New therapies raise hope for a breakthrough in tackling cancer


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February 17

In the summer of 2012, a year after his wife had died of lung cancer, Michael Harris scraped open an old mole on his back and it would not stop bleeding. The doctors said he had stage 4 melanoma, with a virtually inoperable tumor, and that patients in his condition typically lived about eight months. By last June, the cancer had spread to his liver and lungs.

At that point Harris joined a clinical trial at Georgetown University, one of scores that have sprung up around the country to test a new class of cancer drugs called immune-checkpoint inhibitors. Two weeks after his first infusion, Harris’s primary tumor was fading, along with the black cancerous beads around it. A month later, his liver and lungs were clean.

“This stuff was like vanishing cream,” says Harris’s daughter, Rhonda Farrell. Today, Harris, a sun-
leathered 66-year-old Vietnam veteran from Waldorf, Md., is back at work. And though his doctors won’t declare him cured, he says, “I feel like a normal person.”

Because it can be so inexorable and deadly, cancer tends to inspire hopes of miracle cures. Because of all the failed miracle cures, cancer doctors are a cautious lot. This makes it all the more astounding to hear cautious clinicians and scientists describe the treatments Harris and thousands of others are receiving.

“It’s a breakthrough,” says oncologist Michael Atkins, who recruited Harris to the trial at Georgetown’s Lombardi Cancer Center. “This is real,” adds Louis Weiner, the physician who leads the center. “We’re still in a bit of shock,” says Suzanne Topalian, a cancer immunologist at Johns Hopkins University who has been a key player in bringing the substances into clinical trials.

Weighing the impact of cancer by years lost to the disease.

Immune-checkpoint blockade is a form of immunotherapy, meaning it aims to help the patient’s own immune system fight cancer. It uses substances called monoclonal antibodies, which are designed by drug companies to target extremely specific molecules on cell surfaces. In this case, the antibodies unblock a reaction that stops the immune system’s natural attack on invading cancer cells.

Although a range of new cancer treatments, such as targeted chemotherapy for breast cancer and cell-signaling inhibitors for leukemia, have shown positive effects over the past two decades, the checkpoint inhibitors seem to be providing uniquely long-term benefits. At least seven drug companies are testing the antibodies.

Topalian’s husband, Drew Pardoll, also a Hopkins cancer immunologist, predicts that five years from now, half of the 600,000 Americans who receive diagnoses of advanced cancer each year will receive checkpoint inhibitors or other immune-related therapies.

Medical, commercial and patient interest in the new drugs is intense. “Research activity is just going through the roof,” Topalian says. While Bristol-Myers Squibb, Merck and other companies rush to get their versions of the therapy approved by the Food and Drug Administration for treatment of melanoma and lung and kidney cancers, the substances also are being tested in smaller trials against cancers of the blood, colon, stomach, breast, bladder, liver, head and neck and brain. “The field is just afire now,” says immunologist Gordon Freeman of the Dana-Farber Cancer Institute in Boston.

The checkpoint inhibitors may also have uses in battling some chronic infections. Trials using the antibodies against hepatitis B, HIV and even the blood infections that contributes to 200,000 U.S. deaths each year are underway or in planning stages.

Not everyone, though, is convinced that the checkpoint inhibitors are quite so tide-turning. Stephen A. Rosenberg, who has led immunotherapy research for decades at the National Cancer Institute and has studied the checkpoint inhibitors, is a skeptic.

“Because [the antibodies] take advantage of natural immune reactions, they only are likely to work in a small number of cancers,” Rosenberg says. “The path to treatment of cancers that . . . kill 90 percent of cancer patients is likely to be through genetic manipulation of the immune system.” Rosenberg is the pioneer in such genetic treatments. He has had 40 percent cure rates in some small melanoma trials at NIH.

How they work

One way our bodies deal with infections, and with cancer is by activating immune cells, called T-cells, which recognize foreign agents and marshal various parts of the immune system to clear or control them. Certain types of T-cells infiltrate tumors and release chemical signals that tell other parts of the immune system to attack. But one of these signals, a chemical called interferon-gamma, tells tumor cells to produce a molecule that actually blocks the T-cell response.

This inactivation switch probably evolved to keep our immune systems from going haywire — overreacting and damaging organs. In dealing with cancer, however, the mechanism is a Catch-22, because it allows the cancer to grow.

So in the mid-1990s, scientists began designing monoclonal antibodies to short-circuit the immune switch-off. Most of the checkpoint inhibitors under development target a protein on T-cells that scientists in 1992 named “Programmed Death Receptor 1” (at the time they knew only of its role in the natural death process of cells); it is now called PD-1. Other monoclonal antibodies target a tumor molecule that binds with PD-1 and is called PD-L1. This molecule appears only on the surface of certain tumor cells when they are under attack from T-cells; interferon-gamma causes it to appear.

About 3,000 American and European patients have received nivolumab, the anti-PD1 drug that Michael Harris is receiving, according to Michael Giordano, global director of oncology and immunoscience for Bristol-Myers Squibb. Roughly half of the kidney cancer or melanoma patients in PD-1 trials have seen their tumors shrink significantly or disappear, according to Pardoll. Cures are difficult to speak of in drugs this new, but about 24 percent of lung cancer patients receiving the drug, for example, have survived at least two years. With previous treatments, which rely on chemotherapy, only about 5 percent of such patients survived two years.

Even the most enthusiastic supporters of the checkpoint inhibitors acknowledge that about half their patients have not benefited. They don’t entirely know why, but many of those who don’t respond to the antibodies lack the PD-L1 molecule on their tumor cells. Their tumors may be using other molecules to switch off the immune response.

In Harris’s case, it is only six months since he began the therapy. It’s not clear that his melanoma has disappeared altogether. He retains about a dozen black spots on his back that could be active or dead tumor. His doctors at this point classify him as “a partial response.”

“Unfortunately,” Harris says, “there’s no prognosis except that if things stay good, they stay good.”

Harris is a cable installation contractor, a “happy-go-lucky guy who doesn’t fret over his disease on the Internet,” Atkins says. Harris’s daughter makes sure he gets to appointments, and while he does what the doctors say he should do, he focuses on enjoying life — his three children and seven grandchildren and, for example, the country music festival he’ll attend next month in Austin.

Harris has had few side effects, other than a slight rash. A few patients have had toxic immune responses; three early nivolumab patients died of lung inflammations. Since then, clinicians have gotten more vigilant, and they use other drugs to prevent such calamities.

M. Dennis Sisolak, a 72-year-old from Bel Air, Md., had late-stage kidney cancer in 2009 when he began 18 months of nivolumab infusions at Johns Hopkins Hospital. His tumors disappeared a few months after the treatment, and his scans have been clean since. “The only side effect was the annoyance of having to drive an hour and a half to Baltimore every two weeks,” Sisolak says.

‘Breakthrough of the Year’

The emergence of checkpoint inhibitors, which Science magazine declared 2013’s Breakthrough of the Year, is a high point in the long story of cancer immunotherapy. In 1891, William Coley, a New York surgeon, discovered he could keep certain cancer patients alive by giving them bacterial infections, which caused their immune systems to release a healing serum.

Over the years, many intrigued scientists tried to extend Coley’s experiments, and in 1975 they isolated the immune elixir and named it tumor necrosis factor. But immunotherapy had few big successes until 1985, when the NCI’s Rosenberg managed to cure several melanoma patients with another immune chemical, interleukin-2. This work was validated by outside investigators led by Atkins — who was then at Harvard Medical School — leading to FDA approval in 1997. Oncologists have employed it since then against melanoma and kidney cancer, with occasionally wonderful results, but it causes severe side effects.

Many other immunotherapies are being tested on cancers. In fact, when Harris received his diagnosis in August 2012, his doctors recommended that he enter one such clinical trial under Rosenberg’s care. Harris spent eight weeks that fall and winter at the NIH Clinical Center undergoing a delicate and complicated care regimen.

Doctors zapped his immune system after culling his blood for T-cells, which they genetically tweaked to better fight his tumor and then returned to his body. Rosenberg and his staff have had some dramatic cures with variations on this therapy, but it didn’t work for Harris.

By February, his cancer had shrunk a little, but in April new tumors appeared. Rosenberg’s team pressed for Harris to receive checkpoint-inhibiting antibodies. When a trial opened at Georgetown in June, Harris was the first of only 10 patients admitted.

“We had patients coming out of the woodwork trying to enter the trial,” says Atkins, who with other physicians at Lombardi is running several other studies of the blockade inhibitors, sometimes in combination with other drugs. “We had calls from Australia, Israel, Eastern Europe.”

A fundamental difference

Immunotherapy is fundamentally different from other cancer research funded by NIH. Many other lines of investigation are aimed at identifying the genes that turn off and on in a particular cancer and at matching patients to drugs that target the genes of their particular tumor.

These new, sophisticated forms of molecular medicine are clearly a step forward from older chemotherapies, which use powerful drugs to kill cancer cells but often cause severe side effects and provide benefit only as long as the cancer finds ways to evade them — typically an average of six months.

Checkpoint inhibition therapy’s champions believe that its approach holds more long-term promise. Instead of aiming at the tumor and its mutations, or accelerating the immune system the way interleukin-2 does, the checkpoint inhibitor antibodies are designed to take the brakes off the system, Freeman says.

“Cancers are like the Road Runner cartoon character. If you choose one target in the cancer, it will sidestep it eventually by mutating,” he says. Chemotherapy usually fails, eventually, because the tumor evolves a way to beat it. Since the checkpoint inhibitor restores the immune system’s ability to attack, the cancer “can’t change one thing and escape detection, because it’s getting machine-gunned,” Freeman says. “The immune system is an evolutionary learning system. If you can engage it and get it to work successfully, it learns how to attack the cancer. And the wonderful thing is that it works.”

Helen Harris, Michael Harris’s wife of 35 years, became ill too early for these new treatments. A lifetime smoker, she received a diagnosis of lung cancer in 2008 and died about three years later, with severe, heartbreaking complications in the final months.

Harris and his daughter don’t know whether the treatments he received could have helped her back then. “Dad was a wonderful husband to her. She was a lucky lady,” Rhonda Farrell says. “We knew her kind of cancer wasn’t going to go away.”

Allen is a freelance writer and author of “Vaccine: The Controversial Story of Medicine’s Greatest Lifesaver.” His new book, “The Fantastic Laboratory of Dr. Weigl,” will be released in July.

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