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. EX-PERIMENTAL 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.

Oncolytic Viro-Immunotherapy: An Emerging Option in the Treatment of Gliomas

“…CRAd-S-pk7 is an oncolytic adenoviral vector containing a survivin promoter and a pk7 fiber modification to selectively target glioma (93). A recent study found that it could be successfully encapsulated within mesenchymal stem cells (MSCs) as a new delivery strategy to treat diffuse intrinsic pontine glioma (DIPG), one of the deadliest brain tumors in children (94). Another phase I clinical trial using neural stem cells (NSCs) as delivery vehicles is ongoing (NCT03072134).…”

“…An alternative strategy to prevent the injected OVs from clearance before they reach the target tissue are cell-based delivery platforms. These delivery platforms can provide shelter from the host immune response without suppression of the antitumor immune-response (94,179,180).…”

Stem cells for the treatment of glioblastoma: a 20-year perspective

“…An attractive alternative route of noninvasive administration of therapeutic stem cells is represented by intranasal delivery, a method that takes advantage of the anatomical and physiological properties of the nasal mucosa, allowing for transport alongside the olfactory or trigeminal nerves and through the perivascular pathway within the CNS, avoiding the transport restrictions imposed by the BBB and the clearance of therapeutic cells following systemic administration [85]. This method has been established and optimized over the years in several studies, showing promising results in preclinical brain tumor models, albeit with less efficacy than other administration routes [86][87][88][89][90].…”

Cell-Based Therapy for the Treatment of Glioblastoma: An Update from Preclinical to Clinical Studies

“…This is accomplished by inserting genetically modified viruses into MSCs. The MSCs then home into the tumor site, the virus is deployed and selectively infects and kills tumor cells [ 86 , 87 , 88 , 89 , 90 , 91 , 92 ].…”