Trap and ambush therapy using sequential primary and tumor escape-selective oncolytic viruses

Mason J Webb; Timothy Kottke; Benjamin L Kendall; Jack Swanson; Chisom Uzendu; Jason Tonne; Jill Thompson; Muriel Metko; Madelyn Moore; Mitesh Borad; Lewis Roberts; Rosa M Diaz; Michael Olin; Antonella Borgatti; Richard Vile

doi:10.1016/j.omto.2023.05.006

Trap and ambush therapy using sequential primary and tumor escape-selective oncolytic viruses

Mol Ther Oncolytics. 2023 May 22:29:129-142. doi: 10.1016/j.omto.2023.05.006. eCollection 2023 Jun 15.

Authors

Mason J Webb^{1

2}, Timothy Kottke², Benjamin L Kendall², Jack Swanson³, Chisom Uzendu², Jason Tonne², Jill Thompson², Muriel Metko², Madelyn Moore², Mitesh Borad⁴, Lewis Roberts⁵, Rosa M Diaz², Michael Olin⁶, Antonella Borgatti^{7

8

9}, Richard Vile^{2

3}

Affiliations

¹ Division of Hematology/Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA.
² Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
³ Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
⁴ Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ 85259, USA.
⁵ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.
⁶ Division of Pediatric Hematology and Oncology, University of Minnesota, Minneapolis, MN 55455, USA.
⁷ Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, MN 55108, USA.
⁸ Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
⁹ Clinical Investigation Center, University of Minnesota, St. Paul, MN 55108, USA.

Abstract

In multiple models of oncolytic virotherapy, it is common to see an early anti-tumor response followed by recurrence. We have previously shown that frontline treatment with oncolytic VSV-IFN-β induces APOBEC proteins, promoting the selection of specific mutations that allow tumor escape. Of these mutations in B16 melanoma escape (ESC) cells, a C-T point mutation in the cold shock domain-containing E1 (CSDE1) gene was present at the highest frequency, which could be used to ambush ESC cells by vaccination with the mutant CSDE1 expressed within the virus. Here, we show that the evolution of viral ESC tumor cells harboring the escape-promoting CSDE1^C-T mutation can also be exploited by a virological ambush. By sequential delivery of two oncolytic VSVs in vivo, tumors which would otherwise escape VSV-IFN-β oncolytic virotherapy could be cured. This also facilitated the priming of anti-tumor T cell responses, which could be further exploited using immune checkpoint blockade with the CD200 activation receptor ligand (CD200AR-L) peptide. Our findings here are significant in that they offer the possibility to develop oncolytic viruses as highly specific, escape-targeting viro-immunotherapeutic agents to be used in conjunction with recurrence of tumors following multiple different types of frontline cancer therapies.

Keywords: CD200AR-L; CSDE1; VSV; immunotherapy; melanoma; oncolytic virotherapy; tumor escape; vesicular stomatitis virus.

Abstract

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