Targeted Virus Replication Plus Immunotherapy Eradicates Primary and Distant Pancreatic Tumors in Nude Mice

Abstract

Pancreatic cancer is an aggressive neoplasm with no current viable, effective treatment options. In the majority of cases, at first diagnosis, pancreatic cancer has already become metastatic so that conventional treatment regimens provide minimal, if any, clinical benefit in prolonging life or ameliorating the negative prognosis of this disease. These harsh realities underscore the need for developing improved treatment paradigms for this cancer, with gene therapy and immunotherapy currently being evaluated as potential therapeutic options. We currently describe an adenovirus-based therapy for successfully managing pancreatic cancer, the cancer terminator virus (CTV), which is founded on targeted induction of viral replication from a cancer-specific progression elevated gene-3 (PEG-3) promoter (PEG-Prom) and immune modulation by IFN-;. The PEG-Prom functions selectively in cancer cells of diverse lineages compared with their normal cellular counterparts. In the CTV, the PEG-Prom drives expression of the adenoviral early region 1A (E1A) gene, necessary for virus replication, with IFN-; simultaneously being expressed from the E3 region. Infection of normal cells and pancreatic cancer cells with the CTV confirmed cancer cell-selective adenoviral replication, robust IFN-; production coupled with virus replication, growth inhibition, and apoptosis induction. Infection of established pancreatic tumors in nude mice with the CTV promoted viral replication, IFN-; production, and activation of antitumor immunity resulting in complete eradication of both primary and distant tumors, curing animals of disease. The CTV provides a novel reagent for treating pancreatic and other human cancers with potential for eliminating both primary tumors and metastatic disease. (Cancer Res 2005; 65(19): 9056-63)

Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) improves therapeutic efficacy in low CAR prostate cancer cells

“…27 The primary antibodies used were anti-BiP/GRP78 (Santa Cruz Biotechnology, Inc, Santa Cruz, CA), anti-Bcl-x L , anti-Bcl-2, PARP (poly(ADP-ribose) polymerase-1), p38 MAP (mitogenactivated protein) kinase, p-p38MAP kinase, ERK Human prostate cancer xenografts in athymic nude mice DU-145 and PC-3 cells (3 Â 10 6 ) were injected subcutaneously in 100 ml of PBS in the left flank of male athymic nude mice (NCRnu/nu, 4 weeks of age, 20 g body weight). 27,28 After establishment of visible tumors of B75 mm 3 , requiring approximately 8-10 days, intratumoral injections of different Ads were administered only to tumors on the left flank at a dose of 4.5 Â 10 8 p.f.u. (plaqueforming units) in 100 ml.…”

A cancer terminator virus eradicates both primary and distant human melanomas

“…This approach employs a genetically modified adenovirus, CTV, in which replication is controlled by a minimal active region of the promoter of progression-elevated gene-3 (PEG-3), which expresses selectively in diverse cancer cells with limited activity in normal cells. 21,[39][40][41] The PEG-3 gene was cloned using subtraction hybridization as an upregulated transcript from a transformation progression rodent cancer model. 42,43 Of direct relevance for gene therapy applications, activity of the PEG-3 promoter (PEG-Prom) is significantly and often markedly elevated not only in rodent but also in human cancer cells of diverse origin when compared to normal cells.…”

“…42,43 Of direct relevance for gene therapy applications, activity of the PEG-3 promoter (PEG-Prom) is significantly and often markedly elevated not only in rodent but also in human cancer cells of diverse origin when compared to normal cells. 21,[39][40][41] The mechanism underlying the cancer-specific expression of the PEG-Prom implicates two transcription factors, AP-1 and PEA-3, which are expressed at elevated levels, either singly or in combination, in virtually all types of cancers. 21,[39][40][41][42][43][44][45] Using the PEG-Prom to transcriptionally regulate green fluorescence protein (GFP) or luciferase gene expression via a replication-incompetent Ad confirmed targeted cancer-cell-selective transgene expression in human prostate and breast cancer cells, as well as in malignant glioma cells.…”

“…39 Considering these findings, we investigated the use of the PEG-Prom to drive expression of the E1A gene, necessary for Ad replication, to create cancer-cell-specific CRCAs. 21,40,41 One of the engineered CRCAs, which we generated, simultaneously expresses mda-7/IL-24 in the E3 region (Ad.PEG-E1A-mda-7; CTV), thereby inducing robust production of this cytokine as a function of adenoviral replication. 21,40,41 We presently demonstrate that Ad.PEG-E1A-mda-7 CTV effectively eradicates both primary and distant melanomas in a nude mouse xenograft model.…”

“…21,40,41 One of the engineered CRCAs, which we generated, simultaneously expresses mda-7/IL-24 in the E3 region (Ad.PEG-E1A-mda-7; CTV), thereby inducing robust production of this cytokine as a function of adenoviral replication. 21,40,41 We presently demonstrate that Ad.PEG-E1A-mda-7 CTV effectively eradicates both primary and distant melanomas in a nude mouse xenograft model. These observations establish that Ad.PEG-E1A-mda-7 CTV might provide an efficient therapeutic reagent for treating patients with metastatic melanoma.…”