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.What’s new?Oncolytic viruses (OVs) specifically infect and kill tumor cells. In this study, the authors began to examine whether intraperitoneal delivery of an OV could be effective against ovarian cancer. They found that, while the virus does kill ovarian-cancer cells in vitro, this effect is blocked when ascites fluid is added. Cytotoxicity can be restored, however, by using a combination of lymphokine-activated killer and dendritic cells (LAKDC) as carriers, which protect the virus from neutralizing antibodies in the ascites. The LAKDC combination may also support subsequent adaptive immune priming.

Antibody-Neutralized Reovirus Is Effective in Oncolytic Virotherapy

“…Systemic delivery is safe, broadly applicable in a clinical setting, and more suitable for targeting visceral or widespread metastatic disease. We and others have previously investigated an approach that circumvents NAb-mediated neutralization by delivering virus within carrier cells (3,4). This strategy is also clinically challenging but unexpectedly, developments from this work indicated a potential positive role for NAb in OV therapy.…”

Immunotherapy for Ovarian Cancer

“…Reovirus is also oncolytic against human OC cells in vitro [110] . Neutralizing antibodies in malignant ascites can inactivate reovirus oncolytic activity, which can be overcome by loading reovirus onto immature DCs or lymphokine-activated killer cells [111] . A phase I trial of reovirus in platinum-resistant OC patients is ongoing (NCT00602277).…”

Evolution of Reovirus in Cancer Therapy

“…As reviewed by Roy et al, multiple steps have been attempted to ameliorate the systemic delivery of OVs with the use of cell carriers. [98] It is noteworthy that immune cells loaded with reovirus can shield the virus from circulating NARAs and deliver it to tumor cells, [95,99] and represent a clinically feasible means of enhancing systemic reovirus delivery to the tumor cells.…”