Oncolytic virotherapy induced CSDE1 neo-antigenesis restricts VSV replication but can be targeted by immunotherapy

Timothy Kottke, Jason Tonne, Laura Evgin, Christopher B. Driscoll, Jacob Vloten, Victoria A. Jennings, Amanda L. Huff, Brady Zell, Jill M. Thompson, Phonphimon Wongthida, Jose Pulido, Matthew R. Schuelke, Adel Samson, Peter Selby, Elizabeth Ilett, Mark McNiven, Lewis R. Roberts, Mitesh J. Borad, Hardev Pandha, Kevin Harrington, Alan Melcher and Richard G. Vile ()
Additional contact information
Timothy Kottke: Mayo Clinic
Jason Tonne: Mayo Clinic
Laura Evgin: Mayo Clinic
Christopher B. Driscoll: Mayo Clinic
Jacob Vloten: Mayo Clinic
Victoria A. Jennings: The Institute of Cancer Research
Amanda L. Huff: Mayo Clinic
Brady Zell: Mayo Clinic
Jill M. Thompson: Mayo Clinic
Phonphimon Wongthida: Mayo Clinic
Jose Pulido: Mayo Clinic
Matthew R. Schuelke: Mayo Clinic
Adel Samson: University of Leeds
Peter Selby: University of Leeds
Elizabeth Ilett: University of Leeds
Mark McNiven: Mayo Clinic
Lewis R. Roberts: Mayo Clinic
Mitesh J. Borad: Mayo Clinic
Hardev Pandha: University of Surrey
Kevin Harrington: The Institute of Cancer Research
Alan Melcher: The Institute of Cancer Research
Richard G. Vile: Mayo Clinic

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract In our clinical trials of oncolytic vesicular stomatitis virus expressing interferon beta (VSV-IFNβ), several patients achieved initial responses followed by aggressive relapse. We show here that VSV-IFNβ-escape tumors predictably express a point-mutated CSDE1P5S form of the RNA-binding Cold Shock Domain-containing E1 protein, which promotes escape as an inhibitor of VSV replication by disrupting viral transcription. Given time, VSV-IFNβ evolves a compensatory mutation in the P/M Inter-Genic Region which rescues replication in CSDE1P5S cells. These data show that CSDE1 is a major cellular co-factor for VSV replication. However, CSDE1P5S also generates a neo-epitope recognized by non-tolerized T cells. We exploit this predictable neo-antigenesis to drive, and trap, tumors into an escape phenotype, which can be ambushed by vaccination against CSDE1P5S, preventing tumor escape. Combining frontline therapy with escape-targeting immunotherapy will be applicable across multiple therapies which drive tumor mutation/evolution and simultaneously generate novel, targetable immunopeptidomes associated with acquired treatment resistance.

Date: 2021
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DOI: 10.1038/s41467-021-22115-1

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