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: To determine whether the inhibition of reovirus was ascites-specific or systemic, matched plasma and ascites samples from ovarian cancer patients were analyzed. Both plasma and ascites inhibited reovirus-induced cytotoxicity to a similar level, as seen by neutralization of L929 cell death (Fig. 2a). These data suggest a systemic inhibitory factor was responsible; hence, we hypothesized that NAb may play a role in reovirus inhibition. To establish whether reovirus was directly bound to NAb in the ascites, immunoprecipitation assays were performed. Reovirus σ3 capsid protein was successfully immunoprecipitated with IgG in six ascites samples tested; a representative blot is shown in Figure 2b. Furthermore, removing IgG from the ascites, confirmed by ELISA (Fig. 2c), significantly restored reovirus-induced cytotoxicity (Fig. 2d), indicating a major role for IgG inhibiting reovirus-induced cell death in ascites. To determine whether complement proteins were also involved in the inhibition of reovirus, ascites samples were heated to 56°C for 30 min to inactivate complement before neutralization assays were performed. There was no difference observed in reovirus-induced cytotoxicity when comparing heat-inactivated ascites to nonheat-inactivated ascites (Fig. 2e), or heat inactivated plasma versus nonheat inactivated plasma (data not shown), confirming that complement was not involved in the inhibition of reovirus.
Affiliation: Targeted & Biological Therapies Group, Leeds Institute of Molecular Medicine, University of Leeds, United Kingdom.