Glypican-3 as a Target for Immune Based Therapy in Hepatocellular Carcinoma

Abstract

Glypican-3 (GPC3) is expressed on most hepatocellular carcinoma (HCC) cells and associated with liver tumorigenesis. This chapter provides a review of GPC3 as an emerging target in various investigational immunotherapies, with a focus on cancer vaccines, human or humanized antibodies, bispecific antibodies, immunotoxins, and chimeric antigen receptor (CAR) T cells. GPC3 peptide-based vaccines have been shown to prevent HCC recurrence after surgery. Interestingly, the patients with the best protection have anti-GPC3 CD4+ T cell response regardless of CD8+ T cell response. Several monoclonal antibodies including GC33, YP7, HN3 and HS20, each with a distinct epitope on GPC3, are being tested in preclinical or clinical stages. GC33 and YP7 recognize the C terminal end of GPC3. HN3 targets a cryptic Wnt binding site in the core protein of GPC3. HS20 binds a Wnt binding domain on the heparan sulfate chain. The HN3 and HS20 antibodies inhibit Wnt/Yap signaling and suppress HCC cell growth. To improve anti-tumor efficacy, anti-GPC3 immunotoxins and CAR-T cell therapies have been developed. The Wnt-blocking HN3 immunotoxin is more potent than YP7 immunotoxin. With an engineered toxin, the HN3-mPE24 immunotoxin can be given at high doses repeatedly to regress HCC xenograft tumor in mice. The CAR T-cell therapy also shows a great promise. The GC33 CAR T cells inhibit established HCC xenograft tumors in mice. Several CARs targeting different epitopes of GPC3 (including HN3) are being tested. Ongoing preclinical and clinical studies will help define the utility of GPC3 as a therapeutic target for liver cancer therapy.