Killing cancer: Is immunotherapy a "miracle cure"?
【LWBS 2015 04 01 A】(SpringRain edited from Vox) Right now, most cancer patients only have a few options for treatment. They can get chemotherapy or radiation in order to kill bad cells and stop them from dividing, and they can get surgery to cut out the disease. But the success rate of these options is far from perfect.
Now there's a new kind of cancer treatment on the horizon: immunotherapies. These treatments try to stimulate the immune system, often through artificial proteins or vaccines, to help the body attack cancer from within.
Media coverage on cancer immunotherapy has generally struck an excited note. This week, the TV program 60 Minutes called immunotherapies "a big leap forward"; a Vice HBO documentary on the subject recently suggested that they're "miraculous" and "revolutionary," and that "we just might be on the verge of curing cancer."
The positive outcomes for some patients receiving immunotherapy do indeed seem impressive, even remarkable. Doctors have seen deadly tumors disappear, and patients who were supposed to die have gone into remission for years. The prolonged responses to treatment in very sick patients are almost never seen with chemotherapy.
Drug companies are jumping into the fray to bring new immunotherapies to market. The Wall Street Journal reported, half of Standard & Poor’s top-ten list of promising drugs for 2015 included cancer immunotherapies.
Is this really the holy grail scientists have been searching for?
The idea behind immunotherapy is at least a century old
In the 1890s, a New York surgeon named William Coley noted that a patient's cancer seemed to vanish after he came down with a bacterial infection. Coley thought maybe the bacteria had activated his immune system to fight the cancer. Before him, other doctors had also noted the weird link between infections and spontaneous cancer remissions. So Coley started experimenting by injecting people's tumors with bacteria. He found that the cancer regressed in some of those patients.
While Coley is now regarded as the "father of immunotherapy," his peers simply didn't believe his results. The idea of immunotherapy for cancer fell in and out of favor over the next 100 years, particularly as doctors were having success with radiation and chemo.
Immunotherapy can stop cancer — but it occasionally causes serious problems
Flash forward to 1992, when the first immunotherapy for cancer came on the market. It was Interleukin-2 (IL-2), approved by the Food and Drug Administration to treat metastatic renal cell carcinoma, an advanced form of kidney cancer, and, a few years later, to treat advanced skin cancer melanoma.
When patients took large doses of IL-2 — a protein that's made during an immune response — their bodies sometimes attacked cancer cells, and the drug appeared to save lives. Mark Gorman, the first patient who got the treatment, survived a cancer that should have killed him within months.
But IL-2 treatment hasn't been completely positive. "Despite its potential for miracles, IL-2 produces complete remission in only around 6 percent of people with melanoma. The treatment kills as many as 2 percent of recipients," a 2014 Nature review on the state of immunotherapy reads.
"The therapies work wonders for some —but can kill in rare cases"
A similar dynamic has been seen in this field since then. Doctors document incredible results with some treatments for particular cancers, but they mostly work wonders in a minority of patients, don't work at all in others, and can even send some patients' immune systems into overdrive, causing autoimmune disorders that attack healthy cells — or, in very rare cases, death.
As Heidi Ledford, the author of the Nature review, states, "After that 1992 approval, researchers and pharmaceutical companies spent years trying to develop new immunotherapies that could produce success stories like Gorman's [the IL-2 patient]. But those attempts failed to live up to their promise in the clinic, leading to decades of frustration."
There are several new immunotherapies now on the market
Right now, many different kinds of immunotherapies for a variety of cancers are in testing. These include treatments that use engineered viruses — HIV, measles, smallpox — to reprogram cells to destroy cancer. There are also therapeutic cancer vaccines and drugs that get T-cells, the soldiers of the immune system, to work harder to attack cancer.
The type of immunotherapy that appears to be most promising at the moment — the one that really has the medical community excited — is "checkpoint inhibitors."
"T-cells are tightly regulated with 'turn on' and 'turn off' signals," explains Dr. Michael Postow, an oncologist who is researching immunotherapies at Memorial Sloan Kettering. Checkpoint proteins do the work of turning them on or off. Checkpoint inhibitors block the body's checkpoint proteins, freeing them to attack cancer.
They only work on a fraction of patients, and no one really knows why
One of the first approved checkpoint inhibitors was ipilimumab (brand name Yervoy), an infusion that came to market in 2011 and targets a checkpoint protein called CTLA-4. Ipilimumab was also the first drug to extend the overall survival of patients with advanced melanoma.
The average survival rate for patients on the drug was about 10 months (four months more than those who got a cancer vaccine) — but some people had responses lasting years and counting. Still, using the body's immune system to fight cancer isn't always safe: the drug caused severe autoimmune side effects in about 15 percent of patients, and 2 percent (14 people) died as a result of the treatment.
"Using the body's immune system isn't always safe"
Since 2011, two other drugs have also been approved — nivolumab and pembrolizumab — which target a different molecule, PD-1. These drugs treat advanced melanoma, and nivolumab was also approved for lung cancer.
Drugs targeting the PD-1 pathway have shown responses in a variety of cancers such as melanoma, lung cancer, kidney cancers, bladder cancers, and Hodgkins' lymphoma. There are now dozens of clinical trials to test this and other kinds of checkpoint inhibitors for dozens of cancer types.
So these drugs also have promising, but nowhere near perfect, profiles. Take, for example, nivolumab, the checkpoint inhibitor approved for lung cancer several weeks ago. Because the science is new, the long-term data isn't in yet. But so far, researchers found two main effects: some 15 percent of people saw their cancer shrink away or disappear, and about half of the people who had that response found that it lasted for at least six months.
"Although the fraction of people who respond to these agents is small, the durability of responses when they occur represents a substantial step forward," said Dr. Matthew Hellmann, another Memorial Sloan Kettering oncologist and researcher.
As for side effects, he explained, "The most common experience was that patients feel well. But there can be uncommon side effects, where the immune system attacks other parts of the body — like the thyroid gland — that it shouldn't. In those cases, patients have to be treated with steroids, and some, very rarely, have died."
He continued: "When we talk about using the body’s immune system against cancer, there’s a perception that it is natural and safe." That, of course, isn't always the case.
Dr. Hellmann has looked into, among other things why immunotherapy works better in some patients than in others. He has found that for some immunotherapies, patients who had the most heavily mutated tumors responded best.
This insight has left the field with big questions, including: why do these therapies save some lives and not others? "The critical challenge that we have in the scientific community," said Hellmann, "is to figure out who are the patients most likely to benefit from these treatments and how can we develop better treatments to help those patients less likely to benefit from current immunotherapies."
We're not at the precipice of a "cure"
The dramatic progress has been the simple fact that these drugs work for some periods of time in some patients. And one of the major challenges is to understand why, and who will benefit.
As Dr. Hellmann put it, "I think this is true promise." He pointed to the activity in melanoma research and the three drugs now available to patients. But he also said, "About 15 to 20 percent really benefit from the medicines. It's remarkable — in that the benefit, when it occurs, tends to occur for a long time, but the challenge for us is how you identify those 15 to 20 percent.
"This is the beginning of a really important story," he summed up.
CBS 60 Minutes follows brain cancer patients in a Duke University clinical trial of a therapy that uses a re-engineered polio virus to kill cancer cells