Lymphokine-activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites.
Bottom Line: A major obstacle for effective oncolytic virotherapy is effective delivery of OV to tumor cells.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.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.
Affiliation: Targeted & Biological Therapies Group, Leeds Institute of Molecular Medicine, University of Leeds, United Kingdom.Show MeSH
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Mentions: Whilst reovirus-induced oncolysis of ovarian cancer cell lines has been previously demonstrated,7 the effects of reovirus-induced oncolysis on primary human ovarian cancer cells and its effects in the context of ascitic fluid have not been examined. In the absence of ascites, reovirus was cytotoxic against three established ovarian cancer cell lines, Skov-3, OVCA433 and TR175 (Fig. 1a) and, importantly, against 10 primary ovarian cancer cell samples freshly isolated from patients’ ascites, albeit with varying sensitivities (Fig. 1c). However, in the presence of 2.5 % ascitic fluid, reovirus-induced cytotoxicity was significantly inhibited in all cell lines and in four out of four patient tumor samples cultured in autologous ascites (Figs. 1a and 1d). Reovirus replication was also examined following infection of ovarian cancer cells ± ascites. In the absence of ascites, reovirus readily replicated in ovarian cancer cell lines (Fig. 1b) and primary ovarian cancer cells (Fig. 1e, although at 10- to 1000-fold lower levels than those detected in cell lines). However, in the presence of ascites, reovirus replication, in line with tumor cell killing, was significantly abrogated (Figs. 1b and 1e).
Affiliation: Targeted & Biological Therapies Group, Leeds Institute of Molecular Medicine, University of Leeds, United Kingdom.