© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 11, 931-936,
June 7, 2000
© 2000 Oxford University Press
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Immunomodulatory Gene Therapy With Interleukin 12 and 4-1BB Ligand: Long- Term Remission of Liver Metastases in a Mouse Model
Affiliations of authors: O. Martinet (Institute for Gene Therapy and Molecular Medicine and Department of Surgery), V. Ermekova, J. Q. Qiao, B. Sauter, S.-H. Chen (Institute for Gene Therapy and Molecular Medicine), J. Mandeli (Department of Biomathematical Sciences), The Mount Sinai School of Medicine, New York, NY; L. Chen, Department of Immunology, Mayo Clinic, Rochester, MN.
Correspondence to: Shu-Hsia Chen, Ph.D., Institute for Gene Therapy and Molecular Medicine, The Mount Sinai School of Medicine, 1425, Madison Ave., Rm. 13-02, New York, NY 10029-6574 (e-mail: chens01{at}doc.mssm.edu).
Background: The success of immunomodulatory cancer therapy is frequently hampered by the transient nature of the antitumor immune response. We have shown previously in a mouse model that interleukin 12 (IL-12) generates a strong natural killer (NK) cell-mediated antitumor response and reduces liver metastases induced by a colon carcinoma cell line. However, only a small percentage of the treated animals developed the cytotoxic T-lymphocytic response required for a long-term systemic antitumor immunity. 4-1BB is a co-stimulatory molecule expressed on the surface of activated T cells. Interaction of 4-1BB with its natural ligand (4-1BBL) has been shown to amplify T-cell (especially CD8+)-mediated immunity. In this study, we investigated the effects of adenovirus-mediated gene therapy delivering both IL-12 and 4-1BBL genes on mice with hepatic metastases induced by colon cancer cells. Methods: Syngeneic BALB/c mice received intrahepatic injection of poorly immunogenic MCA26 colon cancer cells. Various combinations of replication-defective adenoviruses expressing IL-12 and 4-1BBL genes were injected into the established liver tumors. Changes in tumor size and animal survival were then monitored. All statistical tests were two-sided. Results: The long-term survival rate of mice treated with the combination of IL-12 and 4-1BBL was significantly improved over that of animals in the control group (P = .0001). In vivo depletion of NK cells or CD8+ T cells completely abolished the long-term survival advantage of the IL-12 plus 4-1BBL-treated animals (P<.002). Moreover, the systemic immunity induced by this combination treatment protected these animals against a subcutaneous challenge with parental MCA26 cells. Conclusion: Adenovirus-mediated transfer of IL-12 and 4-1BBL genes directly into liver tumors resulted in tumor regression that required both NK and CD8+ T cells and generated a potent, long-lasting antitumor immunity.
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