William Bradley Coley MD – Pioneer of Immunotherapy

William Bradley Coley (center)

 

William Bradley Coley (1862 – 1936) was an American bone surgeon and cancer researcher and the pioneer of cancer immunotherapy. He developed a treatment based on provoking an immune response to bacteria. In 1968 a protein related to his work was identified and called tumor necrosis factor-alpha.

 

William Coley was born to a very old Connecticut family, on January 12, 1862 in Westfield, to Horace Bradley Coley and Clarina B. Wakeman. He went to college at Yale and graduated from Harvard Medical School in 1888. He then joined the staff of the New York Hospital as an intern on the surgical service, following which he began his career as a bone surgeon at New York Cancer Hospital (which later became part of the Memorial Sloan-Kettering Cancer Center). Coley became more interested in cancer treatment when one of his early patients, Elizabeth Dashiell, died from bone cancer. While going through hospital records, Coley found a sarcoma case study of one patient named Fred Stein, whose tumor disappeared following a high fever from erysipelas infection, now known as Streptococcus pyogenes. This sparked Coley’s interest and drove him to find what few examples of similar cancer treatment had been previously recorded. He discovered that other medical pioneers including Robert Koch, Louis Pasteur, and Emil von Behring, had recorded observations of erysipelas infection coinciding with cancer regression.

 

From 1925 to 1933, Coley served as Surgeon-in-Chief of the Hospital for Special Surgery in New York City, where he developed the theory that post-surgical infections had helped patients to recover better from their cancer by provoking an immune response. In 1891 he began to experiment by deliberately causing this phenomenon, injecting streptococcus bacteria directly into people being treated; later because this had the adverse effect of causing infection, he switched to using dead bacteria. Coley published the results of his work as a case series, making it difficult to interpret them with confidence. According to the American Cancer Society, “More research would be needed to determine what benefit, if any, this therapy might have for people with cancer“. Cancer Research UK say that “available scientific evidence does not currently support claims that Coley’s toxins can treat or prevent cancer“. People with cancer who take Coley’s toxins alongside conventional cancer treatments, or who use it as a substitute for those treatments, risk seriously harming their health. By 1901, the development of x-rays as a cancer treatment showed great promise. In particular, the therapy resulted in immediate tumor destruction and pain relief. Although Coley claimed successful treatment of hundreds of patients, the absence of proven benefit or reproducibility led to broader emphasis on surgery and on the newly developing field of radiation therapy. This decision was borne out by the eventual successful treatment of millions of people worldwide with radiation therapy. Coley arranged for a wealthy friend to provide funds to purchase two x-ray machines for his use. However, after several years of experience, Coley came to the conclusion that the effect of that primitive x-ray therapy in the untrained hands of experimenters was localized, temporary and not curative. The scientific majority disagreed, most notably his contemporary James Ewing. His contemporary critics cited the dangerous and unpredictable effects, predominantly the fever caused by the bacteria, that the vaccine had upon individuals weakened by cancer. Furthermore, the vaccine had to be made to a patient’s exact needs, making it more labor-intensive, time-consuming and expensive.

 

In 2009, Coley’s theory that immune systems in humans functioned in a cycle was demonstrated by a research team led by Associate Professor Brendon Coventry, which could have significant ramifications for cancer treatment. In 2005, drug makers including Pfizer and Sanofi-Aventis had a renewed interest in modern versions of Coley’s Toxins. Pfizer has acquired the Coley Pharmaceutical Group, set up in 1997. The historical results of Coley vaccine therapy are difficult to compare with modern results. Coley’s studies were not well controlled and factors such as length of treatment and fever level were not adequately documented. Many of his patients had also received radiation and sometimes surgery. According to the analyses of Coley Nauts and Starnes, treatment success correlated with length of therapy and the fevers induced by the toxins. Coley’s daughter, Helen Coley Nauts, established the nonprofit Cancer Research Institute in 1953 to study her father’s work. The organization has since become a leader in funding research in immunology and tumor immunology at universities and hospitals worldwide.

 

Today immunotherapy (plus personalized medicine) is cutting-edge cancer treatment. But more than 100 years ago, it was extremely difficult to get other physicians to agree with William Coley MD. Here is a more detailed account of the cases contributing to Dr. Coley’s ideas:

 

In the late summer of 1890 young Coley was getting ready to examine a new patient at his practice in New York City. What he didn’t know was that the young woman waiting to see him would change his life and the future of cancer research. Her name was Elizabeth Dashiell, also known as Bessie. Bessie was 17 and showed up complaining of a problem with her hand. It seemed like a minor injury, just a small bump where she’d hurt it, but it wasn’t getting better, and she was in a lot of pain. She’d seen other doctors but nobody could diagnose the problem. At first Coley thought Bessie must have an infection. But when he took a biopsy, it turned out to be a malignant, very advanced cancer called a sarcoma. In those days there wasn’t very much anyone could do for Bessie. This was before radiation and chemotherapy, so Coley did the only thing he could – he amputated Bessie’s right arm just below the elbow in an attempt to stop the disease from spreading. Sadly, it didn’t work, and within a month, according to David Levine, the cancer had spread “to her lungs, to her liver and all over her body.“ Bessie’s final days were wrenching and painful. Coley was with her when she died on Jan. 23, 1891. Bessie’s death made a huge impression on the young surgeon. “It really shocked him,“ says Stephen Hall, who wrote about Coley in his book A Commotion in the Blood: Life, Death and the Immune System. Bessie’s death also spurred Coley into action. There wasn’t a lot known about cancer at the time, so Coley started digging through dozens upon dozens of old records at New York Hospital. He was looking for something that would help him understand this cruel and aggressive disease. As a student, Coley had read Charles Darwin, and one of the lessons he took away from Darwin, Hall says, was to always pay attention when there’s a biological exception to the rule. “To ask yourself: Why this has happened?“ Coley discovered one of these biological exceptions. It was the case of a German immigrant named Fred Stein. Stein had been a patient in New York Hospital eight years earlier. He had a tumor on his neck that doctors tried to remove several times. Unfortunately for Stein, the tumor kept coming back and doctors expected him to die from the disease. Then Stein contracted a serious infection of the skin caused by the strep bacteria. “It looked like Stein’s days were numbered,“ Levine says. But Stein didn’t die. In fact, his tumor disappeared, and he was discharged. Coley wondered if all these years later, Stein could still be alive. So in the winter of 1891, William Coley the surgeon became William Coley the detective. He headed for the tenements of the Lower East Side of Manhattan where the German immigrant community lived. He knocked on door after door asking for a man named Fred Stein who had a distinctive scar across his neck. After several weeks of searching, Coley found him alive and cancer-free. So why did Stein’s cancer go away and stay away after he got a bacterial infection? Coley speculated that the strep infection had reversed the cancer. and wondered what would happen if he tried to reproduce the effect by deliberately injecting cancer patients with bacteria. He decided to test his idea on people who were the most seriously ill. His first subject was an Italian immigrant named Zola who, just like Bessie Dashiell, was suffering from sarcoma. Zola had tumors riddling his throat. He was so sick he could barely eat or speak or even breathe. For months Coley would try to make Zola sick from infection by creating little cuts and rubbing the strep bacteria into them, Hall says. There would be “a slight response but not too much.“ Then Coley got his hands on a much stronger strain of the bacteria. This time, Zola became violently ill with an infection that could easily have killed him. But within 24 hours, Zola’s orange-sized tumor began to liquefy and disintegrate. “This was a phenomenon that occurred rarely, but when you saw it you were utterly astonished,“ Hall says. Zola completely recovered. Coley knew he was on to something. He kept experimenting and refining his use of bacteria. Eventually, he named the treatment Coley’s toxins.

 

It was an exciting time. Coley was having tremendous success and his efforts were celebrated in America and abroad. But Bradley Coley Jr., William Coley’s grandson, says the American medical establishment at the time was skeptical. Nobody knew how Coley’s toxins worked, or why they worked sometimes and not others. Not even Coley could explain it. That’s largely because the immune system was still a mystery and would remain so for decades to come. When radiation therapy came along in the early 1900s, interest in Coley’s toxins was completely overshadowed by this new therapy. When his grandfather died, Bradley Coley says, “All interest in [Coley’s toxins] stopped.“ And quite possibly, that’s where Coley’s legacy would have ended except for this: After Coley’s death in 1936, his daughter, Helen Coley Nauts, started looking through her father’s papers while doing research for his biography. She found about 1,000 files of patients her father had treated with Coley’s toxins. She spent years carefully analyzing these cases and could see that he had extraordinary rates of success in regressing some cancerous tumors. She couldn’t get anyone interested in studying her father’s work, so she decided to do it herself. With a small grant, in 1953 Helen Coley Nauts started the Cancer Research Institute, dedicated to understanding the immune system and its relationship to cancer. In the more than 60 years since, researchers have expanded their understanding of the immune system dramatically and today, that understanding is paying off. Treatments that harness the power of the immune system are now available for a range of cancers such as stomach, lung, leukemia, melanoma and kidney. Jedd Wolchok, chief of the melanoma and immunotherapeutics service at Memorial Sloan Kettering Cancer Center, says any treatment currently in use that exploits the power of the immune system to fight cancer has to “tip its hat“ to the work William Coley began more than 100 years ago. William Coley’s intuitions were correct: Stimulating the immune system may be effective in treating cancer. He was a model of the clinician-scientist, treating patients and using his practice to initiate research and build theories. But he was a man before his time, and he met with severe criticism. Despite this criticism, however, Coley stuck with his ideas, and today we are recognizing their potential value.

Sources: NIH.gov; The University of Iowa; npr.org; Wikipedia

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