Oncolytic measles and vesicular stomatitis virotherapy for endometrial cancer

Abstract

Objective: Current adjuvant therapy for advanced-stage, recurrent, and high-risk endometrial cancer (EC) has not reduced mortality from this malignancy, and novel systemic therapies are imperative. Oncolytic viral therapy has been shown to be effective in the treatment of gynecologic cancers, and we investigated the in vitro and in vivo efficacy of the Edmonston strain of measles virus (MV) and vesicular stomatitis virus (VSV) on EC.

Methods: Human EC cell lines (HEC-1-A, Ishikawa, KLE, RL95-2, AN3 CA, ARK-1, ARK-2, and SPEC-2) were infected with Edmonston strain MV expressing the thyroidal sodium iodide symporter, VSV expressing either human or murine IFN-β, or recombinant VSV with a methionine deletion at residue 51 of the matrix protein and expressing the sodium iodide symporter. Xenografts of HEC-1-A and AN3 CA generated in athymic mice were treated with intratumoral MV or VSV or intravenous VSV.

Results: In vitro, all cell lines were susceptible to infection and cell killing by all 3 VSV strains except KLE. In addition, the majority of EC cell lines were defective in their ability to respond to type I IFN. Intratumoral VSV-treated tumors regressed more rapidly than MV-treated tumors, and intravenous VSV resulted in effective tumor control in 100% of mice. Survival was significantly longer for mice treated with any of the 3 VSV strains compared with saline.

Conclusion: VSV is clearly more potent in EC oncolysis than MV. A phase 1 clinical trial of VSV in EC is warranted.

Keywords: 50% tissue culture infective dose; CD46; DMEM; Dulbecco Modified Eagle Medium; EC; Edmonston strain MV expressing the thyroidal sodium iodide symporter; Endometrial cancer; GFP; IT; IV; LDLR; M51 protein; MOI; MV; MV-NIS; Measles virus; NIS; NOAEL; OV; Oncolytic virotherapy; PE; PVRL4; R-phycoerythrin; TCID(50); VSV; VSV-M51-NIS; VSV-hIFNβ; VSV-mIFNβ; Vesicular stomatitis virus; cluster of differentiation 46; endometrial cancer; green fluorescent protein; hIFNβ; human IFN-β; intratumoral; intravenous; low density lipoprotein receptor; mIFNβ; measles virus; multiplicity of infection; murine IFN-β; no adverse event level; oncolytic virus; poliovirus receptor-related 4; qRT; quantitative real-time; residue 51 of the matrix protein; sodium iodide symporter; vesicular stomatitis virus; vesicular stomatitis virus expressing human IFN-β; vesicular stomatitis virus expressing murine IFN-β; vesicular stomatitis virus with a methionine deletion at residue 51 of the matrix protein and expressing the sodium iodide symporter.