Arming oncolytic reovirus with GM-CSF gene to enhance immunity.
Vera KempDiana J M van den WollenbergMarcel G M CampsThorbald van HallPriscilla KindermanNadine Pronk-van MontfoortWytske M van WeerdenPublished in: Cancer gene therapy (2018)
Oncolytic reovirus administration has been well tolerated by cancer patients in clinical trials. However, its anti-cancer efficacy as a monotherapy remains to be augmented. We and others have previously demonstrated the feasibility of producing replication-competent reoviruses expressing a heterologous transgene. Here, we describe the production of recombinant reoviruses expressing murine (mm) or human (hs) GM-CSF (rS1-mmGMCSF and rS1-hsGMCSF, respectively). The viruses could be propagated up to 10 passages while deletion mutants occurred only occasionally. In infected cell cultures, the secretion of GM-CSF protein (up to 481 ng/106 cells per day) was demonstrated by ELISA. The secreted mmGM-CSF protein was functional in cell culture, as demonstrated by the capacity to stimulate the survival and proliferation of the GM-CSF-dependent dendritic cell (DC) line D1, and by its ability to generate DCs from murine bone marrow cells. Importantly, in a murine model of pancreatic cancer we found a systemic increase in DC and T-cell activation upon intratumoral administration of rS1-mmGMCSF. These data demonstrate that reoviruses expressing functional GM-CSF can be generated and have the potential to enhance anti-tumor immune responses. The GM-CSF reoviruses represent a promising new agent for use in oncolytic virotherapy strategies.
Keyphrases
- dendritic cells
- induced apoptosis
- bone marrow
- clinical trial
- immune response
- cerebrospinal fluid
- cell cycle arrest
- endothelial cells
- single cell
- oxidative stress
- stem cells
- signaling pathway
- binding protein
- cell therapy
- randomized controlled trial
- electronic health record
- open label
- artificial intelligence
- copy number
- cell proliferation
- wild type
- small molecule
- toll like receptor
- cell death
- phase ii
- induced pluripotent stem cells
- phase iii
- drug induced