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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1766-1777 |
| Number of pages | 12 |
| Journal | Clinical Cancer Research |
| Volume | 27 |
| Issue number | 6 |
| DOIs | |
| State | Published - Mar 2021 |
Funding
This work was supported by NIH R01NS087990, R01NS106379, R33 NS101150, and P50CA221747 SPORE for Translational Approaches to Brain Cancer. We are also grateful to the Nora Redman Endowment Fund of the Community Foundation of Louisville, the IDP Foundation Inc., and to the Isabella Kerr Molina Foundation for generous gifts to support the study. Some of the materials employed in this work were provided by the Texas A&M Health Science Center College of Medicine Institute for Regenerative Medicine at Scott & White through a grant from ORIP of the NIH, grant no., P40OD011050. This work was also supported by the Northwestern University – Flow Cytometry Core Facility, the Center for Advanced Microscopy, and the Mouse Histology and Phenotyping Laboratory, all supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. The authors are also grateful to the Pathology Core Facility of the Robert H Lurie Comprehensive Cancer Center for its excellent service.
ASJC Scopus subject areas
- General Medicine
