Oncolytic measles and vesicular stomatitis virotherapy for endometrial cancer.
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.
['Liu|Yu-Ping|YP|', 'Steele|Michael B|MB|', 'Suksanpaisan|Lukkana|L|', 'Federspiel|Mark J|MJ|', 'Russell|Stephen J|SJ|', 'Peng|Kah Whye|KW|', 'Bakkum-Gamez|Jamie N|JN|']
D000818:Animals D045744:Cell Line, Tumor D016889:Endometrial Neoplasms D005260:Female D006801:Humans D007370:Interferon Type I D008459:Measles virus D051379:Mice D050130:Oncolytic Virotherapy D014721:Vesicular stomatitis Indiana virus
Endometrial cancer Endometrial cancer EC Measles virus Measles virus MV Vesicular stomatitis virus Vesicular stomatitis virus VSV Edmonston strain MV expressing the thyroidal sodium iodide symporter sodium iodide symporter murine IFN-β residue 51 of the matrix protein intratumoral intravenous 50% tissue culture infective dose CD46 DMEM Dulbecco Modified Eagle Medium GFP IT IV LDLR M51 protein MOI MV-NIS NIS NOAEL OV Oncolytic virotherapy PE PVRL4 R-phycoerythrin TCID(50) VSV-M51-NIS VSV-hIFNβ VSV-mIFNβ cluster of differentiation 46 endometrial cancer green fluorescent protein hIFNβ human IFN-β low density lipoprotein receptor mIFNβ measles virus multiplicity of infection no adverse event level oncolytic virus poliovirus receptor-related 4 qRT quantitative real-time 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