The concept of virotherapy for cancer is not an outgrowth of recent advances, but surprisingly of experimentation over the past 60 years. Adenovirus, with its good safety profile, was briefly in vogue in the 1950s, but had low efficacy. In the 1990s, virotherapy was again at the forefront of experimental work in oncology and there has been resurgent interest in adenovirus for cancer therapy. It offers many notable advantages and is the most widely used viral vector for gene delivery.
Combining the unique characteristics of adenovirus with rational genetic modifications has resulted in an entirely new class of therapy. CRAds (conditionally replicative adenoviruses), controlled by tumor-specific promoters, replicate and have cytocidal effects only in the cell environment, but have the disadvantages of limited infection of cancer cells, limited intratumoral spread, limited specificity for cancer cells with off-target effects, and immunogenicity.
Pancreatic ductal adenocarcinoma is a highly lethal disease and it is uncommonly diagnosed at a localized and surgically treatable stage. Recently, alpha interferon (IFNα) has shown promising improvements in survival in multimodality adjuvant therapy. However, this regimen has up to a 95% incidence of side effects, and over 25% of patients cannot tolerate the systemic IFN component. IFN could be a powerful tool for the treatment of pancreas cancer. However, realization requires a means of limiting toxicity of IFN-based therapy. A rationally designed, improved adenovirus for use in pancreatic cancer is the subject of this project. A vector optimized for infectivity to pancreas cancer, with enhanced virulence, controlled by the tumor-specific promoter Cox2, and expressing IFNα solely in the tumor environment is generated and tested in vitro and in vivo. An analogous virus for use in hamsters, a crucial small animal system allowing human adenovirus replication, is also tested against syngeneic hamster pancreas cancer and demonstrates a more powerful effect in vivo than that in nude mice due to host immune activation. It is hoped that this work will lead to gene therapy strategies to deliver IFNα to pancreas cancer patients to enhance its beneficial effects while limiting toxicity.
University of Minnesota M.S. thesis. July 2011. Major: Surgery.Advisors: Dr. Masato Yamamoto and Julia Davydova, MD, PhD. 1 computer file (PDF); v, 61 pages.
Armstrong, Leonard Hart.
Generation and functionality of a novel, Cox2-controlled, conditionally-replicating, adenovirus expressing interferon alpha for pancreatic cancer therapy..
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