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

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-α), interferon-γ (IFN-γ), 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. Wu et al. develop a novel immunotherapeutic vaccine for hepatocellular carcinoma (HCC) treatment through targeting the HCC-specific antigen GPC3. The antigen GPC3 is coupled on and delivered through lymphocytes. The lymphocyte-GPC3 complex vaccine triggers significantly prophylactic and therapeutic antitumor effects in the murine model through regulating systemic and local immune responses.