Split chimeric antigen receptor-modified T cells targeting glypican-3 suppress hepatocellular carcinoma growth with reduced cytokine release
Xuan Liu, Jianyun Wen, Honglei Yi, Xiaorui Hou, Yue Yin, Guofu Ye, Xuedong Wu, Xiaotao Jiang
Abstract
BACKGROUND: Human glypican-3 (hGPC3) is a protein highly expressed in hepatocellular carcinoma (HCC) but limited in normal tissues, making it an ideal target for immunotherapy. The adoptive transfer of hGPC3-specific chimeric antigen receptor T (CAR-T) cells for HCC treatment has been conducted in clinical trials. Due to the rigid construction, conventional CAR-T cells have some intrinsic limitations, like uncontrollable overactivation and inducing severe cytokine release syndrome. METHODS: cytotoxicity and cytokine release of the split anti-hGPC3 CAR-T cells were evaluated against various HCC cell lines and compared with conventional CAR-T cells. RESULTS: HepG2 and Huh7 cells in a dose-dependent manner. Impressively, split anti-hGPC3 CAR-T cells produced and released a significantly lower amount of proinflammatory cytokines, including IFN-γ, TNF-α, IL-6, and GM-CSF, than conventional CAR-T cells. When injected into immunodeficient mice inoculated subcutaneously with HepG2 cells, our split anti-hGPC3 CAR-T cells could suppress HCC tumor growth, but released significantly lower levels of cytokines than conventional CAR-T cells. CONCLUSIONS: We describe here for the first time the use of split anti-hGPC3 CAR-T cells to treat HCC; split anti-hGPC3 CAR-T cells could suppress tumor growth and reduce cytokine release, and represent a more versatile and safer alternative to conventional CAR-T cells treatment.