New drugs spur the body’s own defenses to attack tumors.
John Ryan was running out of options. Four rounds of chemotherapy had left him severely debilitated but had failed to control his lung cancer, which had now spread to his ribs and hip. The pain was unremitting, he could barely eat and he was so weakened from chemo he couldn’t muster the energy to walk down his driveway. “The tumors were progressing exponentially,” recalls the 71-year-old retiree, a nonsmoker who spent much of his nearly 30-year Navy career working on nuclear submarines. “And I was devastated.” An experimental drug offered his only hope. Since October 2013, Ryan has hit the road before dawn every two weeks to beat rush hour traffic on the 75-mile drive from his home in Virginia to Johns Hopkins Kimmel Cancer Center in Baltimore. He spends five hours there receiving infusions of a novel cancer drug called Opdivo.
Within three months of joining the clinical trial, Ryan felt so much better that he helped his son chop down a pine tree. “By Christmas, I had bounced back from being on my knees begging for mercy,” he says; those once fast-growing tumors have shriveled by more than 80 percent and are barely detectable. “This has given me my life back.”
Also known as nivolumab, Opdivo is one of a promising new generation of treatments that fire up the immune system’s response to cancer. Immunotherapy is a radical departure from conventional chemotherapy and radiation, and even from newer medications targeting mutations in cancerous cells, all of which attack the tumors themselves. These drugs – man-made antibodies – latch onto the body’s immune cells and unleash them to vanquish the cancer.
Scientists use terms like “game changers” when they talk about immunotherapies like Opdivo, because the drugs may address one of oncology’s most vexing problems – eventual resistance to treatment – by enlisting the immune system to control tumors even once they’ve spread. Conventional treatments, no matter how efficacious initially, stop working once the cancer cells adapt to outwit them. These novel treatments are being hailed as holding out the possibility of a cure for people like Ryan with advanced cancers once considered invariably fatal. “Up until now, treatments were merely ways of buying time for patients with advanced cancer and extending survival but not fixing their cancer in a more long-term way, because chemo and targeting therapies eventually fail,” says Mark Faries, a melanoma expert at the John Wayne Cancer Institute at Providence St. John’s Health Center in Los Angeles. He, like the other experts on the drugs mentioned, has been involved in company-sponsored trials of them. “These treatments can potentially hit a home run because the immune system can adapt to whatever the tumor does and stay on top of it.”
That promise, though, proves not to be available to many patients. So far, the new drugs work for only about 20 percent of people. Doctors are baffled as to why a handful of patients taking them survive for years, while many don’t respond at all – although new research suggests that certain mutations make cancer cells more visible to the immune system.
“A 20 percent response rate is great, but we want more patients to benefit,” says Julie Brahmer, an oncologist and director of the thoracic oncology program at Johns Hopkins Kimmel Cancer Center. “But figuring out the way each patient’s tumor evades the immune system is tricky.”
The first of these drugs, Yervoy (ipilimumab), was approved in 2011 for advanced melanoma; Opdivo and Keytruda (pembrolizumab), which target different pathways on immune system cells, got the green light for melanoma in 2014. This past March, Opdivo was cleared to treat advanced lung cancer, the leading cause of cancer deaths. In premarket trials, these drugs and others like them are now showing similar response rates against a wide range of tumor types, including head and neck, liver, bladder and some forms of colorectal cancer. Scientists are also experimenting with other methods of stoking immune responses, like bombarding lethal blood and brain cancers with modified polio or measles viruses.
The notion of using the patient’s own immune system as a more durable and precisely targeted weapon against cancer is not new. In fact, it dates back more than 100 years to observations by doctors that some patients seemed to do better after developing infections. But numerous obstacles have impeded medical science’s quest to turn that notion into drugs. Because cancer cells share traits with healthy cells, the immune system has trouble recognizing them as aberrant; the rogue cells are thus able to slip through the body’s defenses.
The body’s immune system “has checks and balances that prevent it from attacking its own cells,” says Antoni Ribas, a melanoma specialist at the UCLA Jonsson Comprehensive Cancer Center. “The tumor cells sense there is this army trying to attack, and the cancer turns off the immune system using the same protective mechanism that other cells have.”
The new drugs, known as checkpoint inhibitors, don’t allow this bit of subterfuge. Yervoy, for example, thwarts the action of a protein that acts as an “off switch” to stop T-cells, the immune system’s foot soldiers, from harming both cancerous and healthy cells. Yervoy, which flips the switch back on and allows T-cells to spot and attack the cancers, is the first melanoma treatment to actually prolong the lives of people with late-stage disease. More than 20 percent of patients tested survived three years or more; normally, their survival would be measured in months. The reprogrammed immune system cells continue working even after treatment has stopped. “Because they generate a memory response in the immune system, it remembers what it is targeting, even after we stop giving the drugs, in the same way that vaccines create long-term immunity,” says Ribas. Keytruda and Opdivo target other proteins on the surface of T-cells called PD-1. Some cancer cells produce proteins that latch onto PD-1, disarming the T-cells. The drugs prevent this sequence of events, removing the immune system’s brakes and restoring its ability to respond. “They gum up the lock,” says Jonathan Cheng, executive director of oncology clinical development at Merck Research Laboratories, the maker of Keytruda. In clinical trials of Opdivo to combat advanced lung cancer, about 1 in 5 patients were still alive after three years, all of whom would otherwise have been long dead, experts say. “People who remain alive after two years usually stay alive,” says Michael Giordano, senior vice president and head of development for oncology at Bristol-Myers Squibb, the maker of Yervoy and Opdivo.
On other fronts, deadly viruses are being called into battle. Certain viruses, like the measles, polio and herpes simplex virus, can be coaxed to selectively zero in on cancer cells while leaving healthy cells intact. Once they slip inside a cancer cell, viruses can either hijack the cell’s genetic machinery to reproduce, generating an army of clone viruses that search out and destroy other cancer cells, or act as tiny cargo ships delivering genes that make cancer cells visible to the immune system.
China is already using cold viruses to combat head and neck cancers. Although the therapy is still in the experimental stages in the U.S., several treatments for a number of cancers have shown encouraging results in human tests. Among the more promising are studies being conducted at the University of Pennsylvania on patients suffering from acute lymphoblastic leukemia. In this case, scientists first removed immune cells from patients. Then the team used a modified HIV virus to genetically reprogram the cells so they would recognize a protein on cancer cells that would prompt them to zero in on the tumors; the cells were then infused back into the patients. Of the 25 children and five adults who were given this regimen, all but three went into complete remission. Their cancer became undetectable.
Researchers at the Mayo Clinic and Duke University have been using genetically engineered versions of the measles virus and poliovirus to treat multiple myeloma and brain cancer, respectively. Two patients suffering from the incurable blood cancer were treated at Mayo; one has been cancer-free for two years, and the other patient, in a weakened condition, has died.
In the Duke study of 22 brain cancer patients who had poliovirus dripped into their brain, 11 have died; two are cancer-free three years after the treatment; and the remaining nine are alive two months to two years later. Stephanie Lipscomb, the first to receive the treatment in 2012, just graduated from nursing school and says she now feels fine. The immune system “thinks it is killing polio. But it is actually killing the brain cancer,” says Annick Desjardins, a neuro-oncologist at Duke. “Based on preliminary studies, we think this therapy could also be effective with any solid tumor cells, such as pancreatic, prostate and lung cancers.”
The new drugs are staggeringly expensive; costs can hit $150,000 a year. And revving up the immune system can trigger attacks on normal cells, too, that result in fevers, colitis, hepatitis, severe skin rashes and inflammation of the pituitary and thyroid glands. “I was so exhausted, I needed a wheelchair to get around,” recalls Kathy Thomas of Redondo Beach, California, who joined a Yervoy trial after a 2011 diagnosis of advanced melanoma that had spread to her breast, liver and brain. The medication did slow the tumor growth but made Thomas, 60, so nauseated she was unable to eat. She lost more than 60 pounds and was forced to retire from her job as a mammography technician. She later enrolled in a test of Keytruda, which melted away the brain metastases and most of the lesions on her liver. The ones that remain have shrunk by 88 percent. “This drug saved my life,” she says.
And then there’s the reality that most people will not respond. To get a better handle on why, scientists at Memorial Sloan Kettering Cancer Center in New York have analyzed the genetic signature of 64 melanoma patients who received Yervoy, roughly half of whom did well on the drug while the others did not. The research revealed that tumors with the most mutations were more likely to respond, a logical finding given that it’s easier for the immune system to recognize that these cells are abnormal.
Consequently, experts predict, the drugs are most likely to work in tumors that are caused by exposure to mutation-causing carcinogens. These include melanoma, the result of too much DNA-damaging UVA sunlight; lung, bladder and head and neck cancers that are caused by smoking; and head and neck or cervical cancers induced by HPV infections. Within the next year or two, this discovery could lead to diagnostic tests that identify which patients are most apt to benefit from the new therapies.
“If you have the genetic signature of a smoker, your response rate to anti-PD-1 therapy is 70 percent, which is immediately useful for lung cancer patients now,” says Timothy Chan, a study co-author and vice chair of radiation oncology and director of the division of translational oncology at MSKCC; in other words, 7 out of 10 of those patients see positive results. “These are the sickest of the sick, and their survival untreated is four to six months. But we have patients who are eight to 10 years out, which is amazing because these people were literally on their deathbeds.”
And this is only the beginning, scientists say. Even more potent treatments, targeting multiple immune system pathways at once, are now under development. In the not too distant future, says Brahmer, “metastatic cancer may no longer be an automatic death sentence.”
By Linda Marsa