Pioneering Studies Apply New Immunologic Insights to Glioblastoma

Clinical trial to launch in 2016

Cleveland Clinic neurosurgeons and cancer biologists are hopeful that recent discoveries they have made about the role myeloid-derived suppressor cells (MDSCs) play in glioblastoma will open a pathway to novel treatments for this uniformly fatal brain tumor. Planning for a clinical trial is underway.

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“This effort is particularly timely because of the current enormous focus on understanding the immune system’s function in the context of cancer,” says Michael A. Vogelbaum, MD, PhD, Associate Director of Cleveland Clinic’s Rose Ella Burkhardt Brain Tumor and NeuroOncology Center. “Currently, the only effective treatments for cancers that arise in the brain itself include surgery, radiation therapy and a very small number of conventional chemotherapies.

“Immunotherapies are showing clinical promise in a variety of cancers,” continues Dr. Vogelbaum, who is also Professor of Neurosurgery at Cleveland Clinic Lerner College of Medicine. “The proving ground has been melanoma, but there are numerous immunotherapy clinical trials now underway for brain tumors as well. While the failure of most chemotherapies can be attributed largely to the fact that they do not get into the brain at effective concentrations, immunotherapies may not be as impacted by that limitation.”

MDSCs in glioblastoma

Dr. Vogelbaum’s work with MDSCs dates back to research he conducted with James H. Finke, PhD, a scientist in Cleveland Clinic’s Lerner Research institute who helped elucidate the biological role MDSCs play in renal cell carcinoma. Now Dr. Vogelbaum is teaming with another Lerner Research Institute scientist, Justin D. Lathia, PhD, and his colleagues in the Department of Cellular and Molecular Medicine to explore the critical role MDSCs play in glioblastoma.

MDSCs are a heterogeneous class of immature immunosuppressive cells found in various tumors and at the sites of inflammation, infection and injury. In the latter, MDSCs modulate the immune response. In cancer, they suppress beneficial cytotoxic immune cell function, in turn contributing to tumor growth and metastasis. Drs. Finke and Vogelbaum’s groups discovered that, as in patients with renal cell carcinoma, MDSCs are upregulated in the peripheral blood of glioblastoma patients. Dr. Lathia’s lab has built on that work most recently by showing that MDSCs find their way into the brain where they communicate with self-renewing cancer stem cells (CSCs) present in many advanced tumors.

“In our preclinical studies with a mouse model of glioblastoma, our key finding was that MDSCs communicate directly with CSCs to modulate their behavior,” Dr. Lathia says. “It is not that the MDSCs migrate into the tumor microenvironment and suppress immunity. Rather, they interact with CSCs, secreting molecules that activate MDSCs. This alters the immune system and promotes tumor growth — and it appears to be an important mechanism in glioblastoma immune evasion.”

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Drs. Lathia (left) and Vogelbaum together in the lab.

Translating to therapeutics

Drs. Vogelbaum and Lathia have collaborated to develop a novel chemotherapeutic strategy aimed at reducing MDSC levels in the bloodstream to reverse immunosuppression and activate the patient’s immune system against tumor progression. They are working with Cleveland Clinic medical oncologist David Peereboom, MD, who specializes in the treatment of patients with brain tumors and will serve as primary investigator of the clinical trial based on this new strategy.

Targeting MDSCs actually reverses the suppressive effects the immune system displays, allowing it to function more normally and recognize tumor cells and stop their growth, Dr. Lathia explains.

What distinguishes this approach

“The rationale behind many immunotherapy efforts is to accelerate the immune system by disrupting immune suppressive mechanisms within the tumor,” Dr. Lathia says. “What we are proposing instead is to use current inhibitors that activate the immune system and at the same time directly eliminate MDSCs from the bloodstream and bone marrow, not within the tumor. We want to prevent MDSCs from reaching the brain in the first place.”

Another exciting aspect of the proposed therapeutic approach is that it does not depend on the MDSC-killing agent crossing the blood-brain barrier, Dr. Vogelbaum notes. Instead, MDSCs will be targeted in the peripheral blood of glioblastoma patients using FDA-approved chemotherapeutic agents, starting with 5-fluorouracil, which has demonstrated effectiveness in killing MDSCs in mouse studies. The team has ongoing efforts looking at other perhaps more effective agents as well.

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Improved understanding portends better-targeted treatment

“Our understanding of how the immune system operates in the brain in normal as well as in pathological conditions is improving,” Dr. Lathia comments. “This knowledge should help us target these infiltrating cell populations as alternative therapies to encourage patients’ own immune systems to successfully attack glioblastoma tumors.”

“We believe that some form of immunotherapy or immunostimulation alone or in combination with conventional treatments has the potential to help people with malignant brain tumors live longer,” concludes Dr. Vogelbaum.

The team hopes to begin enrolling patients in the clinical trial within the next six months.