5 November 2002 14:10 EST
by Kathryn Senior
Neural stem cells engineered to express IL-12, a tumoricidal cytokine,
have been shown to track and kill gliomas in mice as they spread through
brain tissue. Gliomas are currently treated by surgical resection with
adjuvant radio- or chemotherapy. This may eradicate the main tumor, but
gliomas are highly malignant and remaining cells spread quickly, setting
up new tumor satellites. These are extremely difficult to destroy, even
using stereotactic radiotherapy, and tumor recurrence is frequent and is
associated with poor prognosis.
John Yu and colleagues at the Cedars-Sinai Medical Center's neurosurgical institute previously showed that gene transfer of the IL-12 gene into mouse intracranial tumors using adenoviral vectors confers long-lasting immunity and a cytotoxic T cell response. The team decided to use neural stem cells as a delivery system, hypothesizing that IL-12 secretion in the region of tumor satellites may induce a T-cell response more specifically against these problematic regions of tumor growth. "It appears from our data that this may be the case," comments Yu.
Evan Snyder's group at Harvard Medical School first showed more than two years ago that neural stem cells can home in and/or track pathology in the adult mouse brain. "In our study, an oncolytic gene was expressed by the stem cells," explains Snyder, who goes on to say that his group now has a patent nearly issued on this novel approach to cancer. "It is gratifying to see many people beginning to use this technique and validate our findings," he adds. Snyder's work was paralleled by a study showing encouraging results using mouse neural stem cells engineered to express interleukin 4 in mice with experimentally induced glioma.
Yu and colleagues followed up this work and their own previous study on Il-12 by inoculating IL-12 secreting neural stem cells directly into experimentally induced gliomas. The treated mice showed significantly prolonged survival compared to controls, and developed long-term anti-tumor immunity. "We found neural stem cells interspersed within the brain tumor mass and also present in small tumor islands detached from the primary tumor body," says Yu. Neural stem cells could be seen actively tracking outgrowths from the main tumor that extended deep into adjacent normal tissue.
Other researchers in the field welcome the results but warn that this drug delivery strategy is at a very early stage of development. "More extensive analysis characterizing the effectiveness of this method for treating human glioma would be necessary to conclude whether this method is feasible for clinical use," comments Hideyuki Okano of Keio University. John Sinden, Scientific Director or Reneuron, a company in the UK dedicated to researching therapeutic applications of neural stem cells, thinks this is "an excellent approach to glioma treatment, but not a huge step forward, since Benedetti et al reported using IL-4 to similar efficacy over 2 years ago." He stresses that a critical test for neural stem cells would be to investigate whether they could successfully target and treat the gliomas seen in spontaneous tumor models.
Pediatric oncologist Klaus-Michael Debatin of the German Cancer Research Center Heidelberg, Germany) agrees, but also enthuses about the potential of the technique for future exploitation. In July 2002, Debatin and colleagues reported that administering the second mitochondria-derived activator of caspase (Smac), which sensitizes glioma cells to apoptosis, in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) could completely eradicate established gliomas in mice. "The paper by Yu's group is really interesting. Targeting any cytotoxic approach to or into the tumor is a major challenge in the development of new treatment modalities," he comments.
Debatin views vectors or "schlepper" vehicles directed by an intrinsic program to find tumor cells as ideal devices to deliver tumor-killing "weapons" and to target diffuse metastases. "With respect to the Smac peptide sensitizer/inducer approach, using neural stem cells as vectors may be possible, but some technical hurdles would need to be overcome," he says. "Stem cells could certainly be used to deliver TRAIL locally, but Smac peptides are intracellular and secretory sequences would need to be added to the gene to get the peptide out of the cell to where it could work with TRAIL."
Yu's group has recently completed a study using TRAIL protein secretion from stem cells to induce massive apoptosis in tumors and in tumor satellites. The group has also been looking ahead to clinical trials, and at ways to circumvent some of the ethical and practical problems inherent in stem cell therapy. "The stem cells in the IL-12 study were from fetal mice. However, the use of fetal stem cells from humans is difficult, so we have developed a technique to isolate and differentiate neural stem cells from bone marrow cells," explains Yu. This technique should generate a virtually limitless supply of neural stem cells and it would obviate the immunological barriers of using stem cell lines or the ethical concerns of using fetal stem cells.
Genetics professor Mark Noble of the University of Rochester Medical Center points out that neural stem cells used as therapeutic vehicles for brain tumors could also be modified to allow repair of the damage caused by brain tumors themselves, or by the more traditional brain cancer treatments. Snyder, for example, has previous shown that neural stem cells can repair large areas of damaged brain.
"This could happen eventually," he predicts, "but at the moment it seems
like an idealized therapy, of using transplantation of precursor cells
to kill cancer cells and to replace any missing normal cells at the one
and same time, is still far in the future."
© Elsevier Science Limited 2002