Mesenchymal Stem Cells Successfully Deliver Oncolytic Virotherapy to Diffuse Intrinsic Pontine Glioma.

Abstract

PURPOSE:

Diffuse intrinsic pontine glioma (DIPG) is among the deadliest of pediatric brain tumors. Radiotherapy is the standard-of-care treatment for DIPG, but offers only transient relief of symptoms for patients with DIPG without providing significant survival benefit. Oncolytic virotherapy is an anticancer treatment that has been investigated for treating various types of brain tumors.

EXPERIMENTAL DESIGN:

Here, we have explored the use of mesenchymal stem cells (MSC) for oncolytic virus (OV) delivery and evaluated treatment efficacy using preclinical models of DIPG. The survivin promoter drives the conditional replication of OV used in our studies. The efficiency of OV entry into the cells is mediated by fiber modification with seven lysine residues (CRAd.S.pK7). Patients' samples and cell lines were analyzed for the expression of viral entry proteins and survivin. The ability of MSCs to deliver OV to DIPG was studied in the context of a low dose of irradiation.

RESULTS:

Our results show that DIPG cells and tumors exhibit robust expression of cell surface proteins and survivin that enable efficient OV entry and replication in DIPG cells. MSCs loaded with OV disseminate within a tumor and release OV throughout the DIPG brainstem xenografts in mice. Administration of OV-loaded MSCs with radiotherapy to mice bearing brainstem DIPG xenografts results in more prolonged survival relative to that conferred by either therapy alone (P < 0.01).

CONCLUSIONS:

Our study supports OV, CRAd.S.pK7, encapsulated within MSCs as a therapeutic strategy that merits further investigation and potential translation for DIPG treatment.

• Authors: Michael I Chastkofsky, Katarzyna C Pituch, Hiroaki Katagi, Markella Zannikou, Liliana Ilut, Ting Xiao, Yu Han, Adam M Sonabend, David T Curiel, Erin R Bonner, Javad Nazarian, Craig M Horbinski, C David James, Amanda M Saratsis, Rintaro Hashizume, Maciej S Lesniak, Irina V Balyasnikova
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 6 Pg. 1766-1777 (03 15 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 33272983 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Topics

• Adolescent
• Animals
• Apoptosis
• Brain Stem Neoplasms (pathology, therapy)
• Cell Proliferation
• Diffuse Intrinsic Pontine Glioma (pathology, therapy)
• Female
• Humans
• Mesenchymal Stem Cell Transplantation (methods)
• Mesenchymal Stem Cells (cytology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Oncolytic Virotherapy (methods)
• Oncolytic Viruses (genetics)
• Prognosis
• Promoter Regions, Genetic
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays