He Treated Cancer With Bacterial Toxins and Was Condemned by His Peers for Forty Years
Coley used streptococcal toxins to make tumors vanish in some sarcoma patients, but he couldn't standardize the treatment or explain its mechanism, and it was squeezed out by radiation and regulation; his daughter spent the second half of her life building a cancer research institute around it.
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The death of an 18-year-old patient changed him
In 1890, Coley took on 17-year-old Bessie Dashiell, who had persistent pain after injuring her hand and was eventually diagnosed with periosteal sarcoma. Coley amputated below the elbow, but the tumor soon appeared elsewhere, and she died on January 23, 1891, at just 18 years old, only about 10 weeks after Coley first examined her. Coley was 28 at the time, in his first year as a surgeon. Amputation was the only treatment available, and it had not worked, which drove him to comb through the records of roughly 90 cancer surgery patients at New York Hospital over the previous 15 years, looking for something better.
— Tracy V. WilsonIn one record, the tumor disappeared on its own
In the case files, Coley found a case of small round cell sarcoma of the neck in a patient of his colleague Dr. William T. Bull: four recurrences, and by the fifth surgery the tumor had invaded deep structures and could not be removed. After the operation the patient accidentally developed erysipelas of the face and neck, then had a second attack two weeks later. Within days of the first attack the tumor began to soften and shrank rapidly, and by the time the patient was discharged the tumor had completely disappeared. The hospital had no follow-up records, so Coley went door to door in the German immigrant community and found him; in the spring of 1891 he was still alive, with no local or systemic recurrence, seven years after the surgery.
— Tracy V. WilsonHe tried live bacteria first, then switched to toxins
On May 2, 1891, Coley began trying to induce erysipelas in a patient with inoperable sarcoma of the tonsil and neck. The tumor was so large the patient could not eat solid food and could only swallow small amounts of liquid. Coley exposed the patient to bacteria cultured in the lab, but for months could not induce erysipelas, until in October an injection of a culture a colleague had brought from Robert Koch's laboratory in Germany made the patient very ill — but two weeks later the neck tumor had disappeared, the tonsil tumor had shrunk, and the patient lived in good health for eight years. By the end of 1892, after two early patients died of infection, Coley began working with bacteriologists to heat-kill the bacteria and filter out the toxins, rather than using live bacteria directly.
— Tracy V. WilsonThe effect was real, but only in a subset of patients
Coley wrote in his papers that in his own experience, in slightly more than 10% of cases the regression process continued until the tumor was completely absorbed and the patient remained cured; in other cases the improvement was only temporary, and after a few weeks the tumor regrew and the patient died despite continued injections at higher doses; and in a very few cases, especially large, highly vascular tumors, particularly the melanotic type, no clearly beneficial effect was ever observed. By 1909 he recommended it for all inoperable sarcomas (except the melanotic type), for osteosarcoma of the long bones where surgery meant sacrificing a limb, as prophylaxis against recurrence after surgery for primary sarcoma once the wound had healed, and after surgery for all carcinomas to reduce recurrence using the mixed toxins.
— Tracy V. WilsonJAMA first withheld judgment, then declared failure two months later
On May 31, 1894, Coley read his paper before the American Surgical Association. In October of that year, JAMA published an article comparing bacterial toxins to diphtheria antitoxin, saying the best method of use had not yet been determined, that it was still experimental, and calling for patience until the complete results of expert research were in. But only two months later, on December 15, 1894, JAMA published "The Failure of the Erysipelas Toxins," saying there was "no longer much doubt that the toxin injections as a cure for sarcoma and malignant growths have completely failed," that many surgeons had faithfully tried it over the previous six months, and that not one fully verified recovery had been reported. Coley responded the following January, pointing out that he had used not only erysipelas toxins but also Bacillus prodigiosus, and saying that the failure of a few doctors in a limited number of cases would not affect the scientific community's judgment of whether the method succeeded or failed.
— Tracy V. WilsonForty years, a thousand patients, a hundred and fifty papers
Coley worked with these toxins for about 40 years, treated roughly 1,000 cancer patients, and published about 150 papers. In 1909 he wrote that 52 cases of inoperable sarcoma had been successfully treated with a mixed toxin of erysipelas and Bacillus prodigiosus, of which 35 remained healthy for 3.25 to 16 years, 28 for 5 to 16 years, and 14 for 10 to 16 years. Although Park, Davis, and Company produced various preparations starting in 1899, the toxins never became the most common treatment for inoperable sarcoma. The reasons included: tense relations with his boss James Ewing, who opposed his research; the bone sarcoma registry refusing to include his cured patients, insisting they had been misdiagnosed; his insistence that all cancers had a microbial origin, even after that idea had been overturned; the difficulty of producing and standardizing the toxins; and the Biologics Control Act of 1902, which raised the regulatory cost.
— Tracy V. WilsonRadiation stole his window of time
Coley's own method of use was also fairly loose: different patients received different doses by different methods for different lengths of time. Partly this was because he was trying to figure out what worked and how best to do it, but some treatment decisions were made almost by feel rather than by data. He also noted that other doctors using his toxins treated patients for much longer than he did, and admitted that his own shorter courses might explain some patients' recurrences. X-rays were discovered in 1895 and radium in 1898, and radiation quickly became the standard treatment for many inoperable cancers. Both discoveries came early in his writing about the therapy. In 1934, JAMA published a statement from its Council on Pharmacy and Chemistry, slightly more positive in wording than 40 years earlier, saying the mixed toxins of erysipelas and prodigiosus might sometimes play an important role in preventing or delaying malignant recurrence or metastasis, and might occasionally cure hopeless inoperable tumors. But by then Coley had already retired, and he died on April 16, 1936, at the age of 74.
— Tracy V. WilsonHis daughter spent her life building an institute for her father
After Coley died, his daughter Helen Coley Nauts began organizing his papers and correspondence, intending to write a biography, but ended up delving deeply into his work. She had no medical qualifications and no formal education beyond high school, but she carefully combed through all her father's publications, trying to find out why some cases succeeded and others failed. In 1953, she co-founded the Cancer Research Institute with philanthropist Oliver R. Gray Sr., with funding from sources including Nelson Rockefeller. She served as its director until her death in 2001. Her brother Bradley was also an advocate of their father's method and became chief of bone surgery at Memorial Hospital after their father retired. The Cancer Research Institute today has an award named after Coley, recognizing outstanding research in basic and tumor immunology.
— Tracy V. WilsonBCG bladder instillation is a direct descendant of Coley's therapy
In 1959, Lloyd J. Old, the Cancer Research Institute's founding scientific and medical director, and others published a paper in Nature describing how mice injected with Bacillus Calmette-Guérin (BCG) became resistant to implanted tumors. BCG is a tuberculosis vaccine made from an attenuated strain of bovine tuberculosis bacillus. The work grew out of 1920s autopsy studies at Johns Hopkins showing that tuberculosis patients had fewer malignancies. In 1975, Old, working with Elizabeth Carswell and others, combined BCG with one of Coley's toxins to stimulate the immune system in mice, extracted a cytokine from mouse blood, and named it tumor necrosis factor (TNF); it both causes inflammation and kills tumors. In the 1970s, Old and other researchers tried injecting BCG into the bladders of certain bladder cancer patients and found that BCG stimulated the immune system to attack the cancer. The FDA approved BCG for superficial bladder cancer in 1990, and it is still in use today. Old is sometimes called the founder of cancer immunology, but many who have written about Coley believe the two should share that title.
— Tracy V. WilsonIn their own words · checked verbatim
The history stated that when the patient left the hospital, his tumors had entirely disappeared.
Tracy V. Wilson7:15
Three weeks from the date of the attack of erysipelas, both tumors had entirely disappeared.
Tracy V. Wilson12:25
in a certain number of cases, in my own experience, a little over 10%, the degenerative process has gone on until the complete absorption of the tumors has taken place. and the patients have remained cured.
Tracy V. Wilson15:34
There is no longer much question of the entire failure of the toxin injections as a cure for sarcomata and malignant growths.
Tracy V. Wilson20:42
I have had 52 cases of inoperable sarcoma successfully treated with the mixed toxins of erysipelas and bacillus prodigiosus. Of these, 35 have remained well from three and a quarter to 16 years, 28 from five to 16 years, and 14 from 10 to 16 years.
Tracy V. Wilson23:47
the toxins were effective at inducing fever and robust surges in cytokines. One patient with metastatic bladder cancer had a clear clinical response to treatment, experiencing a 50% reduction in his cancer that correlated with elevated levels of cytokines.
Tracy V. Wilson33:01
Figures
| Total number of patients Coley treated | about 1,000 cancer patients | 23:47 |
| Number of papers Coley published | about 150 | 23:47 |
| Number of cases of inoperable sarcoma treated with Coley's toxins | 52 | 23:47 |
| Number of those who remained healthy for 3.25 to 16 years | 35 | 23:47 |
| Age at which Coley died | 74 | 27:56 |
| Year BCG was approved by the FDA for bladder cancer treatment | 1990 | 32:00 |
| Year Coley's toxins were classified by the FDA as an investigational drug | 1963 | 32:00 |
| Year Coley's toxins were placed on the American Cancer Society's list of unproven therapies | 1965 | 32:00 |
| Year Coley's toxins were removed from that list | 1975 | 32:00 |
| Year the Cancer Research Institute funded a phase I trial of Coley's toxins | 2007 | 33:01 |
Glossary
- erysipelas
- A bacterial skin infection caused by Streptococcus pyogenes, presenting as red, swollen, hot, painful skin.
- Bacillus prodigiosus
- Now called Serratia marcescens, a bacterium that produces a red pigment, which Coley used in combination with streptococci.
- BCG
- A tuberculosis vaccine made from an attenuated strain of bovine tuberculosis bacillus, later used in immunotherapy for superficial bladder cancer.
- tumor necrosis factor (TNF)
- A cytokine that both causes inflammation and kills tumor cells, extracted from mouse blood and named in 1975 by Old and colleagues.
How to listen
Founders and investors interested in medical history, the origins of cancer immunotherapy, or the question of why a therapy that works but can't be standardized disappears.
The first two minutes of setup about the definitional fight over vaccines and immunotherapy, and the listener mail at the end.