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William Bradley Coley was born in the Connecticut shoreline village of Saugatuck, just outside of Westport, on January 12, 1862. His parents Horace Bradley Coley and Clarina Wakeman Coley had a family lineage that dated back to the early part of the 17th century and included religious leaders, schoolmasters, and owners of large farms from the west of England. In 1880, William was accepted to Yale, a university he had wanted to attend since he was a boy. During his time off from his studies, he worked as a farm hand for neighboring farmers for $3.50 per day - or for his father and grandfather for no pay.
Father of Immunology:
William Bradley Coley, MD
Following his graduation from Yale in 1884, he relocated to Portland, Oregon, where he taught Greek and Latin at the Bishop Scott Government School. Two years later, he returned to New England to attend Harvard Medical School. He completed what was at the time a 3-year program in just 2 years, receiving his medical degree in 1888. He was awarded an honorary master’s degree in 1910 for his work in advancing surgery.
In the 1890s, he made a series of observations that led him to a genuine, if underappreciated, medical breakthrough in the treatment of cancer.
At New York Hospital, Dr. Coley had interned under two of New York City’s most prominent surgeons: Dr. William T. Bull and Dr. Robert F. Weir, both of whom played significant roles in his research. In 1890, Coley obtained staff privileges at the Hospital for the Ruptured and Crippled, where, upon the death of Dr. Bull in 1890, he was given the title of attending surgeon.
In 1924, he was named Surgeon in Chief of the hospital, simultaneously holding the position of staff surgeon at New York Cancer Hospital (now Memorial Sloan Kettering Cancer Center). His academic appointments included clinical professor of surgery at Cornell University Medical School (1909) and clinical professor of cancer research at the same institution (1915).
Though busy with his medical career, in 1891 he began dating 18-year-old Alice Lancaster, a student at Miss Nott’s Boarding School in New Haven, CT. The two married in 1894. Their first residence was a walk-up apartment in New York City. A year later they had a son, Bradley Lancaster Coley. Dr. Coley’s increasing prominence as a surgeon greatly increased his income and allowed the family to relocate to a large brownstone at East 35th Street.
New York Cancer Hospital
(now Memorial Sloan Kettering Cancer Center)
One of Dr. Coley’s earliest accomplishments was a surgical technique to treat abdominal hernias in children. Dr. Coley and his mentor Dr. Bull wrote of the disappointing results of the surgical procedures then in use. Their paper, published in the Annals of Surgery, reported that of the 19 cases of hernia in children who had undergone surgery, more than 50% had suffered a relapse within the first year - these disappointing results resulted in the abandonment of hernia surgery in children.
During this same period, Europe saw the first efficient inguinal hernia repair. In 1884, a new surgical procedure that eliminated the need for a reinforcement prosthesis (the common practice in hernia surgery at the time) was introduced by Edoardo Bassini. Bassini’s technique involved reconstructing the inguinal canal with sutures only. Although the procedure became common in Europe, it was more than a decade before it was introduced in the U.S.
Among the first to perform the procedure in the U.S. was Dr. Coley, who in 1899 operated on a 15-year-old boy using the Bassini procedure at the Hospital for the Ruptured and Crippled. The procedure eventually became the procedure of choice among U.S. surgeons. Dr. Coley went on to perform the procedure hundreds of times and the hospital became a major treatment center for hernias in the U.S. While Dr. Coley’s surgical skills were widely admired by peers as well as his patients, it was his cancer research for which he was both ridiculed and remembered.
In the summer of 1890, Elizabeth (Bessie) Dashiell, a 17-year-old girl, presented to his office. Bessie had injured her hand and developed a lump at the injury site. Although initially appearing as a relatively minor injury, she suffered increasing pain and numerous physicians had been unable to diagnose her. (She most likely had Ewing's sarcoma in her metacarpal.) In a period before the use of radiation and chemotherapy, the only treatment available to Bessie was amputation, with the goal of preventing the spread of cancer.
Following the amputation, Dr. Coley realized the disease had already metastasized to her lungs and liver. This rapid spread of a lethal cancer had a profound effect on Dr. Coley and he became determined to find an effective treatment.
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.
– William Coley (1891)
Coley’s Toxins
During a review of New York Hospital’s records, Dr. Coley learned of a German immigrant who, seven years prior, had had an inoperable malignant tumor in his neck that seemed to disappear after he developed an infection attributed to Streptococcus pyogenes. The patient was discharged, apparently without evidence of a residual tumor.
During this period, most German immigrants resided in the tenement flats of the Lower East Side of Manhattan. Going door to door, Dr. Coley inquired about a man named Fred Stein who had a distinctive scar across his neck. After several weeks of searching, Dr. Coley found him alive and still cancer-free.
Dr. Coley came to believe that it was the fever from the infection which had helped Mr. Stein recover from cancer. He then hypothesized that Stein’s Streptococcus infection had reversed the cancer and he now began to wonder if by deliberately injecting cancer patients with this bacterium, he would be able to obtain a reproducible result.
So he began to treat only the most seriously ill patients first by injecting Streptococcus pyogenes directly into inoperable tumors.
Dr. Coley’s first patient was an Italian immigrant whose name is recorded simply as Zola. Zola’s cancer was in the throat and prevented him from speaking or eating, and even interfered with his breathing. Dr. Coley began his experimental treatment by making small incisions in Zola and then rubbing the Streptococcus pyogenes into the wound.
After months of attempting to induce a systemic response with little result, he developed a more virulent strain of the bacteria and introduced it directly into Zola’s tumor. Zola became extremely ill for a short time, and Dr. Coley thought he might have overdone it. However, within 24 hours, the tumor began to liquefy and resolve and eventually Zola completely recovered.
Dr. Coley found the treatment was most effective when it provoked a fever and a full-blown infection. While Dr. Coley’s fever therapy was celebrated in many medical quarters in the U.S. and Europe, not everyone was impressed. The old-line orthodox medical community became increasingly skeptical, citing the treatment’s unpredictable effect, mainly a very high fever on a patient already weakened by cancer.
Later, Dr. Coley decided to use a mixture of dead Streptococcus pyogenes and dead Serratia marcescens bacteria. This was subsequently termed “Coley’s Toxin”. In 1893, the first patient to receive “Coley’s Toxin” was John Ficken, a 16-year-old boy with a massive abdominal tumor.
Every few days, Dr. Coley injected this bacterium directly into the tumor mass, which produced the symptoms of an infectious disease, but did not produce the disease itself. With each injection, there was a dramatic rise in body temperature and chills. The tumor gradually diminished in size, and after four months of intensive treatment, the tumor was a fifth its original size. Later that year, the remains of the growth were barely perceptible.1
The boy received no further anticancer treatment and remained in good health until he died of a heart attack 26 years later. Over the next 40 years, as head of the Bone Tumor Service at Memorial Hospital in New York, Dr. Coley injected more than 1000 cancer patients with bacteria or bacterial products. By the end of his career, Dr. Coley had written over 150 papers on the subject.2, 3, 4
Dr. Coley mainly used his bacterial toxins on patients with inoperable bone and soft-tissue sarcomas. However, contrary to what has been suggested by others, Coley’s Toxin was widely and successfully used by other contemporaries for not only sarcomas but also carcinomas, lymphomas, melanomas, and myelomas. A striking feature of his immunotherapy regimen was that even when applied to patients in their final stages of disease, some remarkable recoveries were obtained, with patients often outliving their projected prognosis.
It is often written and believed that Coley’s Toxin was more effective against sarcomas than carcinomas. This is because Dr. Coley primarily treated sarcomas given his specialty, and partially because Dr. Coley initially had less success in treating carcinomas in his early experiments with streptococcus cultures. Dr. Coley, however, later changed his views as his successes with carcinomas, and those reported to him by others, accumulated.
Beginning in 1899, Parke Davis and Company had begun to prepare the Coley’s Toxins, so they were available for all physicians. Because of his widely used treatment, as well as the fact that he was publishing his work, Coley was much in the public eye. Early in his career, he received small donations from the Rockefeller family to help with his research, and in 1902 he arranged a large grant from the Huntington family that supported him and other cancer researchers. This endowment was the first in the U.S. designated specifically to study cancer.5
Despite his reported positive results, Coley's Toxin came under a great deal of criticism because many doctors did not believe it possible. Medical thinking of that period gave very little credit to the human body’s ability to self-heal or evoke spontaneous remission. Instead, physicians believed that outside intervention was necessary for healing to occur. This dogma has persisted in medical circles, particularly oncology. Many oncologists still have not embraced immunological measures in the treatment of cancer, relying solely on cytotoxic chemotherapy, and radiotherapy.
Much evidence is continuing to show immunotherapies - particularly, fever therapy and hyperthermia treatment - can stimulate immunity and destroy tumors. Many physicians now understand that increasing body temperature not only mobilizes the body’s immune system, thus fighting off the infection, but also allows cellular immunity to attack the tumor at the same time.
Coley’s research had one major, damning flaw: He couldn’t explain why his toxins worked.
Until the day he died, Coley tenaciously held to the belief that microorganisms caused cancer - a theory long dismissed by the medical establishment - and that his toxin somehow killed those cancer-causing organisms in the body.
As early as 1894, the Journal of the American Medical Association (JAMA) issued a severe criticism of the use of these toxins:
There is no longer much question of the entire failure of the toxin injections, as a cure for sarcomata and malignant growths. During the last six months the alleged remedy has been faithfully tried by many surgeons, but so far not a single well-authenticated case of recovery has been reported.
Despite JAMA's claim, however, some physicians had success with Coley's Toxin. Additional controversies surrounding Dr. Coley's work reflect the field of oncology struggling to stabilize its understanding of how to treat cancer. For example, James Ewing, perhaps the most famous cancer pathologist in the country, was a leading opponent of Dr. Coley's work. This was a problem for Coley because Ewing was Medical Director of Memorial Hospital, and for many years, Dr. Coley's boss. Their memos to one another reflect constant interpersonal animosity. Ewing himself had become a fanatical supporter of radiation therapy for the treatment of all bone tumors and repudiated any other theories for the treatment of cancer.
Ewing refused to give Dr. Coley permission to use his bacterial toxins at Memorial Hospital. This was ironic, because Coley had more experience than any other surgeon in the country in treating the small round blue-cell sarcoma that still carries Ewing's name.
From 1925 to 1933, Coley served as Surgeon-in-Chief of the Hospital for Special Surgery in New York City. Eventually, in 1934, The Journal of the American Medical Association acknowledged that Coley's Toxin might be of value:
It appears, that undoubtedly the combined toxins of erysipelas and prodigiosus may sometimes play a significant role in preventing or retarding malignant recurrence or metastases; occasionally they may be curative in hopelessly inoperable neoplasms... The Council has, for these reasons, retained Erysipelas and Prodigiosus Toxins-Coley in New and Nonofficial Remedies, with a view to facilitating further studies with the product.
In 1935, Coley was inducted as an honorary fellow into the Royal College of Surgeons of England, becoming just the fifth American to receive that honor.
Dr. William Coley died on April 16, 1936, at the age of 74 in the Hospital for the Ruptured and Crippled (now called the Hospital for Special Surgery) in New York City. He was survived by his wife and two children, who tirelessly worked after his death to preserve his legacy in the field of cancer research.
Coley’s Toxins After his Death
Coley’s Toxins were widely used for the next 30 years and in the first half of the 20th century; different formulas of Coley’s Toxins were manufactured by several U.S. drug companies.
These formulations were used to treat patients with a variety of cancers until the early 1950s, when other forms of cancer treatment became more widely used, such as radiotherapy.
Unfortunately, skepticism and criticism, together with the development of radiation therapy and chemotherapy, caused Coley's Toxin to gradually disappear from use in the U.S. By 1952, the Park Davis Company no longer produced Coley's Toxin.6
In 1962, the FDA refused to acknowledge Coley's Toxin as a proven drug and created strict regulations which rendered it illegal. The FDA considered the treatment to be the introduction of a "new drug" - even though it had been around for well over 50 years.
Following Dr. Coley’s death in 1936, his daughter Helen Coley Nauts started work on his biography. In 1939, she came across more than 15,000 of her father’s papers in a barn on their Connecticut property. She spent years analyzing the data, concluding that her father had a very high rate of success in the treatment of certain tumors. In fact, many results were better than the current treatments of that day and age. Although Nauts herself had no formal medical training, she published more than 18 monographs and identified more than 500 patients who were successfully treated with her father’s toxin.
Though powerful figures in the field of oncology dismissed her efforts, citing her lack of medical credentials, Helen Coley Nauts was undaunted in her enthusiasm for and advocacy of her father’s techniques. On January 29, 1953, Helen Coley Nauts and Oliver R. Grace Sr., with a small grant, founded the Cancer Research Institute (CRI), to honor her father and advance the field of immunotherapy research.
Their legacy is an organization that has built an entire field of cancer research - the field of tumor immunology - that today produces immunotherapies extending and saving lives of cancer patients.
One of the greatest obstacles to the acceptance of Dr. Coley’s work was the American Cancer Society. From 1965 to 1975, they put Dr. Coley’s treatment on their “Unproven methods of cancer management” blacklist. It was only through the determined work of Helen Coley Nauts and Lloyd J. Old, of Sloan Kettering Institute, that Coley’s Toxins were removed from the blacklist. This allowed for further development of cancer immunotherapy unimpaired by the charge of “quackery”.
That immunotherapy is now a thriving field of cancer treatment has everything to do with the passion, commitment, and scholarship of Helen Coley Nauts.
Helen Coley Nauts (1907-2001)
In 1998, Nobel Prize Laureate Bruce Buetler, MD, and his colleagues at the Scripps Institute in La Jolla, CA, showed that bacterial toxins as lipopolysaccharides can activate immune system cells, toll-like receptors. These in turn are effective in killing cancer cells and tumors. These findings further confirmed Dr. Coley’s theories giving him the recognition he deserved.
Coley’s legacy continues through the funding of immunotherapy research by the Cancer Research Institute with many of the more than 25 cancer immunotherapies on the market today having been developed by researchers (some of whom were postdoctoral fellows at CRI) who received early seed money from Helen Coley Nauts’ Cancer Research Institute.
Within the last few years, there has been ongoing research in the U.S. using certain bacteria to stimulate immunity and attack tumors. In 2015, scientists modified or attenuated a strain of salmonella (Salmonella enterica serovar Typhimurium) to attack tumors in mice. These bacteria have been shown not only to colonize solid tumors, but also to exhibit an intrinsic antitumor effect. According to these scientists, these bacteria can also serve as tumor-targeting vectors for therapeutic molecules. However, the pathogenic Salmonella Typhimurium strains used for tumor therapy need to be attenuated for safe application.7 Following this research of antitumor bacterial therapy in 2017, Zheng et al. engineered a weakened strain of Salmonella Typhimurium to produce the flagellin B protein from another bacterium, Vibrio vulnificus. The engineered bacteria induced an effective antitumor immune response, successfully treating tumors in several different mouse models with no evidence of toxicity.8
Another 2017 study published in Science by a Johns Hopkins research team looked at Clostridium novyi, a relative of the microbe responsible for botulism. Because C. noyvi causes infections, the team removed its toxin-producing genes to make it safer for use. The new bacteria strain is called C. noyvi-NT (NT stands for non-toxic). To start testing their hypotheses, the researchers injected bacterial spores directly into rat tumors with brain cancer. They observed an antitumor response that improved the survival rates of the animals. They then injected the modified bacterial spores into the tumors of 16 dogs and observed the responses. In six dogs, the tumor sizes were reduced; in three dogs, the cancer went away completely. The researchers concluded, “Together, these results show that C. novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted.”9
Coley advised that Coley’s Toxin or “Vaccine” was most effective when administered daily, when a fever was repeatedly induced, and when the treatment was continued (at less frequent intervals) well past clinical regression to prevent recurrence. It has been found that solid tumors often show a high degree of leukocyte infiltration. Even micrometastases have been shown to have a high content of infiltrating leukocytes. These tumor-infiltrating leukocytes (TILs) consist of heterogeneous populations of cells, including varying proportions of neutrophils, macrophages, T and B cells, and natural killer cells. As tumors expand, cytokines are released signaling an increasing need for oxygen and nutrients.
It has been proposed that leukocytes, which are also involved in tissue repair, become attracted to growing malignant lesions through the release of these signaling molecules or chemokines, and assume their normal reparative activities such as expanding the vascular network and stimulating tissue regrowth.10
Recent evidence supports the theory that tumors grow with the assistance, rather than the antagonism, of the immune system. So, the administration of Coley’s Toxins is designed to reactivate the defensive activities of these TILs. Active stimulation of TILs by Coley’s Vaccine has been suggested by the frequent observation of inflammation of malignant lesions soon after Coley Fluid injection.
In recent years, the use of genetically modified bacteria for selective destruction of tumors, and bacterial gene-directed enzyme prodrug therapy have shown promising potential. Studies have been numerous and ongoing.11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21
Mechanism of Action
MBVax Bioscience, a Canadian Biotech company, produces Coley Fluid for research and clinical study. A private biotech company, Coley Pharmaceutical Group, has conducted clinical trials using genetic sequences which may have contributed to Coley's Toxin's effectiveness, and was acquired by Pfizer in January 2008.
In addition, the Waisbren Clinic in Wisconsin reports they have used Coley's Toxin to treat patients since 1972. Drug makers including Pfizer and Sanofi-Aventis are interested in modern versions of Coley's Toxins. Pfizer has acquired the Coley Pharmaceutical Group, established in 1997.
Coley's Toxins are generally not available in the United States. Today, bacteria-induced fever therapy and intertumoral injections of attenuated bacteria in the treatment of cancer is still illegal in the U.S., but these therapies continue to be researched and clinically used to treat cancer patients in many other countries, such as Germany, Switzerland, China, Japan (Saisei Mirai Clinics), Mexico, Central America, and others.
Availability
The role of bacteria as an anticancer agent was recognized almost 100 years ago when the German physicians W. Busch and F. Fehleisen separately observed that certain types of cancers regressed following accidental erysipelas (Streptococcus pyogenes) infections that occurred whilst patients were hospitalized. Independently, Dr. Coley spent his life researching and implementing this therapy.
Dr. William Coley was a man before his time, and he met with severe criticism. In retrospect, however, his intuitions were correct. Using fever induction therapy to stimulate the immune system is effective in treating cancer. Dr. Coley was a model of the clinician-scientist; his theories were firmly based in what he observed in practice.
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Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas: with a report of ten original cases. Am J Med Sci. 1893 May;105:487–511.
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Coley WB. The treatment of malignant inoperable tumors with the mixed toxins of erysipelas and bacillus prodigiosus. Brussels: M Weissenbruch; 1914.
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Coley BL. Neoplasms of Bone. New York: Medical Book Department of Harper & Brothers; 1949. pp. 565–570.
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Coley-Nauts H, McLaren JR. Coley Toxins – the first century. Adv Exp Med Biol. 1990;267:483.
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Hall SS. A Commotion in the Blood. New York: Henry Holt and Company, Inc; 1997.
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Hoption-Cann SA, van Netten JP, et al. Dr William Coley and tumour regression: a place in history or in the future. Postgrad Med J. 2003;79(938):672–680.
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Frahm M, Felgner S, Kocijancic D, Rohde M, Hensel M, Curtiss R, III, Erhardt M, Weiss S. 2015. Efficiency of conditionally attenuated Salmonella enterica serovar Typhimurium in bacterium-mediated tumor therapy. mBio 6(2):e00254-15. doi:10.1128/mBio.00254-15.
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Zheng, Jin Hai et al. Two-Step Enhanced Cancer Immunotherapy With Engineered Salmonella Typhimurium Secreting Heterologous Flagellin. Science Translational Medicine 9.376 (2017): eaak9537. Web. 9 Feb. 2017.
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Roberts, N. J. et al. Intratumoral Injection Of Clostridium Novyi-NT Spores Induces Antitumor Responses. Science Translational Medicine 6.249 (2014): 249ra111-249ra111. Web. 9 Feb. 2017.
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S Patyar, R Joshi, DS Prasad Byrav, A Prakash, B Medh, BK Das. Bacteria in cancer therapy: a novel experimental strategy. Journal of Biomedical Science 2010 17:21.
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King I, Itterson M, Bermudes D. Tumor-targeted Salmonella typhimurium overexpressing cytosine deaminase: a novel, tumor-selective therapy. Methods Mol Biol. 2009, 542: 649-659.
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Hagihara N, Walbridge S, Olson AW, Oldfield EH, Youle RJ. Vascular protection by chloroquine during brain tumor therapy with Tf-CRM 107. Cancer Res. 2000, 60: 230-234.
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Puri RK. Development of a recombinant interleukin-4-Pseudomonas exotoxin for therapy of glioblastoma. Toxicol Pathol. 1999, 27 (1): 53-57. 10.1177/019262339902700111.
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Fan D, Yano S, Shinohara H, Solorzano C. Targeted therapy against human lung cancer in nude mice by high affinity recombinant antimesothelin single chain Fv immunotoxin. Mol Cancer Ther. 2002, 1: 595-600.
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Fujimori M, Amano J, Taniguchi S. The genus Bifidobacterium for cancer gene therapy. Curr Opin Drug Discov Devel. 2003, 5: 200-203.
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Tjuvajev J, Blasberg R, Luo X, Zheng LM, King I, Bermudes D. Salmonella-based tumor-targeted cancer therapy: Tumor amplified protein expression therapy (TAPET) for diagnostic imaging. J Control Release. 2001, 74: 313-315. 10.1016/S0168-3659(01)00340-6.
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Kokai Kun JF, Benton K, Wieckowski EU, Mcclane BA. Identification of a Clostridium perfringensenterotoxin region required for large complex formation and cytotoxicity by random mutagenesis. Infect Immun. 1999, 67: 5634-5641.
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Michl P, Buchholz M, Rolke M. Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin. Gasrtoenterology. 2001, 121: 678-684. 10.1053/gast. 2001.27124.
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Kominsky SL, Vali M, Korz D. Clostridium perfringens enterotoxin elicits rapid and specific cytolysis of breast carcinoma cells mediated through tight junction proteins claudin 3 and 4. Am J Pathol. 2004, 164: 1627-1633.
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Ansiaux R, Gallez B. Use of botulinum toxins in cancer therapy. Expert Opin Investig Drugs. 2007, 16 (2): 209-218. 10.1517/13543784.16.2.209.
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Puri RK. Development of a recombinant interleukin-4-Pseudomonas exotoxin for therapy of glioblastoma. Toxicol Pathol. 1999, 27 (1): 53-57. 10.1177/019262339902700111.
References
William Coley and Coley’s Toxins
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