Cytokine release syndrome: grading, modeling, and new therapy

Abstract

Genetically modified T cells that express a chimeric antigen receptor (CAR) are opening a new frontier in cancer immunotherapy. CAR T cells currently are in clinical trials for many cancer types. Cytokine release syndrome (CRS) and neurotoxicities (CAR-related encephalopathy syndrome, CRES) are major adverse events limiting wide deployment of the CAR T cell treatment. Major efforts are ongoing to characterize the pathogenesis and etiology of CRS and CRES. Mouse models have been established to facilitate the study of pathogenesis of the major toxicities of CAR T cells. Myeloid cells including macrophages and monocytes, not the CAR T cells, were found to be the major cells mediating CRS and CRES by releasing IL-1 and IL-6 among other cytokines. Blocking IL-1 or depletion of monocytes abolished both CRS and CRES, whereas IL-6 blocker can ameliorate CRS but not CRES. Therefore, both IL-1 and IL-6 are major cytokines for CRS, though IL-1 is responsible for CRES. It was also demonstrated in the mouse models that blocking CRS does not interfere with the CAR T cell antitumor functions. We summarized new developments in the grading, modeling, and possible new therapeutic approaches for CRS and CRES in this review.

Cytokine Release Syndrome with Pseudoprogression in a Patient with Advanced Non–Small Cell Lung Cancer Treated with Pembrolizumab

“…1 Although its efficacy has been remarkable, immune-related adverse events (irAEs) are often observed. On the other hand, cytokine release syndrome (CRS) has been reported as an irAE of chimeric antigen receptor T-cell therapy 2 and has rarely been seen with anti-programmed cell death 1 (PD-1)/PD-L1 therapies such as pembrolizumab.…”

CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies

“…Death related to CRS has been reported in multiple studies (4,15,36). It has also been suggested that a higher burden of tumor antigens is associated with higher rates and severity of CRS (37).…”

The acceleration of CAR‐T therapy in non‐Hodgkin lymphoma

“…35,44 If no responses are seen to IL-6 inhibition, corticosteroids are often used and rapidly reverse severe CRS without compromising initial antitumor response. 43,45,46 Handwriting changes and the inability to count numbers backwards have been the initial subtle signs of impending neurotoxicity, often missed even by the experienced clinician. 33 The exact pathophysiology of CAR-T related neurotoxicity is under investigation and although CAR-T cells are found in the CNS, anti-IL-6 therapy has not known to be effective in preventing or reversing these symptoms.…”

“…With the persistence of fevers or change in clinical status and hypotension, most physicians will begin treatment with tocilizumab, an IL‐6 receptor inhibitor . If no responses are seen to IL‐6 inhibition, corticosteroids are often used and rapidly reverse severe CRS without compromising initial antitumor response …”