Patients with the aggressive glioblastoma brain cancer lived longer if they were treated with immunotherapy before surgery, according to researchers.
In a small study posted online Monday, patients lived nearly twice as long as the average expectancy for those with glioblastoma if they were given the drug that unleash a brake on the immune system. Previous research involved giving the drugs after surgery
“This is an important first step toward using immunotherapy to benefit patients,” said Robert Prins, the study’s senior author and a tumor immunologist at UCLA, which led the multi-institutional, randomized study.
Some of the patients were enrolled at MD Anderson Cancer Center, home of Allison, who won a Nobel Prize last fall for his identification of the first immune system brake and dogged efforts to turn the finding into treatment for cancer. The drugs, known as checkpoint inhibitors, have produced cures in a subset of patients with particularly deadly forms of the disease, such as lung cancer and melanoma.
Some of the patients were enrolled at MD Anderson Cancer Center, home of Allison, who won a Nobel Prize last fall for his identification of the first immune system brake and dogged efforts to turn the finding into treatment for cancer. The drugs, known as checkpoint inhibitors, have produced cures in a subset of patients with particularly deadly forms of the disease, such as lung cancer and melanoma. Former President Jimmy Carter are their most high-profile beneficiary.
But the treatment, including drugs used in combination, had shown no benefit in patients with glioblastoma, the cancer that killed Delaware Attorney General Beau Biden, U.S. Senator John McCain and, most recently, former MD Anderson President Dr. John Mendelsohn.
On average, the disease kills most patients about 1 1/2 years after diagnosis and six to nine months after it recurs following initial treatment, typically surgery, then chemotherapy and radiation.
The new trial’s findings are significant because there have been few new treatment options for glioblastoma in the past two decades. The previous failure of checkpoint inhibitors was considered a major disappointment.
“It caused a feeling that, like everything else, immunotherapy wasn’t going to work in brain cancer,” said Dr. Frederick Lang, an MD Anderson neurosurgeon who conducts innovative immunotherapy research with glioblastoma but was not involved with the new trial. “That’s why this trial is so exciting — it gives great optimism that if we use it in the correct way, immunotherapy can be effective.”
The trial, published in Nature Medicine, wasn’t designed to test whether the new strategy improved outcomes so much as learn what happens to brain tumors when a checkpoint inhibitor is given, something easier to study when the drug is given before surgery because then tumor samples can be studied after the procedure. There are no such samples to study when the drug is given after surgery.
The trial evaluated 35 patients with recurrent glioblastoma, 16 of whom got the checkpoint inhibitor Keytruda before and after surgery and 19 of whom got it only after surgery. The trial showed not only a strong immune system response in samples of tumors removed from those who received the drug before surgery, but also that those patients lived an average of 417 more days. Patients who got the drug after surgery lived an average of 228 more days.
Prins said a few patients who got the drug before surgery are still alive, now some two years after the disease recurred.
“I don’t think any of us anticipated this,” said Dr. John de Groot, an MD Anderson neuro-oncologist who led the Houston portion of the trial. “These results need to be validated with additional studies, but this is highly significant, the idea that brief three-week treatment prior to surgery has such an impact on survival. It’s prompting us to re-examine how we treat these patients.”
De Groot said the trial results are unlikely due to chance because patients were enrolled at a number of institutions — seven in all — and because a smaller, non-randomized study conducted at MD Anderson showed similar results. Some details of that study has been presented at two cancer meetings but hasn’t been published yet.
The MD Anderson enrolled 15 patients, all in the treatment arm. Average survival time following pre-surgical therapy with Keytruda exceeded a year and two of the patients lived 34 months.
Keytruda targets a brake known as PD-1; Yervoy, the drug developed by Allison, targets a brake known as CTLA-4.
Follow-up plans call for combining Keytruda and Yervoy; therapeutic vaccines that rev up the immune system; and the newest, most radical immunotherapy, the injection of viruses that stimulate the immune system. Such oncolytic viral therapy is the one immunotherapy to previously show promise in brain cancer, including benefiting one patient who’s now lived 12 years since the treatment, but the research is still at an early stage.
Dr. David Baskin, a Houston Methodist Hospital neurosurgeon whose research with oncolytic viral therapy had its greatest success with the 12-year survivor, said he’s seriously considering adding pre-surgical checkpoint inhibitors to his work, but wants to wait because the trial was small and needs to be validated. But he called it “very important” and said it “will provide us with important clues about how to combine the immune response surgery provides with these drugs to improve survival — and may help us with many other forms of cancer elsewhere in the body.”
MD Anderson’s Lang is already conducting research in glioblastoma patients combining viral oncolytic viral therapy and Keyruda.
The researchers aren’t yet sure exactly sure why using Keytruda before surgery worked so much better than giving it after. But they think it’s because the drug primed a systemic immune response until then suppressed by the tumor and that follow-up surgery then removed the immunosuppressant environment along with the tumor. By contrast, when the checkpoint inhibitor is not given until after surgery, immune cells are no longer present to be unleashed because the tumor has been removed.
Prins said biological information collected from the tumor samples also should lead to a better understanding of the mechanisms by which some patients generate strong immune responses to the therapy and others don’t.
The study was funded by a number of groups, including the National Institutes of Health and the Parker Institute for Cancer Immunotherapy, the organization launched in 2016 with a $250 million donation by Napster co-founder Sean Parker.