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

doi:10.1038/s43018-022-00448-0

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

Nat Cancer. 2022 Nov;3(11):1318-1335. doi: 10.1038/s43018-022-00448-0. Epub 2022 Nov 10.

Authors

Lei Tian^#¹, Bo Xu^#¹, Yuqing Chen¹, Zhenlong Li¹, Jing Wang¹, Jianying Zhang², Rui Ma¹, Shuai Cao¹, Weidong Hu³, E Antonio Chiocca⁴, Balveen Kaur⁵, Michael A Caligiuri^{6

7}, Jianhua Yu^{8

9

10}

Affiliations

¹ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA.
² Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA, USA.
³ Department of Immunology and Theranostics, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Los Angeles, CA, USA.
⁴ Department of Neurosurgery, Brigham and Women's Hospital and Harvey Cushing Neurooncology Laboratories, Harvard Medical School, Boston, MA, USA.
⁵ Georgia Cancer Center, Augusta University Medical Center, Augusta, GA, USA.
⁶ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. mcaligiuri@coh.org.
⁷ Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, USA. mcaligiuri@coh.org.
⁸ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. jiayu@coh.org.
⁹ Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, USA. jiayu@coh.org.
¹⁰ Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Los Angeles, CA, USA. jiayu@coh.org.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity
Animals
Brain Neoplasms* / therapy
Cetuximab / pharmacology
Chemokine CCL5 / metabolism
ErbB Receptors / genetics
Glioblastoma* / genetics
Herpesvirus 1, Human*
Mice
Oncolytic Virotherapy*
Oncolytic Viruses* / genetics
Tumor Microenvironment

Substances

Cetuximab
ErbB Receptors
Chemokine CCL5

Abstract

Publication types

MeSH terms

Substances

Grants and funding