Mesenchymal stem cells enhance the oncolytic effect of Newcastle disease virus in glioma cells and glioma stem cells via the secretion of TRAIL

3100 Background: Newcastle disease virus (NDV), an avian paramyxovirus, is tumor selective and oncolytic by induction of apoptosis. Preclinical and clinical studies in patients with glioblastoma (GBM) using NDV demonstrated occasional clinical benefits with no major side effects. Limitations to the use of NDV as virotherapy of GBM is the inefficient delivery into cancer cells in the brain. Methods: Mesenchymal stromal cells (MSCs) can migrate towards cancer cells. We examined potential delivery of oncolytic effect of NDV (MTH-68/H) against glioma cell lines and glioma stem cells (GSCs) and the ability of MSCs to deliver NDV to glioma cells and GSCs in culture. Results: NDV induced a dose-dependent cell death in the glioma cells U87, A172 and U251 with maximal effects at 10 MOI. In contrast, we found only small level of apoptosis or changes in self-renewal in three GSCs infected with NDV. We found that MSCs derived from bone marrow, adipose tissue and cord were successfully infected by NDV and were able to deliver the virus to co-cultured glioma cells and GSCs. In addition, treatment of glioma cells and GSCs with culture supernatant of infected MSCs increase apoptosis of glioma cells as compared to the effect of direct infection of glioma cells. Moreover, the culture supernatants of the infected MSCs induced cell death in GSCs that were resistant to the oncolytic effect of NDV, suggesting that factor(s) secreted by the infected MSCs sensitized the glioma cells and GSCs to the cytotoxic effects of NDV. Using antibody array and ELISA we identified TRAIL as the factor secreted from infected MSCs. Indeed, treatment of infected glioma cells with TRAIL increased the cytotoxic effect of NDV and sensitized GSCs to the oncolytic effects of NDV. Conclusions: MSCs can be employed to deliver NDV to GBM. In addition, MSCs can also sensitize glioma cells and GSCs to oncolysis by NDV. Considering the resistance of GSCs to chemotherapy and radiation therapy, treatment of GBM with MSC-mediated targeted oncolytic NDV may provide a new clinical tool for treatment of GBM and eradication of GSCs.

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Oncolytic Newcastle disease virus delivered by Mesenchymal stem cells-engineered system enhances the therapeutic effects altering tumor microenvironment in a murine papillomavirus tumor model

10.21203/rs.2.21140/v1 ◽

2020 ◽

Author(s):

mohsen Keshavarz ◽

Mir Saeed Ebrahimzadeh ◽

Seyed Mohammad Miri ◽

Hassan Dianat-Moghadam ◽

Seyedeh Sara Ghorbanhosseini ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Immune Responses ◽

Newcastle Disease Virus ◽

Cancer Immunotherapy ◽

Disease Virus ◽

Newcastle Disease ◽

Caspase 3

Abstract Background: Cervical cancer is the most common human papillomavirus (HPV)-related cancer caused by persistent genital high-risk HPV infection. Cancer immunotherapy has represented great potential as a new promising cancer therapeutic approach. Here, we report Mesenchymal stem cells (MSCs) as a carrier for the delivery of oncolytic Newcastle disease virus (NDV) for the treatment of HPV-associated tumor.Methods: For this purpose, MSCs obtained from the bone marrow of C57BL mice, then cultured and characterized subsequently by the flow cytometry analysis for the presence of cell surface markers. In this study, we sought out to determine the impacts of MSCs loaded with oncolytic NDV on splenic T cell and cytokine immune responses, caspase-3 and -9 expression, and myeloid and myeloid-derived suppressor cells (MDSCs) by histological and immunohistochemical studies in the tumor microenvironment (TME).Results: our findings proved that MSCs possess both migratory capacity and tumor tropism toward transplanted tumor tissue after peritumoral administration. Tumor therapy experiments indicated that oncolytic NDV delivered by MSCs-engineered system significantly reduces tumor growth, which is associated with the enhancement of E7-specific lymphocyte proliferation, CD8+ T cell cytolysis responses, and splenic IFN-γ, IL-4 and IL-12 responses compared with control groups. Moreover, the treatment upregulated the concentration of apoptotic proteins (caspase 3 and 9) and increased infiltration of tumor microenvironment with CD11b+myeloid and Gr1+MDSCs cells.Conclusions: Our data suggest MSCs carrying oncolytic NDV as a potentially effective strategy for cancer immunotherapy through inducing splenic Th1 immune responses and MDSCs expansion in the tumor microenvironment.

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Oncolytic Newcastle disease virus delivered by Mesenchymal stem cells-engineered system enhances the therapeutic effects altering tumor microenvironment

Virology Journal ◽

10.1186/s12985-020-01326-w ◽

2020 ◽

Vol 17 (1) ◽

Cited By ~ 2

Author(s):

Mohsen Keshavarz ◽

Mir Saeed Ebrahimzadeh ◽

Seyed Mohammad Miri ◽

Hassan Dianat-Moghadam ◽

Seyedeh Sara Ghorbanhosseini ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Immune Responses ◽

Newcastle Disease Virus ◽

Cancer Immunotherapy ◽

Disease Virus ◽

Newcastle Disease ◽

Therapeutic Effects

Abstract Background Human papillomavirus (HPV)-associated malignancy remain a main cause of cancer in men and women. Cancer immunotherapy has represented great potential as a new promising cancer therapeutic approach. Here, we report Mesenchymal stem cells (MSCs) as a carrier for the delivery of oncolytic Newcastle disease virus (NDV) for the treatment of HPV-associated tumor. Methods For this purpose, MSCs obtained from the bone marrow of C57BL mice, then cultured and characterized subsequently by the flow cytometry analysis for the presence of cell surface markers. In this study, we sought out to determine the impacts of MSCs loaded with oncolytic NDV on splenic T cell and cytokine immune responses, caspase-3 and -9 expression, and myeloid and myeloid-derived suppressor cells (MDSCs) by histological and immunohistochemical studies in the tumor microenvironment (TME). Results Our findings proved that MSCs possess both migratory capacity and tumor tropism toward transplanted tumor tissue after peritumoral administration. Tumor therapy experiments indicated that oncolytic NDV delivered by MSCs-engineered system significantly reduces tumor growth, which is associated with the enhancement of E7-specific lymphocyte proliferation, CD8+ T cell cytolysis responses, and splenic IFN-γ, IL-4 and IL-12 responses compared with control groups. Moreover, the treatment upregulated the concentration of apoptotic proteins (caspase 9) and increased infiltration of tumor microenvironment with CD11b + myeloid and Gr1 + MDSCs cells. Conclusions Our data suggest MSCs carrying oncolytic NDV as a potentially effective strategy for cancer immunotherapy through inducing splenic Th1 immune responses and apoptosis in the tumor microenvironment.

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Correction to: Oncolytic Newcastle disease virus delivered by Mesenchymal stem cells-engineered system enhances the therapeutic effects altering tumor microenvironment

Virology Journal ◽

10.1186/s12985-020-01444-5 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Mohsen Keshavarz ◽

Mir Saeed Ebrahimzadeh ◽

Seyed Mohammad Miri ◽

Hassan Dianat-Moghadam ◽

Seyedeh Sara Ghorbanhosseini ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Microenvironment ◽

Newcastle Disease Virus ◽

Disease Virus ◽

Newcastle Disease ◽

Therapeutic Effects

An amendment to this paper has been published and can be accessed via the original article.

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Oncolytic Newcastle disease virus delivered by Mesenchymal stem cells-engineered system enhances the therapeutic effects altering tumor microenvironment

10.21203/rs.2.21140/v2 ◽

2020 ◽

Author(s):

mohsen Keshavarz ◽

Mir Saeed Ebrahimzadeh ◽

Seyed Mohammad Miri ◽

Hassan Dianat-Moghadam ◽

Seyedeh Sara Ghorbanhosseini ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Immune Responses ◽

Newcastle Disease Virus ◽

Cancer Immunotherapy ◽

Disease Virus ◽

Newcastle Disease ◽

Therapeutic Effects

Abstract Background: Human papillomavirus (HPV)-associated malignancy remain a main cause of cancer in men and women. Cancer immunotherapy has represented great potential as a new promising cancer therapeutic approach. Here, we report Mesenchymal stem cells (MSCs) as a carrier for the delivery of oncolytic Newcastle disease virus (NDV) for the treatment of HPV-associated tumor.Methods: For this purpose, MSCs obtained from the bone marrow of C57BL mice, then cultured and characterized subsequently by the flow cytometry analysis for the presence of cell surface markers. In this study, we sought out to determine the impacts of MSCs loaded with oncolytic NDV on splenic T cell and cytokine immune responses, caspase-3 and -9 expression, and myeloid and myeloid-derived suppressor cells (MDSCs) by histological and immunohistochemical studies in the tumor microenvironment (TME).Results: our findings proved that MSCs possess both migratory capacity and tumor tropism toward transplanted tumor tissue after peritumoral administration. Tumor therapy experiments indicated that oncolytic NDV delivered by MSCs-engineered system significantly reduces tumor growth, which is associated with the enhancement of E7-specific lymphocyte proliferation, CD8+ T cell cytolysis responses, and splenic IFN-γ, IL-4 and IL-12 responses compared with control groups. Moreover, the treatment upregulated the concentration of apoptotic proteins (caspase 9) and increased infiltration of tumor microenvironment with CD11b+myeloid and Gr1+MDSCs cells.Conclusions: Our data suggest MSCs carrying oncolytic NDV as a potentially effective strategy for cancer immunotherapy through inducing splenic Th1 immune responses and apoptosis in the tumor microenvironment.

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Safety and Clinical Usage of Newcastle Disease Virus in Cancer Therapy

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/718710 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 35

Author(s):

Han Yuen Lam ◽

Swee Keong Yeap ◽

Mehdi Rasoli ◽

Abdul Rahman Omar ◽

Khatijah Yusoff ◽

...

Keyword(s):

Cancer Therapy ◽

Newcastle Disease Virus ◽

Disease Virus ◽

Newcastle Disease ◽

Human Tumor ◽

Wild Type ◽

Anticancer Effect ◽

Human Tumor Cells ◽

Immunological Effects ◽

Oncolytic Effect

Newcastle disease virus (NDV) is an avian virus that causes deadly infection to over 250 species of birds, including domestic and wild-type, thus resulting in substantial losses to the poultry industry worldwide. Many reports have demonstrated the oncolytic effect of NDV towards human tumor cells. The interesting aspect of NDV is its ability to selectively replicate in cancer cells. Some of the studies have undergone human clinical trials, and favorable results were obtained. Therefore, NDV strains can be the potential therapeutic agent in cancer therapy. However, investigation on the therapeutic perspectives of NDV, especially human immunological effects, is still ongoing. This paper provides an overview of the current studies on the cytotoxic and anticancer effect of NDV via direct oncolysis effects or immune stimulation. Safety of NDV strains applied for cancer immunotherapy is also discussed in this paper.

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