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Open Access 01-12-2019 | Vaccinia Virus | Research

Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers

Authors: Dobrin D. Draganov, Antonio F. Santidrian, Ivelina Minev, Duong Nguyen, Mehmet Okyay Kilinc, Ivan Petrov, Anna Vyalkova, Elliot Lander, Mark Berman, Boris Minev, Aladar A. Szalay

Published in: Journal of Translational Medicine | Issue 1/2019

Abstract

Background

Previous studies have identified IFNγ as an important early barrier to oncolytic viruses including vaccinia. The existing innate and adaptive immune barriers restricting oncolytic virotherapy, however, can be overcome using autologous or allogeneic mesenchymal stem cells as carrier cells with unique immunosuppressive properties.

Methods

To test the ability of mesenchymal stem cells to overcome innate and adaptive immune barriers and to successfully deliver oncolytic vaccinia virus to tumor cells, we performed flow cytometry and virus plaque assay analysis of ex vivo co-cultures of stem cells infected with vaccinia virus in the presence of peripheral blood mononuclear cells from healthy donors. Comparative analysis was performed to establish statistically significant correlations and to evaluate the effect of stem cells on the activity of key immune cell populations.

Results

Here, we demonstrate that adipose-derived stem cells (ADSCs) have the potential to eradicate resistant tumor cells through a combination of potent virus amplification and sensitization of the tumor cells to virus infection. Moreover, the ADSCs demonstrate ability to function as a virus-amplifying Trojan horse in the presence of both autologous and allogeneic human PBMCs, which can be linked to the intrinsic immunosuppressive properties of stem cells and their unique potential to overcome innate and adaptive immune barriers. The clinical application of ready-to-use ex vivo expanded allogeneic stem cell lines, however, appears significantly restricted by patient-specific allogeneic differences associated with the induction of potent anti-stem cell cytotoxic and IFNγ responses. These allogeneic responses originate from both innate (NK)- and adaptive (T)- immune cells and might compromise therapeutic efficacy through direct elimination of the stem cells or the induction of an anti-viral state, which can block the potential of the Trojan horse to amplify and deliver vaccinia virus to the tumor.

Conclusions

Overall, our findings and data indicate the feasibility to establish simple and informative assays that capture critically important patient-specific differences in the immune responses to the virus and stem cells, which allows for proper patient-stem cell matching and enables the effective use of off-the-shelf allogeneic cell-based delivery platforms, thus providing a more practical and commercially viable alternative to the autologous stem cell approach.

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Title: Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers
Authors: Dobrin D. Draganov
Antonio F. Santidrian
Ivelina Minev
Duong Nguyen
Mehmet Okyay Kilinc
Ivan Petrov
Anna Vyalkova
Elliot Lander
Mark Berman
Boris Minev
Aladar A. Szalay
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Vaccinia Virus
Vaccinia Virus Infection
Published in: Journal of Translational Medicine / Issue 1/2019
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-019-1829-z

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EV-associated miRNAs from peritoneal lavage as potential diagnostic biomarkers in colorectal cancer

Upregulation of mitotic bookmarking factors during enhanced proliferation of human stromal cells in human platelet lysate

Role of MAML1 in targeted therapy against the esophageal cancer stem cells

Revealing the pathogenic changes of PAH based on multiomics characteristics

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page