Measles Vaccine Strains for Virotherapy of Non–Small-Cell Lung Carcinoma

• Published in: Journal of thoracic oncology Vol. 9; no. 8; pp. 1101 - 1110
• Main Authors: Patel, Manish R., Jacobson, Blake A., Belgum, Holly, Raza, Ahmad, Sadiq, Ahad, Drees, Jeremy, Wang, Hengbing, Jay-Dixon, Joseph, Etchison, Ryan, Federspiel, Mark J., Russell, Stephen J., Kratzke, Robert A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2014
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Antimetabolites, Antineoplastic - pharmacology; Apoptosis; Carcinoembryonic Antigen - drug effects; Carcinoembryonic Antigen - genetics; Carcinoembryonic Antigen - metabolism; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - therapy; Cell Adhesion Molecules - antagonists & inhibitors; Cell Adhesion Molecules - metabolism; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival - drug effects; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Epithelial Cells - virology; Eukaryotic Initiation Factor-4E - metabolism; Gemcitabine; Green Fluorescent Proteins - genetics; Humans; Hydrazones - pharmacology; Lung; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - therapy; Measles Vaccine; Measles virus; Measles virus - genetics; Measles virus - physiology; Membrane Cofactor Protein - antagonists & inhibitors; Membrane Cofactor Protein - metabolism; Mice; Non–small-cell lung cancer; Oncolytic Virotherapy; Phosphoproteins - metabolism; Sirolimus - pharmacology; Thiazoles - pharmacology; Translation; Tumor Burden; Virus Replication; Non–small-cell lung cancer; Translation; Measles virus
• ISSN: 1556-0864; 1556-1380
• DOI: 10.1097/JTO.0000000000000214

Oncolytic virus therapy is a promising therapy for numerous tumor types. Edmonston-strain measles virus (MV) has been tested in clinical trials for ovarian cancer, glioma, and myeloma. Therefore, the antitumor activity of MV against non–small-cell lung cancer (NSCLC) was assessed. Human NSCLC cells and immortalized lung epithelial cell lines, Beas2B, were infected with either MV-producing green fluorescent protein or MV-producing carcinoembryonic antigen. Cells were assessed for viability, induction of apoptosis by caspase and poly-ADP ribose polymerase cleavage, and for viral transgene production. The dependency of MV entry on CD46 and nectin-4 were determined using blocking antibodies. The role of host translational activity on viral replication was assessed by overexpression of eIF4E and translation inhibition. Antitumor activity was assessed by measuring treated NSCLC xenografts from flanks of nude mice. MV infection of NSCLC cells results in potent cell killing in most of the cell lines compared with immortalized Beas2B cells and induces apoptosis. MV infection was prevented by blocking of CD46, however independent of nectin-4 blockade. Tumor weights are diminished after intratumoral injections of MV-producing carcinoembryonic antigen in one of two cell lines and result in detectable viral transgene in serum of mice. These data indicate that MV is oncolytic for human NSCLC and this was independent of nectin-4 expression. Dysregulated protein translational machinery may play a role in determining tumor tropism in NSCLC. MV combined with gemcitabine could be explored further as chemovirotherapy for NSCLC.