In the Eye of the Storm: Immune-mediated Toxicities Associated With CAR-T Cell Therapy

Abstract

The success of chimeric antigen receptor (CAR)-T cell therapy with impressive response rates in hematologic malignancies but also promising data in solid tumors came along with the cognition of unexpected, potentially life-threatening immune-mediated toxicities, namely the cytokine release syndrome (CRS) and neurotoxicity recently referred to as "immune effector cell-associated neurotoxicity syndrome" (ICANS). These toxicities require urgent diagnostic and therapeutic interventions and targeted modulation of key cytokine pathways represents the mainstay of CRS treatment. However, as the underlying mechanisms of ICANS are not well understood, treatment options remain limited and further investigation is warranted. Importantly, after the recent market approval of 2 CAR-T cell constructs, the application of CAR-T cells will expand to nonacademic centers with limited experience in the management of CAR-T cell-associated toxicities. Here, we review the current evidence of CRS and ICANS pathophysiology, diagnostics, and treatment.

Figure 1

Proposed pathomechanism of cytokine release syndrome. Activation of manly T cells or lysis of immune cells induces a release of interferon gamma (IFN-γ) or tumor necrosis factor alpha (TNF-α). This leads to the activation of macrophages, dendritic cells, other immune cells, and endothelial cells. These cells further release proinflammatory cytokines. Importantly, macrophages and endothelial cells produce large amounts of interleukin 6 (IL-6) which in a positive feedback loop manner activates T cells and other immune cells leading to a cytokine storm. CAR = chimeric antigen receptor, FiO₂ = fraction of inspired oxygen, IFN-γ = interferon gamma, IL-6 = interleukin 6, TNF-α = tumor necrosis factor alpha.

Figure 2

Grading and management of CRS. Considerations and approaches for the grading and management of CRS. The symptoms are divided into grade 1 to grade 4 according to the ASBMT consensus grading. Tocilizumab: a maximum of 800 mg per dose is recommended; a maximum of 3 doses in 24 hours are recommended. Low-dose corticosteroids: ie, 10 mg dexamethasone every 6 hours or equivalent. High-dose corticosteroids: 1000 mg methylprednisolone every 24 hours or equivalent. CRS = cytokine release syndrome. ASBMT = American Society for Blood and Marrow Transplantation.

Figure 3

Pathomechanism of ICANS. Shown are some of the discussed pathomechanism for ICANS. (A) Systemic inflammation and expression of IL-1 leads to activation of by-standing monocytes and an expression of different cytokines leading to an aggravation of the systemic inflammation by activation of T cells and macrophages. (B-C) A disruption of the blood-brain barrier (BBB) leads to migration of T cells (including CAR-T cells) in the brain parenchyma, and to elevated levels of cytokines and protein in the cerebrospinal fluid leading to an inflammation of the CNS.^,,,,, (D) Endothelial activation shown by elevated Ang-2:Ang-1 ratio aggravates the systemic inflammation and the BBB disruption.^, Ang-2 = angiopoetin, BBB = blood-brain barrier, CAR = chimeric antigen receptor, CNS = central nervous system, ICANS = immune effector cell-associated neurotoxicity syndrome, IFN-γ = interferon gamma, IL-1 = interleukin 1, IL-6 = interleukin 6, vWF = von Willebrand factor.

Figure 4

ICANS grading and management. Considerations and approaches for the grading and management of ICANS. The symptoms are graded according to the ASBMT consensus grading Immune Effector Cell-Associated Encephalopathy (ICE) score, is a nonvalidated neurological scoring system to easily asses the neurological status of CAR-T cell patients (Items: orientation, naming 3 objects, following easy commands, writing, counting backwards; a maximum score of 10 points indicates no neurological impairment). Low-dose corticosteroids: ie, 10 mg dexamethasone every 6 hours or equivalent. High-dose corticosteroids: 1000 mg methylprednisolone every 24 hours or equivalent. A concurrent CRS should be treated additionally as shown in Figure 2. Further treatment should be evaluated individually, that is, anakinra or other experimental approaches as reported previously. ASBMT = American Society for Blood and Marrow Transplantation, CAR = chimeric antigen receptor, CRS = cytokine release syndrome, ICANS = immune effector cell-associated neurotoxicity syndrome.