John Matzke faced terrible odds when melanoma
invaded his lungs but survived for 18 years.
Image courtesy of the Matzke family
Today researchers are just beginning to piece together the clues they hope will allow them to see what makes a deadly cancer sometimes reverse course and melt away. Much of their research focuses on the immune system, which they describe as a sort of military unit that protects the body from foreign invaders. T lymphocytes, a type of white blood cell, serve as a frontline defense against invading bacteria and viruses. A subtype of T lymphocyte, known as a natural killer (NK) cell, patrols the body, attacking and killing viruses and cancer cells. Researchers are studying how NK cells recognize cancer cells as abnormal and how other cells, known as regulatory T cells, can command NK cells to hold their fire, in order to prevent them from attacking the body’s own tissues.
Despite the remarkable insights researchers now have about the immune system, it remains a daunting task to develop immune modulators—drugs that can mimic the immune system or trigger it into action. That is because there are a few dozen distinct immune cells that release between 50 and 100 signaling molecules—molecules that tell the other cells what to do and when. When the relationships among these cells and molecules are graphed, the result looks like a plate of spaghetti. Altering the behavior of one cell or molecule can upset the entire system. Barnett Kramer, a medical oncologist and director of the Office of Medical Applications of Research within the National Institutes of Health (NIH), says the complexity of these relationships makes it as difficult to cure cancer with immune modulators as it is to “repair a fine watch with a screwdriver and a hammer.”
Even when the immune system is aided by immune-modulating drugs, cancer remains a wily adversary: Cancer cells can dress up in a clever disguise by cloaking themselves in clumps of platelets (cells that assist in blood clotting) as they travel through the bloodstream. Since the immune system does not normally attack its own platelets, the camouflage provides safe passage to the cancer cells as they migrate to distant parts of the body. According to Robert Weinberg, a leading cancer researcher and founding member of the Whitehead Institute in Cambridge, Massachusetts, a number of “built-in native defenses” usually prevent the development of cancer. For example, the body’s cells can recognize “signaling imbalances” in their own internal circuitry that might cause them to proliferate wildly, causing cancer. When an imbalance is recognized, the bad cells are “hard wired,” says Weinberg, to kill themselves, “to commit suicide.” In the absence of this and other defense mechanisms, Weinberg says, “cancer development would be inevitable, and we would be covered by tumors by the time we’re several years old.”
Because cancers have to trick the immune system and defeat a number of the body’s other defenses in order to grow to the point where they become clinically apparent, it is surprising that some people with late-stage cancers like Matzke’s can undergo spontaneous remission. On the other hand, regression of early microscopic cancers may occur more readily and may be common. A microscopic cancer can be likened to a paper fire in a wastebasket: A small fire may be easily contained and may even burn out without incinerating the house. But once a fire escapes the wastebasket and the drapes and furniture go up in flames, the chances that the house will escape destruction are slim indeed. Even more remarkable is that when the body does somehow induce a late-stage spontaneous remission, sending metastatic cancers spinning in reverse until they vanish, the body not only overcomes the evasions and counterattacks mounted by the cancer, it does so without the terrible side effects that can accompany current cancer treatments. The holy grail of cancer therapy is certainly to find a way to trigger this most remarkable of nature’s defenses. But is it possible?
Life-Saving Infections?
One of the earliest systematic efforts to understand spontaneous remission was made by William Coley, an American bone surgeon born in 1862. Coley was driven to his research following the death of the first patient he would diagnose with sarcoma, a cancer that affects bone and muscle. The patient, 17-year-old Bessie Dashiell, who was a close friend of John D. Rockefeller Jr., came to Coley with pain and swelling in her right hand. When a biopsy revealed that the girl had sarcoma, Coley amputated her arm just below the elbow in a desperate bid to save her life. Despite his efforts, the cancer spread throughout her body, and she died nearly three months after Coley diagnosed her.
Badly shaken by Dashiell’s death, Coley pored over the medical records of previous sarcoma patients. Anecdotal observations of patients dating back to the 1700s had already provided a curious clue that pointed to the immune system as a possible player in the body’s fight to ward off cancer. Doctors noticed that some cancer patients who suffered serious infections recovered from their cancer shortly afterward. This led doctors to infect patients with organisms that cause syphilis, gangrene, and erysipelas—a serious skin infection, known in the Middle Ages as Saint Anthony’s fire, that could invade the lymph nodes, a part of the body’s immune system. Unfortunately, a number of patients died from the infections instead of their cancer; just how many is hard to say since medical studies in the 1800s were not methodical and often consisted of case reports.
Coley nevertheless believed there was something to be gained from such experiments, and so he scoured hospital medical records for cases of spontaneous remission in sarcoma patients. In 1891, when he came across a report of a German immigrant in New York City who had recovered from sarcoma after he developed erysipelas, Coley spent weeks tracking him down among the city’s tenements. When he found the patient quite alive and fully recovered, Coley became determined to test his hypothesis that sarcoma patients could be cured by infection. Coley declared, “Nature often gives us hints to her profoundest secrets and it is possible that she has given us a hint which, if we will but follow, may lead us on to the solution of this difficult problem.”
