416. Immunotherapy of Hepatocellular Carcinoma With T Cells Engineered To Express Glypican-3-Specific Chimeric Antigen Receptors

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide, with no curative therapies for unresectable HCC. Glypican-3 (GPC3), a membrane bound heparan sulfate proteoglycan is selectively expressed on HCC and has recently emerged as an attractive target for immunotherapy. GPC3-specific monoclonal antibody, GC33 has been shown to be safe in recent a Phase 1 clinical study. However, objective clinical responses to GC33 treatment were modest and transient. We hypothesized that the therapeutic efficacy of GPC3-targeting immunotherapy can be enhanced by combining the specificity of GC33 mAb with the advantages of adoptive cell therapy. To that end, we generated T cells genetically engineered to express GPC3 specific chimeric antigen receptors (GPC3 CARs).The signaling parts of GPC3 CAR constructs contained CD3ζ chain only (1st generation), with CD28 or 4-1BB (2nd generation), or both (3d generation) costimulatory endodomains. We found that GPC3 CAR T cells efficiently and specifically killed GPC3-positive HCC cell lines in vitro (figure 1); released IL-2 and IFN-γ, and proliferated in response to stimulation by HCC cell lines. View Large Image | Download PowerPoint SlideThe 2nd and 3rd generation GPC3 CARs induced superior killing, cytokine release and T cell expansion compared to 1st generation GPC3 CAR. Importantly, 2nd and 3rd generation GPC3 CAR T cells demonstrated curative antitumor activity by eliminating established orthotopic GPC3-positive Huh-7 xenografts in NOD/SCID/IL2gnull (NSG) mice. View Large Image | Download PowerPoint SlideThe results provide justification for testing safety and efficacy of GPC3 CAR T cells in a Phase 1/2a clinical trial in HCC patients.