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

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. Electronic supplementary material The online version of this article (10.1186/s12967-019-1829-z) contains supplementary material, which is available to authorized users.

Myxoma Virus-Loaded Mesenchymal Stem Cells in Experimental Oncolytic Therapy of Murine Pulmonary Melanoma

“… 10 MSCs were used for delivering measles virus, 13 , 14 herpes simplex virus, 15 adenovirus, 16 and vaccinia virus. 17 Here, we used human bone-marrow-derived MSCs to deliver recombinant oncolytic myxoma virus (MYXV).…”

Myxoma Virus Expressing LIGHT (TNFSF14) Pre-Loaded into Adipose-Derived Mesenchymal Stem Cells Is Effective Treatment for Murine Pancreatic Adenocarcinoma

“…Ex-vivo-expanded hypoimmunogenic human adipose-derived stem cells (ADSCs) represent a unique delivery platform for OVs. They combine a natural capacity to home to inflammatory sites with a tumor tropism that is coupled with potent amplification of the OV load and transient suppression of anti-viral innate immunity, which hinders OVs from colonizing the tumor site and infecting cancer cells [ 33 ]. Importantly, IFNγ, which is involved in the induction of an anti-viral state, also modulates immunosuppressive features of ADSCs, counteracting anti-viral immunity.…”

“…In a previous study, we showed that the therapy targeting experimentally induced lung melanoma in mice with IL-15-encoding MYXV construct (vMyx-IL15Rα-tdTr) delivered by MSCs was effective and was able to reduce the tumor burden as well as triggering the inflow of CD8+ cells [ 33 ]. Here, we demonstrate another ADSC-shielded recombinant MYXV that expresses LIGHT protein, used to extend the survival of treated mice and to increase the influx of T lymphocytes into the tumor.…”

Current strategies to circumvent the antiviral immunity to optimize cancer virotherapy

“… 27 High costs associated with loading cells with OVs ex vivo may be reduced using off-the-shelf, allogeneic stem cells. 30 Delivery of OVs using cellular carriers is already being investigated in the clinical arena. 34 For instance, MSCs loaded with AdV were shown to be safe in pediatric and adult solid tumors.…”