Chemovirotherapy of Pancreatic Adenocarcinoma by Combining Oncolytic Vaccinia Virus GLV-1h68 with nab -Paclitaxel Plus Gemcitabine

Abstract

Oncolytic viruses have proven their therapeutic potential against a variety of different tumor entities both in vitro and in vivo. Their ability to selectively infect and lyse tumor cells, while sparing healthy tissues, makes them favorable agents for tumor-specific treatment approaches. Particularly, the addition of virotherapeutics to already established chemotherapy protocols (so-called chemovirotherapy) is of major interest. Here we investigated the in vitro cytotoxic effect of the oncolytic vaccinia virus GLV-1h68 combined with dual chemotherapy with nab-paclitaxel plus gemcitabine in four human pancreatic adenocarcinoma cell lines (AsPc-1, BxPc-3, MIA-PaCa-2, and Panc-1). This chemovirotherapeutic protocol resulted in enhanced tumor cell killing in two tumor cell lines compared to the respective monotherapies. We were thereby able to show that the combination of oncolytic vaccinia virus GLV-1h68 with nab-paclitaxel and gemcitabine has great potential in the chemovirotherapeutic treatment of advanced pancreatic adenocarcinoma. However, the key to a successful combinatorial chemovirotherapeutic treatment seems to be a profound viral replication, as tumor cell lines that were non-responsive to the combination therapy exhibited a reduced viral replication in the presence of the chemotherapeutics. This finding is of special significance when aiming to achieve a virus-mediated induction of a profound and long-lasting antitumor immunity.

New frontiers in oncolytic viruses: optimizing and selecting for virus strains with improved efficacy

“…The oncolytic GLV1h68 was further evaluated in combination with chemotherapy applying nab -paclitaxel and gemcitabine, which provided enhanced tumor-cell killing in two of four human pancreatic adenocarcinoma cell lines. 145 The feasibility of chemovirotherapy seemed to be related to efficient viral replication, as the nonresponsive tumor-cell lines showed only low levels of viral replication.…”

Immune responses in the thyroid cancer microenvironment: making immunotherapy a possible mission

“…ICD may be a critical mechanism for the success of radiotherapy, especially due to the high mutational load in thyroid cancers, which creates neoantigens; a prerequisite for robust T cell responses in immunotherapies like immune checkpoint blockade (Rizvi et al 2015, Bailey et al 2016. OVs may be wellsuited for the treatment of thyroid cancers because many have been shown to elicit ICD through divergent cell death pathways (Donnelly et al 2013, Koks et al 2015 and have synergistic effects when used in combination with standard of care such as radiotherapy (Harrington et al 2010, Markert et al 2014, Wilkinson et al 2016) and chemotherapy (Kuryk et al 2016, Binz et al 2017). OVs may not only provide additional inflammatory stimuli in the form of pathogen-associated molecular patterns, but also limit the escape of tumors with mutations in key ICD pathways.…”

Development of oncolytic virotherapy: from genetic modification to combination therapy

“…Researchers have recently attempted to combine OVT with other antitumor therapies, including chemotherapy [43][44][45], radiotherapy [46,47], small molecules [48,49], and other immunotherapies [50,51], to achieve increased therapeutic effects against tumors. Among these treatments, the combination of OVT with other immunotherapies, especially regimens involving immune checkpoint inhibitors (ICIs) and chimeric antigen receptor-engineered T cell (CAR-T cell) immunotherapies, has shown promise as a cancer treatment [51,52].…”