Specific targeting of glioblastoma with an oncolytic virus expressing a cetuximab-CCL5 fusion protein via innate and adaptive immunity

Lei Tian, Bo Xu, Yuqing Chen, Zhenlong Li, Jing Wang, Jianying Zhang, Rui Ma, Shuai Cao, Weidong Hu, E. Antonio Chiocca, Balveen Kaur, Michael A. Caligiuri, Jianhua Yu

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Chemokines such as C-C motif ligand 5 (CCL5) regulate immune cell trafficking in the tumor microenvironment (TME) and govern tumor development, making them promising targets for cancer therapy. However, short half-lives and toxic off-target effects limit their application. Oncolytic viruses (OVs) have become attractive therapeutic agents. Here, we generate an oncolytic herpes simplex virus type 1 (oHSV) expressing a secretable single-chain variable fragment of the epidermal growth factor receptor (EGFR) antibody cetuximab linked to CCL5 by an Fc knob-into-hole strategy that produces heterodimers (OV-Cmab-CCL5). OV-Cmab-CCL5 permits continuous production of CCL5 in the TME, as it is redirected to EGFR+ glioblastoma (GBM) tumor cells. OV-Cmab-CCL5 infection of GBM significantly enhances the migration and activation of natural killer cells, macrophages and T cells; inhibits tumor EGFR signaling; reduces tumor size; and prolongs survival of GBM-bearing mice. Collectively, our data demonstrate that OV-Cmab-CCL5 offers a promising approach to improve OV therapy for solid tumors.

Original languageEnglish (US)
Pages (from-to)1318-1335
Number of pages18
JournalNature Cancer
Volume3
Issue number11
DOIs
StatePublished - Nov 2022
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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