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 van 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 HarringtonAlan Melcher, Richard G. Vile

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number1930
JournalNature communications
Issue number1
StatePublished - Dec 1 2021

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology


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