Strategic combination of trastuzumab emtansine (T-DM1) with oncolytic rhabdoviruses leads to therapeutic synergy Rozanne Arulanandam1, Vanessa Garcia1 and Jean-Simon Diallo1* 1Ottawa Hospital Research Institute
The key to the success of combination therapy strategies for the treatment of malignancies is to achieve mechanistic synergy while retaining a favorable selectivity and safety profile. Our pioneering work in combining oncolytic viruses (OV) such as vesicular stomatitis virus (VSV) with small molecule “viral sensitizers” (or VSes), such as microtubule destabilizing agents (MDAs), supports this rationale where synergy in tumor cell death leads to increased therapeutic efficacy in various murine models of cancer (1). However, hurdles to the clinical advancement of our strategy include inadequate drug delivery and systemic toxicity of naked MDAs. Antibody-drug conjugate (ADC) technology facilitates the homing of covalently bound small molecules to the tumor compartment where the target antigen is expressed. Notably, the approved T-DM1 (Kadcyla), based on the well-established HER2-targeting mAb trastuzumab, employs an MDA as payload. We set out to evaluate whether the combination of T-DM1 with oncolytic VSV could lead to improved therapeutic outcomes. In line with our published data using MDAs, we reveal that combining T-DM1 with VSV can increase viral infection and spread of tumor cells expressing HER-2 with no impact on normal cells, while trastuzumab alone had no effect. This tumor killing synergy was demonstrated in VSV-resistant and HER2-low (albeit trastuzumab-binding) cells, as well as HER2-high breast and ovarian carcinoma lines. In vivo, co-treatment of VSV and T-DM1 delayed tumor progression in HER2 overexpressing but trastuzumab-refractory JIMT-1 human breast cancer xenografts compared to monotherapies. Furthermore, viral spread in cultured HER2+ human ovarian cancer patient-derived ascites samples was also enhanced by the combination of VSV and T-DM1. Our proof of concept data using the clinically approved T-DM1 in combination with VSV suggests that targeted delivery of a viral-sensitizing molecule using the ADC platform can indeed enhance OV activity and provides a rapid path to translation of this novel approach.
(1) Arulanandam et al., Nature Communications, 2015