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

Author

Listed:
  • Zaid Taha

    (Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
    University of Ottawa)

  • Mathieu Joseph François Crupi

    (Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
    University of Ottawa)

  • Nouf Alluqmani

    (Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
    University of Ottawa)

  • Duncan MacKenzie

    (Centre for Cancer Therapeutics, Ottawa Hospital Research Institute)

  • Sydney Vallati

    (Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
    University of Ottawa)

  • Jack Timothy Whelan

    (Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
    University of Ottawa)

  • Faiha Fareez

    (McMaster University)

  • Akram Alwithenani

    (Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
    University of Ottawa)

  • 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
    University of Ottawa)

  • Timothy Kit Hin Lee

    (Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
    University of Ottawa)

  • Dylan Anthony Thomas

    (Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
    University of Ottawa)

  • Ben Zhen Huang

    (Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
    University of Ottawa)

  • 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
    University of Ottawa)

  • 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
    University of Ottawa)

  • John Cameron Bell

    (Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
    University of Ottawa)

  • Jean-Simon Diallo

    (Centre for Cancer Therapeutics, Ottawa Hospital Research Institute
    University of Ottawa)

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.

Suggested Citation

  • 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 Spi, 2024. "Complementary dual-virus strategy drives synthetic target and cognate T-cell engager expression for endogenous-antigen agnostic immunotherapy," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51498-0
    DOI: 10.1038/s41467-024-51498-0
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    References listed on IDEAS

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