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

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, vesic...

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Published in:	Nature communications Vol. 15; no. 1; pp. 7267 - 20
Main Authors:	Taha, Zaid, Crupi, Mathieu Joseph François, Alluqmani, Nouf, MacKenzie, Duncan, Vallati, Sydney, Whelan, Jack Timothy, Fareez, Faiha, Alwithenani, Akram, Petryk, Julia, Chen, Andrew, Spinelli, Marcus Mathew, Ng, Kristy, Sobh, Judy, de Souza, Christiano Tanese, Bharadwa, Priya Rose, Lee, Timothy Kit Hin, Thomas, Dylan Anthony, Huang, Ben Zhen, Kassas, Omar, Poutou, Joanna, Gilchrist, Victoria Heather, Boulton, Stephen, Thomson, Max, Marius, Ricardo, Hooshyar, Mohsen, McComb, Scott, Arulanandam, Rozanne, Ilkow, Carolina Solange, Bell, John Cameron, Diallo, Jean-Simon
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 23-08-2024 Nature Publishing Group Nature Portfolio
Subjects:	13/106 13/31 14 38 42 59 59/5 631/67/1059/2325 631/67/580 692/4028/67/580 82/29 82/51 96/35 Animals Antigens Biocompatibility Cancer Cancer therapies CD3 antigen Cell Line, Tumor Disease resistance Effectiveness ErbB-2 protein Female Humanities and Social Sciences Humans Immunotherapy Immunotherapy - methods Lymphocytes T Mice Mice, Inbred BALB C multidisciplinary Oncolysis Oncolytic Virotherapy - methods Oncolytic Viruses - genetics Oncolytic Viruses - immunology Plant viruses Receptor, ErbB-2 - genetics Receptor, ErbB-2 - immunology Receptor, ErbB-2 - metabolism Science Science (multidisciplinary) Stomatitis T-Lymphocytes - immunology Trastuzumab Trastuzumab - pharmacology Trastuzumab - therapeutic use Tumor microenvironment Tumor Microenvironment - immunology Tumors Vaccinia virus - genetics Vaccinia virus - immunology Vesiculovirus - genetics Vesiculovirus - immunology Viruses Xenograft Model Antitumor Assays
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Summary:	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. Oncolytic viruses (OVs) represent a treatment option for patients with cancer. Here the authors propose a tumour-agnostic dual-virus strategy for cancer therapy by generating a vesicular stomatitis virus encoding a truncated version of HER2, combined with a vaccinia virus as a delivery platform for a HER2-targeted T-cell engager.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-51498-0