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Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model.

Publication ,  Journal Article
Cheema, TA; Wakimoto, H; Fecci, PE; Ning, J; Kuroda, T; Jeyaretna, DS; Martuza, RL; Rabkin, SD
Published in: Proc Natl Acad Sci U S A
July 16, 2013

Glioblastoma (World Health Organization grade IV) is an aggressive adult brain tumor that is inevitably fatal despite surgery, radiation, and chemotherapy. Treatment failures are attributed to combinations of cellular heterogeneity, including a subpopulation of often-resistant cancer stem cells, aberrant vasculature, and noteworthy immune suppression. Current preclinical models and treatment strategies do not incorporate or address all these features satisfactorily. Herein, we describe a murine glioblastoma stem cell (GSC) model that recapitulates tumor heterogeneity, invasiveness, vascularity, and immunosuppressive microenvironment in syngeneic immunocompetent mice and should prove useful for a range of therapeutic studies. Using this model, we tested a genetically engineered oncolytic herpes simplex virus that is armed with an immunomodulatory cytokine, interleukin 12 (G47-mIL12). G47Δ-mIL12 infects and replicates similarly to its unarmed oncolytic herpes simplex virus counterpart in mouse 005 GSCs in vitro, whereas in vivo, it significantly enhances survival in syngeneic mice bearing intracerebral 005 tumors. Mechanistically, G47-mIL12 targets not only GSCs but also increases IFN-γ release, inhibits angiogenesis, and reduces the number of regulatory T cells in the tumor. The increased efficacy is dependent upon T cells, but not natural killer cells. Taken together, our findings demonstrate that G47Δ-mIL12 provides a multifaceted approach to targeting GSCs, tumor microenvironment, and the immune system, with resultant therapeutic benefit in a stringent glioblastoma model.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

July 16, 2013

Volume

110

Issue

29

Start / End Page

12006 / 12011

Location

United States

Related Subject Headings

  • Simplexvirus
  • Oncolytic Virotherapy
  • Neoplastic Stem Cells
  • Mice, Inbred C57BL
  • Mice
  • Kaplan-Meier Estimate
  • Interleukin-12
  • Immunotherapy
  • Immunohistochemistry
  • Glioblastoma
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Cheema, T. A., Wakimoto, H., Fecci, P. E., Ning, J., Kuroda, T., Jeyaretna, D. S., … Rabkin, S. D. (2013). Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model. Proc Natl Acad Sci U S A, 110(29), 12006–12011. https://doi.org/10.1073/pnas.1307935110
Cheema, Tooba A., Hiroaki Wakimoto, Peter E. Fecci, Jianfang Ning, Toshihiko Kuroda, Deva S. Jeyaretna, Robert L. Martuza, and Samuel D. Rabkin. “Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model.Proc Natl Acad Sci U S A 110, no. 29 (July 16, 2013): 12006–11. https://doi.org/10.1073/pnas.1307935110.
Cheema TA, Wakimoto H, Fecci PE, Ning J, Kuroda T, Jeyaretna DS, et al. Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model. Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):12006–11.
Cheema, Tooba A., et al. “Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model.Proc Natl Acad Sci U S A, vol. 110, no. 29, July 2013, pp. 12006–11. Pubmed, doi:10.1073/pnas.1307935110.
Cheema TA, Wakimoto H, Fecci PE, Ning J, Kuroda T, Jeyaretna DS, Martuza RL, Rabkin SD. Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model. Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):12006–12011.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

July 16, 2013

Volume

110

Issue

29

Start / End Page

12006 / 12011

Location

United States

Related Subject Headings

  • Simplexvirus
  • Oncolytic Virotherapy
  • Neoplastic Stem Cells
  • Mice, Inbred C57BL
  • Mice
  • Kaplan-Meier Estimate
  • Interleukin-12
  • Immunotherapy
  • Immunohistochemistry
  • Glioblastoma