Intravenously deliverable oncolytic virus VET3-TGI favorably alters the tumor microenvironment.

Authors

Ming Zhang, Katy Barrett, Carly Carter, Padma Sampath, Gabriella Acosta-Barreto, Sydney Audino, Jirapach Moongdee, Rachel Bouchard, Deanna Dunstane, Nick Matteo, Kyle Biery, Evalien Duyvesteyn, Monica Cantos, Kimberly M Brothers, Dan Byrd, Taylor Dietrich, Ravikumar Muthuswamy, Stephen H Thorne

Published in

Journal for immunotherapy of cancer. Volume 14. Issue 9. Sep 21, 2026. Epub Sep 21, 2026.

Abstract

Oncolytic viruses have pledged to combat cancer by causing immunogenic cell death of cancerous cells while priming cancer-specific immune responses. These outcomes have proven elusive in the clinic. Current-generation vectors rarely reach effective concentrations inside tumors when given intravenously, and consequently are limited to intratumoral administration. Even after direct tumor infusion, these therapies frequently fail to overcome local immunosuppression caused by inappropriate activation of transforming growth factor beta (TGF-β) signaling throughout the tumor microenvironment.
VET3-TGI is a vaccinia virus that expresses the chemokine receptor C-X-C chemokine receptor 3 (CXCR3) in infected cells within the first hours after infection. Circulating cells infected in situ on intravenous infusion are driven to migrate to tumors that express cognate chemokines, thus delivering the virus to its target. Infected tumor cells subsequently secrete interleukin-12 (IL-12) and a soluble TGF-β inhibitor.
Expression of CXCR3 from vaccinia virus boosted delivery of virus to tumors containing C-X-C motif chemokine 9 and C-X-C motif chemokine 10, which are known to be upregulated in many human cancers. VET3-TGI effectively combated tumor growth when administered intravenously as a single agent in multiple mouse tumor models. In these models, IL-12 provoked inflammation-driven antitumor activity from immune cells. This activity was strengthened by local TGF-β blockade, which crippled the ability of tumors to suppress the immune response.
VET3-TGI demonstrates the efficacy of three different transgenes with distinct and complementary activities: CXCR3 for tumor targeting to enable intravenous delivery, a TGF-β inhibitor to disrupt immunosuppression, and IL-12 to promote antitumor immunity.

PMID:
42767770
Bibliographic data and abstract were imported from PubMed on 22 Sep 2026.

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