Host: The Japanese Society of Toxicology
Name : The 50th Annual Meeting of the Japanese Society of Toxicology
Date : June 19, 2023 - June 21, 2023
Cytokine release (CRS) is the most common side effect during clinical CAR-T cell therapy, which includes excessive cascade release of various cytokines such as IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, INF-γ, and GM-CSF, etc., and the CRS can result in high fever, hypotension, myalgia, coagulation disorder, dyspnea, organ failure and even death in patients. However, T-cell activation and proliferation were the only observations in commonly used immune-deficient mouse model with tumor-bearing in preclinical studies for CAR-T cell therapeutic products. Cytokine releases observed in mice mainly included IL-2 and INF-γ, and cytokine-induced toxicity was rarely observed. At the reported efficacy and safety study for CD22-specific CAR-T cells in NOG-Raji mouse model, CAR-T cells associated toxicities were observed including transient body weight loss and animal death. The results of plasma cytokine assays showed that abnormally elevated TNF-α level might be associated with the toxic reactions in mice. Treatment with anti-TNF-α monoclonal antibodies protected mice from weight loss and reduced animal mortality without affecting the anti-tumor effect of CAR-T cells. The above results demonstrated that elevation of TNF-α levels were the root cause of animal death, and also indicated that peripheral blood TNF-α levels may be a useful toxicity marker in future clinical use of the CAR-T cell product. Treatment of anti-TNF-α monoclonal antibodies may be an effective regimen for prevention and therapy of CRS during clinical application.
