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 |
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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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