Interleukin-12 (IL-12) is a cytokine that has been shown to generate potent NK and Th1 response to a variety of cellular antigens in laboratory animals. In an orthotopic model of colon carcinoma established in the liver of syngeneic mice, the applicant has previously shown that natural killer (NK) cells induced by adenoviral-mediated intratumoral delivery and expression of the murine interleukin-12 gene (Adv.mIL-12) were the main immune effector cells responsible for tumor rejection. The NK response alone, however, was insufficient to reject all tumors, and most of the treated animals eventually succumbed to relapsing tumors. At the maximal tolerable dose of the vector, a small fraction of the treated animals developed a tumor-specific cytolytic T lymphocyte (CTL) response, which was critical to their achieving long-term survival. The NK activity and tumor specific CTL response after Adv.mIL-12 treatment were dramatically elevated in the tumor bearing animals by co-administration of an agonistic monoclonal antibody against murine 4-1BB, an activation molecule that is expressed on primed CD4+ and CD8+ T cells. The combination treatment resulted in the induction of a strong anti-tumoral immunity and long-term survival in 80-100% of the tumor bearing animals, even with significantly reduced doses of the Adv.mIL-12 vector. The antitumor immune response was systemic, as it was able to reject tumor cells implanted at distal sites. These results indicate that the induction of NK and tumor specific CTL activities can be an effective treatment modality for metastatic colon carcinoma. In order to better understand the mechanism(s) involved in the induction of such a potent systemic anti-tumoral immune response, three specific aims will be pursued: 1) To determine whether intratumoral 4-1BB ligand gene delivery and expression is as effective as 4-1BB antibody when co-delivered with the IL-12 gene; 2) To examine the role of 4-1BB ligand on the activation of NK or NKT cells and their subsequent involvement in Th1 development and tumor specific cytotoxic T (Tc) cell activation; and 3) To determine whether persistent tumor specific Tc cells arise through cytokine-mediated regulation of antigen presenting cells and T cells by IL-12 and 4-1BB ligand activated NK cells. Successful conduct of this investigation will form a scientific foundation of active genetic immunization for future clinical applications in the treatment of metastatic colon cancer in humans.
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