<p>Cytokine Release Syndrome: Current Perspectives</p>

Abstract

Chimeric antigen receptor T cell (CART) therapy represents a novel and a paradigm-shifting approach to treating cancer. Recent clinical successes have widened the applicability of CD19 CART cells for the treatment of relapsed/refractory B-cell NHL, namely tisagenleclucel and axicabtagene ciloleucel. Tisagenleclucel is also approved for relapsed and/or refractory BALL up to age 25. CART therapy is associated with unique and potentially life-threatening toxicities, notably cytokine release syndrome (CRS). A better understanding of the pathogenesis of CRS is crucial to ensure proper management. In this review, CRS definitions, profiles, risk factors and grading systems are discussed. Finally, current and novel investigational approaches and therapies for CRS are summarized.

Cytokine Release Syndrome in COVID-19 Patients, A New Scenario for an Old Concern: The Fragile Balance between Infections and Autoimmunity

“…CRS has been under tight evaluation since it caused the admission to the intensive care unit of six healthy individuals enrolled in the phase I trial for the anti-CD28 mAb TGN1412A in 2006 [9]. CRS has been also observed in patients treated with immune checkpoint inhibitors or T cell therapy (CAR T cells) [10]. It is noteworthy that the cytokine storm due to massive T cell stimulation is also considered a relevant mechanism to the H5N1 influenza pathogenesis [11].…”

A rapid, sensitive, and reproducible in vivo PBMC humanized murine model for determining therapeutic‐related cytokine release syndrome

“…8 CRS is characterized by the rapid production of cytokines following exposure to infectious agents, immune stimulating agents and therapeutics, and symptoms range from mild, including self-limiting fever, to a systemic inflammatory event with severe pathology and multi-organ failure. 9,10 In addition, the pathology associated with SARS-CoV-2 infection and COVID-19 appears to be in part mediated by cytokine storm in patients. 11 The first reports of CRS stimulated by immunotherapies were in patients that were treated with anti-CD3 mAb (muromonab or OKT3), and this response was characterized by the rapid and self-limiting release of inflammatory cytokines and fever.…”

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). These cytokines later activate endotheliocytes and bystander immune cells, formatting the vicious circle of a cytokine storm in a waterfall manner.…”

“…IL-6 primarily released by macrophages seems to play a central role in CRS (125). Additionally, other cytokines like granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor (TNF), interferon (IFN)-γ, and IL-1,2,8,10 participate in CRS (124).…”

“…Grade 4 CRS entails the presence of hypotension that needs multiple vasopressors excepting vasopressin and hypoxia that needs positive pressure ventilation systems, representing a lifethreatening complication. 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).…”