Chemovirotherapy for pancreatic cancer: Gemcitabine plus oncolytic measles vaccine virus

Abstract

Oncolytic virotherapy with vaccine viruses employs replicative vectors, which quite selectively infect tumor cells leading to massive virus replication followed by subsequent profound tumor cell death (oncolysis). Measles vaccine virus (MeV) has already shown great oncolytic activity against different types of cancers, including pancreatic cancer. Gemcitabine is a first line chemotherapeutic drug used for pancreatic cancer in palliative treatment plans. Furthermore, this drug can be used to induce senescence, a permanent cell cycle arrest, in tumor cells. In our preclinical work, three well-characterized immortalized human pancreatic cancer cell lines were used to investigate the combinatorial effect of MeV-based virotherapy together with the chemo therapeutic compound gemcitabine. Viability assays revealed that the combination of only small amounts of MeV together with subtherapeutic concentrations of gemcitabine resulted in a tumor cell mass reduction of >50%. To further investigate the replication of the oncolytic MeV vectors under these distinct combinatorial conditions, viral growth curves were generated. As a result, viral replication was found to be only slightly diminished in the presence of gemcitabine. As gemcitabine induces senescence, the effect of MeV on that phenomenon was explored using a senescence-associated β-galactosidase assay. Notably, gemcitabine-induced tumor cell senescence was not impaired by MeV. Accordingly, the chemovirotherapeutic combination of gemcitabine plus oncolytic MeV constitutes a novel therapeutic option for advanced pancreatic carcinoma that is characterized by the mutual improvement of the effectiveness of each therapeutic component.

Measles Virus as an Oncolytic Immunotherapy

“…Synergistic effects of oncolytic MeV and radiotherapy against glioblastoma were observed in vitro and in a xenograft model [ 48 ]. In vitro studies have also demonstrated successful combination of oncolytic MeV with chemotherapies such as paclitaxel [ 49 ], camptothecin [ 50 ], and gemcitabine [ 51 ]. Combination with the anti-epidermal growth factor receptor (EGFR) monoclonal antibody nimotuzumab was reported to result in increased antitumor efficacy in laryngeal cancer models [ 52 ].…”

The Interaction of Viruses with the Cellular Senescence Response

“…Thus, infection with MV has been reported to accelerate the lysis of a panel of cancer cell lines induced into senescence after treatment with chemotherapeutic drugs [ 140 ]. The combinatorial effect of measles-based virotherapy, together with the chemotherapeutic agent that induces senescence, gemcitabine, on human pancreatic cancer cell lines, has also been evaluated [ 141 ]. The authors found that the combination was significantly more effective than the individual treatments reducing cell viability.…”

Expanding the Spectrum of Pancreatic Cancers Responsive to Vesicular Stomatitis Virus-Based Oncolytic Virotherapy: Challenges and Solutions

“…The chemovirotherapeutic combination of gemcitabine plus oncolytic MeV resulted in improved tumor reduction in vitro (hPDAC cell lines) [157].…”