Dual Use of Human Mesenchymal Stem Cells in both Detection and Delivery of an Oncolytic Virus to Brain Tumors

Lay Summary

Imaging Whether Bone-Marrow Stem Cells Migrate to Brain Tumors, and Can Deliver Therapy

Researchers will use cellular imaging in an animal model of brain tumor to see whether human mesenchymal stem cells—which have been removed from patients’ bone marrow and inserted into the animal—migrate to brain tumor areas to guide surgical removal and deliver therapies directly to the tumors.

Deadly glioblastoma (brain tumors) remains stubbornly resistant to surgical and medical treatment.  Recent research, though, suggests that adult neural stem cells have the potential to seek out, migrate to, and infiltrate brain tumors.  The need to generate large numbers of these cells, however, coupled with ethical considerations, has led to interest in the possibility of using mesenchymal stem cells, which are derived from patients’ bone marrow. The investigators hypothesize that mesenchymal stem cells better delineate areas of tumor infiltration in the brain, and can therefore guide surgical removal of the tumor, while sparing unaffected brain tissue, and, that these stem cells also can deliver tumor-killing agents directly to tumor-containing brain areas.

To test these hypotheses, they will remove and label mesenchymal stem cells from patients’ bone marrow and insert the cells into an animal model of brain tumor.  The cells will be labeled with particles that are both magnetic and fluorescent. This will facilitate MRI imaging in the anesthetized animals to monitor the stem cells’ distribution in the brain, and, through cellular fluorescence imaging, to visualize the stem cells throughout the whole body and also in post-mortem animal tissues. If their hypotheses are correct, the imaging will reveal that the stem cells have migrated and accumulated primarily in the tumors, regardless of their size or location in the brain; moreover, any of the stem cells that migrated to other parts of the body will have been cleared away by the body.  In addition, they will fluorescently label a tumor-killing virus, which is harmless to humans, infect the stem cells with the virus, and use imaging to determine if the virus surrounds the tumors and kills tumor cells, reducing the tumor mass.

Significance:  Imaging may reveal that mesenchymal stem cells can both identify brain tumors and define their margins (boundaries) to guide surgical removal. The research also may demonstrate that these stem cells can be used to target therapies directly to the tumor, providing improved and new treatment options for patients.

Abstract

Dual Use of Human Mesenchymal Stem Cells in both Detection and Delivery of an Oncolytic Virus to Brain Tumors

Human mesenchymal stem cells (hMSCs) are a fibroblastic cell population commonly isolated from the bone marrow. These cells are characterized by an enhanced self‐renewal potential and the ability to undergo multilineage differentiation. They are the precursors that create bone marrow stroma by differentiating into adipocytes, chondrocytes, and osteoblasts. Recent evidence suggests that hMSCs selectively home to tumors and contribute to the formation of tumor‐associated stroma. This selective migration of hMSCs towards brain tumors is further enhanced following radiation therapy or treatment with temozolamide, the combination of which is the current standard of treatment for patients with malignant gliomas.

The use of hMSCs as cellular delivery vehicles, particularly to deliver anticancer agents directly into the tumor microenvironment where these cells selectively engraft and participate in tumor stroma development, is an emerging attractive therapeutic strategy. This approach would be a “Trojan‐horse” concept. Human MSCs can be incorporated into the tumor architecture, and hMSC‐based cellular mini‐pumps produce and release anticancer agents in situ.

Recent studies have demonstrated that hMSCs effectively integrate within gliomas when injected intracranially or intra‐arterially in a mouse xenograft model. Further, it was demonstrated that hMSCs successfully migrate to more remote tumor regions, thus providing an alternative to deliver therapeutic agents to gliomas. The use of hMSCs has other attractive qualities, such as the ease of obtaining them from patients through bone marrow aspirates, or from other easily obtained tissues including subcutaneous adipose tissue. Importantly, this strategy allows for autologous transplantation, which obviates immunologic incompatibilities.

All these qualities make hMSCs a prime candidate for multiple applications in patients with brain tumors. Due to the fact that hMSCs migrate and integrate within brain tumors regardless of size and location in the brain allows for the possibility of using hMSCs in the detection of newly developing smaller tumors or areas of tumor infiltration that would otherwise be less easily detected. Further, ex vivo manipulation of hMSCs to transform them into producers of anticancer agents should allow for the in situ delivery of these traceable agents into the growing tumor once hMSCs integrate into the tumor architecture.