William Coley - the founder of cancer immunotherapy

The founder of cancer immunotherapy is now recognized by William Coley (William B. Coley, 1862-1936), who in 1891 first introduced streptococcal bacteria in a patient with inoperable cancer. Over the next 40 years, he administered bacteriological preparations to more than 1,000 patients. In the future, these drugs were called the vaccine (or toxin ) Kohli . Coley and other doctors who used his method reported excellent results, especially in the treatment of patients with sarcoma of bones and soft tissues.

However, Kolya’s technique was not widely used during his lifetime and was not introduced into medical practice, despite all the efforts and evidence provided. And only now, when scientific research has once again led to a revival of interest in immunotherapy, the merits of Kolya to medicine were recognized.

William Bradley Coley was born in 1862 in one of the oldest families of Connecticut. He studied at Yale and later graduated from Harvard Medical School in 1988. After university, he began working as an intern at the Memorial Hospital in New York - the first cancer hospital in America.
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One of his first patients in 1890 was 17-year-old Elizabeth Dashiel, a close friend of John D. Rockefeller. Elizabeth turned to William Coley about a tumor on her arm, subsequently diagnosed as Ewing's sarcoma. Despite the amputation of her forearm, Elizabeth died from multiple metastases after 10 weeks.

Such a rapid spread of deadly cancer deeply shook William Coley. He decided to make every effort to find a more effective treatment. He studied the case histories of patients at the New York Hospital and discovered an unusual case with one of the patients who, seven years earlier, had an inoperable form of a malignant neck tumor that regressed completely after the patient had erysipelas (or scarlet fever). The patient was discharged for lack of any signs of illness. William Coley personally decided to find and examine this patient who lived in Manhattan. After some time, Kolya finally sought out the patient — the German émigré Stein — and found no signs of residual cancer in him, that is, Stein was completely cured of a malignant neck tumor.

Kohl began to study the medical literature, and found indications of a number of similar cases dated to different years since the 18th century. It is curious that one of these sources was the writer Anton Chekhov, who once worked as a doctor.

Coley began to selectively infect patients with scarlet fever, and some of them began to cure cancer, although there were a number of cases of death of patients from the infection itself, since erysipelas itself is a very serious disease.

Then Kohl began to use dead scarlet fever bacteria killed by heat instead of live infection. The effect was very weak in comparison with live bacteria, but Kolya continued to experiment, and finally found the right combination. To the dead bacteria that cause scarlet fever (Streptococcus pyogenes), he began to add bacteria killed by heating another infection - Serratia marcescens, and achieved a good therapeutic effect. The resulting mixture of dead bacteria has been given the name Kolya vaccine , or Kolya toxins .

Koli conducted the treatment in the following way: every day he injected the patient with an intravenous solution with the Koli vaccine, after which the patient began a fever that lasted for several hours in a row. This procedure was performed on patients every day for a period of 3 weeks to 2 months.

Kohl's only patient, who survived to this day, is Donald Foley, 77, a year old. At the age of 13, he was diagnosed with bone cancer. After the diagnosis was made, the doctors told his parents that he would be able to live for another 3 months if his arm was amputated. Donald's parents refused to amputation and appealed to William Coley. After 21 days of daily procedures, there was a complete recovery, after which the disease never returned.


Donald Foley - the last patient of William Coley, who lived to this day

However, Kolya’s technique was not widely spread during his lifetime and was not introduced into medical practice, despite all his efforts and the evidence provided. The politically correct point of view on this question is that at that time the mechanism of action of Kolya's vaccine was not clear. But it seems to me that this point of view does not fully reflect reality. For example, James Ewing, the boss of William Coley at the New York Memorial Hospital, received a large grant to buy radiation therapy equipment from rich industrialist James Douglas, and saw a panacea for cancer exclusively in radiation therapy. Despite Kolya’s success, he imposed a total ban on continuing treatment of cancer patients with Kolya vaccine at Memorial Hospital.

And then they invented chemotherapy, and Kohl was completely forgotten about the vaccine. The only enthusiast of this method was Kolya's daughter, who founded the Cancer Research Institute in New York for grant money received from Rockefeller.

And only now, when scientific research has once again led to a revival of interest in immunotherapy, the merits of Kolya to medicine were recognized. In 2008, the private company Coley Pharmaceutical Group, which conducted a number of interesting studies on the use of Kolya vaccine, was bought by the pharmaceutical giant Pfizer. Another giant of the pharmaceutical market, Sanofi-Aventis, is also actively investing in research on this vaccine.

Currently, immunotherapy is recognized as the most promising direction in the treatment of cancer. Its essence is as follows:

The immune system can work in one of two modes:

• in the mode of maintaining the growth and functioning of cells, and
• in the mode of cell destruction.

Usually, the killing mode is activated if the “monitoring” system detects “wrong” cells (for example, infected with a virus, etc.). In this case, the immune response is formed differently each time, depending on what needs to be destroyed.

The problem is that cancer cells are not identified as “abnormal,” and the immune system continues to support their vital activity and growth. Normal (healthy) cells act in accordance with the program embedded in their DNA, and (despite the favorable conditions created by the immune system) at some point cease to divide and self-destruct after a while. In an adult, up to 80 billion cells are suicidal in one day.

Cancer cells lack internal mechanisms of self-destruction, they continue to grow and divide, regardless of the “outside” signals and the genetic program of DNA. This is due to the fact that, for example, their gene disappears as a result of mutations, which triggers a chain reaction of self-destruction or blocks division (i.e., mutation damages DNA, and, accordingly, a whole piece of cell life management program disappears) . Actually, this is why these cells cause tumors, since they begin to divide and devour the body’s resources uncontrollably. Their survival also contributes to the fact that they can do without oxygen, and feed on glucose alone.

The goal of immunotherapy is to enable the same “attack mode”, which will be aimed specifically at destroying cancer cells. Although cancer cells can not kill themselves, but, nevertheless, they retain mechanisms that allow them to cause death "outside." For example, they have special receptors - long molecules that stick out at one end inside the cell, and at the other end - outside. Other specific molecules that the immune system can emit chemically react with the outer end of the receptors, causing the inner (ie, the one inside the cell) end of the long receptor molecule to transform and cause the death of the cancer cell.

Thus, cancer can be defeated by forcing the immune system to switch to the NECESSARY attack mode. The key word here is “necessary,” since the attack mode against the influenza virus does not help fight cancer.

Kohl's vaccine works just because the mode of attack against scarlet fever and cancer cells is the same. A curious fact is that Kolya's sample method gradually increased the dosage of the vaccine until it reached the effect of the appearance of fever (fever), which for him, in essence, was the only sign of the effectiveness of the vaccine. For a long time, there was even a myth that high fever can be cured of cancer. However, studies in recent years have shown that high temperature is not a cause at all, but a consequence of the therapeutic effect. It is the result of the release of cytokines - a sharp release of a large number of immunomediators as a result of the rapid destruction of tumor cells, which is accompanied by fever, chills and a decrease in blood pressure.

However, currently Kolya vaccine is practically not used for the treatment of cancer. The main reason is strict regulation of medical practice.
For example, in the United States, the use of Kolya vaccine in medical practice is impossible due to the fact that this drug is still in “new drug” status according to the Food and Drug Administration (FDA) classification, and therefore it can only be used for clinical research. At the same time, research is also very sluggish, since the production of only one batch of bacterial vaccine for research in accordance with established Good Clinical Practice (GCP) standards costs $ 1.2 million.

In Germany, the Koli vaccine is used by a number of specialized doctors, since there is “ Therapiefreiheit ”, and the doctor can choose the treatment method at his own discretion, as well as make his own Koli vaccine for use (but not for sale!) In the laboratory.

A real breakthrough in the application of immunotherapy for the treatment of cancer was the study of American scientists, the preliminary results of which were presented on February 14, 2016 at the annual rally of the American Association for the Advancement of Science (AAAS) in Washington. In the early clinical trials of a new technique, it was possible to achieve a complete cure for patients who were considered hopeless.

The strategy for the new technique was based on learning how to translate the immune system into that very necessary “attack mode” on cancer cells. And if Kohl achieved this by provoking the body with scarlet fever infection, then researchers from the Fred Hutchinson Cancer Research Center in Seattle decided to isolate immune cells from the blood that are responsible for “attack” and enhance their “combat” qualities and ability to reproduce by means of genetic engineering.

These cells, which protect people from their own malignantly regenerated cells, are T-lymphocytes. However, in the case of the usual development of cancer, the immune response is not strong enough or long enough to eliminate the tumor.

Researchers invited patients with lymphocytic blood tumors (acute lymphoblastic leukemia, non-Hodgkin's lymphoma and chronic lymphoblastic leukemia), relapsed or resistant to high doses of chemotherapy to participate in the experiment.

T-lymphocytes were isolated from patients' blood samples and a chimeric antigen receptor (CAR) was inserted into their DNA with the help of a neutralized lentivirus. This receptor contains an antigen-recognizing extracellular domain that selectively binds to the B19 lymphocyte receptor, the intracellular signaling domains of CD28 and CD3-zeta, which are necessary for T-lymphocyte activation and survival, and a shortened form of human epidermal growth factor (EGFRt), which has immunostimulating and antitumor cells. .

The obtained cells (autologous CD19CAR-4-1BB-CD3zeta-EGFRt-expressing T-lymphocytes) were intravenously administered to patients. Since lymphocytes are able to divide in the body, they were prescribed once with the possibility of repeated administration after 21 days with insufficient effect.

A few weeks later, in 27 of 29 patients with acute lymphoblastic leukemia, the analysis of the bone marrow showed a complete absence of cancer cells. 19 out of 30 volunteers with non-Hodgkin's lymphoma were fully or partially cured. A few patients completely absorbed the kilogram mass of the tumor.


Resorption of tumor masses in lymphoma in the fifth month of treatment (computed tomogram)

The main complication of therapy was the cytokine release syndrome noted above - the abrupt release of a large number of immunomedients as a result of the rapid destruction of tumor cells, which is accompanied by fever, chills, and a decrease in blood pressure. It was mainly observed in patients with the highest tumor mass with the introduction of a high dose of modified lymphocytes. Seven such patients needed help in the conditions of the intensive care unit. After dose adjustment in the next stages of the study, no patient needed such help.

Undoubtedly, the new method will save millions of lives in the near future. Well, and before that ... involuntarily you think that since William Kohli was able to manufacture his vaccine 100 years ago, then it is quite possible to manufacture this drug even in our modern times. But personally, alas, I was not allowed to do this (or rather, to apply) .