1129. Ad.Interferon Beta Is an Effective Treatment in an Orthotopic Model of Broncho-Alveolar Non-Small Cell Lung Cancer Via NK Cell and CD 8+ T Cell Mechanisms

Abstract

Top of pageAbstract Introduction: Broncho-Alveolar Carcinoma (BAC) is a diffuse (but non-metastasizing) highly lethal lung tumor. To date, it has been difficult to model in mice. However, an orthotopic mouse model for BAC involving a conditionally expressed mutated K ras protein has recently been developed (Jackson et al. Genes & Dev. 15: 3243, 2001). After removal of a lox-flanked stop codon by intra-pulmonary administration of an adenovirus expressing Cre-recombinase (Ad.Cre), localized mutant Kras transcription occurs leading to the development of lung cancer. The tumors progress in a controlled fashion from small diffuse adenomas to widespread sheets of lung cancer. These mice thus offer the ideal model to study new therapeutic approaches for BAC. We have previously shown in mesothelioma models that Ad.interferon |[beta]| (Ad.IFN |[beta]|) can eradicate tumors. We hypothesized that Ad.IFN |[beta]| could be similarly effective in the Kras lung cancer mouse model. Methods: K ras mutant mice were given Ad.Cre intra-nasally. At 3 and 4 weeks after Ad.Cre instillation, groups of mice (n=8) were either untreated or treated intra-nasally with 109 plaque forming units (PFU) of Ad.IFN |[beta]| or a control virus, Ad.LacZ. The mice were studied for survival. In addition, cells derived from K ras mutated lung tumors were grown in the flanks of mice to study some of the mechanisms behind these responses. Results: The untreated tumor-bearing mice all died by day 57 (median survival of 49 days); the mice treated with Ad.LacZ were all dead by day 71 (median survival of 65 days); all mice treated with Ad.IFN |[beta]| were long term survivors (> 105 days) (p<0.001). This experiment was independently repeated with virtually identical results. Using tumor-derived cells grown in vitro and in the flanks of syngeneic mice, we found that Ad. IFN |[beta]| worked via both direct cell killing, and by stimulation of natural killer (NK) cells and CD+8 T cells; depleting NK or CD+8 T cells, but not CD+4 T cells with antibodies attenuated the effect of Ad. IFN |[beta]|. Conclusions: Two doses of Ad.IFN |[beta]| delivered intranasally into mice pre-sensitized with adenovirus lead to remarkably effective anti-tumor activity in an orthotopic model of BAC. Effects were dependent on activation of both CD8+ T cells and NK cells. These studies provide strong preclinical support for a trial of Ad.IFN |[beta]| to treat human BAC.