Oncolytic Vesicular Stomatitis Virus in an Immunocompetent Model of MUC1-Positive or MUC1-Null Pancreatic Ductal Adenocarcinoma

Abstract

Vesicular stomatitis virus (VSV) is a promising oncolytic agent against various malignancies. Here, for the first time, we tested VSV in vitro and in vivo in a clinically relevant, immunocompetent mouse model of pancreatic ductal adenocarcinoma (PDA). Our system allows the study of virotherapy against PDA in the context of overexpression (80% of PDA patients) or no expression of human mucin 1 (MUC1), a major marker for poor prognosis in patients. In vitro, we tested three VSV recombinants, wildtype VSV, VSV-green fluorescent protein (VSV-GFP), and a safe oncolytic VSV-⌬M51-GFP, against five mouse PDA cell lines that either expressed human MUC1 or were MUC1 null. All viruses demonstrated significant oncolytic abilities independent of MUC1 expression, although VSV-⌬M51-GFP was somewhat less effective in two PDA cell lines. In vivo administration of VSV-⌬M51-GFP resulted in significant reduction of tumor growth for tested mouse PDA xenografts (؉MUC1 or MUC1 null), and antitumor efficacy was further improved when the virus was combined with the chemotherapeutic drug gemcitabine. The antitumor effect was transient in all tested groups. The developed system can be used to study therapies involving various oncolytic viruses and chemotherapeutics, with the goal of inducing tumor-specific immunity while preventing premature virus clearance.

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

“…Although the exact mechanism of oncoselectivity of such non-replicating VSV particles is unclear, the study showed that, compared to normal cells, the cancer cells were more sensitive to replication-deficient VSV-mediated cell death due to their defective type I IFN signalling [53]. In contrast to this study, one of our own studies showed that UV-killed VSV-DM51-GFP enhanced tumour growth in an immunocompetent mouse model of pancreatic ductal adenocarcinoma (PDAC) [54]. The mechanism is unclear and will be examined in our future studies.…”

“…Combining VSV with chemical agents Previously, combining VSV with the chemotherapeutic drug doxorubicin improved therapeutic effect [87]. Our own group combined VSV-DM51-GFP with the chemotherapeutic drug gemcitabine and observed improved antitumour efficacy in a mouse PDAC xenograft model [54]. It has been previously shown that combining VSV with obatoclax, a B-cell lymphoma 2 (Bcl-2) inhibitor, reversed resistance of cancer cells to VSV-mediated oncolysis [88].…”

“…Our laboratory tested VSV in an immunocompetent mouse model of PDAC overexpressing or not expressing human mucin 1 (MUC1), a major marker for poor PDAC (and some other cancers) prognosis in patients [142]. In vivo administration of VSV-DM51-GFP resulted in significant, but transient, reduction of tumour growth for tested mouse PDAC xenografts (+MUC1 or MUC1 null) [54]. A recent review describes in detail murine tumour models for VSV efficacy studies [143].…”

An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells

“…and centrifuged at 4,000 × g for 10 min at 4°C to remove large cellular debris. Virus was purified by the method of Kalvodova et al with slight modifications described previously (Hastie et al, 2013; Kalvodova et al, 2009). Cell specific viral titers were obtained using plaque assay.…”

Oncolytic Rhabdoviruses

“…[73][74][75][76][77][78][79][80][81][82] Each has shown modest to promising success when combined with a VSV OV in cancer cells and/or murine tumor models. Some chemotherapeutics, such as Sunitinib and rapamycin, suppress the antiviral response, which sensitizes resistant tumors to OV therapy.…”