“Cytokine sponge” tumor immunotherapy is superior

Recently, the research group of Liang Xingjie and Wu Yan, researchers of the National Center for Nanoscience, have made progress in preventing cytokine release syndrome induced by chimeric antigen receptor T cells (CAR-T). The research was published online in Nature Biomedical Engineering.

CAR-T immunotherapy has shown great advantages in the treatment of hematologic malignancies, especially B-cell lymphoma. However, while CAR-T cells kill tumors, they also stimulate immune cells, especially macrophages, to release a large number of inflammatory factors, which can cause high fever, low blood pressure, weight attenuation, vascular leakage, organ failure and other symptoms, and even lead to the death of patients. These CAR-T-related symptoms are collectively referred to as cytokine release syndrome (CRS).

“Cytokine sponge” inhibits inflammation. Photo courtesy of the National Center for Nanoscience

Although CRS induced by CAR-T cells is a high-probability event, CRS itself does not have specific physiological indicators for diagnosis, so it is difficult to accurately assess whether CRS occurs, when it occurs and its severity in advance. Current medical interventions usually follow the advent of CRS, which can relieve or suppress the symptoms to some extent, but symptoms that have occurred, such as leaky blood vessels, can cause irreversible damage to the patient.

The U.S. Food and Drug Administration (FDA) currently approves interleukin 6 (IL-6) blocking antibodies for the treatment of CAR-T-induced cytokine release syndrome, but these monoclonal antibodies still face some serious problems, including systemic toxicity and short time to exert effect. Moreover, because under normal conditions, IL-6 molecules themselves also maintain some important physiological functions, such as promoting the proliferation of B cells. Therefore, injecting blocking antibodies early or when CRS does not occur will have a certain impact on IL-6 concentration and related functions under normal conditions.

Based on the characteristics of the disease and the current drug problems, the team of Liang Xingjie and Wu Yan of the National Center for Nanoscience proposed the strategy of “cytokine sponge” (IL-6 antibody-hydrogel conjugate) for the prevention of cytokine release syndrome induced by CAR-T cells. In the study, the researchers chemically attached IL-6 antibodies to a temperature-sensitive hydrogel. Before the CAR T cell infusion, a cytokine sponge is injected subcutaneously. When CAR-T cells induce the production of inflammatory factor storms, the injected cytokine sponge can adsorb the inflammatory factor IL-6 in real time and controllably, thereby preventing and suppressing CRS-related symptoms.

By controlling the proportion of antibodies in the hydrogel, the cytokine sponge injected subcutaneously does not have an effect on IL-6 concentration under normal conditions. Only when the IL-6 concentration is elevated or higher than normal, the cytokine sponge adsorbs the inflammatory factor IL-6 in real time. This responsive adsorption property not only bypasses the complex disease assessment process, but also shifts the strategy of CRS management from traditional antibody blockade remission to effective preventive inhibition.

The team verified the therapeutic effect of “cytokine sponge” on CRS on a variety of models, including humanized CRS models. “Cytokine sponge” can not only effectively inhibit the elevation of a variety of inflammatory factors, but also greatly alleviate CRS-related symptoms and improve the survival rate of tumor model mice. At the same time, the “cytokine sponge” did not affect the anti-tumor effect of CAR-T cells in vivo, which proved its excellent safety performance. (Source: Zhang Shuanghu, China Science News)

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