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For Glioblastoma Immunotherapy, Is Timing Everything?

NBTS-funded research shows a significant survival advantage for patients receiving immunotherapy before surgery


In recent years, immunotherapy – a treatment strategy to coax the body’s own natural defenses (the immune system) to recognize, target, and destroy tumor cells – has begun to transform cancer research and treatment, stealing headlines along the way.

Dr. Tim Cloughesy of UCLA

While there are a number of different methods being tested to harness the immune system to treat cancer, the most successful approach to date has been a form of immunotherapy known as “checkpoint inhibitors.”

These treatments work by targeting molecules in cells known as “immune checkpoints.” Immune checkpoints are aptly named, as they literally function to keep the immune system in “check” from becoming overactive and attacking healthy tissue. However, tumor cells are often able to over-produce these molecules, shielding themselves from the immune system by putting up a figurative “Stop!” signal and causing potentially tumor-killing T-cells to jam on the brakes. Checkpoint inhibitors remove these stop signs and thus “release the breaks” on T-cells, allowing them to attack tumors.

Various checkpoint inhibitors have been approved to treat certain forms of skin, kidney, lung, bladder, head and neck, liver, colorectal, lymphoma, stomach, and cervical cancers as well as any unresectable or metastatic solid tumor with certain genetic anomalies (known as mismatch repair deficiency or microsatellite instability). You’ve maybe even seen the frequent television commercials advertising checkpoint inhibitors like Opdivo, Yervoy, and Keytruda. However, clinical trials evaluating these treatments for glioblastoma have so far ended in disappointment.

But now a new pilot study, published today in Nature Medicine and supported in part by funding and leaders from the National Brain Tumor Society’s Defeat GBM Research Collaborative, is suggesting a simple change in timing for the administration of checkpoint inhibitors could help realize this immunotherapy’s potential to successfully treat recurrent glioblastoma patients.

Typically, researchers test a potential new treatment in clinical trials as add-ons — or “adjuvants” — to current standard therapies. So, for glioblastoma that means the experimental treatment is usually given after the patient has already had surgery and at the same time as radiation and chemotherapy (this is called the “adjuvant setting”). This is how previous trials of checkpoint inhibitors for GBM were designed.

In the new trial, collaborators from seven premier brain tumor centers across the U.S. – including Defeat GBM-funded researchers Drs. Timothy Cloughesy, Ingo Mellinghoff, and John de Groot – evaluated what impact giving the checkpoint inhibitor Keytruda (pembrolizumab) to patients even before they had surgery might have on the effectiveness of this treatment. Giving a new therapy prior to main treatments is referred to in medicine as “neoadjuvant.” Half the patients in the trial got the drug in the neoadjuvant setting – with continued adjuvant therapy following surgery – while the other half got the treatment only in the more traditional adjuvant manner.

In the study, patients treated with the pembrolizumab prior to surgery to remove the recurrent tumor lived nearly twice as long as those who were treated with the drug after surgery only, surviving 417 days (13.7 months) on average compared to 228 days (7.5 months). Historically, these patients live an average of only six to nine months after recurrence. The treatment was generally well-tolerated with no unexpected toxicities in this patient population.

The team also collected blood and surgically-removed tumors from patients in the study. They used these samples to perform subsequent laboratory tests to further analyze what was happening, biologically, in the tumors from both the neoadjuvant and adjuvant-only groups. This work allowed researchers to better understand if the survival effects they were seeing from the clinical trial could be isolated and attributed to an enhanced immune system response in the tumor.

In the samples taken from patients who received pembrolizumab prior to surgery, the researchers found a number of immune cells, other molecules, and changes to the expression of key genes that were not found in the tumors samples obtained from patients who only got the drug after surgery.

The presence of these characteristics in the tumor samples from the neoadjuvant group indicated that the drug was able to enhance the anti-tumor immune response. This suggests that the survival benefit derived from pembrolizumab is largely driven by the immune response.

The researchers believe that immune system cells, like T-cells, which exist in the milieu around tumors (called the “tumor microenvironment”) can be coaxed into action by using pembrolizumab if the treatment is given prior to surgical removal of the tumor. But, after surgery, it may be the case that too many of these tumor-fighters got taken out with the tumor during resection, so that the remaining T-cells are insufficient to mount a strong enough attack on the cancer.

“This data may lead us to better understanding the mechanisms by which some patients generate significant immune responses to this therapy while others do not,” said Dr. Robert Prins of UCLA, who along with Dr. Cloughesy were the primary co-leaders of the study.

Other centers involved in the trial included, Dana-Farber Cancer Institute, Huntsman Cancer Institute, M.D. Anderson Cancer Center, Massachusetts General Hospital, Memorial Sloan Kettering Cancer Center, and the University of California, San Francisco.

Patients were enrolled and randomized between October 2016 and September 2017. Sixteen patients were randomized into the neoadjuvant pembrolizumab group and 19 into the adjuvant-only group.

To be included the study, patients had to have recurrent, surgically resectable glioblastoma, previous treatment with at least radiation, first or second relapse with unequivocal evidence of tumor progression, no prior use of the drug Avastin, and no high dose systemic corticosteroids (however, many patients continued to receive or were started on low doses of the steroid dexamethasone during their treatment course).

“This isn’t a very big study, and our data need to be replicated, but we have a foot in the door,” said Dr. Cloughesy. “We have found a way to use these checkpoint inhibitors in glioblastoma that we previously thought were ineffective. We now have a rational and logical way to develop immunotherapies going forward and a clinical development process for doing it.”

The researchers are now evaluating this approach for other types of immunotherapy, as well as in different combinations. One specific combination that the team believes may be particularly promising is combining checkpoint inhibitors that target molecules called PD-1/PD-L1 like pembrolizumab with another type of checkpoint inhibitors called CTLA-4 blockades.

Given the noted improvement in survival, we intend to expand the current study and pursue further clinical trials with neoadjuvant combination immunotherapeutics,” the researchers concluded in their paper.


Visit www.defeatgbm.org to learn more and/or support the Defeat GBM Research Collaborative.

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