The first study involved an investigational antibody drug, known as MPDL3280A and manufactured by Roche Genentech, which was designed to prevent a cancer cell's overexpressed PD-L1 protein from putting the immune system to sleep. The overexpressed PD-L1 protein turns off the immune system's T-cells by binding to its PD-1 and B7.1 proteins. In doing so, it disguises itself and evades detection and destruction by the body's immune response.
In blocking the cancer tumor's PD-L1 protein, MPDL3280A frees the immune system to do its job. This PD-L1 targeted antibody was specially engineered to increase safety and efficacy over earlier immunotherapy agents.
October 14, 2013
Breaking Through Cancer’s Shield
By GINA KOLATA
For more than a century, researchers were puzzled by the uncanny ability of cancer cells to evade the immune system. They knew cancer cells were grotesquely abnormal and should be killed by white blood cells. Why, then, could cancers survive in the body?
The answer, when it finally came in recent years, arrived with a bonus: a way to thwart a cancer’s strategy. Researchers discovered that cancers wrap themselves in an invisible protective shield. And they learned that they could break into that shield with the right drugs.
When the immune system is free to attack, cancers can shrink and stop growing or even disappear in lucky patients with the best responses. It may not matter which type of cancer a person has. What matters is letting the immune system do its job.
So far, the drugs have been tested and found to help patients with melanoma, kidney and lung cancer. In preliminary studies, they also appear to be effective in breast cancer, ovarian cancer and cancers of the colon, stomach, head and neck, but not the prostate.
It is still early, of course, and questions remain. Why do only some patients respond to the new immunotherapies? Can these responses be predicted? Once beaten back by the immune system, how long do cancers remain at bay?
“Amazing,” said Dr. Drew Pardoll, the immunotherapy research director at Johns Hopkins School of Medicine. This period will be viewed as an inflection point, he said, a moment in medical history when everything changed.
Researchers and companies say they are only beginning to explore the new immunotherapies and develop others to attack cancers, like prostate, that seem to use different molecules to evade immune attacks. They are at the earliest stages of combining immunotherapies with other treatments in a bid to improve results.
The story of the new cancer treatments started with the discovery of how cancers evade attacks. It turned out that they use the body’s own brakes, which normally shut down the immune system after it has done its job killing virus-infected cells.
One braking system, for example, uses a molecule, PD-1, on the surface of T-cells of the immune system. If a target cell has molecules known as PD-L1 or PD-L2 on its surface, the T-cell cannot attack it.
So some cancer cells drape themselves in those molecules. The effect, when T-cells are near, is like turning off a light switch. The T-cells just shut down.
Cancers that do not use PD-L1 or PD-L2 are thought to use other similar systems, just starting to be explored. Body systems have a lot of redundancy to tamp down immune attacks. But for now, the PD system showed researchers how cancer cells can evade destruction.
“That is what has been realized in the past few years,” said Ira Mellman, vice president of research oncology at Genentech. “Tumor cells are making use of this brake.”
The discovery led to an idea: Perhaps a drug that covered up any of those PD molecules, on the cancer cells or on white blood cells, would allow the immune system to do its job.
The first indication that a cancer’s protective shield might be breached came in 2010, after a trial of the drug ipilimumab in patients with otherwise untreatable melanoma. The drug unleashes the immune system, letting it overwhelm tumors even if they have a protective shield.
Patients who took the drug survived an average of 10 months, or 4 months longer than those randomly assigned to a different treatment. And about 20 percent of patients who responded have now survived up to 10 years. It was the first drug to improve survival for patients with metastatic melanoma in a randomized trial.
The drug was approved for melanoma in March 2011, with a high price tag — $120,000 for a course of therapy.
It had another drawback. By unleashing the immune system, it sometimes led to attacks on normal cells. In some cases, the reaction was fatal. But the trial was a proof of concept. It showed that cancers can succumb to an attack by the immune system.
“That opened the door a crack,” said Dr. Pardoll, of Johns Hopkins. “People stood up and took notice.”
Dr. Suzanne Topalian, a professor of surgery and oncology at Johns Hopkins, was one of the first to test the new drugs in patients. The trial began in 2006, with 39 patients who got a PD-1 blocker, made by Medarex, since bought by Bristol-Myers Squibb. The study included patients with a variety of advanced cancers, who had failed all traditional treatments; most had tried at least three, without any luck.
The study looked at safety, not effectiveness. But Dr. Topalian noticed something intriguing. One patient with lung cancer treated at a collaborating medical center had a partial regression of her tumor.
That was surprising because researchers had assumed the cancers most vulnerable to an immune system attack were melanoma and kidney cancer.
“Julie and I got on the phone with Medarex and said, ‘You have to include lung cancer in your next clinical trial,’ ” Dr. Topalian said, referring to her colleague Dr. Julie Brahmer.
That led to studies of two Bristol-Myers drugs: one that blocks PD-1 and another that blocks PD-L1. The studies included a 503 patients with a variety of advanced cancers who had exhausted other options.
The findings, presented in October last year at a meeting of the American Society of Clinical Oncology, were striking. A significant proportion of patients responded, including 18 percent of 76 lung cancer patients who got the PD-1 drug and 10 percent of 49 who got PD-L1 drug. Dr. Pardoll, who is married to Dr. Topalian, said that when she and her colleagues presented the data, “it was almost like a hush fell over the room: ‘Can this really be?’ ”
As researchers continue to study the new drugs and ask if they can improve their results by combining them with other therapies, they are heartened by some of the rare patients whose cancers were halted by the drugs. They caution that these patients are unusual; critical studies to reveal the drugs’ effects on populations of cancer patients are still under way.
But some patients, like two treated at Hopkins, have become emblems of hope.
Last edited by lancepeace; 10-15-2013 at 09:27 PM.