Oncolytic virotherapy induced CSDE1 neo-antigenesis restricts VSV replication but can be targeted by immunotherapy.
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Embargo End Date
ICR Authors
Authors
Kottke, T
Tonne, J
Evgin, L
Driscoll, CB
van Vloten, J
Jennings, VA
Huff, AL
Zell, B
Thompson, JM
Wongthida, P
Pulido, J
Schuelke, MR
Samson, A
Selby, P
Ilett, E
McNiven, M
Roberts, LR
Borad, MJ
Pandha, H
Harrington, K
Melcher, A
Vile, RG
Tonne, J
Evgin, L
Driscoll, CB
van Vloten, J
Jennings, VA
Huff, AL
Zell, B
Thompson, JM
Wongthida, P
Pulido, J
Schuelke, MR
Samson, A
Selby, P
Ilett, E
McNiven, M
Roberts, LR
Borad, MJ
Pandha, H
Harrington, K
Melcher, A
Vile, RG
Document Type
Journal Article
Date
2021-03-26
Date Accepted
2021-02-25
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.
Citation
Nature communications, 2021, 12 (1), pp. 1930 - ?
Source Title
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Research Team
Targeted Therapy
Targeted Therapy
Targeted Therapy