Arming oncolytic reovirus with GM-CSF gene to enhance immunity.

Abstract:

: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.

journal_name

Cancer Gene Ther

journal_title

Cancer gene therapy

authors

Kemp V,van den Wollenberg DJM,Camps MGM,van Hall T,Kinderman P,Pronk-van Montfoort N,Hoeben RC

doi

10.1038/s41417-018-0063-9

subject

Has Abstract

pub_date

2019-09-01 00:00:00

pages

268-281

issue

9-10

eissn

0929-1903

issn

1476-5500

pii

10.1038/s41417-018-0063-9

journal_volume

26

pub_type

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