Last time I told you a story about a common parasite— Toxoplasma gondii — that might help fight tumors (What?). Can parasites also cure cancer? 》)。 Using potentially dangerous parasites to fight cancer may sound a little inconceivable: Isn't that worse for already frail patients?
Still, the idea of using pathogens to treat cancer dates back more than a century. In addition to Toxoplasma gondii, there are many other pathogens that are also used in anti-cancer treatment. Today Xiaobian will introduce you to the story behind a bacterium that can fight cancer.
Young and promising surgeon
The story begins with a doctor named William Coley. Born in Connecticut in 1862, Coley received a bachelor's degree in classics from Yale University and a medical degree from Harvard Medical School in 1888. After completing his studies, Curley began working at New York Hospital (now Weill Cornell Medical Center) as a surgical intern.
Figure 1. Young and promising surgeon William Corley (1891). Source: Cancer Research Institute
A young girl who died of sarcoma
In the late summer of 1890, Dr. Colley was preparing to examine a new patient. What he didn't know was that the young woman waiting for him to see a doctor would change his life and the future of cancer research.
Her name was Elizabeth Dashiell, or Bessie for short. Bessie was only 17 years old and had a hand injury that looked like a small inconsequential injury, just a small bump in the area where she was injured, but it showed no signs of getting better and was painful. She had seen other doctors, but no one could diagnose anything wrong.
At first, Dr. Corley thought Bessie's condition was caused by an infection. But when he did a biopsy, it turned out to be a malignant advanced sarcoma.
Treatment of cancer patients was limited at the time, and radiation and chemotherapy had not yet appeared. Dr. Collie did the only thing he could do: cut Bessie's right arm from below the elbow to try to stop the tumor from spreading. Unfortunately, this didn't work, and within a month, the cancer had spread throughout his body.
Bessie's last days were painful. When she died on January 23, 1891, Dr. Curley was by her side. Bessie's death touched the young surgeon so much that he began to seek more effective anti-cancer treatments.
Cancer patients are miraculously cured, and doctors turn into detectives
Collie began digging through old case records at New York hospitals and found an interesting case.
The patient's name was Fred Stein, a German immigrant. Stein had been a patient at a New York hospital eight years earlier with a tumor in his neck that doctors had tried several times to remove, but Stein's tumor kept coming back and doctors expected him to die of the disease.
Next, Stein became infected with streptococcus and developed a serious skin infection. Doctors believe Stein is running out of time. But he wasn't dead, and his tumor was gone! Soon he was discharged from the hospital.
Dr. Colley wondered if Stein was still alive after all these years. In the winter of 1891, Dr. Curley became a detective and traveled to his apartment in the German immigrant community on Manhattan's Lower East Side. He knocked on doors door to door, looking for a man named Fred Stein with a distinctive scar around his neck.
The kung fu paid off, and after weeks of searching, Corley found that Stein was still alive! And there is no cancer!
Bacterial infection, blessed by misfortune?
Why did Stein's tumor disappear after he was infected with the bacteria and not recur? Dr. Coley speculated that the streptococcal infection reversed the cancer. He wondered if such a miracle could be recreated if he took the initiative to inject cancer patients with bacteria.
He decided to test his thoughts on those who were most ill. His first subject was an Italian immigrant named Zola, who, like Bessie, suffered from sarcoma. Zora was so sick that he had a tumor in his throat and could barely eat or speak, or even breathe.
For months, Curley tried to make Zora sick from an infection by creating small wounds and rubbing streptococcus into them. Possibly because of the small dose, or the mild strain, Zola had some mild reactions, but there were no other changes.
Next, Dr. Curley got a more powerful strain of bacteria. This time, Zora had a severe infection and looked bad.
However, within 24 hours, Zola's orange-sized tumor began to liquefy and disintegrate, and he recovered.
Figure 2. The beginning of immunotherapy was an article published by Dr. Colly describing the therapy in 1891. W.B. COLEY, "CONTRIBUTION TO THE KNOWLEDGE OF SARCOMA," _ANNALS OF SURGERY_, 14:199-220, 1891
The famous Coli toxin
After treatment, many patients' tumors shrank, which gave Dr. Colley a lot of confidence and continued to conduct experiments to improve the use of bacteria. Since live streptococci are a bit harmful to the human body, Curley treated it with a mixture of streptococcus that was heated and another bacterium (we now call Serratia marsii). This mixture was later known as "Coli toxin". Dr. Curley was a huge success and became famous in one fell swoop. In 1899, the pharmaceutical company Parke Davis & Company began producing Coli toxin, and bacterial therapies were widely used for the next three decades.
Figure 3. Dr. Collie (1936). Source: The Welch Library of the History of Medicine.
After Coley's death in 1936, his daughter (Helen Coley Nauts) began flipping through his documents while researching her father's biography. She found about 1,000 files of cancer patients who had been treated with bacteria, mainly bone and soft tissue sarcoma patients who could not be treated surgically, mainly because Colley observed that the therapy did not work well in other tumor patients. The tumors of about 500 of these patients showed regression. His daughter spent years carefully analyzing the cases and founded the Cancer Research Institute in 1953 to understand the relationship between the immune system and cancer.
The decline of bacterial therapy
However, the American medical community at the time was skeptical of this therapy. No one knows how Coli toxins work, and why they sometimes work and sometimes don't. Coley himself could not explain. This is mainly because the immune system was still a mystery to people at the time.
In addition, the clinical trials and promotion of Coli toxins have been hindered by inconsistencies in manufacturing, use and management, for example, there are 13 manufacturing methods, some are effective, some are not so good; the use of the way is not uniform, intravenous injection, intramuscular injection, direct injection into the tumor, there are various ways.
Some doctors have been successful in using Coli toxin. However, many of these doctors were skeptical of Curley, who insisted that cancer is caused by microbes, and even after being widely rejected by the scientific community, he held on to it for a long time.
For all these reasons, when radiation therapy appeared in the early twentieth century, interest gradually shifted from bacterial therapy to radiation therapy. By 1952, Parke Davis & Company was no longer producing Coli toxin; in 1962, the FDA refused to recognize Coli toxin as a validated drug; and in 1965, the American Cancer Society listed Coli toxin as an Unproven Cancer Treatment.
Ironically, Colley experimented with many other cancer treatments while experimenting with bacterial therapy, and he helped bring radiation therapy to the hospital where he worked, as shown in the picture below of Curley's radiation therapy in 1902, just seven years after the discovery of X-rays. The hospital's president, James Ewing, worked to develop radiotherapy and eventually banned Collie from using his toxins to treat hospital patients.
Figure 4. Collie implemented radiation therapy in 1902. Source: ROBERT HOKE, THE MEMORIAL SLOAN KETTERING CANCER CENTER ARCHIVES
The resurgence of immunotherapy
Over the next six decades, scientists have finally studied some of the skin of the immune system, and the understanding of cancer and immunity has deepened. Now we know that these cancer-fighting pathogens do not directly attack tumor cells, but trigger the patient's own anti-tumor response. Now, rapidly evolving immunotherapies use this response to improve the immune system's ability to recognize and destroy cancer cells.
Although Dr. Curley did not know how his bacteria worked at the time and did not know that the immune system played an important role in it, it is undeniable that today we can use the power of the immune system to treat a range of cancers, and Dr. Curley's curiosity and clinical practice have played a huge role in the development of this field, and is a well-deserved "father of immunotherapy".
参考文献："The Toxins of William B. Coley and the Treatment of Bone and Soft-Tissue Sarcomas", Iowa Orthop J. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1888599/#) 2006; 26: 154–158.