Targeting Gastric Cancer with the Innovative MG7-CAR T-Cell Therapy: A Breakthrough Approach

Stomach cancer is a significant health issue in China, with a high rate of occurrence and mortality. It is the second most prevalent cancer, affecting approximately 680,000 individuals and resulting in nearly 500,000 deaths annually. Consequently, there is an urgent need for an effective treatment strategy. The MG7 antigen, discovered in the late 1980s, is a specific marker for stomach cancer. However, research has primarily concentrated on its diagnostic value rather than its therapeutic potential.

A cutting-edge approach to cancer treatment is the Chimeric Antigen Receptor T (CAR-T) cell therapy, which involves modifying a patient's T cells to target and destroy cancer cells. This technique has shown remarkable success in treating blood cancers but has not yet achieved the same level of success in solid tumors.

In this research, we have engineered a novel CAR-T cell therapy targeting the MG7 antigen for stomach cancer treatment. We transformed the MG7 antibody into a single-chain variable fragment (scFv) and developed an MG7-CAR-T cell. This marks the first time CAR-T therapy has been explored for stomach cancer.

Our initial investigation focused on the specificity of the MG7 antigen in stomach cancer. We conducted an immunohistochemistry study on 485 samples, including 325 stomach cancer samples. The results indicated that the MG7 antigen was undetectable in normal stomach tissue and present in only 8% of chronic atrophic gastritis samples. However, its presence increased to 58% in gastric dysplasia tissues and 70% in stomach cancer tissues.

Furthermore, we compared the MG7 antigen with other biomarkers in stomach cancer tissues and found that the MG7 antigen had a significantly higher positive rate of 73% compared to other markers such as CA199, CEA, CA72-4, and CA125.

We successfully converted the MG7 antibody into an scFv without compromising its antigen-binding affinity and constructed the MG7-CAR using the "scFv-CD8-41BB-CD3z" structure. The expression of the MG7-CAR was efficient, with a transduction rate of nearly 40%. In vitro studies demonstrated that the MG7-CAR-T cells were capable of effectively killing the stomach cancer cell line KATO3, but not the colorectal cancer cell line SW620, which overexpresses the CEA antigen.

Additionally, cytokine release assays showed a strong correlation between IFN-gamma release and cell killing efficacy. To evaluate the therapeutic potential of the MG7-CAR, we established a patient-derived xenograft (PDX) model with stomach samples expressing both CEA and MG7 antigens. A single intratumoral injection of 1.5 million CAR-T cells resulted in tumor regression in both MG7 CAR-T and CEA CAR-T treated PDX models, with the MG7 CAR-T showing superior efficacy and achieving complete regression in 80% of the models.

Our findings suggest that the MG7 antigen is highly specific to stomach cancer and presents a promising new target for CAR-T cell therapy.