In the Lab

On Cancer: Immune Cells in the Brain Could be Enlisted to Fight Glioblastoma

By Eva Kiesler, PhD, Science Writer/Editor  |  Tuesday, October 15, 2013
Mouse glioblastoma tumor with phagocytic macrophages This image shows part of a glioblastoma tumor from a mouse treated with a CSF-1R inhibitor. The drug was shown to induce tumor-associated macrophages (green) to phagocytose or eat tumor cells (red).

White blood cells called macrophages patrol almost every tissue of the body to gobble up bacteria, dead cells, and other waste. About ten percent of the cells in the brain are macrophages, also known as microglia. These cells have many important functions such as protecting against infections and repairing damaged nerve tissue but have also been shown to promote brain diseases including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.

Now a recent study led by Memorial Sloan Kettering scientists reveals that macrophages can support the growth and progression of glioblastoma brain tumors – the commonest and most deadly form of primary brain cancer – and that it might be possible to control the disease by manipulating these cells with a drug. The research was done in mice and published in the October issue of the journal Nature Medicine.

“Tumors are often infiltrated by macrophages and can ‘hijack’ these cells to spur their own growth,” explains Johanna Joyce, a member of the Sloan Kettering Institute’s Cancer Biology and Genetics Program and the senior author of the study. “Our findings suggest macrophages represent a potent therapeutic target in glioblastoma,” a disease that is exceptionally hard to treat with existing therapies.

Complex Tumors

Less than five percent of people with glioblastoma survive longer than five years after they are diagnosed even if they undergo intensive treatment with surgery, chemotherapy, or radiation. “There’s a crucial need for better strategies to control these aggressive tumors,” Dr. Joyce emphasizes.

So far scientists have had little success in developing targeted drugs against glioblastoma cells – drugs that home in on specific genetic mutations or biological pathways. “This is partly because glioblastoma tumors are very heterogeneous,” Dr. Joyce explains, referring to the fact that these tumors contain a highly diverse set of cancer cells with different genetic attributes.

In contrast, tumor-associated macrophages – which often make up as much as one third of the total tumor mass – tend to be more biologically uniform and could therefore be easier to target. Dr. Joyce and her colleagues looked at these cells in mouse models of a subtype of the disease called proneural glioblastoma. They noticed that the more advanced a tumor was, the more infiltrated by macrophages it tended to be.

“A similar pattern has been found when samples of tumor tissue from patients were analyzed,” Dr. Joyce says. “It seemed as if the tumor-infiltrating macrophages were helping the cancer advance.”

The investigators set out to test what would happen if the mouse proneural glioblastoma tumors were depleted of macrophages. They treated the mice with a drug that has been shown to eradicate macrophages in the brain and other organs. It works by inhibiting CSF-1R, a protein known to be essential for macrophage survival.

Surprise Findings

“There were a couple of surprises,” Dr. Joyce says. The first was how striking the drug’s effect was. It stopped newly formed tumors from progressing, caused more-established tumors to shrink, and made the mice live significantly longer.

The second surprise was no less positive, but initially confounding to the researchers. “We thought CSF-1R inhibition would wipe out the tumor-associated macrophages,” Dr. Joyce explains. “But when we looked at the tumors of mice who had been treated, the macrophages were still there” even though the drug had killed macrophages in the surrounding, normal brain tissue.

The researchers found that the macrophages residing in tumors had not succumbed to the drug because certain proteins secreted by the tumors were keeping them alive. But the therapy changed the macrophages’ behavior, blunting their tumor-promoting functions while making them more prone to elicit an anti-tumor response.

For example, these macrophages were induced to attack tumors by “eating” glioblastoma cells, a process known as phagocytosis.

“Our research suggests CSF-1R inhibition actually re-educates macrophages to attack tumor cells rather than support their growth,” Dr. Joyce says. “This is intriguing because if tumor-associated macrophages could be manipulated in the same way in the clinic – and be enlisted to actively fight a person’s cancer – this might ultimately be a more effective therapeutic strategy than to deplete the cells.”

Bringing Macrophage-Targeting Therapies to Patients

There could be several other advantages to developing glioblastoma drugs that act on macrophages and using these drugs in combination with existing therapies such as chemotherapy or radiation.

“Macrophages are genetically more stable than cancer cells, and therefore less likely to develop acquired drug resistance as glioblastoma cells often do,” Dr. Joyce explains. “In addition, we and other researchers have shown that targeting macrophages can increase the effectiveness of some chemotherapy drugs.”

CSF-1R inhibitors are currently being tested in early-stage clinical trials of glioblastoma patients and could be applicable in other diseases as well. “Studies have shown that in several cancer types, including breast, ovarian, thyroid, and pancreatic neuroendocrine tumors, increased numbers of tumor-associated macrophages correlate with poor patient prognosis, so it would be logical to test the drug in these diseases as well,” Dr. Joyce notes. 

This research was funded by the Cycle for Survival, the Brain Tumor Center at Memorial Sloan Kettering, the National Institutes of Health under grants CA126518 and CA148967, and other sources.

Comments

My son has glioblastoma ,enduring 5 surgeries in the last year . He has just started your clinical trial on BKM 120? Is the drug applying the logic above?

Nancy, thank you for writing. We are sorry to hear about your son's illness. BKM120 does not act in the same way as the drug used in this study. It belongs to a family of drugs called PI3 kinase inhibitors, which target tumor cells.

felicitations pour le magnifique travail que vous faites le monde vous en sera redevable

Hello, I am past surgery - 90% actually removed, 2 cycles of termodar - Oct 14th MRI showed growth in Tumor (that were just a hint in the previous scans). I am suppose to start on Avastin. I am looking for a good clinical trial with Avastin. Any suggestion?

Dear Vic, While we cannot give medical advice to individuals on the blog, we do have several clinical trials involving Avastin as well as other therapies. Please go to this link and search for bevacizumab (the generic name for Avastin), or by the disease type (e.g., brain tumors, primary): www.mskcc.org/cancer-care/clinical-trials/clinical-trial. If any of these trials seem right for you, the number to call is listed there. You can also search for trials through the National Cancer Institute: www.cancer.gov/clinicaltrials. Thanks for your comment, and we wish you all the best.
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Vic,

I am in a clinical trial for Avastin at NYU Langone Cancer Center on E 34th St in NYC. Dr Debra Gruber, 212-731-5577. Call, & good luck!!

Our 3 year old granddaughter has undergone surgery and chemotherapy for neuroblastoma. Three tumors remain in her skull's bone structure but appear to have low activity. Would your current study have any possible application to her condition?

George, we are sorry to hear about your granddaughter. We are unable to answer individual medical questions on our blog. If you'd like to make an appointment for her to see someone in our Department of Pediatrics, you can call 212-639-5954. Thank you for your comment.

My 52 year old has been diagnosed with a GBM stage 4. Currently going through radiation and tremodar . Tumor is midbrain tectorial section. His sneak peek MRI is weds and I was wondering what my options would be at Sloan Kettering. I presume the oncologist is going to use avastin next. I am his care giver and want him to fight and win!

Lisa, if you would like to learn about treatment options at MSKCC, including the possibility of participating in a clinical trial, you can call our Physician Referral Service at 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment to learn more. Thank you for your comment.

Are GBM genetically inherited? My paternal grandmother and my father both died from GBM's. .

Kathy, thank you for your question. Most cases of glioblastoma occur randomly by chance but there are a small percentage that may have a hereditary component. If you would like to have your family history evaluated you can call our Clinical Genetics Service at 646-888-4050 or go to http://www.mskcc.org/cancer-care/hereditary-genetics for more information. We're sorry for your loss.

I am so happy to hear of ongoing research into this type of brain tumor. My son was diagnosed in 1987 with DIPG and passed in 1988, a month before his 5th birthday. At the time he was diagnosed we were told that this tumor had been researched for over 20 years with still no known reason for it and no known cure. Keep up the good work!!!!! God bless you!!!

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