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On Christmas Eve 1995, I was in my first year of oncology training when a patient asked me a question I didn’t know how to answer. He was a charismatic, 23-year-old former high-school football star whose body had been sacked by colon cancer, and he was looking to me to provide some hope. “There’s a lot in the newspaper about using your immune system to fight cancer,” he said. “Can I get a new immune system to cure my colon cancer?”
At the time, doctors knew that organ transplant patients who took immune suppression drugs were at high risk for some cancers. And a small cohort in the scientific community believed that revving up the immune system (known as immunotherapy) could one day work as a cancer treatment. But the short answer to my patient’s question was no; a new immune system would not cure his colon cancer.
The question couldn’t have come at a worse time. That same day, my patient’s father had landed in our intensive care unit with what would turn out to be a lethal case of acute leukemia, and I didn’t know how to tell him that the findings he’d read about were based mostly on anecdotal data, not a rigorous scientific study. I didn’t know the best way to explain to him that a handful of immune therapy success stories did not mean some silver-bullet treatment existed. I wrote his question on my hand to remind myself to mull it over and told him we would discuss it at his next appointment.
A few months later he died from his cancer.
Since this young man’s untimely death, patient access to information has increased dramatically. On the whole, this is a good thing because knowledge empowers patients to direct their own treatment. The problem is that more information also increases the risk of bad information - more access doesn’t always translate into more knowledge. This is especially true in medicine as we so often wants to hear good news and are unaware of how data can be spun to get a paper published or to get a grant funded. Reproducibility and correct interpretation of clinical value are not guaranteed in our web of information.
In 2009, the actor Alan Alda founded the Alan Alda Center for Communicating Science, a division of Stony Brook University whose mission is to “enhance understanding of science by helping train the next generation of scientists and health professionals to communicate more effectively with the public, public officials, the media, and others outside their own discipline.” It’s a noble goal, and one that is crucial to ensuring that both laypeople and professionals can make the best decisions for themselves and their communities.
The challenge for those in medicine however is, how do you relay inconclusive information accurately while still giving your patients hope?
It wasn’t odd that my patient in 1995 had heard about immune therapy. As far back as 1891, surgeon William Coley was testing immune therapies by injecting bacteria into tumors in an attempt to induce inflammatory responses he hoped would kill the cancers. Since then, scientists have wavered between doubtful and energized by the notion that one’s own body can be used to thwart cancer, and only systematic studies from this century have convinced us that we can harness the immune system to treat cancers. Unfortunately for my patient, all we knew during his time was that attempts to treat colon cancer with immune therapies had failed.
But that has changed. In 2015, the New England Journal of Medicine reported that researchers had identified a group of colon cancer patients with unprecedented responses to immune therapy. These “lucky” patients were those with Lynch Syndrome, a genetic disorder that predisposes patients to colon and other cancers. The study, conducted by Dung T. Le and others at Johns Hopkins Comprehensive Cancer Center, used the drug pembrolizumab (trade name Keytruda) to disable the protein PD-1, one of the so-called “checkpoint proteins.” Checkpoint proteins inhibit the immune system by preventing aggressive T cells from killing normal cells. Think of them as the brakes on the immune system; if the brakes don’t work, the immune system can’t stop itself and autoimmunity develops. This is what happens in diseases like lupus or scleroderma.
Although these checkpoint therapies can lead to inflammation of the normal colon, kidney, lung, liver, and endocrine tissues, the effects on cancer have been impressive and the cancer research community is excited to do more. Those with Lynch Syndrome, it turns out, respond particularly well to immune therapy because Lynch Syndrome mutations prevent our genes from repairing the unrepaired mutations that result from normal wear and tear on DNA. When DNA is not repaired, cancer cells house “neoantigens”—mutant proteins that our immune systems can recognize and target as foreign. The average tumor already contains lots of neoantigens, but those with Lynch Syndrome produce many thousands more. The larger number of abnormal proteins increases the chance that the immune system will attack the cancer. In the study by Le and his colleagues, all of the colon cancer patients who had Lynch Syndrome benefited from pembrolizumab.
This was the first study to use a person’s genetic profile to guide immune therapy and to identify which patients are most likely to benefit from such therapies. And in March 2016, the Journal of Clinical Oncology reported data that suggested if a child inherits two Lynch Syndrome mutations and is afflicted with the lethal brain cancers two of these mutations induce, they too may benefit from immune therapy.
Since a third of colon cancer patients under the age of 35 have a genetic predisposition to colon cancer due to Lynch Syndrome, there is a good chance my 23-year-old patient could have benefited from immune therapy. Regrettably, there was no way for us to know that at the time. New discoveries often begin with anecdotes that are followed by bigger observational studies and then randomized controlled trials (if data continues to show promise). Nobody in the 1990s could have predicted that the anecdotes from Coley and his successors would lead to the incredible findings reported by Dung T. Le and his colleagues in 2015.
Thankfully, any doctor faced with a 23-year-old colon cancer patient today can give him better answers than I could twenty years ago. We still can’t give colon cancer patients new immune systems, but we can analyze them (and their family members) for a genetic predisposition to cancer and prescribe an appropriate therapy. We cannot promise success, but we can, in at least a few cases, promise hope.
