The strategic combination of trastuzumab emtansine with oncolytic rhabdoviruses leads to therapeutic synergy

Autor: Anabel Bergeron, Vanessa Garcia, Rozanne Arulanandam, Fanny Tzelepis, Jean-Simon Diallo, Harsimrat Kaur Birdi, Anne Landry, Andrew Chen, Anna Jirovec, Oliver Varette, Keara Sutherland, Mohammed Selman, Zaid Taha, Nouf Alluqmani, Elizabeth Macdonald, Barbara C. Vanderhyden
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Medicine (miscellaneous)
Apoptosis
Mice
chemistry.chemical_compound
0302 clinical medicine
Trastuzumab
Antineoplastic Combined Chemotherapy Protocols
Tumor Cells
Cultured
Medicine
skin and connective tissue diseases
lcsh:QH301-705.5
Oncolytic Virotherapy
biology
Drug Synergism
Combined Modality Therapy
Vesicular stomatitis virus
030220 oncology & carcinogenesis
Female
Rhabdoviridae
General Agricultural and Biological Sciences
medicine.drug
Combination therapy
Mice
Nude
Breast Neoplasms
Article
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Targeted therapies
mental disorders
Animals
Humans
Chemotherapy
Maytansine
neoplasms
Cell Proliferation
business.industry
Cancer
biology.organism_classification
medicine.disease
Xenograft Model Antitumor Assays
Oncolytic virus
030104 developmental biology
chemistry
lcsh:Biology (General)
Trastuzumab emtansine
Cancer cell
Cancer research
business
Ovarian cancer
Zdroj: Communications Biology, Vol 3, Iss 1, Pp 1-10 (2020)
Communications Biology
ISSN: 2399-3642
Popis: We have demonstrated that microtubule destabilizing agents (MDAs) can sensitize tumors to oncolytic vesicular stomatitis virus (VSVΔ51) in various preclinical models of cancer. The clinically approved T-DM1 (Kadcyla®) is an antibody-drug conjugate consisting of HER2-targeting trastuzumab linked to the potent MDA and maytansine derivative DM1. We reveal that combining T-DM1 with VSVΔ51 leads to increased viral spread and tumor killing in trastuzumab-binding, VSVΔ51-resistant cancer cells. In vivo, co-treatment of VSVΔ51 and T-DM1 increased overall survival in HER2-overexpressing, but trastuzumab-refractory, JIMT1 human breast cancer xenografts compared to monotherapies. Furthermore, viral spread in cultured HER2+ human ovarian cancer patient-derived ascites samples was enhanced by the combination of VSVΔ51 and T-DM1. Our data using the clinically approved Kadcyla® in combination with VSVΔ51 demonstrates proof of concept that targeted delivery of a viral-sensitizing molecule using an antibody-drug conjugate can enhance oncolytic virus activity and provides rationale for translation of this approach.
Arulanandam et al. demonstrate that HER2 positive cancer cells are sensitized to oncolytic rhabdovirus by an antibody-drug conjugate consisting of HER2- targeting trastuzumab linked to the microtubule destabiliser DM1. This study suggests the potential of such combination therapy in the treatment of HER2-positive cancers.
Databáze: OpenAIRE
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