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

• Published in: Journal of translational medicine 2019-03, Vol.17 (1), p.100-22, Article 100
• Main Authors: Draganov, Dobrin D, Santidrian, Antonio F, Minev, Ivelina, Nguyen, Duong, Kilinc, Mehmet Okyay, Petrov, Ivan, Vyalkova, Anna, Lander, Elliot, Berman, Mark, Minev, Boris, Szalay, Aladar A
• Format: Article
• Language: English
• Subjects: A549 Cells; Adaptive Immunity - physiology; Adipose Tissue - cytology; Adipose Tissue - immunology; Adult Stem Cells - immunology; Adult Stem Cells - transplantation; Adult Stem Cells - virology; Allogeneic Cells - cytology; Allogeneic Cells - immunology; Animals; Antiviral agents; Autografts; Cancer; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; Cells, Cultured; Chlorocebus aethiops; Comparative analysis; Cytotoxicity; Data processing; Disease susceptibility; Feasibility studies; Flow cytometry; Humans; Immune response; Immune Tolerance; Immunity, Innate - physiology; Immunomodulation - physiology; Immunotherapy; Immunotherapy, Adoptive - methods; Infections; Investigations; K562 Cells; Leukocytes (mononuclear); Malware; Mesenchyme; Mice; Oncolysis; Oncolytic Virotherapy - methods; Oncolytic virus; Oncolytic Viruses - immunology; Peripheral blood mononuclear cells; Plaque assay; Statistical analysis; Stem Cells; Test procedures; Transplantation, Homologous - methods; Tumor cells; Tumors; Vaccinia; Vaccinia virus - immunology; Vaccinia virus - physiology; Vaccinium; Viral infections; Virotherapy; Viruses; γ-Interferon
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-019-1829-z

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. 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. 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. 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.