A Novel Vaccine Targeting Glypican-3 as a Treatment for Hepatocellular Carcinoma

作者：Wu, Qunfeng; Pi, Liya; Thu Le Trinh; Zuo, Chaohui; Xia, Man; Jiao, Yu; Hou, Zhouhua; Jo, Sung; Puszyk, William; Pham, Kien; Nelson, David R.; Robertson, Keith; Ostrov, David; Rameshwar, Pranela; Xia, Chang Qing^*; Liu, Chen^*

来源：Molecular Therapy, 2017, 25(10): 2299-2308.

DOI：10.1016/j.ymthe.2017.08.005

• DENDRITIC CELLS
• PHASE-I
• HUMANIZED ANTIBODY
• DOWN-REGULATION
• T-CELLS
• CANCER
• TUMOR
• ANTIGEN
• IDENTIFICATION
• IMMUNOTHERAPY

Hepatocellular carcinoma (HCC) has a high morbidity and mortality rate worldwide, with limited treatment options. Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored glycoprotein that is overexpressed in most HCC tissues but not in normal tissues. GPC3-targeting antibody therapy shows limited response in a clinical trial due to the lack of a tumor specific cytotoxic T lymphocyte (CTL) response. Here, in C57/B6 mice, we demonstrated that intravenous infusion of GPC3-coupled lymphocytes (LC/GPC3(+)) elicited robust GPC3-specific antibody and CTL responses, which effectively restricted proliferation and lysed cultured-HCC cells. Treatment with LC/GPC3(+) induced durable tumor regression in HCC-bearing C57/B6 mice. Administration of LC/GPC3(+) induced elevated levels of the cytotoxic T cell bioactive factors tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma), granzyme B, and perforin, and substantially increased the number of infiltrating CD8(+) T cells in tumor tissues. Moreover, immune responses elicited by LC/GPC3(+) selectively suppressed GPC3(+) tumors, but didn't affect the GPC3(-) tumors in BALB/c mice. Our findings provide the first preclinical evidence that intravenous infusion of the LC/GPC3(+) complex can induce a strong anti-HCC effect through regulating systemic and local immune responses. These results indicate that the LC/GPC3(+) complex could be developed as precision therapeutics for HCC patients in the future.

• 出版日期2017-10-4
• 单位湖南省肿瘤医院; rutgers; 中南大学