Development of CAR T cell therapy targeting glypican-3 in liver cancer
Year: 2018
Type: article
Abstract: Objective: Glypican-3 (GPC3) is a promising therapeutic targetin hepatocellular carcinoma (HCC). We have generated theHN3 and hYP7 antibodies that recognize the N-lobe and C-lobeof GPC3, respectively. Here, we engineered human T cells thatexpress GPC3-specific chimeric antigen receptors (CARs) andevaluated their potential for the treatment of HCC. Methods: The GPC3-specific CARs (CAR.HN3 and CAR.hYP7) contain a CD3ζ chain and the 4-1BB co-stimulatoryendodomain along with a truncated human epidermal growthfactor receptor (huEGFRt) polypeptide that retains thecetuximab epitope. A set of GPC3-positive liver cancer celllines were engineered to express the firefly luciferase gene.These cells were co-cultured with CAR T cells at various ratiosfor cell killing assays. A bioluminescent luciferase reporterassay was then used to evaluate the cytolytic activity of CART cells. We also evaluated the anti-tumor activity of CAR Tcells in xenograft models via intraperitoneal or orthotopicimplantation of luciferase-expressing HCC cells into NOD/SCID/IL2gnull (NSG) mice. Tumor growth was measured viabioluminescence tumor imaging. Results: CAR.hYP7 cells, which target the C-lobe of GPC3,showed the highest cytolytic activity against GPC3-positiveHCC cells. In HCC intraperitoneal xenograft models,tumor cells preferentially grew on the mouse liver. A singleintraperitoneal treatment with CAR.hYP7 cells exhibitedsustainable antitumor efficacy in mice, and all of the micesurvived more than 9 weeks after CAR T cell treatmentwithout recurrence. The serum levels of alpha-fetoprotein inmice treated with CAR.hYP7 cells were less than 50 ng/mL,the threshold value for HCC diagnosis. Conclusions: GPC3-targeting CAR T cells, in particular CAR.hYP7, are a promising therapeutic intervention for liver cancerthat can be translated to human use. DOI: 10.20892/j.issn.2095-3941.2018.S035
Source: Cancer Biology and Medicine
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2898634014