Tumor vascularization is critical for oncolytic vaccinia virus treatment of peritoneal carcinomatosis

Ottolino‐Perry, Kathryn; Tang, Nan; Head, Renee; Ng, Calvin S.H.; Arulanandam, Rozanne; Angarita, Fernando A.; Acuña, Sergio A.; Chen, Yonghong; Bell, John C.; DaCosta, Ralph S.; McCart, J. Andrea

doi:10.1002/ijc.28395

Cited by 16 publications

(27 citation statements)

References 42 publications

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“…We believe that this model simulates the setting of advanced disease, and other groups have used a similar model in mice to demonstrate the effectiveness of intraperitoneal virus therapy 41 . In our experiment, there was a statistically significant increase in the survival of the animals treated with just one dose of the IFN-expressing virus.…”

Section: Discussionmentioning

confidence: 99%

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%

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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“…Clearly, tumor vascularization is critical for the pathogenesis of of peritoneal metastasis. Because of neoangiogenesis and Enhanced permeability and retention, vascularization also plays a major role for the success of therapy with small molecules, proteins or even with genes [90].…”

Section: Discussionmentioning

confidence: 99%

Functional vascular anatomy of the peritoneum in health and disease

Solaß

Horvath

Struller

et al. 2019

Pleura and Peritoneum

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Abstract:The peritoneum consists of a layer of mesothelial cells on a connective tissue base which is perfused with circulatory and lymphatic vessels. Total effective blood flow to the human peritoneum is estimated between 60 and 100 mL/min, representing 1-2 % of the cardiac outflow. The parietal peritoneum accounts for about 30 % of the peritoneal surface (anterior abdominal wall 4 %) and is vascularized from the circumflex, iliac, lumbar, intercostal, and epigastric arteries, giving rise to a quadrangular network of large, parallel blood vessels and their perpendicular offshoots. Parietal vessels drain into the inferior vena cava. The visceral peritoneum accounts for 70 % of the peritoneal surface and derives its blood supply from the three major arteries that supply the splanchnic organs, celiac and superior and inferior mesenteric. These vessels give rise to smaller arteries that anastomose extensively. The visceral peritoneum drains into the portal vein. Drugs absorbed are subject to firstpass hepatic metabolism. Peritoneal inflammation and cancer invasion induce neoangiogenesis, leading to the development of an important microvascular network. Anatomy of neovessels is abnormal and characterized by large size, varying diameter, convolution and blood extravasation. Neovessels have a defective ultrastructure: formation of large "mother vessels" requires degradation of venular and capillary basement membranes. Mother vessels give birth to numerous "daughter vessels". Diffuse neoangiogenesis can be observed before appearance of macroscopic peritoneal metastasis. Multiplication of the peritoneal capillary surface by neoangiogenesis surface increases the part of cardiac outflow directed to the peritoneum.

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“…For bio-distribution of vvDD-RFP in normal, tumor, and wounded vasculature, 3E5 MC38 colon carcinoma cells were used in a window chamber model as previously described (Guba et al, 2002;Ottolino-Perry et al, 2014). 1E9 PFU vvDD was administered i.p.…”

Section: Mouse Models and Treatment Protocolsmentioning

confidence: 99%

VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection

et al. 2015

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Oncolytic viruses designed to attack malignant cells can in addition infect and destroy tumor vascular endothelial cells. We show here that this expanded tropism of oncolytic vaccinia virus to the endothelial compartment is a consequence of VEGF-mediated suppression of the intrinsic antiviral response. VEGF/VEGFR2 signaling through Erk1/2 and Stat3 leads to upregulation, nuclear localization, and activation of the transcription repressor PRD1-BF1/Blimp1. PRD1-BF1 does not contribute to the mitogenic effects of VEGF, but directly represses genes involved in type I interferon (IFN)-mediated antiviral signaling. In vivo suppression of VEGF signaling diminishes PRD1-BF1/Blimp1 expression in tumor vasculature and inhibits intravenously administered oncolytic vaccinia delivery to and consequent spread within the tumor.

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Tumor vascularization is critical for oncolytic vaccinia virus treatment of peritoneal carcinomatosis

Cited by 16 publications

References 42 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

Functional vascular anatomy of the peritoneum in health and disease

VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection

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