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.

Adoptive Cell Therapy: A Novel and Potential Immunotherapy for Glioblastoma

“…The ACT is correlated with life-threatening side effects, notably immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS), which require urgent attention (123). CRS is a systemic and excessive inflammatory response initially caused by adoptive T cells through generating and releasing proinflammatory cytokines (124).…”

“…Clinically, the symptoms of CRS may be light and limiting, or serious that require vasopressor or ventilator support. Fever is a symbolic symptom, occurring in the early phase with other mild discomforts such as myalgia, rash, headache, and arthralgia (123). Seriously, symptoms will progress to vascular leakage, hypotension, disseminated intravascular coagulation (DIC), and even multiple organ failure (MOF).…”

“…It is critical to exclude infections and sepsis for the diagnosis of CRS, notably bacterial infections, and the identification of elements predicting severe CRS is developing (124,127). Tocilizumab (an antibody against humanized IL-6 receptor) that is recommended with a maximum of 800 mg per dose and a maximum of 3 doses in 24 h and corticosteroids are the core of CRS therapy (123).…”

“…The recommended dose of dexamethasone is 10 mg per 6 h until clinical cure. However, patients with grade 4 ICANS require 1,000 mg methylprednisolone per 24 h (123,128). Additionally, tocilizumab is absolutely recommended for patients with concurrent CRS (128).…”

Identification of Human Immune Cell Subtypes Most Vulnerable to IL-1β-induced Inflammatory Signaling Using Mass Cytometry

“…Cytokine storm is suspected of producing the overzealous immune response driving the severe cardiopulmonary complications that are fueling the high morbidity and mortality rates in certain COVID-19-infected individuals 1,2 . Cytokine storm or macrophage activation syndrome or secondary haemophagocytic lyphohistocytosis has previously been described as a serious complication in other clinical contexts including individuals with rheumatologic disorders such as systemic onset juvenile inflammatory arthritis also known as Still's disease 3 , sepsis 4 , and CAR-T cell therapy 5 . IL-1β is one of the key inflammatory cytokines implicated in the cytokine storm syndrome 4,6,7 .…”