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

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

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2299-2308
Number of pages10
JournalMolecular Therapy
Volume25
Issue number10
DOIs
StatePublished - Oct 4 2017

Keywords

  • cytotoxic T lymphocyte response
  • glypican-3
  • hepatocellular carcinoma
  • immunotherapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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  • Cite this

    Wu, Q., Pi, L., Le Trinh, T., Zuo, C., Xia, M., Jiao, Y., Hou, Z., Jo, S., Puszyk, W., Pham, K., Nelson, D. R., Robertson, K., Ostrov, D., Rameshwar, P., Xia, C. Q., & Liu, C. (2017). A Novel Vaccine Targeting Glypican-3 as a Treatment for Hepatocellular Carcinoma. Molecular Therapy, 25(10), 2299-2308. https://doi.org/10.1016/j.ymthe.2017.08.005