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Intensification of Antitumor Effect by T Helper 1-dominant Adoptive Immunogene Therapy for Advanced Orthotopic Colon Cancer¹

Second Department of Surgery, Wakayama Medical University, School of Medicine, Wakayama 641-8510, Japan [Mi. N., M. I., Ma. N., K. U., H. Y.], and Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030 [Mi. N., X. Z.]

Purpose: T helper (Th) 1/Th2 balance, controlled by Th1 or Th2 cells producing cytokines, plays important roles in antitumor immunity. Interleukin-18 (IL-18) can act together with IL-12 in promoting the generation of IFN- producing Th1 cells. The goal of this study was to determine whether cytotoxic T lymphocyte (CTL) secreted in a murine IL-18-induced Th1-dominant state inhibited the development of primary tumors and synchronous liver metastases in orthotopic colon cancer model.

Experimental Design: Murine IL-18 gene was transduced into activated T lymphocytes by an adenovirus vector encoding IL-18 (AdIL-18) liposome complex method. Efficacy of adoptive immunogene therapy using AdIL-18 with or without IL-12 was tested in advanced orthotopic xenograft of murine colon cancer. To elucidate the mechanism responsible for the adoptive immunogene therapy, serum IL-4, IL-6, IFN-, and tumor necrosis factor production in Th1/Th2 cytokine balance and quantification of tumor vascularity were investigated.

Results: By a modified method of adenoviral gene transduction, T lymphocytes achieved efficient IL-18 production without cell toxicity. Against orthotopic colon cancer, when combined with low dose of recombinant (r) IL-12 (AdIL-18-CTL/rIL-12), the therapeutic efficacy showed much smaller tumors with no liver metastases and no disseminated tumors. There was a significant difference in the volume of primary tumors and the number of liver metastases compared with the group treated with AdIL-18-CTL alone or other group (P < 0.01). In addition, the median survival time of the group treated with AdIL-18-CTL was 53.7 ± 5.8 days and that of AdIL-18-CTL/rIL-12 was 78.4 ± 6.1 days, which was also a significant difference (P < 0.01). These antitumor mechanisms were involved with Th1-dominant response in serum Th1/Th2 cytokine balance and suppression of neovascularization at primary tumor site.

Conclusion: These data suggest that a strategy of Th1/Th2 balance-based adoptive immunogene therapy might be useful for advanced cancer patients.

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