Recently, Liang Xingjie and Wu Yan, researchers at the National Center for Nanoscience, collaborated to prevent cytokine release syndrome induced by chimeric antigen receptor T cells (CAR-T).The research is published online in Nature-Biomedical Engineering.
CAR-T immunotherapy has shown great advantages in the treatment of malignant hematoma, especially B-cell lymphoma.However, CAR-T cells kill tumors and stimulate immune cells, especially macrophages, to release large amounts of inflammatory factors that cause high fever, low blood pressure, weight loss, vascular leakage, organ failure, and even death.These CAR-T-related symptoms are collectively referred to as cytokine release syndrome (CRS).
Cytokine sponge inhibits inflammation.National Nanoscience Center
Although CAR-T cell-induced CRS is a high-probability event, CRS itself has no specific physiological indicators to diagnose, so it is difficult to accurately assess whether, when, and its severity in advance.Current medical interventions are usually followed by CRS, which can alleviate or suppress symptoms, but symptoms that have occurred, such as vascular leakage, can cause irreversible damage to patients.
The U.S. Food and Drug Administration (FDA) has approved interleukin-6 (IL-6) blocking antibodies for the treatment of CAR-T-induced cytokine release syndrome, but these monoclonal antibodies still face serious problems, including systemic toxicity and short duration.Moreover, under normal conditions, IL-6 molecules themselves maintain some important physiological functions, such as promoting the proliferation of B cells.Therefore, the injection of blocking antibodies in advance or in the absence of CRS may affect IL-6 concentration and related function under normal conditions.
Based on the characteristics of the disease and current drug use problems, Liang Xingjie and Wu Yan team proposed a "cytokine sponge" (IL-6 antibody-hydrogel coupling) strategy to prevent CAR-T cell-induced cytokine release syndrome.In the study, the researchers chemically linked IL-6 antibodies to temperature-sensitive hydrogels.Cytokine sponges were injected subcutaneously before CAR-T cells were transfused back.When CAR-T cells induce inflammatory factor storms, injected cytokine sponges can adsorb inflammatory factor IL-6 in real time, thus preventing and suppressing CRS-related symptoms.
By controlling the proportion of antibodies in the hydrogel, the cytokine sponge injected subcutaneously did not affect IL-6 concentration under normal conditions.Cytokine sponges adsorb inflammatory factor IL-6 in real time only when IL-6 concentration is higher or higher than normal.This responsive adsorption not only bypasses the complex disease assessment process, but also transforms CRS management strategies from traditional antibody blocking mitigation to effective prevention and inhibition.
The team validated the effectiveness of cytokine sponges in the treatment of CRS, including humanized CRS models.Cytokine sponge not only can effectively inhibit the increase of various inflammatory factors, but also greatly alleviate CRS-related symptoms and improve the survival rate of tumor model mice.At the same time, cytokine sponge did not affect the anti-tumor effect of CAR-T cells in vivo, which proved its excellent safety performance.