Unleashing the Immune System – Against Cancer
WHY YOU SHOULD CARE
Because treating the immune system might be more effective at fighting cancer than attacking tumor cells directly — and offer hope for even the most devastating diagnoses.
Thèrése Bocklage thought she had bruised her leg lugging a Christmas tree from her garage in late 2011. But when the hard nodule refused to disappear, the University of New Mexico pathologist asked her colleague to perform a biopsy. She then presented microscope slides of the tissue samples to the other pathologists in her department as a case study.
These so-called cancer immunotherapies offer hope to patients with advanced, otherwise untreatable cancers.
Their diagnosis was unanimous: advanced melanoma, the deadliest form of skin cancer. It had already spread deep into her muscles — placing her odds of surviving another year at just 15 to 20 percent. “I felt pure shock,” she said. “It was unreal.” A month later, she enrolled in a clinical trial of an experimental melanoma drug led by oncologist Antoni Ribas at UCLA’s Jonsson Comprehensive Cancer Center.
These drugs have also been tested and shown to help patients with kidney cancer. Preliminary studies have also found them to be effective in breast, ovarian, colon, stomach, and head and neck cancers.
Fast-forward two years, and 54-year-old Bocklage is melanoma free. Slowed by fatigue only occasionally, she went back to working full time and recently trekked 28 miles through the mountains. “It almost seems miraculous,” she said. “If I hadn’t linked up with [Dr. Ribas], I’d probably be dead.”
Bocklage had taken Merck’s MK-3475, one of a promising class of drugs that works in a radically new way — by unleashing the immune system to attack cancer cells. These so-called cancer immunotherapies offer hope to patients with advanced, otherwise untreatable cancers that have already invaded their body, leaving them with only months to live. And while today’s anti-cancer drugs target specific types of tumor cells, these drugs target the immune system — meaning they may be able to treat any type of cancer. “I think they’ll become a standard form of therapy,” Ribas said. “It’s a big step forward.”
Normally the immune system attacks any cell it recognizes as dangerous or abnormal. Since cancer cells display unusual proteins on their surface, the immune system should technically attack them too. But cancer cells can evade these attacks by using the body’s own brakes, which normally shut down the immune system after it finishes its job of killing infected cells. To “hit the brakes,” molecules known as PD-L1 and PD-L2 bind to PD-1, a protein found on the surface of the immune system’s T cells. So some cancer cells cloak themselves in PD-L1 and PD-L2, causing nearby T-cells to shut down.
In the trial, MK-3475 wiped out or shrank tumors in nearly 80 percent of patients — roughly four times the response seen with chemotherapy…
But MK-3475 latches on to PD-1, blocking out PD-L1 and PD-L2 and freeing T-cells to attack cancer. In Ribas’s trial, MK-3475 wiped out or shrank tumors in nearly 80 percent of patients — roughly four times the response seen with chemotherapy, the main course of treatment for advanced melanoma. Thanks partly to these findings, published in the New England Journal of Medicine last July, Merck began filing for FDA approval of MK-3475 as a treatment for advanced melanoma last month. The FDA has also granted breakthrough status to another PD-1 inhibitor called nivolumab to speed up its approval process after it yielded promising clinical trial results for non small-cell lung cancer.
The first hint that the immune system might hold a key to cancer therapy came in 2010, after a clinical trial of ipilimumab, which disables another immune system brake called CTLA-4. In the trial, nearly 11 percent of advanced melanoma patients who received ipilimumab alone responded to treatment and survived an average of 10 months — four months longer than those who didn’t take the drug. The FDA approved ipilimumab, or Yervoy, for advanced melanoma in 2011.
Some researchers suspected that disabling the PD-1 system would trigger a much bigger immune response than CTLA-4, since it controlled a later stage of the immune response — when the T-cells had already infiltrated the tumor, ready to attack. The tumor cells, wrapped in PD-L1 and PD-L2 molecules, had simply switched them off.
Meanwhile, some oncologists had turned their attention to the PD-1 immune braking system. When a clinical trial of the PD-1 inhibitor nivolumab yielded promising preliminary results in melanoma patients, Ribas decided to test whether MK-3475 could also treat the disease. He enrolled 135 patients with advanced melanoma to receive MK-3475 through an IV infusion every two or three weeks.
As each week passed, Bocklage felt the nodule on her leg shrinking. Ribas allowed her to examine biopsies of her nodule under a microscope. With each biopsy, she saw more and more T-cells swarming in, and the tumor cells gradually disappearing. Then one day, she didn’t see any tumor cells — and the nodule had vanished. “I was stupefied,” she said.
Many patients continue to respond — even after going off MK-3475.
The results for the other participants were equally stunning. MK-3475 shrank or destroyed tumors in 77 percent of participants — much higher than the response to Yervoy. Since the vast majority of participants still aren’t showing signs of relapse, it isn’t known yet how long patients can expect to respond to the drug. What’s more, many patients continue to respond, even after going off MK-3475. “The immune system seems to remember that the melanoma is the enemy and continues to control it long term,” Ribas said.
Still, cancer is notoriously unpredictable. In some cases, the results seen in controlled clinical trial settings don’t translate to the real world. What’s more, these drugs may not be for everyone. Even if they could theoretically be used to treat any type of cancer, some cancers might be more susceptible than others to immune attack. Most patients will probably need to undergo other treatments in addition to immunotherapy. And since such drugs stimulate the immune system, they might be dangerous for people with lupus, multiple sclerosis, or other diseases caused by an overactive immune system.
But for cancer patients with few options, MK-3475 and other immunotherapies offer hope — possibly allowing them to enjoy a cancer-free life for much longer than they could have with chemotherapy. As for Bocklage? “I’m elated,” she said. “I can hardly even think of myself as a cancer patient.”