Giving patients with lethal brain tumors a powerful new form of cancer treatment before they underwent surgery helped them live longer on average than patients who started the drugs after surgery, researchers reported in a study published Monday.
While the study was small, and while most patients still died by the end of the study period, researchers said the results suggested timing could be an important factor when trying to treat glioblastoma, or GBM, with immunotherapies, which are designed to unleash the immune system on cancer cells. Previous attempts to use immunotherapies to help GBM patients have failed to yield broad clinical benefits, and any positive results catch attention with a cancer as formidable as GBM, which has a median survival time of just a few years.
“We’ve at least found a window,” said Robert Prins, a tumor immunologist at the UCLA Jonsson Comprehensive Cancer Center and a senior author of the paper. “Before we just hadn’t seen anything. Now, I think we’re seeing a signal.”
Outside experts echoed Prins, noting that this was a randomized trial — patients were divided into different treatment groups to compare the results — which lends more weight to the findings. While they cautioned that many initially exciting study results do not hold up in larger investigations, they said the study, which was published in the journal Nature Medicine, laid the groundwork for research that would combine different immune-boosting strategies at this point in a patient’s disease.
“It’s exciting because up to now, immunotherapies looked like they were going down the road for everything else — ‘Oh, they work in peripheral tumors, but not in the brain,’” said Dr. Frederick Lang, the chair of neurosurgery at MD Anderson Cancer Center, who was not involved in the research. “This study really infuses hope back into the field, that these checkpoint inhibitors may be effective if we use them in the correct way,” he added, referring to the type of immunotherapy used in the trial.
The study focused on 32 patients who had recurrent GBM — people who already had a first round of treatment (GBM is initially treated with surgery, radiation, and a chemotherapy called temozolomide) and whose cancers started growing again. For the study, half of them started on a checkpoint inhibitor before they had surgery to remove as much of the regrowing tumor as possible, and half waited to begin the drug until after the surgery.
Patients in the first group had a median survival of 417 days, while patients in the second group had a median survival of 228 days. Patients who received the drug before surgery also went longer before the tumor started progressing again.
The research was conducted at seven centers from October 2016 to September 2017. By July 2018, when the researchers stopped tracking them for the study, 12 of the patients in the later-start group had died, and nine of the earlier-start group had died.
By awakening immune cells and pulling down the defenses of cancer cells, immunotherapies have enabled remarkable recoveries for some patients with some cancers. But brain tumors have proved among the hardest cancers to target. In December, two research teams reported they could rally a promising immune response in GBM patients with another type of immunotherapy called a neoantigen vaccine, but that it didn’t lead to improved outcomes for patients.
Brain tumors are particularly difficult to treat for a number of reasons. It’s hard for medicines in general to penetrate into the brain. More specifically, brain tumors don’t have as many genetic vulnerabilities for cancer therapies to pounce on as other tumors. They are also able to tamp down immune activity — making them so-called immunologically cold cancers.
In this study, researchers tested a checkpoint inhibitor. Checkpoints are one of cancer’s ways of stopping immune cells from demolishing tumor cells, so inhibitors work by interfering with those checkpoints. The study used pembrolizumab, which blocks the PD-1 checkpoint and is approved for some forms of cancer as Keytruda. (Merck, which makes Keytruda, provided the drug for the study.)
Researchers initially designed the study just as a scientific survey to compare what happened to the immune system and tumor in the different patient groups; they weren’t expecting to uncover an apparent clinical benefit when it came to the timing of the treatments.
“The original idea was really to understand what PD-1 blockade does to the tumor microenvironment, what it does to the immune response to the tumor in the brain,” said Prins, who is also affiliated with Parker Institute for Cancer Immunotherapy.
Researchers aren’t sure why the patients who received pembrolizumab before surgery lived longer, but it’s possible that providing the drug and surgery in that order amounted to a one-two punch. Perhaps, experts said, the drug needs to be activated by being exposed to proteins on the outside of the tumor cells called antigens — which act as little flags identifying invaders the immune system should attack. Then, when the tumor was removed, the curtain of immunosuppression that the tumor holds up was dropped, so the drug could swarm the cells the surgery left behind.
When researchers looked at what was going on inside the immune and tumor cells, they found that in patients who received the drug before surgery, immune cells were geared to attack and kill cancer cells, while their cancer cells were slower to copy themselves.
But even if these patients lived longer, most of them had still died by the end date of the study. Dr. Hideho Okada, the director of the brain tumor immunotherapy program at University of California, San Francisco, likened GBM to a car with a host of issues — brakes, transmission, the engine, and so on. A PD-1 inhibitor like pembrolizumab is only designed to take care of one of those problems, but the cancer has a bevy of other challenges that need to be addressed if the tumor is to be fully vanquished.
“In order to make the car start running again safely, you have to fix each of these problems,” said Okada, who was not involved with the study. “PD-1 is addressing one mechanism, so to build on this preliminary success, we have to plan rational combinations of immunotherapy drugs.”