Augmented Antitumor Effects of Killer Cells Induced by Tumor Necrosis Factor Gene-Transduced Autologous Tumor Cells from Gastrointestinal Cancer Patients

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Abstract
The purpose of this study was to determine the feasibility of a vaccine therapy using tumor necrosis factor (TNF) gene-transduced autologous tumor cells for the treatment of human gastrointestinal cancers, which tend to have lower immunogenicity than other cancers such as melanoma and renal cell carcinoma. We succeeded in establishing primary cultured tumor cells from 12/54 carcinomatous effusions (4 liver cancer patients, 5 gastric cancer patients, 1 pancreatic cancer patient, and 2 colon cancer patients) and in transducing the TNF gene to the tumor cells by using the retrovirus vector MFG-TNF. Even after irradiation, TNF production (0.3–3.5 U/ml per 106 cells per 72 hr) was confirmed for 10 of 12 transfectants, and the other two transduced cells were found to have approximately one TNF gene copy. In 7 of the 12 patients, the cytotoxic activity of killer cells to nontransduced autologous tumor cells incubated with these TNF gene transfectants was augmented. This activity was blocked with anti-HLA class I antibody or BrefeldinA (BFA), suggesting that the killer cells were cytotoxic T lymphocytes (CTL) and tumor antigens are presented with HLA class I molecules. Indeed, enhanced expression of HLA class I and/or ICAM-1 molecules on the surface of the TNF gene-transduced tumor cells were observed by fluorescence-activated cell sorting (FACS) analysis. Furthermore, natural killer (NK) and/or lymphokine-activated killer (LAK) activities determined by using K562 or Daudi cells as targets were also enhanced in some of these cases when they were incubated with TNF gene-transduced tumor cells. These findings indicate the feasibility of using TNF gene-transduced tumor cells as a vaccine in gastrointestinal cancer patients. Injection of tumor necrosis factor (TNF)-secreting tumor cells has been shown to elicit a host antitumor immune response capable of eliminating established tumors in murine tumor models. This approach is currently being applied to the treatment of various human cancers. However, there have been few reports of genetically modified tumor vaccines for gastrointestinal cancers. The present work describes studies of the TNF gene transfer in primary cultures of human gastrointestinal cancer cells using the retroviral vector MFG-TNF. We have achieved high-efficiency gene transduction without requiring long-term culture or selection and have demonstrated that TNF gene-transduced tumor cells induced augmented cytotoxic T lymphocyte (CTL) activity as well as other killer cell activities. These results suggest that tumor vaccination therapy with TNF gene transduction may be useful in some gastrointestinal cancer patients.

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