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

Abstract

Type I interferons (e.g. IFNa2b) 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-IFNa2a1) inhibited 4T1 mammary carcinoma tumor growth and induced tumor regression in a dose-dependent manner. Moreover, rAd-IFNa2a1 treatment reduced hepatic and pulmonary metastatic burden. A comparison of local and systemic routes of administration demonstrated that intratumoral delivery of rAd-IFNa2a1 was sufficient for inhibition of tumor growth. Moreover, it reduced toxicity associated with high-dose systemic IFNa2a1 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-IFNa2a1 potentiated the immunotherapeutic effect induced by local intralesional delivery of empty-rAd vector. These results suggest continuous interferon-a exposure may provide improved antitumor responses for metastatic carcinomas. Additionally, immunostimulatory responses induced by rAd-IFNa2a1 may mitigate the immune-evasive tumor microenvironment.

Evaluation of an Attenuated Vesicular Stomatitis Virus Vector Expressing Interferon-β for Use in Malignant Pleural Mesothelioma: Heterogeneity in Interferon Responsiveness Defines Potential Efficacy

“…Our group and others have shown in preclinical studies that delivery of type I IFNs using an adenoviral vector induces strong antitumor immune responses and has been highly effective in eliminating tumors in mice (Ahmed et al, 2001;Odaka et al, 2002;Brin et al, 2006). This antitumor activity appears to be present in patients also.…”

“…We next sought to determine how well each cell line could respond to external IFN-b stimulation by measuring the ability of these cells to upregulate and synthesize the mRNAs for three well-described ISGs, MxA, 2 0 5 0 -OAS, and PKR, which are known to inhibit the replication of VSV in normal host cells (Balachandran and Barber, 2000;Lichty et al, 2004;Brin et al, 2006;Sterman et al, 2006). We therefore incubated each cell line with 10 U=ml hIFN-b (approximately 50 pg=ml) for 6 hr and then harvested the cells for quantification of the mRNA levels of each gene using real-time RT-PCR (Table 3A).…”

Tumor-specific dendritic cells generated by genetic redirection of Toll-like receptor signaling against the tumor-associated antigen, erbB2

“…Some antitumor effects have been observed using these strategies, [17][18][19][20] but it is not feasible to treat most patients in this manner. In addition, effective distribution of TLR agonists throughout the entire tumor mass is generally not feasible using simple injection at one site.…”

Targeted delivery of interferon-alpha via fusion to anti-CD20 results in potent antitumor activity against B-cell lymphoma

“…33,34 Tumor-specific IFN␣ delivery via transduced monocytes or adenoviral vectors is also effective in inhibition of tumor growth and angiogenesis in glioma and metastatic carcinoma tumor models. 35,36 Despite promising efficacy in mouse models, clinical use of viral vectors in humans is problematic. An attractive alternative approach to improving efficacy while reducing toxicity is to deliver IFN␣ via an antibody fusion protein.…”