Preclinical evaluation of the gorilla‐derived HAdV‐B AdV‐lumc007 oncolytic adenovirus ‘GoraVir’ for the treatment of pancreatic ductal adenocarcinoma

• Published in: Molecular oncology 2024-05, Vol.18 (5), p.1245-1258
• Main Authors: Bots, Selas T. F., Harryvan, Tom J., Groeneveldt, Christianne, Kinderman, Priscilla, Kemp, Vera, Montfoort, Nadine, Hoeben, Rob C.
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenoviruses; CD46; CD46 antigen; Cell culture; Cell cycle; Cloning; Drug therapy; Health aspects; Immunotherapy; Infections; Laboratories; Malignancy; non‐human primate oncolytic adenovirus; Oncolysis; Pancreatic Cancer; pancreatic ductal adenocarcinoma; Spheroids; Stroma; Tumor microenvironment; Tumors; tumour‐stroma; Viral proteins; Viruses; xenograft model
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.13561

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy which shows unparalleled therapeutic resistance due to its genetic and cellular heterogeneity, dense stromal tissue, and immune‐suppressive tumour microenvironment. Oncolytic virotherapy has emerged as a new treatment modality which uses tumour‐specific viruses to eliminate cancerous cells. Non‐human primate adenoviruses of the human adenovirus B (HAdV‐B) species have demonstrated considerable lytic potential in human cancer cells as well as limited preexisting neutralizing immunity in humans. Previously, we have generated a new oncolytic derivative of the gorilla‐derived HAdV‐B AdV‐lumc007 named ‘GoraVir’. Here, we show that GoraVir displays oncolytic efficacy in pancreatic cancer cells and pancreatic‐cancer‐associated fibroblasts. Moreover, it retains its lytic potential in monoculture and co‐culture spheroids. In addition, we established the ubiquitously expressed complement receptor CD46 as the main entry receptor for GoraVir. Finally, a single intratumoural dose of GoraVir was shown to delay tumour growth in a BxPC‐3 xenograft model at 10 days post‐treatment. Collectively, these data demonstrate that the new gorilla‐derived oncolytic adenovirus is a potent oncolytic vector candidate that targets both pancreatic cancer cells and tumour‐adjacent stroma. Oncolytic adenovirus ‘GoraVir’ has strong lytic potential in both pancreatic cancer cells and cancer‐associated fibroblasts, which may be facilitated by its use of CD46 for viral entry. Moreover, GoraVir demonstrates superior oncolytic efficacy compared to HAdV‐C5 in spheroid cultures as well as in vivo. This shows that GoraVir exhibits unique oncolytic properties and seems a promising candidate for the treatment of pancreatic cancer.