Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy

Abstract

With immunotherapy innovations for cancer treatment, in particular chimeric antigen receptor (CAR) T cells, becoming more successful and prevalent, strategies to mitigate and manage their toxicities are required. Anti-CD19 CAR T-cell therapy has revolutionized the treatment of relapsed/refractory pediatric and adult acute lymphoblastic leukemia and refractory adult non-Hodgkin lymphoma, resulting in the expanded use of CAR T cells in multicenter trials and as US FDA-approved products. Cytokine release syndrome (CRS) and CAR-associated neurotoxicity, which can occur independently or concurrently with CRS, are two potentially life-threatening toxicities of CAR T-cell therapy. In this review, we will focus on describing the pathophysiology behind CRS, the proposed definitions of and grading systems for CRS, and innovative options for treating this potentially lethal systemic inflammatory condition.

Keywords: CAR-associated neurotoxicity; CD19 CAR T cells; Immune Effector Cell-Associated Neurotoxicity Syndrome; adoptive cellular immunotherapy; leukemia; tocilizumab.

Conflict of interest statement

Disclosure DWL serves as a consultant for Juno Therapeutics, a Celgene company, and receives clinical trial support from Kite Pharma, a Gilead company. The other authors report no conflicts of interest in this work.

Figures

Figure 1

Symptoms of CRS. Notes: CRS affects a number of organ systems. It requires fever at a minimum but is frequently associated with any of the symptoms shown. Additional manifestations may also rarely occur. Abbreviations: GI, gastrointestinal; CRS, cytokine release syndrome.

Figure 2

Mechanisms of IL-6 signaling. Notes: IL-6 potentiates its effects in one of two mechanisms. (A) Classic IL-6 signaling involves IL-6 binding to the high-affinity IL-6 receptor bound to the membrane of the effector cell. This in turn dimerizes gp130 resulting in JAK/STAT pathway activation. (B) Trans IL-6 signaling occurs at high serum IL-6 levels when it binds to the lower affinity sIL-6R. This complex can dimerize gp130 independent of the membrane-bound IL-6 receptor leading to JAK/STAT activation. (C, D) Tocilizumab, a monoclonal antibody, can inhibit IL-6 signaling by competing with IL-6 for both the membrane-bound and soluble receptors. Abbreviation: sIL-6R, soluble IL-6 receptor.

Figure 3

CRS management algorithm by Lee et al. Notes: The Lee criteria were designed in such a way so that grading can be tied to a management algorithm. Supportive care is the backbone of therapy with anti-cytokine therapy in the form of tocilizumab with or without corticosteroids implemented for grade 3 or higher CRS or for grade 2 in high-risk patients. *Grade of organ toxicities determined by CTCAE v4.03. Abbreviations: CRS, cytokine release syndrome; CTCAE, Common Terminology Criteria for Adverse Events.

Figure 4

CRS management recommendations by Neelapu et al. Notes: These recommendations suggest using anti-cytokine therapies for grade 1 CRS and require them for grade 2 or higher CRS. Supportive care is also suggested for each grade. Abbreviation: CRS, cytokine release syndrome; IVF, intravenous fluid; ICU, intensive care units; q, every; CPAP, continuous positive airway pressure.