Coley's Toxins and the Origins of Immunotherapy

William B. Coley started using a bacterial infection to treat cancers in the late 19th century, one of the earliest uses of immunotherapy.

Research:

• Ahuja, Sana and Sufian Zaheer. “The evolution of cancer immunotherapy: a comprehensive review of its history and current perspectives.” Korean Journal of Clinical Oncology 2024; 20(2): 51-73. DOI: https://doi.org/10.14216/kjco.24009
• Atkins, Douglas. “Helen Coley Nauts: Advocate for Immunotherapy.” National Library of Medicine. 4/19/2016. https://circulatingnow.nlm.nih.gov/2016/04/19/helen-coley-nauts-advocate-for-immunotherapy/
• Cancer Research Institute. “The History of Cancer Immunotherapy.”
• Coley, William B. “Therapeutic Value of the Mixed Toxins of the Streptococcus of Erysipelas and Bacillus Prodigiosus in the Treatment of Inoperable Malignant Tumors. With a Report of 160 Cases.” American Journal of the Medical Sciences. September 1896.
• College of Physicians of Philadelphia. “Cancer Vaccines and Immunotherapy.” History of Vaccines. https://historyofvaccines.org/vaccines-101/future-immunization/cancer-vaccines-and-immunotherapy/
• Colley, William B. “The Treatment of Inoperable Sarcoma by Bacterial Toxins (the Mixed Toxins of the Streptococcus erysipelas and the Bacillus prodigiosus).” Reprinted from the “ Proceedings of the Royal Society of Medicine,” November, 1909. London. John Bale, Sons & Danielsson, LTD. 1909. https://archive.org/details/b22425949/mode/1up
• Decker WK, da Silva RF, Sanabria MH, Angelo LS, Guimarães F, Burt BM, Kheradmand F and Paust S (2017) Cancer Immunotherapy: Historical Perspective of a Clinical Revolution and Emerging Preclinical Animal Models. Front. Immunol. 8:829. doi: 10.3389/fimmu.2017.00829
• Devaraja, K. et al. “Coley’s Toxin to First Approved Therapeutic Vaccine—A Brief Historical Account in the Progression of Immunobiology-Based Cancer Treatment.” Biomedicines 2024, 12, 2746. https://doi.org/10.3390/biomedicines12122746
• Dobosz, Paula and Tomasz Dzieciatkowski.” The Intriguing History of Cancer Immunotherapy. Frontiers in Immunology. 12/17/2019. doi: 10.3389/fimmu.2019.02965
• Hall, Stephen S. “A Commotion in the Blood: Life, Death, and the Immune System.” Henry Holt and Company. Excerpted at New York Times. https://archive.nytimes.com/www.nytimes.com/books/first/h/hall-commotion.html 
• Harutyunyan, Mariam. “How William Coley Became The Father of Cancer Immunotherapy.” OncoDaily Magazine. 7/31/2026. https://oncodaily.com/magazine/william-coley-549446
• Hiroaki Ikeda, Cancer immunotherapy in progress—an overview of the past 130 years, International Immunology, Volume 37, Issue 5, May 2025, Pages 253–260, https://doi.org/10.1093/intimm/dxaf002
• Journal of the American Medical Association. “Erysipelas Toxins in the Treatment of Malignant Tumors.” 10/27/1894.
• Journal of the American Medical Association. “The Failure of the Erysipelas Toxins.” Vol 23 Iss 24. 12/15/1894.
• Kokolus, Katie. “The History of Immunotherapy: Toxins, Targets & T Cells.” LabRoots. 10/18/2021. https://www.labroots.com/trending/cancer/21449/history-immunotherapy-toxins-targets-cells?srsltid=AfmBOooP1eoVP2LbWKR5m-HLu1PSBFhOyPH1jSJWWcxvyK6EA4-hBu47
• Levine, David B. “The Hospital for the Ruptured and Crippled: William Bradley Coley, third Surgeon-in-Chief 1925-1933.” HSS journal : the musculoskeletal journal of Hospital for Special Surgery vol. 4,1 (2008): 1-9. doi:10.1007/s11420-007-9063-2
• McCarthy, Edward F. “The Toxins of William B. Coley and the Treatment of Bone and Soft-tissue Sarcomas.” The Iowa Orthopaedic Journal. Vol. 26.
• Memorial Sloan Kettering Cancer Center. “MSK Immunotherapy — Timeline of Progress.” https://www.mskcc.org/timeline/immunotherapy-msk
• National Library of Medicine. “Harnessing the Power of You: The History of Immunotherapy.” https://www.nlm.nih.gov/exhibition/the-history-of-immunotherapy/index.html
• Nauts, Helen Coley. “Coley’s Toxins – The First Century.” Townsend Letter for Doctors and Patients. June 2004.
• Nawrat, Allie. “Charting the history of immunotherapy, cancer treatment’s fourth pillar.” Pharmaceutical Technology. 7/28/2020. https://www.pharmaceutical-technology.com/features/charting-the-history-of-immunotherapy-cancer-treatments-fourth-pillar/?cf-view&cf-closed
• Oiseth SJ, Aziz MS. “Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead.” J Cancer Metastasis Treat. 2017;3:250-61. http://dx.doi.org/10.20517/2394-4722.2017.41
• Tontonoz, Matthew. “What E

Episode Transcript

Speaker 1 (00:01):
Welcome to Stuff You Missed in History Class, a production
of iHeartRadio. Hello and welcome to the podcast. I'm Tracy V. Wilson.
And I'm Holly Frey. I don't usually watch the news
on television, but I do at my parents' house because

(00:21):
my parents watch it. Oh. And I was visiting them
recently and saw some news coverage of a clinical trial
of a vaccine that is meant to help prevent recurrences
of melanoma in people who have melanoma. And one of
the things that came up in this news segment was
a move to describe these kinds of therapies as immunotherapy

(00:45):
rather than as vaccines. because of the anti-vaccine movements and
its impacts on things like funding for mRNA research. And
as I was being frustrated about that, I thought, hey,
don't you have something about immunotherapy on your shortlist for episodes?
And I did. Over the course of working on this episode, though,

(01:08):
it shifted from an overall history of immunotherapy to focus
on one specific part of that history. And that's the
work of William B. Coley, who started using a bacterial
infection to treat cancers in the late 19th century, which
was one of the earliest uses of an immunotherapy. So

(01:31):
we're going to start here with a little bit of background.
Immunotherapy can be defined as anything that modifies the immune
system in some way, generally activating or suppressing it. Sometimes
prophylactic vaccines are included under the broad definition of immunotherapy,
so some histories of immunotherapy start with variolation. That is

(01:54):
using material from smallpox sores to stimulate the immune system
to create antibodies, leading to a typically milder case of
smallpox and lifelong immunity to it. The practice of variolation
dates back hundreds of years, at least, and it is
something that we have talked about in our episodes on
Edward Jenner and the eradication of smallpox. As I was

(02:17):
researching this, there seemed to be some... not exactly debate,
but kind of a lack of consistency about whether people
considered things like the smallpox vaccine, the flu shot, that
kind of thing to fall under the umbrella of immunotherapy
or not, or whether it's only the therapeutic vaccines, not

(02:39):
the more preventive ones that are considered immunotherapy. I can't
answer that question conclusively. I do not work in that field.
But today, the term immunotherapy is most often used in
the context of cancer treatment, activating a person's own immune
system to recognize and fight cancer cells. One of the

(03:02):
first attempts to intentionally do this, although it's not necessarily
what the doctors involved understood that they were doing, started
in the 19th century. Two different doctors in Germany documented
patients whose malignant tumors shrank or disappeared completely after they
contracted a bacterial skin infection known as erysipelas. Sometimes these

(03:28):
infections were contracted during surgery that attempted to treat the cancers,
and that was one of the many risks of surgery
before Joseph Lister developed his antiseptic system for infectious control.
These doctors were Friedrich Felicin and Wilhelm Busch, and they
each tried to investigate whether this was a coincidence. In 1868,

(03:50):
Busch intentionally infected a cancer patient with erysipelas using another
patient's bedsheets, and he reported that the patient's tumor shrank.
By 1882, Felicin had identified and isolated the bacteria that
caused erysipelas. At the time, it was called Streptococcus erysipelas,

(04:11):
but now it is known as Streptococcus pyogenes. That is
the same bacterial strain that causes strep throat, scarlet fever,
and other illnesses and infections. Felicin injected these bacteria directly
into his patient's tumors. In 1887, German surgeon Paul von
Bruns also published a paper describing a patient whose tumor

(04:35):
shrunk after being injected with streptococcus bacteria. William B. Coley
was not aware of this work when he started working
as a doctor. He was born in Connecticut on January 12, 1862.
He went to college at Yale, and then after spending
some time teaching in Oregon, he went to Harvard Medical School.

(04:56):
Medical education in the United States was not nearly as
formalized or extensive as it is today, and he was
able to enter a three-year medical program as a second-year student,
thanks to having spent some time accompanying his physician uncle
on his rounds. I like how it's kind of like
the way you could get college credit for certain high

(05:18):
school courses, but it really didn't correlate, except this is
dealing with people's lives and bodies. Yeah, it doesn't seem
like he spent all that much time with his uncle,
but it was considered enough to skip a whole year
of med school. Coley spent the summer between his two
years of medical school working as an acting junior surgeon

(05:38):
at New York Hospital. He had friends who worked there,
and he was filling in for one of the surgeons
on staff who was out on leave. Coley started a
surgical internship at the hospital after graduating from Harvard in 1888,
and he became a house surgeon there in 1889. Not
long after that, he was also appointed to the staff

(06:00):
of the Hospital for the Ruptured and Crippled, later known
as the Hospital for Special Surgery. That is an orthopedic
and rheumatologic hospital that still exists today. In 1890, Coley
treated 17-year-old Elizabeth Daschle, known as Bessie, who had injured
her hand while on a train trip and was still

(06:20):
having pain more than a month later. She had seen
other doctors and tried various treatments and was eventually referred
to Coley. After some investigation and eventually a biopsy, Coley
diagnosed her with a periosteal sarcoma, The standard course of
treatment for this was an amputation, with the hope that

(06:42):
the cancer had not already spread beyond the amputation site.
Coley amputated Dashiell's arm below the elbow, but soon there
were more tumors in other parts of her body. She
died on January 23, 1891, at the age of 18,
only about 10 weeks after Coley first examined her. Bessie

(07:04):
Dashiell's death had a profound effect on William Coley. As
Tracy said, she was only 18, and she had been
healthy and active, so the rapid progression of her illness
and her death seemed particularly shocking and tragic. Coley was
also only 28 himself, and he was in his first
year of working as a surgeon. It really bothered him

(07:26):
that amputation was the only thing that he had been
able to offer her as a treatment option, and that
such a life-altering surgery had not even worked. He wanted
to find some more effective treatments, and he started poring
over the records at New York Hospital, studying the cases
of past cancer patients. He went through all the details

(07:48):
of about 90 cancer patients who had undergone surgery at
the hospital in the previous 15 years. One record stood out,
and that was a patient of his colleague, Dr. William T. Bull.
In Coley's words, quote, among these cases was a small,
round-celled sarcoma of the neck, four times recurrent. At the

(08:10):
fifth operation in 1884, Dr. Bull found the tumor to
involve the deep structures so extensively that it was impossible
to remove it, and he gave up the attempt. The
case was regarded as absolutely hopeless when, shortly after the operation,
the man developed a very severe attack of accidental erysipelas
in the face and neck, followed two weeks later by

(08:33):
a second attack. Within a few days after the beginning
of the first attack, the tumor began to soften and
decrease rapidly in size. The history stated that when the
patient left the hospital, his tumors had entirely disappeared. And
the hospital didn't have any further record of this patient
after he left, so Coley tracked him down, going door

(08:57):
to door in the German immigrant community where he was
likely to have lived. Coley, quote, finally found him alive
and well, with no evidence of any local or general
recurrences in the spring of 1891, seven years later. He
was examined both by Dr. Bull and myself. Coley started

(09:17):
looking through historical medical literature, and he found other reports
of patients whose tumors shrank or disappeared after some kind
of infection. Like Felicin and Bush, Coley decided to see
if he could replicate this effect. On May 2, 1891,
he started trying to induce erysipelas in a patient who
had an inoperable sarcoma of the tonsil and neck. The

(09:41):
tumors were so large that this patient could not eat
solid food and could only swallow very small amounts of liquid.
Coley exposed this patient to bacteria that had been cultured
in a lab. But for months, he was not able
to induce a case of erysipelas, no matter how the
culture were prepared or what method he used to expose

(10:03):
the patient to them. Finally, in October, he tried a
culture that a colleague brought him from Robert Koch's laboratory
in Germany. This injection made the patient very ill, but
in Coley's words, quote, At the end of two weeks,
the neck tumor had disappeared and the tonsil tumor had
decreased in size. The patient remained well for eight years

(10:27):
and then died in Italy of a local recurrence. We'll
talk about how Coley started trying to replicate these results
after a sponsor break. Music In 1892, as his experiments

(10:48):
with erysipelas were ongoing, William Coley was appointed to the
staff of New York Cancer Hospital, which was the first
cancer hospital in the United States. It had opened in 1887.
It was later renamed Memorial Hospital, and after various moves
and mergers, it's now known as Memorial Sloan Kettering Cancer Center.

(11:10):
One of the funders of Coley's work and donor of
the land where this hospital built a new facility in
the 1930s was someone else who had been profoundly affected
by Bessie Daschle's death. That was John D. Rockefeller Jr.,
who had referred to Bessie as his adopted sister. For
about two years, Coley continued to work with live bacterial cultures.

(11:34):
His patients were all people whose cancers were considered to
be incurable, so his this seemed like it could be
worth the very obvious risks involved. But he continued to
have difficulty actually inducing an infection. Most of the first
10 patients he tried to inoculate with the bacteria did
not develop erysipelas, but a few did seem to have

(11:57):
what he described as a slight temporary improvement in their tumors.
But the two patients who did develop erysipelas had startling results.
One had an inoperable sarcoma on his back, and that
had metastasized to his groin. It took weeks for an
erysipelas infection to take hold, but once it did, in

(12:18):
Coley's words, the results were, quote, nothing short of marvelous.
Three weeks from the date of the attack of erysipelas,
both tumors had entirely disappeared. When this patient's tumor recurred,
Coley tried the technique again, and the tumor once again disappeared.
This went on in cycles of recurrence and treatment. Eventually,

(12:41):
the patient started developing sporadic recurrences of erysipelas, which were
milder than what Coley had induced and also seemed to
have a mild effect on the tumors that continued to recur.
When Coley eventually switched from using live bacteria to using toxins,
and that's something that we're going to get to in
just a second, this patient was treated again, and this

(13:04):
time he remained well for more than three years before
developing a tumor in his abdomen, which was probably a metastasis.
The other patient was a woman with a sarcoma in
her breast, which had already been surgically treated and had
recurred twice. When Coley treated her, she had three active tumors.

(13:24):
She developed a case of erysipelas, which Coley described as
moderately severe after her first treatment, and all three tumors
decreased in size, with one of them almost completely disappearing.
But in her case, these tumors never totally went away,
even after repeated treatment, and she died about six months later.

(13:45):
All of these first patients had some type of sarcoma,
Coley was not able to induce an erysipelas infection in
any of the first carcinoma patients that he tried to treat.
He also acknowledged how risky this was, which was one
of the reasons why he was only trying it on
patients whose cancers were considered inoperable, many of whom had

(14:06):
already had multiple surgeries and recurrences. He also thought that
at least a portion of the seeming ability for these
bacteria to treat cancer came from the toxins that the
bacteria produced, not from the bacteria on its own. Isolating
and using the toxins was also potentially less risky than

(14:27):
trying to intentionally induce a bacterial infection in a patient.
Two of his early patients after that first group of
10 actually died of infection. So in late 1892, he
started working with bacteriologists to culture the bacteria, kill them
with heat, and then filter out the toxins. Cooley observed

(14:48):
that all the tumors that started to shrink went through
a similar process. Their vascularity decreased, so they started to
become a lot paler, and they also became more movable
and less connected to surrounding tissues. They would then soften
and degrade, and in some cases, they would completely disappear.

(15:08):
This effect was the same regardless of whether the toxins
were injected directly into the tumor or elsewhere in the
patient's body. In words from a paper that he published
later on, quote, 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

(15:30):
has taken place. and the patients have remained cured. In
other cases, improvement is only temporary, and after a few weeks,
in spite of continued injections and increased doses, the tumor
again begins to show signs of growth and continues until
a fatal issue. In a very few instances, especially in
cases of very large and vascular tumors, particularly the melanotic type,

(15:54):
which of late many pathologists are inclined to class as
carcinoma instead of sarcoma, no marked beneficial effects have been
noted at any time. In a paper that he published
in 1909, Coley outlined which patients he had come to
believe this treatment was suited for. Quote, I would at
present advocate their use first in all cases of inoperable sarcoma,

(16:19):
except the melanotic, which are classed as of epithelial origin
by many pathologists. Second, in cases of sarcoma originating in
the long bones in which operation means a sacrifice of
the limb. If in these cases no improvement is noted
at the end of two to three weeks, I would
then advise excision, resection, or amputation according to the individual case. Third,

(16:45):
in all cases of operation for primary sarcoma directly after
wound healing as a prophylactic against recurrence. Fourth, in addition
to the foregoing, I think there is a good ground
for believing that that the use of the mixed toxins
after all operations for carcinoma would greatly lessen the number
of recurrences. Coley's belief for why this worked, which I'm

(17:11):
going to say was not correct, but this is what
he thought was going on, was that he thought that
all tumors had a, quote, extrinsic or microbic origin, meaning
that they were caused by some kind of organism. Uh,
There are some cancers today that are known to be
connected to things like specific viruses, but he was sort

(17:33):
of saying that there is an organism that is causing
all of these cancers. And he thought that whatever this
organism was, that humans had a natural immunity to it,
but that immunity, if it was lowered for some reason,
meant that the organism could find a site to establish
itself in the body and start growing a tumor. Injuries

(17:54):
and mechanical irritation could produce a site in the body
that was favorable for this organism to establish itself, and
in his mind, that explained some other research that connected
some cancers to chronic inflammation or irritation. In his words, quote,
assuming such extrinsic origin, the action of the toxins appears

(18:15):
to me to produce certain changes in the blood or serum.
that restore the weakened or lost immunity or natural resisting
power of the tissues. And the sarcoma cell, no longer
finding conditions favorable for further growth and development, undergoes a
process of degeneration, with absorption in some cases and the
formation of a slough in others. He also thought the

(18:39):
fevers that followed exposure to the toxins might also play
a role. Coley's explanation for why some of his patients
saw no beneficial effects was that, quote, the tumor cells,
by reason of great vigor or better nourishment, are more
resistant and, although receiving a temporary setback by reason of
the changes in the blood produced by the toxins, soon

(19:03):
accommodate themselves to the new environment and continue to grow
as before. Coley presented a paper on this work before
the American Surgical Association on May 31, 1894. That October,
an article in the Journal of the American Medical Association
compared this use of bacterial toxins to the newly developed

(19:25):
antitoxin treatment for diphtheria. It mentioned the work of Coley,
as well as that of a Dr. Spronk in Paris
and Dr. German in Chicago. This report said in part, quote,
the best method for the utilization of these toxins is
not as yet positively determined. It is still under experiment,

(19:45):
and the results thus far demonstrate the necessity of great
care in the culture of the bacteria and the preparation
of their toxic products. It ended, quote, let us wait
patiently the full developments to be made by expert investigations.
But Coley's work was also unsurprisingly controversial. To some, the

(20:07):
idea of intentionally exposing patients to a bacterial infection or
injecting them with toxins seemed antithetical to the practice of medicine.
Some other doctors who tried to replicate Coley's techniques had
not been successful. Some of his critics claimed that his
supposed cures were really just misdiagnoses or coincidences. And it

(20:31):
just didn't work on some people, which was something that
Coley acknowledged. On December 15, 1894, so just a few
months after that October peace, the Journal of the American
Medical Association published another piece that was called The Failure
of the Erysipelas Toxins. This read in part, quote, There
is no longer much question of the entire failure of

(20:54):
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 so far
as our reading has extended. And the personal experience of
surgeons of our acquaintance with whom we have conversed demonstrates

(21:17):
that in all cases in which they tried the erysipelas toxin,
the result was no improvement. Coley's response was printed in
the journal in January. He described his surprise at the
journal's change of views, considering what it had printed in October,
and he pointed out that he was not just using
erysipelas toxins, he was also using another bacterium, Bacillus prodigiosus.

(21:43):
We're going to talk more about that in just a bit.
He walked through what he had observed in the cases
that we just discussed and said that, contrary to the
December 15th article, there were other surgeons that had seen
positive results. He ended, quote, that a few physicians in
a very limited number of cases within different preparations of

(22:03):
the toxins have failed to obtain good results will not,
I am sure, have great weight in the minds of
the scientific portion of the profession in determining failure or
success of this method of treatment of sarcoma. We'll have
what happened next after a break. Bacillus prodigiosus is known

(22:31):
today as Serratia marcescens, and it can cause a range
of infections. Today, those infections most often take place in
hospitals or long-term care facilities. French physiologist Georges-Henri Roger observed
that growing Streptococcus erycepolis together with Bacillus prodigiosus produced more

(22:53):
virulent cultures. William Coley decided to see if he could
use that trait to make his erycepolis toxins more effective.
One of the people that he worked with to do
this was Dr. Martha Tracy, assistant pathologist to the Huntington
Cancer Research Fund, which was another of Coley's sources of funding. Together,

(23:14):
the two of them concluded that when it came to
their impact on tumors, it wasn't just that Bacillus prodigiosus
had a heightening effect on Streptococcus erysipelas' virulence. Bacillus prodigiosus
had its own effect on tumors. So Dr. Tracy continued
to culture them separately, establishing standardized doses for each toxin.

(23:36):
In addition to her work with Coley, Tracy had a
huge career of her own, including serving as dean of
Women's Medical College of Pennsylvania starting in 1917. Coley worked
with these toxins for about 40 years. Over that time,
he treated roughly 1,000 cancer patients, and he published about
150 papers on his work. And while his results were mixed,

(24:00):
when the treatment worked, it seemed really incredible. Here's what
he described in 1909. Quote, 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

(24:21):
five to 16 years, and 14 from 10 to 16 years.
To the 36 successful cases published in the American Journal
of the Medical Sciences in March 1906, I have been
able to add 16 others. Although Park, Davis, and Company
produced various preparations of these toxins for medical use starting

(24:45):
in 1899, they were never the most common treatment for
inoperable sarcomas for an assortment of reasons. Coley also seems
to have had a really contentious relationship with James Ewing,
who was his boss at the cancer hospital, first director
of the American Association for Cancer Research, and a proponent
of radiation therapy. Ewing was an opponent of Coley's research.

(25:10):
Somewhat ironically, many of the cancers Coley was treating would
later be named Ewing's sarcoma, and Coley also wasn't against
radiation therapy at all. he was instrumental in getting the
hospital's first equipment to administer it. Yeah, it really doesn't
seem like Ewing wanted him working on this bacteria or
toxin thing at all. Coley's detractors also included the doctors

(25:35):
who managed the bone sarcoma registry, which was established in
the 1920s to keep an up-to-date list of living people
whose bone sarcomas were considered to be cured. Coley had
difficulty getting his own patients added to this registry, even
though he was one of the foremost bone cancer surgeons
in the country. The list's maintainers insisted that his cures

(25:59):
were really incorrect diagnoses. which seems like a lot of
times to say that somebody had made an incorrect diagnosis.
And it probably did not help that he continued to
believe that all cancers had some kind of microbial origin,
even after that idea was being disproved. That understandably made

(26:21):
people question his other conclusions as well. The toxins were
also difficult to produce and difficult to standardize, and the
Biologics Control Act of 1902 added an additional layer of
expense and difficulty. This act gave the Food and Drug
Administration's Center for Biologics Evaluation and Research the authority to

(26:43):
regulate biological products, like Coley's toxins, to ensure their safety. Yeah, that,
of course, added more steps to getting things approved. Aside
from the innate difficulty in producing standardized versions of these toxins,
Coley's own methods in using them were kind of all
over the place. People got different amounts of toxin by

(27:06):
different methods for different amounts of time. Some of this
was him trying to figure out what worked and how
to do it the best, but it also seems like
some of his treatment decisions were almost made on vibes
rather than data. He also noted that some of the
other doctors who used his toxins kept up their patients'

(27:27):
treatments for much longer than he would have, acknowledging that
his shorter length of treatment might explain some of his patients'
own recurrences. It's possible, though, that Coley's toxins would have
been more widely used if the timing had been different.
X-rays were discovered in 1895, and radium was discovered in 1898.

(27:50):
Radiation therapy quickly became the standard treatment for many inoperable cancers. Yeah,
both of those discoveries were within the early years of
him doing and writing about this treatment. In 1934, the
Journal of the American Medical Association published a statement from
the Council on Pharmacy and Chemistry that was slightly more

(28:11):
favorable toward Coley's methods than what the journal had published
40 years before. It said in part, quote, it appears
that undoubtedly the combined toxins of erysipelas and prodigiosis may
sometimes play a significant role in preventing or retarding malignant
recurrence or metastases. Occasionally, they may play a curative in

(28:34):
hopelessly inoperable neoplasms. The council has, for these reasons, retained
erysipelas and prodigiosus toxins, Coley, in new and non-official remedies
with a view to facilitating further studies with the product.
By that point, though, Coley had retired. He died on

(28:55):
April 16, 1936, at the age of 74. Coley's daughter,
Helen Coley Knotts, started going through his papers and correspondence
after his death with the intent that she would write
a biography of him. Soon, she found herself on a
deep dive of his work. She was not a doctor.
She had no formal education beyond high school. But she

(29:17):
went through all of his publications with a fine-toothed comb
to try to pinpoint the reasons behind his successes and failures.
In 1953, she partnered with philanthropist Oliver R. Gray Sr.
to establish the Cancer Research Institute. One of her other
sources of funding was Nelson Rockefeller, son of John D.

(29:39):
Rockefeller Jr. Jr. She served as director of the Cancer
Research Institute until her death in 2001. Her brother Bradley
was also an advocate of further study of their father's methods,
and he became chief of bone surgery at Memorial Hospital
after their father's retirement. The Cancer Research Institute has an

(30:00):
award named after Coley today. That is an award for
distinguished research in basic and tumor immunology. The exact reasons
for the effects of Coley's toxins on some carcinoma are
not fully understood, and the parts that are somewhat understood,
I don't understand. They are not within my ability to explain.

(30:22):
But there is a cancer treatment today that has some
definite similarities. In 1959, Lloyd J. Old, the Cancer Research
Institute's founding scientific and medical director, published a paper in
the journal Nature, along with other authors. This paper described
how mice injected with Bacillus calmetgaran, or BCG, became resistant

(30:48):
to implanted tumors. BCG is a tuberculosis vaccine that is
made from a weakened version of bovine tuberculosis bacteria. This
work grew from research that stretched back to the 1920s
when autopsies conducted at Johns Hopkins showed that people with

(31:08):
tuberculosis had fewer malignancies than people who did not have it.
In 1975, Old collaborated with Dr. Elizabeth Carswell and others
to use BCG in conjunction with one of Coley's toxins
to stimulate the immune system of mice. They were able
to extract a cytokine from the mice's blood. That's a

(31:31):
protein that affects how cells interact and communicate. They named
this cytokine tumor necrosis factor, or TNF. It both causes
inflammation and kills tumors. Also in the 1970s, Old and
other researchers tried introducing BCG into the bladders of patients
with certain bladder cancers, and they found that BCG stimulated

(31:56):
the immune system to attack the cancer. The FDA approved
this use of BCG as a superficial bladder cancer treatment
in 1990, and it is still used today. Old is
sometimes described as the founder of cancer immunology, although a
number of people who have written about Coley argue that

(32:16):
the two of them should share that title. Coley's toxins
are not approved for use in the U.S. today. Under
laws passed in 1962 in the wake of the thalidomide disaster,
the pharmaceutical industry in the U.S. became a lot more regulated.
Many drugs that were already in widespread use were exempt
from the law. But in 1963, the FDA classified Coley's

(32:40):
toxins as an investigational drug. That meant that it would
need to go through rigorous clinical testing to be approved
for use in the U.S. In 1965, the American Cancer
Society added the toxins to its Unproven Methods of Cancer
Therapy list. The toxins were removed from that list in 1975,

(33:01):
but the stigma associated with having been on the list continued.
and the difficulty and expense of producing the toxins and
putting them through trials led to their being almost entirely abandoned.
The Cancer Research Institute did fund a phase one trial
of the toxins in 2007. In the words of a
blog post about the toxins at the CRI website, quote,

(33:23):
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. But
the difficulty of producing the toxins continues to be an

(33:47):
issue with the idea of doing further studies on this.
And also at this point, there are just other newer,
more sophisticated cancer immunotherapy treatments available. than Coley's toxins. It's
sort of like something that seems like it could have potential,
but there's also other stuff that is newly developed and

(34:07):
is potentially more powerful and more specific. Ba-da-da! Do you
have listener mail? I do have listener mail. This listener
mail is from Bruce, and Bruce wrote about our Flying
Gang episode. and the email is titled, Pirates and Our

(34:27):
Then Teenager. And it says, Greetings, ladies. I was listening
to the Flying Gang episode, and you briefly mentioned Anne Bonny.
I'm old enough that my summer camp experiences included making
physical things like wallets, belts, or bolo neckties. I will
pause and say, I also am that old. Yeah. So

(34:48):
the email goes on to say, one of our daughter's
summer camps involved making short movies. The camps, in her case,
were hosted on the beautiful Oglethorpe University campus in the
Atlanta area. The campers, being teens, tended to make mystery
or horror-adjacent movies. However, one year, our daughter's group made
a comedy. The premise was that Anne Bonny had been

(35:11):
found alive and preserved in the Bermuda Triangle. The government
is trying to rehabilitate her and get her adapted to
life in the 21st century. At one point, she's enrolling
in college. Anne muses, I was skeptical at first. I mean,
what major is there for someone who loots and pillages
for a living? Then I realized the answer was staring

(35:33):
me in the face. Anne then enters a classroom that
is labeled political science. Anne also applies for a job
at Starbucks because of the mermaid, of course. When asked
during her interview if she has any questions, she says,
what's the conversion from dollars to doubloons? Anyway, thanks for

(35:53):
the great show and triggering a fun memory. Pod Pet
Tax is our late German shepherd. Scooby helping wake up
our also then teenager Bruce. I think this play sounds great.
It's a movie, right? It's a short film? Yes, it's
a short film. I said play because I am an
old person, and that's what we would have been doing
at summer camp. We would not have been filming anything. So, yeah,

(36:17):
this is delightful. I'm always so charmed by how hilarious
and sometimes savage children and teens can be in their humor.
And then we have a picture of the then teenager
is entirely obscured. By the German shepherd who is supposedly

(36:40):
helping be an alarm clock. Shepies. So funny. So thank you.
I also love that they filmed that at Overthorpe. Because
I'm like, was that when I was working there? Because
we used to sometimes have crazy summer camp things going
on on the quad and about campus. And I would
be like, ah, these kids. Well, I drank my coffee and.

(37:02):
When I read this the first time through, I thought,
do kids not make wallets, belts, or bolo neckties at
summer camp anymore? I have no idea. I think some do.
I only went to day camp, and we definitely had
craft projects that would fit in that genre. My question was,
do you think you have to go to camp to
do that stuff? No. I just do it at my house. No. Yeah.

(37:26):
Now I'm thinking of... Childhood of craft making. So thank
you so much, Bruce, for this email and this delightful
story of teens being hilarious. If you're a political science
major and you are feeling upset by these teenagers' short film,
it was funny, in my opinion. If you would like

(37:48):
to send us a note, we're at historypodcasts at iheartradio.com.
If you would like to see the show notes to
our episode today, including... All these papers printed back in
the late 19th, early 20th century. That is at MissingHistory.com. Also,
you can subscribe to our show on the iHeartRadio app
and anywhere else you like to get your podcasts. Stuff

(38:14):
You Missed in History Class is a production of iHeartRadio.
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