Antitumor efficacy of AAV-mediated systemic delivery of interferon-β

Abstract

Type I interferons (a/b) have significant antitumor activity although their short half-life and systemic side effects have limited their clinical utility. An alternative dosing schedule of continuous, low-level delivery, as is achieved by gene therapy, rather than intermittent, high concentration pulsed-dosing, might avoid the toxicity of interferon while maintaining its antitumor efficacy. We have tested a gene therapy approach in murine tumor models to treat malignancies that have shown responsiveness to interferon in clinical trials. The tumor cell lines used were moderately sensitive to the direct effects of human interferon-b (hIFN-b) in vitro. For in vivo testing, systemic delivery of hIFN-b was generated following liver-targeted delivery of adeno-associated virus (AAV) vector carrying the hIFN-b transgene. This prevented engraftment of subcutaneous human gliomas, and orthotopic, localized (intrarenal) and disseminated (primarily pulmonary) human renal cell carcinomas; and caused regression of established tumors at these sites. In a syngeneic, immunocompetent model of melanoma, AAV IFN-b treatment limited subcutaneous tumor growth and prevented disseminated disease. A significant decrease in mean intratumoral vessel density was demonstrated in hIFN-b-treated tumors, suggesting that in addition to a direct tumoricidal effect, the antitumor efficacy of AAV IFN-b in this study was due to its ability to inhibit angiogenesis.

Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

“…3B and C). The mean endothelial cell density, as assessed by CD34 staining, was unchanged in treated U87 tumors (14,816 . To help distinguish perivascular cells from activated fibroblasts, both of which can be detected by aSMA staining, additional sections from control and IFN-h -treated tumors (four each) were stained with an anti -platelet-derived growth factor receptor h (PDGFRh) antibody because PDGFRh + cells within tumors have previously been shown to be perivascular cells (21).…”

“…These cell lines were chosen because they are only moderately sensitive to the direct cytotoxic effects of IFN-h (14,15). Treatment was initiated with administration of either AAV IFN-h or a control AAV encoding human clotting factor IX (FIX) via the tail vein, after established disease had been documented either by palpation (subcutaneous tumors) or by ultrasonography (retroperitoneal tumors).…”

Using lentiviral vectors for efficient pancreatic cancer gene therapy

“…36 Targeting PC by molecular abnormality remains elusive because of the accumulation of multiple genetic changes during its multistep carcinogenesis. During the last decade, numerous studies illustrated the gene transfer or systemic delivery of IFN-b to inhibit tumor growth in multiple animal models from gliomas, 37 to hepatocellular carcinoma, 38 metastatic breast cancer, 39 prostate cancer, [40][41][42] rectum, colon and endometrial tumors, [43][44][45] lung tumors, 46,47 renal cell carcinomas and melanoma, 48,49 neuroblastoma, 50,51 disseminated peritoneal cancer, 52 bladder cancer, 53 malignant mesothelia 54 and fibrosarcomas. 55 Recently, a cancer gene therapy trial for gliomas based on the intratumoral administration of IFN-b) was shown to be feasible and associated with apoptosis induction.…”

Reconstructed Adeno-Associated Virus with the Extracellular Domain of Murine PD-1 Induces Antitumor Immunity

“…A variety of gene therapy-based anticancer strategies have been tested in animal tumor models, including selective activation of prodrugs, genetic immunotherapy, antiangiogenic actions and replacement of tumor suppressor genes (Sangro et al, 2002;Borghouts et al, 2005;Cao et al, 2010), successful of these approaches was depend on efficient gene transfer process, numerous gene transfer vectors have been developed, most of these approaches have used retroviral vector producer, naked DNA, oligodendromer DNA coatings, electroporation or adenoviral vectors (Qian et al, 2000;Cross et al, 2006). However, retroviral vector producers may be impractical for human use due to low titer of the vector, and the transfer of naked DNA is typically an inefficient, transient process; adenoviralmediated gene transfer is also complicated by transient (Streck et al, 2006). Adeno-associated virus (AAV) is a recently identified, nonpathogenic, helper-dependent member of the parvovirus family and becoming a promising alternative in cancer gene therapy which offer some potential advantages for gene transfer as compared to other gene delivery systems just mentioned.…”