Combination Therapy with Interleukin-2 and Wild-Type p53 Expressed by Adenoviral Vectors Potentiates Tumor Regression in a Murine Model of Breast Cancer
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abstract
Although cytokine gene transfer for cancer treatment can stimulate immune recognition and tumor regression in animal models, there is still a need for improvements to these strategies. In this study, we examined the efficacy of a combination gene therapy using adenovirus (Ad) 5 vectors expressing human interleukin-2 and the wild-type (wt) human p53 gene under control of the human cytomegalovirus immediate early promoter (AdIL-2 and Adp53wt, respectively). Infected murine cell lines and primary mouse tumor cells secreted high levels of IL-2 and over expressed the p53 protein for at least 9 days. After infection of cells with Adp53wt, DNA synthesis was significantly inhibited and apoptosis was induced within 3-5 days. Both vectors were tested in a transgenic mouse mammary adenocarcinoma model for antitumor response. Following a single intratumoral injection of mice bearing PyMT induced tumors, the combination of Adp53wt (1 x 10(9) pfu) plus a relatively low dose of AdIL-2 (1.5 x 10(8) pfu) caused regressions in 65% of the treated tumors without toxicity. Fifty percent of the treated mice remained tumor free and were immune to rechallenge with fresh tumor cells. In contrast, injection of either vector alone at this does resulted in only a delay in tumor growth. Only mice co-injected with Adp53wt and AdIL-2 showed specific antitumor cytolytic T lymphocyte (CTL) activity, indicating that the immune response involved in tumor regression was promoted by the combination therapy. These results suggest that cancer treatment strategies involving combined delivery of immunomodulatory and antiproliferative genes may be highly effective.
