologic malignancies and solid tumors. While highly efficacious, post-infusion T cell activity often results in massive cytokine release precipitating cytokine release syndrome (CRS), the signature toxicity of CAR T cells. This toxicity is characterized by systemic immune activation resulting in fever, hypotension, respiratory insufficiency and capillary leak. Either in conjunction with or in the absence of CRS, a subset of patients may also develop mild to severe neurotoxicity. Although the precise pathogenesis of CRS and neurotoxicity aren’t fully elucidated, risk factors and mitigation strategies have been reported.

Areas covered: This manuscript provides an in-depth overview of the pathogenesis, clinical characteristics, current toxicity management strategies, and future perspectives pertaining to CRS and neurotoxicity.

Expert Opinion: As CAR T cell based therapies gain popularity in the management of various malignancies, the complimentary toxicities of CRS and neurotoxicity pose a clinical challenge in practice. Risk adaptive modeling incorporating disease profile, patient demographics, lymphodepletion, cell dosing, CAR T construct, and potentially cytokine gene polymorphisms may be instructive to assess individualized risk and optimal CRS/neurotoxicity management.

KEYWORDS:

• Cytokine release syndrome
• chimeric antigen receptor T- cell therapy
• CAR T cell therapy
• cellular therapy
• non-Hodgkin lymphoma
• acute lymphoblastic leukemia
• chronic lymphocytic leukemia

Article highlights

• Chimeric antigen receptor T cell (CART) immunotherapy is an effective option for relapsed/refractory CD19+ leukemias and aggressive lymphomas.

• Cytokine-release syndrome (CRS) and neurotoxicity are frequent and potentially serious adverse events linked with CART therapy

• CRS is a systemic inflammatory response associated with high cytokine levels (IL-6, IFN-γ, and others) and characterized by activation of CAR T cells upon tumor recognition and clinical symptoms ranging from fever and flu-like symptoms to hypotension, hypoxia, and organ injury.

• Neurotoxicity, presenting as a range of symptoms from mild expressive aphasia and confusion to coma, remains a poorly understood phenomenon and is often associated with CRS.

• Tocilizumab, an antibody targeting the IL-6 receptor reverses most cases of CRS that do not respond to aggressive supportive care.

• Close clinical monitoring, accurate assessment of CRS severity and timely intervention are critical to minimizing the toxicity of CRS and maximizing the anti-tumor benefit of CAR T cells.

Declaration of interest

UH Acharya has consulted for TEVA, Kite Pharma, Karyopharm and has had research funding through JUNO Therapeutics. JC Chavez has consulted Kite Pharma, Novartis, Genetech, Bayer, Karyopharm, Janssen and has had research funding from Merck. CA Jacobson has consulted for Kite and receives research funding from Kite Pharma. JD Ramos is employed by Seattle Genetics. DG Maloney has consulted for Genentech/Roche, Kite Pharma, Eureka Therapeutics and Novartis, and his institution has received research funding from Juno Therapeutics and Kite Pharma for clinical trials for which he is primary investigator. DG Maloney is also a co-inventor of intellectual property assigned to the Fred Hutchinson Cancer Research Center for potential future licensing to Juno Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.