What if the path to curing cancer has been part of the body all along?
For generations the three pillars of cancer treatment have been surgery, radiation, and chemotherapy. But both chemotherapy and radiation are crude weapons with significant collateral damage to healthy tissue, and surgery can leave cancerous cells behind. Scientists have long tried to understand how to get the immune system—the body’s natural defense mechanism—to recognize cancer cells as the enemy and destroy them. And now we may finally be turning the corner: Doctors are finding that clinical regimens known as immunotherapies can empower a patient’s immune system to fight the disease like it might an infection, while sparing a person’s normal cells.
“Before now, physicians in the field have always been extremely hesitant to use the ‘cure’ word for cancer,” said Dr. Axel Hoos, head of the immuno-oncology discovery performance unit at GlaxoSmithKline Pharmaceuticals. “But because of the incredible advances in immunotherapy, that’s no longer true. Individual physicians are actually using the word ‘cure’ for some patients with diseases that were almost universally fatal just five years ago.”
Last fall, scientists at the Fred Hutchinson Cancer Research Center in Seattle gathered at the bedside of a lymphoma patient as oncologist Dr. David Maloney reinfused a patient with the person’s own T-cells that had been genetically programmed. This form of immunotherapy harvests a person’s immune cells and recodes them to become better cancer drones.
Maloney has been working with targeted cancer therapies since the early 1980s. As a student at Stanford, Maloney was part of a team that developed antibodies specifically targeting non-Hodgkin’s lymphoma while avoiding healthy cells. Today, he is one of the oncologists on the forefront of the next major advance in immunotherapy. He infuses lymphoma patients with their own T-cells, re-engineered to produce a chimeric antigen receptor (or CAR T-cells) that, once triggered, can eliminate cancer. The infusion is only a 30-minute procedure, though the entire process takes several weeks. But unlike antibodies, which are broken down by the body over time, CAR T-cells may continue to multiply, serving as a “living therapy” throughout a patient’s life— staying on guard for any subsequent relapses.
“We are moving away from a bottle-off-a-shelf model, one-size-fits-all approach,” Maloney explained, “to a way of fighting cancer where we are essentially custom-making treatments for patients, training a person’s immune system to go after a target and remember what that target looked like in the future.”
This June, at the annual meeting of the American Society of Clinical Oncology, for the second year in a row, the big news was immunotherapy for multiple types of cancer, including kidney, lung, bladder, and melanoma. Researchers presented new data that drugs designed to unlock a patient’s immune system are significantly extending the lives of some patients with the most advanced stages of the disease.
Take the 2013 Bristol-Myers Squibb study led by Dr. Jedd Wolchok at Memorial Sloan-Kettering Cancer Center in New York City. Doctors used a combination of two drugs—one approved, the other experimental—in 52 melanoma patients, and found that treatment with both immunotherapy drugs resulted in rapid and deep tumor regressions about one-third of the time. This type of immunotherapy uses antibodies, given intravenously, which rev up the immune system. “We are talking about very significant survival rates here, with all the caveats of cross-trial comparison, of course,” Wolchok said. “But these are materially distinct numbers. We have spent several decades in cancer research learning better ways to treat the tumor. Now we are learning how to treat the patient.”
While the FDA only approved the first modern immuno-oncology drug, Yervoy, in 2011, the concept of immunotherapy dates back to the 19th century. In the 1890s, William Coley, a bone-sarcoma surgeon at New York Cancer Hospital (now Memorial Sloan Kettering Cancer Center), tried using heat-killed bacteria to cure cancer. He noticed that some patients seemed to live longer if they developed an infection after their cancer surgery, and he hypothesized that their immune system had been mobilized, fighting not just the infection, but their cancer too. Over the next 40 years, he injected more than 1,000 patients with bacteria known as Coley’s Toxins—reporting “excellent results” in bone and soft-tissue cancers.
“Immunotherapy is very exciting because the immune system is a natural and highly effective tool to fight disease,” Hoos explained. “No other drug or course of treatment has been able to generate the long-term benefits and promise for patients seen with cancer immunotherapies.”
The beautiful thing about the immune system, according to Dr. Roy S. Herbst, professor of medicine at Yale Cancer Center and chief of medical oncology at Smilow Cancer Hospital Center at Yale-New Haven, is its durability. Unlike chemotherapy, the immune system is highly specific and adaptive, able to distinguish between self-markers (the body’s own tissues) and foreign invaders that might make us sick. Herbst, a leader in lung cancer treatment and research, draws an analogy to childhood vaccinations. Vaccines trigger our immune system to respond on its own, as though we have been infected with the disease. Similarly, antibody immunotherapies block specific proteins that cancer cells use to hide from the immune system, allowing the body to recognize a tumor as a foreign invader.
“We all get vaccinated when we are kids, and we know boosters can work for incredibly long periods of time,” Herbst explained. “That’s because the immune system has such a long memory. And with immunotherapy, if a tumor changes, the immune system can change to attack it too.”
Unfortunately, immunotherapies do come with side effects, and the immune system can be turned on too high. In April, a clinical stage company temporarily halted its cell therapy trials after two patient deaths. But for the most part, unsurprisingly, adverse reactions mirror autoimmune diseases, where immune cells become hyper-activated and react to normal tissues. “Patients can experience nausea and fatigue,” Maloney said. “As well as in some cases, [symptoms can resemble] classic autoimmune diseases like colitis or Crohn’s, but this is only temporary. Immunotherapies do not create these diseases in the patient and they will subside.”
Herbst cautions that immunotherapy is not a cure-all, and conventional forms of cancer treatment will endure. The future, rather, is one in which patients may receive a combination of therapies. In his estimation, 15 to 20 percent of people with lung cancer will benefit greatly from immno-oncology drugs alone, while the remaining 80 percent will likely need a mix of the more conventional options like chemotherapy and radiation as well.
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