Glioblastoma: Surgical advances and immunologic findings

Glioblastomas, the most common and aggressive primary brain tumors, have been called grow-and-go tumors. They not only grow rapidly at a given site, they also move rapidly to new sites.

As a neurosurgeon and immunobiologist, Ian F. Parney, M.D., Ph.D., approaches glioblastoma from both a clinical and a research perspective. In the clinical sphere, he is using novel techniques to reduce functional complications during surgical resection of large tumors. On the research front, he and his coinvestigators at Mayo Clinic have made two recent discoveries that help explain mechanisms of immune suppression and tumor recurrence and that advance understanding of potential targets for immunotherapy.

Tumor resection: Improvements in preserving function

Dr. Parney notes that there is increasing evidence that in low- to intermediate-grade gliomas, the more tumor removed, the better the outcome—a difference that can be measured in years, not just weeks or months.

Removing large gliomas while sparing as much function as possible is a difficult challenge. To meet it, Dr. Parney and colleagues have been combining intraoperative MRI (iMRI) with functional brain mapping during awake craniotomy. Among the few institutions worldwide that have reported using this technique, Mayo Clinic has the largest series of cases.

Initial reports of combining electrophysiologic brain mapping (EPM) with iMRI used low-field (0.2-0.5 tesla) scanners. Mayo is fortunate to have a high-field (1.5 tesla) scanner that generates high-resolution 3-D images for presurgical planning and image reregistration during surgery. High-field iMRI improves image guidance and accuracy of brain-shift measurements during surgery. It thus facilitates more extensive tumor resection.

Functional imaging, such as fMRI, can be incorporated into image-guidance systems, but brain shift during surgery can make fMRI interpretation problematic.

EPM is considered the gold standard for functional brain mapping, offering the most precise localization of eloquent cortex. Use of EPM with high-field scanners, however, has been difficult because the patient's head and entire upper body must be cocooned in sterile drapes. Extensive draping can interfere with airway protection in sedated patients and can make alert patients feel claustrophobic during brain monitoring.

To address the problem, Dr. Parney and colleagues designed a technique of minimal draping that allows safe and comfortable intraoperative EPM while high-field iMRI is used. The utility of the combined techniques was demonstrated in a patient in whom EPM showed a critical speech area to be approximately 1 cm away from the speech areas identified on fMRI (World Neurosurgery, in press). Dr. Parney states, "Combining EPM and iMRI is the best of both worlds. We've been very successful in removing more tumor while keeping our complication rates extremely low."

Treatment outcomes in elderly patients

Aggressive management of glioblastoma in the elderly must be weighed against age-related health risks. However, in a recent 5-year retrospective study of 105 patients aged 65 years and older, Dr. Parney, Shota Tanaka, M.D., and colleagues found that elderly patients who had standard surgery, irradiation, and chemotherapy had more positive outcomes than those who did not have treatment and those who had been treated in a previous 10-year retrospective study.

Dr. Parney speculates that one reason for this result may be that chemotherapy drugs, such as temozolomide, have improved outcomes in the general population. He cautions that deciding to treat glioblastoma in elderly patients must be done on a case-by-case basis but that although the risks may be higher for them, the benefits are there.

New directions in immunotherapy research

Dr. Parney notes that "even with the most aggressive resection, microscopic tumor cells that the surgeon cannot see will remain." The growth of these cells, combined with their possible immune-suppressing mechanisms, may explain relentless recurrence of glioblastoma and its resistance to chemotherapy. Previous immunotherapies, such as dendritic cell vaccines and immunogene therapy, have not successfully translated from animals to humans.

Two recent discoveries by Mayo researchers under the direction of Dr. Parney and Allan B. Dietz, Ph.D., head of Mayo's Human Cellular Therapy Laboratory, however, have helped explain why. Their work sheds light on the role of glioma-mediated immunosuppression and points to a new direction in designing immune-mediated treatments.

Tumor-based reeducation of normal monocytes

As in other cancers with tumor burden, glioblastomas are heavily infiltrated with myeloid-derived suppressor cells (MDSCs), which are white blood cells similar to a normal macrophage but specialized to suppress immune responses within the tumor.

Drs. Dietz and Parney and their colleagues hypothesized that normal human monocytes exposed to glioblastoma cells assume an immune-suppressing phenotype similar to MDSCs and that the level of MDSCs is increased in the peripheral blood of patients with glioblastoma compared with healthy control subjects. Their findings support these hypotheses and help explain the systemic (vs local) suppression effects of gliomas on the immune system.

From their research, it appears that normal monocytes infiltrate the tumor, where they receive an immunosuppressive education before returning to the bloodstream. When they are again in the peripheral blood supply, they, like MDSCs, work to suppress the immune system.

A new vaccine target: Brainstem tumor cells

Until the discovery of neural stem cells that can produce neurons in the adult CNS, glioblastoma was thought to be caused by changes in the astrocyte. That theory has been called into question with the discovery of another type of stem cell called brainstem tumor cell (BSTC). Newer theories suggest that these cells might arise from normal stem cells. BSTCs help drive tumor growth and may be a major factor in tumor recurrence. They also may be the cells that are the most resistant to chemotherapy and irradiation.

For all these reasons, Dr. Parney and his team decided to focus on BSTCs as potential targets for immunotherapy. The first step was to investigate ways in which BSTCs differ from normal neural stem cells. Using a neurosphere culture system, Dr. Parney and colleagues have been able to reproduce BSTC survival and proliferation independent of exogenous mitogenic stimulation both in vitro and in vivo. Their findings have important implications for identifying the reproductive mechanisms of BSTCs and the pathways that might be used to target them without affecting normal neural stem cells. Together with improved understanding of the mechanism's immunosuppression, this work represents a critical step toward the development of an effective vaccine.