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

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

Communications biology (2020-05-24)
Rozanne Arulanandam, Zaid Taha, Vanessa Garcia, Mohammed Selman, Andrew Chen, Oliver Varette, Anna Jirovec, Keara Sutherland, Elizabeth Macdonald, Fanny Tzelepis, Harsimrat Birdi, Nouf Alluqmani, Anne Landry, Anabel Bergeron, Barbara Vanderhyden, Jean-Simon Diallo
摘要

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.

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Sigma-Aldrich
OptiPrep密度梯度培养基, used for cell and subcellular organelle isolation
Sigma-Aldrich
秋水仙碱, ≥95% (HPLC), powder
Sigma-Aldrich
酸性蓝83, Dye content ~50 %, Technical grade