Adenovirus delivery provides extended interferon-alpha exposure and augments treatment of metastatic carcinoma.

ABSTRACT

Type I interferons (e.g. IFNalpha2b) have been successfully used to treat a variety of hematological malignancies, but have not been efficacious for treatment of most solid tumors. We tested the hypothesis that delivery of type I interferon utilizing recombinant adenovirus (rAd) vectors may improve treatment efficacy of metastatic carcinomas by providing increased interferon exposure resulting from continuous transgene expression. Treatment of mice with a rAd-vector expressing hybrid-IFN (rAd-IFNalpha2alpha1) inhibited 4T1 mammary carcinoma tumor growth and induced tumor regression in a dose-dependent manner. Moreover, rAd-IFNalpha2alpha1 treatment reduced hepatic and pulmonary metastatic burden. A comparison of local and systemic routes of administration demonstrated that intratumoral delivery of rAd-IFNalpha2alpha1 was sufficient for inhibition of tumor growth. Moreover, it reduced toxicity associated with high-dose systemic IFNalpha2alpha1 exposure. Interestingly, antitumor activity following intratumoral treatment was due, in part, to the immunostimulatory capacity of the rAd vector component. Furthermore, systemic administration of rAd-IFNalpha2alpha1 potentiated the immunotherapeutic effect induced by local intralesional delivery of empty-rAd vector. These results suggest continuous interferon-alpha exposure may provide improved antitumor responses for metastatic carcinomas. Additionally, immunostimulatory responses induced by rAd-IFNalpha2alpha1 may mitigate the immune-evasive tumor microenvironment.