Vaccinia virus and peptide-receptor radiotherapy synergize to improve treatment of peritoneal carcinomatosis

• Published in: Molecular therapy. Oncolytics 2023-06, Vol.29, p.44-58
• Main Authors: Ottolino-Perry, Kathryn, Mealiea, David, Sellers, Clara, Acuna, Sergio A., Angarita, Fernando A., Okamoto, Lili, Scollard, Deborah, Ginj, Mihaela, Reilly, Raymond, McCart, J. Andrea
• Format: Article
• Language: English
• Subjects: colorectal cancer; oncolytic virus; Original; peptide-receptor radiotherapy; somatostatin receptor; vaccinia; virotherapy
• ISSN: 2372-7705; 2372-7705
• DOI: 10.1016/j.omto.2023.04.001

Tumor-specific overexpression of receptors enables a variety of targeted cancer therapies, exemplified by peptide-receptor radiotherapy (PRRT) for somatostatin receptor (SSTR)-positive neuroendocrine tumors. While effective, PRRT is restricted to tumors with SSTR overexpression. To overcome this limitation, we propose using oncolytic vaccinia virus (vvDD)-mediated receptor gene transfer to permit molecular imaging and PRRT in tumors without endogenous SSTR overexpression, a strategy termed radiovirotherapy. We hypothesized that vvDD-SSTR combined with a radiolabeled somatostatin analog could be deployed as radiovirotherapy in a colorectal cancer peritoneal carcinomatosis model, producing tumor-specific radiopeptide accumulation. Following vvDD-SSTR and 177Lu-DOTATOC treatment, viral replication and cytotoxicity, as well as biodistribution, tumor uptake, and survival, were evaluated. Radiovirotherapy did not alter virus replication or biodistribution, but synergistically improved vvDD-SSTR-induced cell killing in a receptor-dependent manner and significantly increased the tumor-specific accumulation and tumor-to-blood ratio of 177Lu-DOTATOC, making tumors imageable by microSPECT/CT and causing no significant toxicity. 177Lu-DOTATOC significantly improved survival over virus alone when combined with vvDD-SSTR but not control virus. We have therefore demonstrated that vvDD-SSTR can convert receptor-negative tumors into receptor-positive tumors and facilitate molecular imaging and PRRT using radiolabeled somatostatin analogs. Radiovirotherapy represents a promising treatment strategy with potential applications in a wide range of cancers. [Display omitted] Peptide-receptor radiotherapy (PRRT) is a targeted cancer therapy applicable to somatostatin receptor (SSTR)-positive neuroendocrine tumors. Here we have used an oncolytic vaccinia virus (vvDD) to facilitate receptor gene transfer into SSTR-negative tumors. This facilitates molecular imaging and PRRT in tumors without endogenous SSTR overexpression, a strategy termed radiovirotherapy.