Generation of a novel, cyclooxygenase-2–targeted, interferon-expressing, conditionally replicative adenovirus for pancreatic cancer therapy

Armstrong, Leonard; Arrington, Amanda K.; Han, Joohee; Gavrikova, T. A.; Brown, Eric J.; Yamamoto, Masato; Vickers, Selwyn M.; Davydova, Julia

doi:10.1016/j.amjsurg.2012.02.016

Cited by 29 publications

(44 citation statements)

References 36 publications

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“…Our research group has developed a tumor-selective IFN-expressing oncolytic adenovirus which is driven by the Cox2 promoter 21 and tested it in an immunocompetent Syrian hamster model. We have demonstrated the direct antitumor effect of IFN, as well as its species-specific nature.…”

Section: Discussionmentioning

confidence: 99%

“…The IFN-expressing vectors (Figure 1) were based on adenovirus type 5 (Ad5) and contained the Ad-ΔE3-ADP structure as we have previously described 21, 22, 28 . Briefly, most of the non-essential adenovirus E3 genes have been deleted (with the exception of the adenovirus death protein (ADP) which is designed to facilitate viral spread and oncolysis) and replaced with the hamster IFN gene 29, 30 .…”

Section: Methodsmentioning

confidence: 99%

“…As control vectors, the identical adenoviral vectors expressing the firefly luciferase (Luc) gene have been used 21, 31, 32 .…”

Section: Methodsmentioning

confidence: 99%

“…The vectors were titrated by plaque forming assay, and the viral particle (vp) number was measured spectrophotometrically. Viral quality was confirmed by polymerase chain reaction for the presence of the Cox2 promoter, the fiber structure, and the absence of contamination with a mutant replication competent adenovirus as described previously 21, 22, 31, 33 .…”

Section: Methodsmentioning

confidence: 99%

“…To further enhance the effect of an IFN-expressing adenovirus, our group developed an infectivity-enhanced, conditionally replicative adenovirus (CRAd) that is designed to selectively replicate and spread within pancreatic cancer cells expressing cyclooxygenase 2 (Cox2). The incorporation of the human IFN transgene into the E3 region of the adenovirus genome allows for a high concentration of IFN to be locally produced at the tumor site with each successful cycle of viral replication 21, 22 . To overcome the low infectivity and improve upon the oncolysis of conventional CRAds, the virus was designed to include an Ad5/Ad3 chimeric fiber and overexpression of the adenovirus death protein (ADP).…”

Section: Introductionmentioning

confidence: 99%

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Oncolytic adenovirus expressing interferon alpha in a syngeneic Syrian hamster model for the treatment of pancreatic cancer

LaRocca

Han

Gavrikova

et al. 2015

Surgery

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Background The addition of interferon alpha (IFN) to adjuvant chemoradiotherapy regimens resulted in remarkable improvements in survival for pancreatic cancer patients. However, systemic toxicities and insufficient levels of IFN at the tumor sites have limited its widespread adoption in treatment schemes. We have previously developed an IFN-expressing conditionally replicative oncolytic adenovirus and demonstrated its therapeutic effects both in vitro and in vivo. Here, the same vectors were tested in a syngeneic and immunocompetent Syrian hamster model to better understand the roles of adenoviral replication and of IFN’s pleiotropic effects on pancreatic tumor growth suppression. Methods Oncolytic adenoviruses expressing human or hamster IFN were designed and generated. Viral vectors were tested in vitro to determine qualitative and quantitative cell viability, Cox2 promoter activity, and IFN production. For the in vivo studies, subcutaneous hamster pancreatic cancer tumors were treated with one intratumoral dose of virus. Similarly, one intraperitoneal dose of virus was used to prolong survival in a carcinomatosis model. Results All cell lines tested demonstrated Cox2 promoter activity. The oncolytic potential of a replication competent adenovirus expressing the IFN cytokine was clearly demonstrated. These viruses resulted in significant tumor growth suppression and survival increases compared to controls in a hamster model. Conclusions The profound therapeutic potential of an IFN-expressing oncolytic adenovirus for the treatment of pancreatic cancer was demonstrated in a syngeneic Syrian hamster model. These results strongly suggest the potential application of our viruses as part of combination regimens with other therapeutics.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…As control vectors, the identical adenoviral vectors expressing the firefly luciferase (Luc) gene have been used 21, 31, 32 .…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oncolytic adenovirus expressing interferon alpha in a syngeneic Syrian hamster model for the treatment of pancreatic cancer

LaRocca

Han

Gavrikova

et al. 2015

Surgery

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Oncolytic Adenoviruses: Design, Generation, and Experimental Procedures

Davydova

Yamamoto

2013

CP Human Genetics

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Oncolytic adenoviruses are designed to take advantage of the virus' native ability to replicate in cancer cells to induce oncolysis. Subsequently, the released viral progeny spread and kill the neighboring cancer cells. These characteristics, together with the ability of adenovirus to infect a broad spectrum of cells, its well understood replication machinery, and relative ease of manufacture have led to the intensive use of adenovirus as an anticancer agent. This unit describes cloning strategies, procedures to turn the intended design into virus, and quality analyses of resultant adenoviral vectors. Most of these procedures were optimized especially for oncolytic adenoviral vectors.

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Oncolytic Immunotherapy for Treatment of Cancer

Tsun¹,

Miao²,

Wang³

et al. 2016

Advances in Experimental Medicine and Biology

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Immunotherapy entails the treatment of disease by modulation of the immune system. As detailed in the previous chapters, the different modes of achieving immune modulation are many, including the use of small/large molecules, cellular therapy, and radiation. Oncolytic viruses that can specifically attack, replicate within, and destroy tumors represent one of the most promising classes of agents for cancer immunotherapy (recently termed as oncolytic immunotherapy). The notion of oncolytic immunotherapy is considered as the way in which virus-induced tumor cell death (known as immunogenic cancer cell death (ICD)) allows the immune system to recognize tumor cells and provide long-lasting antitumor immunity. Both immune responses toward the virus and ICD together contribute toward successful antitumor efficacy. What is now becoming increasingly clear is that monotherapies, through any of the modalities detailed in this book, are neither sufficient in eradicating tumors nor in providing long-lasting antitumor immune responses and that combination therapies may deliver enhanced efficacy. After the rise of the genetic engineering era, it has been possible to engineer viruses to harbor combination-like characteristics to enhance their potency in cancer immunotherapy. This chapter provides a historical background on oncolytic virotherapy and its future application in cancer immunotherapy, especially as a combination therapy with other treatment modalities.

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Generation of a novel, cyclooxygenase-2–targeted, interferon-expressing, conditionally replicative adenovirus for pancreatic cancer therapy

Cited by 29 publications

References 36 publications

Oncolytic adenovirus expressing interferon alpha in a syngeneic Syrian hamster model for the treatment of pancreatic cancer

Oncolytic adenovirus expressing interferon alpha in a syngeneic Syrian hamster model for the treatment of pancreatic cancer

Oncolytic Adenoviruses: Design, Generation, and Experimental Procedures

Oncolytic Immunotherapy for Treatment of Cancer

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