Allison’s Nobel heralds new era in immunotherapy
Trials underway in next chapter of cancer treatment
Steve Johnson figures he’d be a dead man now if not for therapy that’s transforming cancer care but appeared to be a dud for his diagnosis: a tumor that’s spread from the prostate to other parts of the body.
Johnson only learned he had the disease, which kills about 30,000 American men annually, when doctors in Florida discovered it was the cause of a hairline fracture in his hip. They told him he probably had one to three years to live.
They also advised him to get to MD Anderson Cancer Center.
At the elite Houston research hospital, home of more clinical trials than any cancer center in the nation, Johnson initially got standard treatment regimens — cocktails of testosterone lowering drugs, surgery and chemotherapy — that worked for a while. Then the cancer roared back.
MD Anderson doctors asked Johnson if he wanted
to participate in a trial investigating immunotherapy, the cuttingedge therapy that’s made longterm survivors of many patients whose cancer was considered incurable. Dr. Jim Allison, the MD Anderson immunologist most responsible for the field’s newfound success, last week received the Nobel Prize in medicine for his discovery of a brake on the immune system and development of a drug to unleash it to attack tumors.
“Sounds good,” Johnson, now 63, told doctors. “When you think you’re going to die, you’re up for anything.”
There was one problem, though. In trials for patients with advanced prostate cancer resistant to drugs that reduce testosterone, Allison’s drug had failed. So had a drug for a second brake identified by a Japanese scientist, Tasuku Honjo, who shared in the 2018 Nobel.
The failure isn’t hard to explain. Prostate cancer is considered “immunologically cold,” a term for those tumors characterized by a lack of T cells, the foot soldiers of the immune system. Taking the brake off T cells doesn’t do a lot of good if there aren’t many around to mount an attack.
Allison and Dr. Padmanee Sharma, his wife and leader of the prostate cancer trial, didn’t see a dead end. From tumor biopsies collected at MD Anderson, they found that Allison’s drug, Yervoy, actually drove T cells into the tumor, only to be incapacitated there when the cancer exploited the second immune system brake.
Sharma and Allison figured combining the two drugs might give a better effect. Johnson went on the trial testing that hypothesis.
A next chapter
Combination therapy represents the next chapter in the book of immunotherapy, researchers say, the best hope for extending the treatment to more people.
The therapy won the 2018 Nobel Prize, the culmination of nearly 25 years of research, mostly on the basis of interventions with a single drug. It followed Allison's discovery that a protein — CTLA-4 — reins in the immune system, his development of the first drug targeting the protein and his single-minded push to convince drug companies to invest in the idea.
The cures came most dramatically and most strikingly in advanced melanoma and lung cancer, two cancers historically considered death sentences. Yervoy and drugs that target the second brake — the PD-1 protein — provided enduring benefits never before seen with surgery, radiation and chemotherapy, the tradition pillars of treatment. Suddenly patients once diagnosed with Stage 4 disease were cancer free and thriving more than a decade after treatment.
The class of drugs, known as checkpoint inhibitors, are now approved for not just melanoma and lung cancer, but also Hodgkin’s lymphoma and cancers of the kidney, bladder, stomach, liver, cervix, colon and rectum, and head and neck, an unprecedented variety of tumor types for one drug class.
Despite all that, immunotherapy efforts remain at a relatively early stage of development, considering only a minority of patients benefit from the approach. At MD Anderson and around the nation, scientists are working to extend the benefits to more patients.
“Combination therapy promises to do in many cancers what single-agent immunotherapy hasn’t,” Allison said last week, still glowing from his Nobel win. “We need to do even more combination trials, coupled with basic science research to understand why the intervention does or doesn’t work.”
Allison says there are nearly 2,000 immunotherapy trials in progress around the nation — most combining approaches — including about 200 at MD Anderson. A little more than half of those, part of the institution’s Moon Shots initiative, involve taking tissue biopsies of trial participants to conduct the sort of basic science Allison says is necessary.
That effort is providing key insights into immunotherapy’s successes and failures, the multiple mechanisms tumors employ to resist the immune system.
The combination prostate cancer trial, Yervoy plus the PD-1 checkpoint inhibitor Opdivo, should provide some of the first evidence of the effort. Results in its 90 patients aren’t yet ready — they’ll be reported at a conference early next year. But Sharma says they’re promising enough that she hopes to design a larger trial, at least 200 patients, that if successful could lead to Food and Drug Administration approval.
Johnson, who owns a construction business in Florida, is a poster child for the trial. Back at work and doing “wonderful” 16 months after he began the experimental treatment, he says the combination of the two checkpoint inhibitors “has given me my life back.”
Customized vaccines
J.T. Burk got his grim diagnosis in 2014: his colorectal cancer had spread to his lungs. His tumor type wasn’t one of the 2 percent of such cancers that respond dramatically to checkpoint inhibitors.
In such patients, the tumor is considered immunologically hot. In all the rest, the immune system doesn’t recognize the tumor.
To help out the immune system, MD Anderson scientists are experimenting with therapeutic vaccines, customized to each patient’s tumor. The personalized vaccine is based on 10 specific targets that researchers identify after analyzing the patient’s surgically removed tumor.
“It’s all about priming the immune system,” said Dr. Scott Kopetz, a professor of gastrointestinal medical oncology and one of the study leaders. “These customized vaccines tell the immune system, ‘Here’s the scent you’re looking for.’ ”
The trial combines the vaccine and PD-1 checkpoint inhibitor Keytruda to prevent T cells from shutting down the immune response.
Burk spent 3½ years on chemotherapy before the vaccine work was ready, a harsh time, he said, but it kept him alive. Initially thereafter, he received just the vaccine, which worked for about a year before he had to drop out of the study when his tumor grew by 20 percent.
After a few months back on chemotherapy, Burk moved to the trial’s second stage, Keytruda plus the vaccine. He got the two drugs for a year, and now, two months after the trial finished, he’s still stable — the tumors are there, but they have not grown.
“I feel like I’m playing with house money,” said Burk, 67, a Houston architect. He’s again able to work, to eat what he wants, and watch the Astros with his buddies at sports bars.
“After the diagnosis, I never felt like I’d live this long. People look at me and can’t believe I have Stage 4 cancer,” he said. “It’s amazing.”
Kopetz is encouraged by the positive responders, but said it’s too early to draw any conclusions given that all the trial participants won’t finish their regimen for six months. He figures he’ll publish results sometime in late 2019.
The stakes are considerable. Colorectal cancer kills more than 50,000 patients a year, the No. 2 cancer kill behind only lung cancer.
Handicapping the Nobel
People had been predicting Allison would win the Nobel since the middle of the decade — he was the 2016 pick of Nobel prognosticator David Pendlebury — but the timing of his 2018 selection nevertheless surprised some because checkpoint inhibitors only became a true force in clinics five years earlier. Nobel Prizes often aren’t awarded until decades after the fact.
The timing was more in line with Allison’s landmark discoveries about the immune system, which occurred in the mid-1990s.
The dual discovery-therapy achievement made the AllisonHonjo prize unique. There have been previous Nobels for cancer discovery (a number of them linking viruses and cancer) and cancer therapy (estrogen therapy to control prostate cancer, bone marrow transplantation to treat leukemia), but none that so combined the two, an achievement alluded to in the committee’s literature.
“Given the perhaps unprecedented research activities in the immune checkpoint field, it is likely that there will be major developments regarding this therapy at all levels,” the Nobel committee’s summary said. “This demonstrates how influential the discoveries of Allison and Honjo have been. Their findings have conferred great benefit on mankind; they add a new pillar to the existing cancer treatments.”
Pendlebury, who conducts journal citation research for Clarivate Analytics, said Allison checked all the boxes the Nobel committee typically likes: highly cited papers; a debunking of the conventional wisdom; numerous awards already won; and a discovery that has had a dramatic effect.
Indeed, the impact of checkpoint inhibitors are particularly dramatic in comparison to the history of cancer therapy, which is characterized by painstakingly slow, incremental advances and usually concerns just one type of tumor. What’s more, some advances that seem dramatic often don’t last. For example, drugs that target cancer at the molecular level looked like a home run in the early 2000s, but it became clear the cancer would eventually find a way to outwit them.
It also didn’t hurt that Allison’s breakthrough finally realized the potential of a field that had tantalized researchers for decades.
“The reason checkpoint inhibitors stand out is because they can, in the best cases, induce long-term remissions — and apparently cures — in patients with very advanced disease,” said Dr. Bert Vogelstein, director of the Ludwig Center at Johns Hopkins in Maryland. “No other therapy does this.”
A powerful weapon
Heather Handsford arrived at MD Anderson from the Dallas area this year, four years after she was diagnosed with Stage 2 triple negative breast cancer — one of the nastiest forms of the disease — and six months after tumors spread to her spinal cord and neck. The one on her neck protruded like a large bulb.
Radiation and chemotherapy knocked down the tumors, but follow-up scans showed new ones had grown.
Thinking a clinical trial was probably the only way to prolong her life, Handsford, 46, found her way to Dr. Jennifer Litton, who’s conducting 14 studies treating breast cancer with immunotherapy and a second drug. One of the studies, for patients with triple negative breast cancer, combines chemotherapy with an experimental new immunotherapy, which removes an immune brake and blocks a different kind of protein that suppresses the immune system.
Studies combining immunotherapy and conventional treatment lag behind the use of two immunotherapies, mostly because the effects on the immune system are unknown. But it’s considered a potentially powerful weapon because the debris from dead cancer cells can provide a target for the immune system.
Breast cancer is another immunologically cold tumor and has missed out on the successes of immunotherapy, a limitation that hasn’t had as profound an impact as some cancers because, detected early, most forms of the disease respond well to existing therapy.
Still, given the disease kills 40,000 women a year, there’s a need, says Litton. Such breast cancers as triple negative and inflammatory breast cancer resist most all existing therapy and, when any types spread to other organs, most treatments work for only a period of time before they fail.
“There’s a need for something that produces durable responses with metastatic cancer,” said Litton. “Something that’s less toxic, that lasts longer, that more profoundly gets rid of all the tumors.”
Handsford was one of the first patients on Litton’s combination triple negative breast cancer trial, which started in mid-September. She reports much improvement in those three weeks, particularly the immediate shrinkage of the protruding neck tumor. She said it’s no longer visible and harder to find by touch, a dramatic benefit she hadn’t previously seen in her four years of treatment.
Three weeks means little in such uncharted waters, of course — only time will tell if the benefit lasts. Still, Handsford says she feels “very positive about the treatment — I have less side effects, less pain, my outlook is much better.”
That's just what Allison likes hearing.
“I hope the Nobel gives patients more hope, makes them more likely to participate in trials, less likely to think the disease is a death sentence,” said Allison. “We’re still just at the tip of the iceberg, but immunotherapy has potential to save a lot more lives.”