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

Kathryn Ottolino-Perry; David Mealiea; Clara Sellers; Sergio A Acuna; Fernando A Angarita; Lili Okamoto; Deborah Scollard; Mihaela Ginj; Raymond Reilly; J Andrea McCart

doi:10.1016/j.omto.2023.04.001

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

Mol Ther Oncolytics. 2023 Apr 10:29:44-58. doi: 10.1016/j.omto.2023.04.001. eCollection 2023 Jun 15.

Authors

Kathryn Ottolino-Perry^{1

2}, David Mealiea^{1

2}, Clara Sellers¹, Sergio A Acuna¹, Fernando A Angarita^{1

2}, Lili Okamoto², Deborah Scollard³, Mihaela Ginj², Raymond Reilly⁴, J Andrea McCart^{1

2

5}

Affiliations

¹ Toronto General Research Institute, University Health Network, 200 Elizabeth Street, M5G 2C4 Toronto, ON, Canada.
² Institute of Medical Science, University of Toronto, 1 King's College Circle, M5S 1A8 Toronto, ON, Canada.
³ STTARR, Radiation Medicine Program, Princess Margaret Hospital, UHN, 610 University Avenue, M5G 2C1 Toronto, ON, Canada.
⁴ Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, M5S 3M2 Toronto, ON, Canada.
⁵ Department of Surgery, Mount Sinai Hospital and University of Toronto, 600 University Avenue, M5G 1X5 Toronto, ON, Canada.

Abstract

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.

Keywords: colorectal cancer; oncolytic virus; peptide-receptor radiotherapy; somatostatin receptor; vaccinia; virotherapy.