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

溶瘤病毒 水泡性口炎病毒 牛痘 病毒 癌症研究 病毒学 抗原 T细胞 免疫疗法 生物 免疫学 免疫系统 生物化学 基因 重组DNA
作者
Zaid Taha,Mathieu J.F. Crupi,Nouf Alluqmani,Duncan S. MacKenzie,Sydney Vallati,Jack T. Whelan,Faiha Fareez,Akram Alwithenani,Julia Petryk,Andrew X. Chen,Marcus M. Spinelli,K. W. Ng,Judy Sobh,Christiano Tanese de Souza,Priya Rose Bharadwa,Timothy Kit Hin Lee,Dyna Susan Thomas,Ben Zhen Huang,Omar Kassas,Joanna Poutou,Victoria H. Gilchrist,Stephen Boulton,Max Thomson,Ricardo Marius,Mohsen Hooshyar,Scott McComb,Rozanne Arulanandam,Carolina S. Ilkow,John C. Bell,Jean‐Simon Diallo
出处
期刊:Nature Communications [Springer Nature]
卷期号:15 (1)
标识
DOI:10.1038/s41467-024-51498-0
摘要

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.
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