A stunning cancer recovery inspires new research

    CT scans of David Bolgiano's lungs: At the time of his immunotherapy treatment (first row)

    CT scans of David Bolgiano's lungs: At the time of his immunotherapy treatment (first row)

    Half a year after discontinuing treatment, David Bolgiano’s advanced cancer was almost entirely gone. His stunning recovery sent Penn researchers on a new path in search of better therapies.

    After an experimental immune therapy drug wracked his body and did little to shrink the tumors that riddled his lungs and ribs, David Bolgiano stopped his cancer treatment in the winter of 2011. The Wilmington resident shopped for a hospice and, after re-discovering his Catholic faith, was read his last rites.

    By June of that year, after no further curative treatment, almost all of his cancer had disappeared.

    His doctors credit his surprising recovery to a decades-old effect still shrouded in mystery—one that, with a new class of drugs on the market, has spurred research into novel treatment combinations for advanced cancer.

    “You’re not here for a normal mole”

    A Baltimore cop turned career military man, Bolgiano, now 55, was studying at the Army War College in Carlise, Pennsylvania, in the winter of 2009, when his wife discovered a mole on his back.

    “A week after having the mole excised by a dermatologist, I got that call, ‘Come in to see the doctor’,” Bolgiano said. “It’s right out of the movies, you just get that sixth sense, you’re not here for a normal mole.”

    He was diagnosed with melanoma, the most dangerous type of skin cancer. A follow-up test of his lymph nodes came up clean, indicating that his cancer hadn’t spread. But a year later, as he was doing sit-ups to prepare for a physical fitness test, he felt a pain in his left side.

    “I thought I had pulled a muscle…and it progressively got worse,” Bolgiano said.

    That pain was the cancer that had spread to his ribs, lungs, and some nearby tissue. Doctors opened up his chest, and after removing three ribs and the lower half of his left lung, confirmed the cancer had advanced to stage four.

    That surgery is still noticeable in Bolgiano’s speech, which, because of his decreased lung function, is slow as he frequently stops for a big breath.

    Breakthrough therapies harness immune system to fight cancer

    After the advanced cancer diagnosis, Bolgiano sought treatment from melanoma expert Dr. Lynn Schuchter at the Abramson Cancer Center of the University of Pennsylvania. At the time, Schuchter was enrolling patients in clinical trials for a new class of drugs called “checkpoint inhibitors,” a breakthrough therapy in the decades-long quest to harness a patient’s immune system to fight cancer.

    “We used to step on the gas, and that was how we were trying to rev up the immune system,” Schuchter said of previous generations of immune therapy drugs.

    But, more recently, doctors have changed their approach.

    “If you’re trying to move a car, you can put on the gas or you can take off the breaks, so these new advances are taking the brakes off,” Schuchter said.

    These “brakes” in the immune system are checkpoints—proteins on the outside of healthy cells that bond with receptors on T-cells. That bond tells the immune system not to attack and destroy the healthy cells.

    Cancer cells are sneaky, and they also make these proteins, but with an incidious motive—to fool the immune system into thinking they are healthy cells. New checkpoint inhibiting drugs prevent the proteins from bonding to T-cells and sending that “don’t attack” signal. With the drugs, T-cells can then find and kill cancer cells.

    “For the first time, we have real tears of joy in clinic, not just tears,” Schuchter said. “We’re beginning to use the word ‘cure’ for some patients with advanced cancer.”

    New drugs work in relatively few patients

    After no success with chemotherapy, Shutter put Bolgiano on one of these checkpoint inhibitors, tremelimumab, which hasn’t made it to market. For him, the side effects were unbearable.

    “I almost levitated off the bed,” Bolgiano said. “I had rigors so bad, for 20 or 30 minutes I was stiffening up and my heart was racing up to 200 beats per minute. They had to give me a very strong sedative to get me out of that.”

    Worse still, checkpoint inhibitors are effective in only about one in five patients, and Bolgiano wasn’t one of them. His lungs remained pocked with tumors,

    Shortly after starting, he was removed from the trial.

    “I was literally picking out a hospice to die in,” Bolgiano said.

    Bolgiano experiences “almost magical” effect

    But then, about five months after he stopped immunotherapy, he got a phone call from Schuchter, bearing news neither of them expected: his cancer was almost entirely gone.

    “It was a dream,” Bolgiano said. “I was incredulous….it took me a few visits to actually believe her.”

    Schuchter, too, was surprised and wanted to study what made the tumors throughout Bolgiano’s lungs disappear after curative treatment had been abandoned. Bolgiano’s doctors now believe the key was in palliative radiation he got shortly after stopping his immune therapy treatment.

    During the worst of his illness, in the winter of 2011, when it was hard for him to breathe and fluid was building up in his lungs, Bolgiano got radiation at a hospital in Maryland on one portion of his lung. Not to save his life, but to prevent a particularly nasty tumor from rupturing.

    “You could feel an orange under my skin, and they were afraid it was going to actually burst through my skin, so they had to do something,” Bolgiano said.

    Like surgery, radiation is a local treatment. It is used to treat the exact area where the beam is targeted. However, in a tiny minority of elusive cases, radiation seems to have a system-wide effect, shrinking tumors beyond the borders of where the treatment was applied, as in Bolgiano’s case.

    “Sometimes, very rarely, in the radiation oncology literature, folks have reported cases where you take a patient with cancer that has cancer in many, many sites and then you radiate one of them, and then all of them go away,” said Hopkins oncologist Charles Drake.

    This is called the “abscopal effect,” from the Latin prefix “ab” meaning “position away from,” and “scopos,” or “target.”

    Doctors have long speculated that radiating a tumor in one place boosts the immune system everywhere. But the effect is rare and poorly understood, so it’s often described with words scientists don’t often use.

    “It’s actually almost like magical,” Drake said. “It’s probably less than one in 10,000 patients who get radiation have this happen.”

    Effect on the rise with new immune system drugs

    This abscopal effect has been noticed, anecdotally at least, more frequently as patients are now taking these new immunotherapy drugs. Researchers have been able to force the effect in lab mice using checkpoint inhibitors and radiation.

    Another Abramson Cancer Center oncologist, Dr. Robert Vonderheide, wanted to try the immunotherapy-radiation combination in humans after helping to treat Bolgiano.

    “This has been lurking in my mind for some time, and so I was in the past constantly bouncing this idea off folks,” Vonderheide said. “Mostly people thought it was a crazy idea, but when I brought the idea to the radiation oncologist here at Penn, it was embraced and accelerated.”

    Similar conversations were bubbling up at other medical centers around the same time. As checkpoint inhibitors were tested—and even before the first hit the market in 2010—doctors were thinking of ways to make the drugs work for more people.

    “There have been a couple anecdotal reports that really ignited the field, and got the field excited about how immunotherapy and radiation can have clinical benefit,” said Dr. Adam Dicker, head of radiation oncology at Jefferson’s Kimmel Cancer Center.

    The anecdotal report that seems to have made the biggest splash was one published in the New England Journal of Medicine in March of 2012, almost a year after David Bolgiano’s stunning recovery.

    Recreating the effect in patients

    The Penn team’s theory on how radiation could boost the effectiveness of immunotherapy goes like this: radiation kills tumor cells and serves them up on a silver platter for the immune system, jump-starting T-cells already made more effective by immunotherapy drugs. Just like modified measles virus trains your body to kill measles, modified tumor cells could train your body to fight your own cancer.

    “It’s hard to develop a cancer vaccine, so we are in effect trying to turn the patient’s own tumor into a vaccine,” Schuchter said.

    They like the analogy so much, they’ve dubbed the trial “RadVax,” short for “radiation vaccine.”

    In 2012, a Penn team started testing the combination of a checkpoint inhibitor called ipilimumab and radiation on patients. Currently, there are about two dozen trails similar trails going on around the country. The Penn results were among the first of these trials to be published, this week, online in the journal Nature.

    “We had some quite remarkable responses, some patients actually did very well,” said Andy Minn, a Penn radiation oncologist and one of the lead authors of the study.

    A few patients—four out of 22 enrolled in the small trial—saw significant tumor shrinkage. However, most patients did not respond to the therapies.

    “[That] was really the reason that we decided to also look at the mice at the same time,” Minn said, describing an atypical combination of clinical trial and mouse trials the Penn team used to drive research ahead faster.

    The team found that when they gave lab mice a second checkpoint inhibiting drug—a newer one thought by many oncologists to be more active than ipilimumab—80 percent of them saw their tumors disappear. Parallels between mice and human samples bolstered the researcher’s confidence that this triple-threat treatment—two drugs plus radiation—may work in humans.

    “It’s an important paper not because of the clinical result,” said Hopkins oncologist Charles Drake. “But the point of the paper was, by going back to animal models and then going back again to the clinic, they seem to have figured out a strategy to make [the therapy] work better in the future.”

    Drake said the Penn trial showed less of an effect of combining immunotherapy with radiation than previous mouse models would have suggested.

    Jefferson’s Dicker, whose own team is studying immunotherapy and radiation in brain cancers, said the mouse models opens up a pathway for further research: “The fact that we may not have seen as robust an effect or clinical benefit for reasons that we may not have fully understood, this shows that there may be new opportunities. I think, based on this data, we would be conducting different types of trails for the future.”

    While this work is promising, it doesn’t come without a price tag. Combining these two drugs with radiation in humans heightens toxicity significantly, and also raises costs. The price of a course of ipilimumab alone is $120,000.

    “These are not trivial drugs,” Dicker said.

    Five years on, Bolgiano sees his life as a gift

    Five years after his initial diagnosis, David Bolgiano’s cancer is still almost entirely gone, and according to regular CT scans, the remaining bits aren’t growing. He is doing Cross Fit to try to get back into shape. But he still struggles with fatigue, has an increased risk of dangerous blood clots in the lungs, and is nagged by constant pain in his chest and ribs after his surgery.

    His bones, he said, are a very accurate predictor of cold fronts rolling in.

    Bolgiano believes a combination of divine intervention and modern medicine kept him alive. Though his doctors haven’t been able to widely replicate Bolgiano’s surprising recovery in other patients, he hopes they soon will.

    “The miracle isn’t about David Bolgiano personally,” he says about himself, “Whether I live or die is a speed bump in history. The miracle is that my body was used as a platform to test a treatment modality that literally could save thousands of lives. Wow. That’s what blows me away.”

    Bolgiano’s case serves as a reminder that the quest of modern medicine is making the extraordinary patient into the ordinary one—making the miracle the norm.

    Often scientists fail, but on occasion a new treatment is born.

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