Abstract 3766: MG7-car, a first-in-class T-cell therapy for gastric cancer

Abstract

Abstract Gastric Cancer, with increasing incidence and mortality, has become a major public health problem in China. According to the most recent study in China, Gastric Cancer is the second most common cancer with an incidence of 680,000 cases and mortality of close to 500,000 cases. Therefore, it is important to find an effective way to treat the gastric cancer. MG7 antigen is a highly specific gastric cancer antigen identified by immunohistochemistry in late 80’s, unfortunately most work since then has been focused on MG7 antigen as a diagnosis marker without any treatment approach. Chimeric Antigen Receptor (CAR) T cell therapy is a newly developed technique called adoptive cell transfer. T cells from the patient are able to recognize and kill the tumor cell by grafting a tumor specific antigen binding single chain variable fragment (scfv) onto the T cell. In the past couple of years, CART therapy has demonstrated tremendous success in eradicating hematological malignancies, but no big improvement has been achieved in solid tumors. In this study, we converted an MG7 antibody into a scfv and engineered the T cell as an MG7-CART for the treatment of Gastric Cancer. To our knowledge, this is the first CART therapy being studied on gastric cancer. First to investigate the Gastric Cancer specificity of MG7 antigen, we did immunohistochemistry study on 485 samples (including 325 gastric cancer samples). It showed that MG7 antigen can’t be detected in normal gastric samples (0/50) and only 8% in chronic atrophic gastritis samples (4/50), but the positive rate increased to 58% and 70% in gastric dysplasia tissues (35/60) and gastric cancer tissues samples (227/325). At the same time, we compared MG7 antigen with other cancer biomarkers in gastric cancer tissues. Within 50 cancer samples, MG7 antigen has positive rate of 73%, much higher than the other markers, including CA199 (53%), CEA (51%), CA72-4 (31%) and CA125 (14%). For MG7-CAR, we converted the MG7 antibody to a scfv without losing any antigen binding affinity and “scfv-CD8-41BB-CD3z” structure was used for the MG7-CAR. The study showed that the MG7-CAR can be well expressed with transduction rate close to 40%. The in vitro data showed that MG7-CART can efficiently kill gastric cancer cell line KATO3, but not colorectal cancer cell line SW620 with cancer antigen CEA overexpressed. The cytokine release assay also showed that IFN-gamma releasing result is highly correlated to the cell killing result. In order to further estimate the efficacy of the MG7 CAR, we set up a patient derived xenograft (PDX) model with gastric samples highly expressing both CEA and MG7 antigen. With one time intratumoral injection of 1.5 million CART cells, both MG7 CART and CEA CART regressed the PDX models, while the MG7 CART has the better efficacy with complete regression observed in 80% of the PDX models. Our work demonstrated that MG7 antigen is very specific for gastric cancer and can be a novel treatment target by applying CAR T cell therapy. Citation Format: Jijun Yuan. MG7-car, a first-in-class T-cell therapy for gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3766. doi:10.1158/1538-7445.AM2017-3766