title: Lymphokine-activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites.
abstract: Reovirus is an oncolytic virus (OV), which acts by both direct tumor cell killing and priming of antitumor immunity. A major obstacle for effective oncolytic virotherapy is effective delivery of OV to tumor cells. Ovarian cancer is often confined to the peritoneal cavity and therefore i.p. delivery of reovirus may provide the ideal locoregional delivery, avoiding systemic dissemination. However, ovarian cancer is associated with an accumulation of ascitic fluid, which may interfere with oncolytic viral therapy. Here, we investigated the effect of ascites on reovirus-induced oncolysis against primary ovarian cancer cells and ovarian cancer cell lines. In the absence of ascites, reovirus was cytotoxic against ovarian cancer cells; however, cytotoxicity was abrogated in the presence of ascitic fluid. Neutralizing antibodies (NAb) were identified as the cause of this inhibition. Loading OV onto cell carriers may facilitate virus delivery in the presence of NAb and immune cells which have their own antitumor effector activity are particularly appealing. Immature dendritic cells (iDC), Lymphokine-activated killer (LAK) cells and LAKDC cocultures were tested as potential carriers for reovirus for tumor cell killing and immune cell priming. Reovirus-loaded LAKDC, and to a lesser degree iDC, were able to: (i) protect from NAb and hand-off reovirus for tumor cell killing; (ii) induce a proinflammatory cytokine milieu (IFNɣ, IL-12, IFNα and TNFα) and (iii) generate an innate and specific antitumor adaptive immune response. Hence, LAKDC pulsed with reovirus represent a novel, clinically practical treatment for ovarian cancer to maximise both direct and innate/adaptive immune-mediated tumor cell killing.
authors: Targeted & Biological Therapies Group, Leeds Institute of Molecular Medicine, University of Leeds, United Kingdom.
authors: V A
authors: VA
authors: Jennings
authors: E J
authors: EJ
authors: Ilett
authors: K J
authors: KJ
authors: Scott
authors: E J
authors: EJ
authors: West
authors: R
authors: R
authors: Vile
authors: H
authors: H
authors: Pandha
authors: K
authors: K
authors: Harrington
authors: A
authors: A
authors: Young
authors: G D
authors: GD
authors: Hall
authors: M
authors: M
authors: Coffey
authors: P
authors: P
authors: Selby
authors: F
authors: F
authors: Errington-Mais
authors: A A
authors: AA
authors: Melcher
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D017209:Apoptosis; D001201:Ascites / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D050130:Oncolytic Virotherapy; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D012087:Reoviridae / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D057134:Antibodies, Neutralizing; D016207:Cytokines
keywords: antitumor immunity; malignant ascites; neutralizing antibodies; reovirus
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