Courtesy of STAT News New cancer drugs that unleash the immune system on tumors are all the rage, getting credit for curing former President Jimmy Carter’s advanced melanoma and inspiring tech billionaire Sean Parker to pledge $250 million to cancer research. Behind the excitement, however, is the hard truth that these therapies work in only a minority of patients.
Now scientists are finding hints of a solution in an unexpected place: Older, out-of-favor cancer treatments such as chemotherapy and radiation may make the cutting-edge immune-based drugs effective against more cancers — even hard-to-treat ovarian and pancreatic tumors.
The growing body of research raises the possibility that it might not be necessary to invent new medications to make meaningful progress against cancer. “If we just take the drugs we have and combine them in the right way, I think there is huge potential” for beating more cancers into remission, said Dr. Patrick Hwu of M.D. Anderson Cancer Center in Houston.
Yearly successes pan out in animal experiments and dozens of clinical trials now underway, patients would have more options and a better chance at a true cure. Another plus: radiation and generic chemotherapy are relatively cheap compared with new immuno-oncology medicines.
Tumors disable the immune system’s killer T cells, which can find and destroy certain cancer cells. Immunotherapy drugs work by preventing tumors from using this devious tactic. But if no T cells are swarming the tumor in the first place, the drugs don’t help. It’s like playing the San Antonio Spurs with NBA defensive player of the year Kawhi Leonard sitting on the bench, but then not getting your own players past midcourt.
The trick, therefore, is to turn “cold” tumors that T cells ignore into “hot” tumors that attract T cells. Or, at the risk of torturing the metaphor, to get those T cells past midcourt. “If the T cells don’t exist, the question is, how do you make them exist?” said Hwu.
One answer: through chemotherapy or radiation. When these old-line treatments begin to kill tumor cells, those cells release molecules that can attract T cells to join in the attack. “They have the potential to prime the pump for immunotherapies,” said Dr. Gary Gilliland, president of the Fred Hutchinson Cancer Research Center in Seattle.
Biologists in England recently got an inkling of that. Researchers led by Frances Balkwill of Queen Mary University of London compared 54 women with serious ovarian cancer who received standard chemotherapy (carboplatin or paclitaxel) before surgery to six who did not. In the women treated with chemo, there was significantly more activation of the kind of T cells that attack cancer cells than in the other six, the scientists reported in June in Clinical Cancer Research. “There is a belief that chemotherapy suppresses the immune system, but weeks after treatment, we found lots of T cells in the tumor environment,” Balkwill said.
Just having the T cells clearly isn’t enough; if it were, ovarian cancer wouldn’t be so deadly. Indeed, Balkwill found, the surviving tumor cells were disabling the swarming T cells. But immunotherapy such as Merck’s pembrolizumab and Bristol-Myers Squibb’s ipilimumab can stop tumor cells from doing that.
Balkwill’s results, therefore, suggest that a form of chemotherapy invented in the 1960s might let 21st century immunotherapies work against more cancers, and that pairing immunotherapies with legacy chemotherapies (which cancers quickly become resistant to) might make each more effective. A cold tumor like ovarian cancer might be turned into a hot, T cell-attracting one like, say, melanoma, against which immunotherapies have had some of their best results.
Radiation, which was first used against cancer at the turn of the 20th century, can also turn cold tumors hot. In a study published in June, scientists led by radiation oncologist Dr. Ralph Weichselbaum of the University of Chicago Medical Center found exactly that in mice with pancreatic cancer, which is notorious for being nearly untreatable, as well as for not attracting tumor-destroying T cells. (The only immunotherapy having any effect on pancreatic cancer in people slowed tumor growth in a mere 8 percent of them.)
“We think radiation turned a cold tumor into one that attracts T cells, while the immunotherapy kept the T cells from being disabled,” Weichselbaum said. “I think some cancers that aren’t now treated with radiation might be,” as long as immunotherapy follows.
“If we just take the drugs we have and combine them in the right way, I think there is huge potential.”
Paul Mihocko, a retired iron worker in Hyde Park, N.Y., is living proof of that strategy’s promise. Happily retired after working on many of the iconic Hudson River bridges, he was diagnosed with metastatic melanoma nine years ago after a lump was found in his right armpit. Although chemo seemed to drive the cancer into remission, it returned in 2009.
Mihocko then volunteered for an early clinical trial of ipilimumab at Memorial Sloan-Kettering Cancer Center in New York. Ipilimumab, too, worked for a few years, but while in the trial he developed another tumor, above his heart.
“They told me, evidently the ipi stopped working,” Mihocko said.
He was referred to Dr. Chris Barker, a radiation oncologist at Sloan-Kettering. “He said he was 90 percent sure they could get the tumor with radiation. And the ipi was still in me,” Mihocko said — or, at least the T cells it had pumped up to attack tumors seemed to be. But for some reason, the T cells were not finding the cancer cells. Mihocko enrolled in a clinical trial Barker was leading. He felt “cooked, completely wasted, and exhausted” by the radiation treatments twice a week for five weeks, Mihocko said, but “they seemed to kickstart the ipi, and the tumor vanished.”
Now he’s able to walk, play golf, and mow his five-eighths-of-an-acre lawn. “I figured I was on my way out,” he said. “I’m very fortunate, that’s all.”
Luck helps, but Barker thinks other factors were also at work. “Radiation might make tumor cells more vulnerable to immunotherapy,” he said, including by changing how tumor cells look to the immune system; that would “make them a more attractive target to attack.” Barker is helping to lead several studies combining radiation therapy with an immunotherapy, including one for metastatic melanoma and one for metastatic breast cancer, while other researchers are testing the combination in metastatic head and neck cancer and metastatic colorectal cancer.
At M.D. Anderson, the department of lung, head, and neck cancer alone is running 36 clinical trials of combinations. There are dozens more trials at the country’s other leading academic cancer centers, and “the big pharmaceutical companies are looking at potentially every combination out there,” said the Hutch’s Gilliland, who oversaw development of what became pembrolizumab when he was at Merck.
At the annual meeting of the American Association for Cancer Research in April, scientists presented more than a dozen studies investigating radiation or chemotherapy plus an immunotherapy. A years-old, three-drug chemotherapy for head-and-neck cancers changes those tumors in a way that should make them more vulnerable to immunotherapies, French scientists reported, while other researchers unveiled promising combinations for pancreatic cancer and non-small-cell lung cancer.
With more than 200 approved cancer drugs and more in companies’ pipelines, the number of possible combinations is essentially infinite, said Dr. Chris Boshoff, senior vice president for immune-oncology at Pfizer. “We want to focus on those where you have a biological, rational basis” for expecting to see a benefit, he said. For instance, Pfizer is testing its experimental immunotherapy avelumab (developed with Merck KGaA) in combination with the chemotherapy doxorubicin in ovarian cancer and with radiation for advanced head and neck cancer.
Other cancer biologists think it makes sense to try as many combinations as possible and see what works.
With the see-what-sticks approach, said M.D. Anderson’s Hwu, “you might get lucky, like a chimp at a keyboard might get lucky and type out Hamlet, but I always think more science is better.” The quest for combinations has become so heated, however, that “a lot of it is just putting together combinations with minimal data” to support a particular pairing.
One obstacle to choosing effective combinations is that traditionally, cancer drugs and radiation have been tested in mice lacking an immune system, so that the human tumor transplanted into them (the standard study design) wouldn’t be rejected and ruin the experiment. As a result, there was no chance to see how the drugs affected the ability of the immune system to attack the tumor.
“We therefore don’t have a detailed understanding of how chemotherapy and radiation affect the immune response,” said Dr. Padmanee Sharma of M.D. Anderson. But now scientists are using mice with functional immune systems to fill in the gaps in their knowledge. If they do, cutting-edge immuno-oncology drugs could get a huge boost from cancer treatments often dismissed as primitive and ineffective. Call it back to the future.