Adenovirus delivery provides extended interferon-alpha exposure and augments treatment of metastatic carcinoma.
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.
Brin
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E
Canji Inc., San Diego, CA, USA.
Atencio
I
I
Helmich
B K
BK
Maneval
D
D
Laface
D
D
D000256:Adenoviridae; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D007167:Immunotherapy; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins