Complementary dual-virus strategy drives synthetic target and cognate T-cell engager expression for endogenous-antigen agnostic immunotherapy

Zaid Taha (), Mathieu Joseph François Crupi (), Nouf Alluqmani, Duncan MacKenzie, Sydney Vallati, Jack Timothy Whelan, Faiha Fareez, Akram Alwithenani, Julia Petryk, Andrew Chen, Marcus Mathew Spinelli, Kristy Ng, Judy Sobh, Christiano Tanese Souza, Priya Rose Bharadwa, Timothy Kit Hin Lee, Dylan Anthony Thomas, Ben Zhen Huang, Omar Kassas, Joanna Poutou, Victoria Heather Gilchrist, Stephen Boulton, Max Thomson, Ricardo Marius, Mohsen Hooshyar, Scott McComb, Rozanne Arulanandam, Carolina Solange Ilkow, John Cameron Bell () and Jean-Simon Diallo ()
Additional contact information
Zaid Taha: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Mathieu Joseph François Crupi: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Nouf Alluqmani: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Duncan MacKenzie: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Sydney Vallati: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Jack Timothy Whelan: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Faiha Fareez: McMaster University
Akram Alwithenani: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Julia Petryk: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Andrew Chen: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Marcus Mathew Spinelli: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Kristy Ng: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Judy Sobh: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Christiano Tanese Souza: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Priya Rose Bharadwa: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Timothy Kit Hin Lee: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Dylan Anthony Thomas: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Ben Zhen Huang: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Omar Kassas: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Joanna Poutou: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Victoria Heather Gilchrist: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Stephen Boulton: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Max Thomson: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Ricardo Marius: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Mohsen Hooshyar: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Scott McComb: Cancer Immunology Team, National Research Council of Canada, Human Health Therapeutics
Rozanne Arulanandam: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Carolina Solange Ilkow: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
John Cameron Bell: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
Jean-Simon Diallo: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Targeted antineoplastic immunotherapies have achieved remarkable clinical outcomes. However, resistance to these therapies due to target absence or antigen shedding limits their efficacy and excludes tumours from candidacy. To address this limitation, here we engineer an oncolytic rhabdovirus, vesicular stomatitis virus (VSVΔ51), to express a truncated targeted antigen, which allows for HER2-targeting with trastuzumab. The truncated HER2 (HER2T) lacks signaling capabilities and is efficiently expressed on infected cell surfaces. VSVΔ51-mediated HER2T expression simulates HER2-positive status in tumours, enabling effective treatment with the antibody-drug conjugate trastuzumab emtansine in vitro, ex vivo, and in vivo. Additionally, we combine VSVΔ51-HER2T with an oncolytic vaccinia virus expressing a HER2-targeted T-cell engager. This dual-virus therapeutic strategy demonstrates potent curative efficacy in vivo in female mice using CD3+ infiltrate for anti-tumour immunity. Our findings showcase the ability to tailor the tumour microenvironment using oncolytic viruses, thereby enhancing compatibility with “off-the-shelf” targeted therapies.

Date: 2024
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DOI: 10.1038/s41467-024-51498-0

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