Lehigh Valley plays key role in trials that have pulled some from brink of death
BY SAM KENNEDY OF THE MORNING CALL
Richard Dey, a 69-year-old retired plumber, had a round of X-rays and other tests, and now he’d find out the news — good or bad.
Dey and his wife, Patti, of Washington Crossing, Bucks County, were ushered into the exam room of Dr. Suresh Nair, head of oncology at Lehigh Valley Health Network. The couple exchanged greetings with the doctor and took seats under the wash of fluorescent lighting — Dey on the padded chair with paper covering that crinkled with his every move.
“We were just going over your scans,” Nair said casually, moving the conversation along to the matter at hand.
If Richard Dey was nervous, he didn’t show it. But Patti Dey was up, leaning over Nair’s shoulder to get a better look at the laptop screen displaying the ghostly before-and-after images of her husband’s lungs.
In the fall of 2011, a toenail on Dey’s left foot became badly infected. He assumed it was a fungus, but a biopsy proved otherwise: melanoma, skin cancer. The toe was amputated. As a precautionary measure, the lymph nodes in his left groin were surgically removed too. All was well for about a year and a half, when the shape-shifting melanoma suddenly reappeared, this time in the form of multiple lung tumors.
“I can’t help you anymore,” his Philadelphia area surgeon told him. The final stage of cancer — the one bracketed on one end by death — is Stage 4. This is what he had.
“I figured, well, it’s pretty close to being over now,” Dey said. A reasonable assumption, but it turned out to be wrong.
If Dey was incredibly unfortunate to have been diagnosed with Stage 4 melanoma, he was also extremely lucky to have been diagnosed when he was — and where. He sought entry into a clinical trial just in time to snag a coveted spot in the one Nair was about to start at Lehigh Valley Hospital-Cedar Crest, just over an hour’s drive from his home. Thanks to Nair’s efforts, LVH was one of eight sites nationally selected to participate in a clinical trial testing the effectiveness of combining two new immunotherapy drugs, nivolumab and ipilimumab.
Until recently, modern medicine had come up with but three ways to treat cancer: excising it (surgery), obliterating it (radiation) and poisoning it (chemotherapy). But immunotherapy is something completely different — a revolutionary approach giving rise to talk of a miracle cure.
Surgery, radiation and chemotherapy are each in their own ways brutal, direct assaults on cancer that can leave survivors physically, mentally and emotionally diminished, whereas immunotherapy coaxes the body’s immune system to do the fighting, often with minimal side effects.
Dey submitted to 41 intravenous infusions of experimental immunotherapy drugs. That he even managed to come back again and again for so many infusions was itself a notable achievement. For just about as long as Nair had been in oncology, which was long enough for his hair to fade from black to white and his name to become known outside Pennsylvania, a diagnosis of Stage 4 melanoma left little room for hope. The only real question was one of time — how much of it was left — and all too often the answer was in increments not of years, but months.
And yet here was Richard Dey, back one day early this year, more than four years after his diagnosis, for another checkup. As Patti looked on, Nair pointed to the place on one of the lung scans where a tumor had been.
“That’s gone.” He continued pointing here and there. “That’s gone. That’s gone. This was the biggest one. It’s gone.”
Dey’s tumors had melted like ice cubes. His cancer was, as Nair put it, gone. The worst reaction over the course of his treatment was a thyroid problem. “It’s a good trade-off for being cured,” he told Nair.
Now, the doctor suggested, the Deys could go to Florida for the long-deferred vacation the couple hadn’t been sure they’d ever be able to take.
Whether melanoma or leukemia, lymphoma or lung, cancer in all its myriad manifestations shares a single common denominator: an uncontrollable growth of an abnormal cell. Mitosis, or cell division, which is an elemental function of all life, turns deadly.
In his State of the Union address in January, President Barack Obama called for a new, national “moon shot” to eliminate cancer, pledging $1 billion to jump-start the initiative. The terminology optimistically called to mind a previous president’s challenge, met with success, to put a man on the moon by the end of the 1960s.
The more common cancer metaphor, however, is hardly so positive. The nation is said to have been at war with cancer at least since President Richard Nixon signed the National Cancer Act of 1971, and perhaps since President Franklin D. Roosevelt approved creation of the National Cancer Institute in Bethesda, Md., in 1937. Given the other “wars” — on terrorism, drugs, poverty — this use of this term might seem hackneyed if not for the fact that cancer killed about 600,000 Americans last year alone, or more than died in all of World War II. Clearly, cancer is at war with us.
Though now, quite suddenly and dramatically, the momentum appears to have shifted in our favor, according to those leading the counterattack.
Immunotherapy of the kind used to treat Dey’s melanoma has also shown promise in a variety of other cancers and on people of all ages. Consider the remarkable turnaround of President Jimmy Carter. In August of last year, Carter announced that after surgery for a small mass on his liver, doctors found he had cancer and it had metastasized, or spread, to his brain. Then in December came the head-spinning news that the 91-year-old was cancer-free and teaching Sunday school once again after undergoing treatment with an immunotherapy drug called pembrolizumab.
“The power of the immune system is that it has memory,” Dr. Jedd Wolchok of the Memorial Sloan Kettering Cancer Center in New York told a packed auditorium at LVH-Cedar Crest in December. “This is truly curative.”
At the same time, a completely different approach, eagerly anticipated for more than a quarter century, is beginning to fulfill its promise as well. It’s called targeted gene therapy, and it attacks cancer at its genetic source.
“We are on to something not just big, but something huge,” said Dr. Sanjiv Agarwala, chief of medical oncology and hematology for St. Luke’s University Health Network in Fountain Hill. Like Nair, Agarwala has gotten an advance look at the new treatments through participation in clinical trials.
At this turning point in the war on cancer, the Lehigh Valley is perched on the front lines, with an upfront view of the action. Not only are doctors such as Nair and Agarwala involved in important scientific work, but this year LVHN entered into an alliance with Memorial Sloan Kettering. The arrangement allows LVHN doctors to collaborate with and learn from peers at Memorial Sloan Kettering, the world’s oldest cancer research and treatment center. Memorial Sloan Kettering benefits too by expanding its clinical trials to a larger population.
Breakthroughs at the molecular level of cancer research, it turns out, are reverberating far beyond the laboratory, spurring innovation and collaboration at the institutional level.
Discoveries and advances
On the one hand, immunotherapy seems to have come out of nowhere. In Siddhartha Mukherjee’s Pulitzer Prize-winning history of cancer, published just six years ago, immunotherapy doesn’t even rate an index entry. On the other hand, the first indication that the immune system could be coaxed into fighting cancer was documented more than a century ago by William Coley, a surgeon at the New York Cancer Hospital, the precursor to Memorial Sloan Kettering.
Coley noticed one of his cancer patients experienced a complete remission following an unrelated bacterial infection. Over the next several decades, Coley injected the bacteria, which became known as Coley’s toxins, into more than 900 cancer patients, most of whom had inoperable sarcomas, or tumors. About 10 percent of the patients were entirely cured, apparently because the toxins somehow jogged the immune system into action. Even so, lacking a theoretical framework to explain the underlying biological mechanisms at work, Coley’s insights were widely dismissed and nearly forgotten.
Not until the end of the 20th century did researchers give immunotherapy a second, serious look. In the mid-1990s, James Allison led a team of scientists at the University of California, Berkeley Cancer Research Laboratory that determined a biological molecule called CTLA-4 regulated immune system T cells. Allison theorized, correctly, that CTLA-4 was inhibiting T cells from attacking cancer cells. In a landmark paper published in 1996, Allison’s team showed that blocking CTLA-4 could slow and even stop tumor growth in mice. The findings launched a race to develop drugs for human use.
But the race was a marathon, and it was still in progress in 2008 when Bill Cantwell, a landscaper in Mahoning Valley, Carbon County, noticed an odd mole on his thigh. It seemed to be morphing by the day. His wife, Crimsin Kern, persuaded him after much prodding to see a doctor who, after tests, informed him he had nodular melanoma.
“It’s one of the rarest and deadliest, but I’m here seven and a half years later,” Cantwell, then 47, said in December.
After his diagnosis, Cantwell underwent the established course of treatment, which had varied little in decades. The mole on his thigh was removed surgically, as were lymph nodes in his groin. Stubborn and fun-loving, he remained positive. But a year and a half later, the cancer resurfaced in the scar tissue on his thigh, prompting additional surgery, including the removal of more lymph nodes.
Cantwell gave up his landscaping business, taking an office job at a payroll company, in part for the health insurance. “That was the hardest time,” Kern recalled. “It was mentally challenging for him to accept his life was different. … He was stuck indoors.” But not one to despair, Cantwell soon came to genuinely enjoy his new line of work, she said.
After the surgeries in 2010, Nair put him on a regime of interluken 2 via intravenous infusions. A first-generation immunotherapy in use since the 1990s, IL 2 is a synthetic form of a protein the body produces naturally. It works by increasing the immune system’s production of T cells and so-called natural killer cells, curing about 1 in 10 melanoma patients.
Bill Cantwell (left) with his wife, Crimsin Kern.
“We were making slow, steady progress — too slow when you are dealing with Stage 4 cancer,” Nair said.
Nair was eager to get his hands on the next generation of immunotherapy drugs which, after more than a decade of painstaking development, were finally ready to test on human melanoma. Having led the National Cancer Institute group that oversees early-phase clinical trials, he was well aware of the drugs’ potential. And so, under his direction, LVHN applied for and won an NCI matching grant that helped cover the cost of expanding the network’s clinical trials program, mostly by hiring specially trained nurses.
Cantwell seemed likely to be among the first beneficiaries. In 2013, after more than two healthy years, his cancer reappeared, this time on his liver. It was categorized as Stage 4-M1c, which signifies the final stage of the final stage. The prognosis could hardly have been bleaker, though advance word of immunotherapy drugs offered hope of a miracle.
In December of that year, Science magazine named immunotherapy its “breakthrough of the year,” exulting, “The field hums with stories of lives extended.”
Cantwell wanted to be part of Nair’s upcoming Phase 2 clinical trial testing two drugs concurrently. The trial, however, had been designed for patients who had cancer in more than one organ, and Cantwell no longer did — or so it seemed at the time, based on his scans. He was ineligible because of the apparent success of his earlier interventions. He had cancer, just not enough of it.
If Nair couldn’t get Cantwell onto the two immunotherapy drugs, he could at least get him onto the one — ipilimumab, sold under the brand name Yervoy by Bristol-Myers Squibb — that had by then received approval by the U.S. Food and Drug Administration. Like IL 2, ipilimumab stimulates the immune system, but in a novel way — by disabling CTLA-4. Think of the immune system as a car. IL 2 slams the immune system’s accelerator to the floor, while ipilimumab releases the brakes. In this hyper state, the immune system attacks cancer cells.