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- Title
Immunomodulatory gene therapy with interleukin 12 and 4-1BB ligand: long- term remission of liver metastases in a mouse model.
- Authors
Martinet, Olivier; Ermekova, Vanadyia; Martinet, O; Ermekova, V; Qiao, J Q; Sauter, B; Mandeli, J; Chen, L; Chen, S H
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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.
- Subjects
GENE therapy; ADENOVIRUS diseases; THERAPEUTICS; TUMOR treatment; ANIMAL experimentation; BIOLOGICAL models; IMMUNOMODULATORS; COLON tumors; COMPARATIVE studies; GENES; KILLER cells; INTERLEUKINS; LIVER tumors; RESEARCH methodology; MEDICAL cooperation; MICE; RESEARCH; T cells; TUMOR necrosis factors; VIRUSES; EVALUATION research; CANCER cell culture
- Publication
JNCI: Journal of the National Cancer Institute, 2000, Vol 92, Issue 11, p931
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/92.11.931