Coley's Toxins
Encyclopedia
Coley's toxins is a mixture consisting of killed bacteria of species Streptococcus pyogenes
and Serratia marcescens
, named after William Coley
, a surgical oncologist who developed the mixture in the late 19th century as a treatment for cancer
.
and remission of cancer predate Coley. For example, Anton Chekhov
, in his capacity as a physician, recorded such a relationship in 1884.
Coley started his investigations after the death of one of his first patients, Elizabeth Dashiell, from sarcoma
. Dashiell was a close childhood friend of John D. Rockefeller, Jr.
, who later indicated that her death was what first motivated his subsequent funding of cancer research.
Frustrated by this case, Coley's subsequent research led him to find evidence of the apparent relationship between infection and cancer regression, which he published in 1891. His initial attempts at deliberate infection were mixed, but in 1893 he began combining Streptococcus pyogenes
and Serratia marcescens
, based upon research from G.H. Roger indicating that this combination led to greater virulence.
The so-called Coley's Toxins were used against different types of cancer from the year 1893 through the year 1963. From 1923 on, Parke-Davis
was the only source of Coley's Toxins in the United States
. In the wake of the thalidomide
controversy and the Kefauver Harris Amendment
of 1962, Coley's Toxins were assigned "new drug" status by the Food and Drug Administration
(FDA), making it illegal to prescribe them outside of clinical trial
s. Since then, several small clinical trials have been conducted with mixed results.
Coley's Toxins were also produced by the small German pharmaceutical company Südmedica and sold under the trade name Vaccineurin. However, production ceased by 1990 because of a lack of re-approval by German Federal Institute for Drugs and Medical Devices
.
s are either in "repair mode", furthering the growing of cancer, or in "defense mode", destroying cancer. However, macrophages are in "defense mode" only if there is some recognized enemy. As cancer tissue is not recognized as enemy (but as normal body tissue), there is a need to bring more macrophages into "defense mode" by simulating an infection
. The simulated infection results in a real fever
. Unlike hyperthermia
, real fever not only means heating of the body but also higher activity of the immune system
. Thus, fever is seen as a precondition for a therapy using Coley's Toxins to succeed.
which causes fever. The resulting fever from the lipopolysaccaride is thought to increase lymphocyte activity and boosts tumor necrosis factor (TNF). Tsung and Norton in Surgical Oncology reported that the active agent was thought to be interleukin-12, rather than TNF.
(produced by bacteria of type "streptococcus" together with plasminogen from the patient) is the active agent of Coley's toxins. This hypothesis is supported by the fact that streptokinase has been associated with successful treatment of thromboangiitis obliterans.
s (DC), leading to the activation of anergic T cells, maybe accomplished by a second process, where a possible physical damage of cancer cells leads to a sudden supply of cancer antigens to DC.,
found in bacterial DNA. The CpG motif is recognized by toll like receptor 9 (TLR9
) and can induce a strong TH1
response.
in January 2008. In addition, the Waisbren Clinic in Wisconsin reports they have used Coley's toxin to treat patients since 1972. Coley's toxins are generally not available where approval or licence is required (in particular in the United States and Germany).
Drug makers including Pfizer
and Sanofi-Aventis
are interested in modern versions of Coley's toxins; Pfizer has acquired the Coley Pharmaceutical Group, set up in 1997
"), the legal right to apply whichever therapy a physician considers to be appropriate in the light of their medical knowledge. For example, Dr Josef Issels
used several unconventional and controversial treatments, including Coley's toxins, for cancer patients in the second half of the 20th century.
This kind of therapy is offered as "Fiebertherapie" (fever therapy). Hyperthermia therapy
or thermotherapy is not the same type of treatment, although sometimes incorrectly called "fever therapy".
Streptococcus pyogenes
Streptococcus pyogenes is a spherical, Gram-positive bacterium that is the cause of group A streptococcal infections. S. pyogenes displays streptococcal group A antigen on its cell wall. S...
and Serratia marcescens
Serratia marcescens
Serratia marcescens is a species of Gram-negative, rod-shaped bacterium in the family Enterobacteriaceae. A human pathogen, S. marcescens is involved in nosocomial infections, particularly catheter-associated bacteremia, urinary tract infections and wound infections, and is responsible for 1.4% of...
, named after William Coley
William Coley
William Bradley Coley was an American bone surgeon and cancer researcher, pioneer of cancer immunotherapy. He developed a treatment based on provoking an immune response to bacteria...
, a surgical oncologist who developed the mixture in the late 19th century as a treatment for cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
.
History
Observations of a relationship between infection and cancer regression date back to at least the 18th century. More specifically, observations of an apparent relationship between erysipelasErysipelas
Erysipelas is an acute streptococcus bacterial infection of the deep epidermis with lymphatic spread.-Risk factors:...
and remission of cancer predate Coley. For example, Anton Chekhov
Anton Chekhov
Anton Pavlovich Chekhov was a Russian physician, dramatist and author who is considered to be among the greatest writers of short stories in history. His career as a dramatist produced four classics and his best short stories are held in high esteem by writers and critics...
, in his capacity as a physician, recorded such a relationship in 1884.
Coley started his investigations after the death of one of his first patients, Elizabeth Dashiell, from sarcoma
Sarcoma
A sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
. Dashiell was a close childhood friend of John D. Rockefeller, Jr.
John D. Rockefeller, Jr.
John Davison Rockefeller, Jr. was a major philanthropist and a pivotal member of the prominent Rockefeller family. He was the sole son among the five children of businessman and Standard Oil industrialist John D. Rockefeller and the father of the five famous Rockefeller brothers...
, who later indicated that her death was what first motivated his subsequent funding of cancer research.
Frustrated by this case, Coley's subsequent research led him to find evidence of the apparent relationship between infection and cancer regression, which he published in 1891. His initial attempts at deliberate infection were mixed, but in 1893 he began combining Streptococcus pyogenes
Streptococcus pyogenes
Streptococcus pyogenes is a spherical, Gram-positive bacterium that is the cause of group A streptococcal infections. S. pyogenes displays streptococcal group A antigen on its cell wall. S...
and Serratia marcescens
Serratia marcescens
Serratia marcescens is a species of Gram-negative, rod-shaped bacterium in the family Enterobacteriaceae. A human pathogen, S. marcescens is involved in nosocomial infections, particularly catheter-associated bacteremia, urinary tract infections and wound infections, and is responsible for 1.4% of...
, based upon research from G.H. Roger indicating that this combination led to greater virulence.
The so-called Coley's Toxins were used against different types of cancer from the year 1893 through the year 1963. From 1923 on, Parke-Davis
Parke-Davis
Parke-Davis is a subsidiary of the pharmaceutical company Pfizer. Although no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history.- History :...
was the only source of Coley's Toxins in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
. In the wake of the thalidomide
Thalidomide
Thalidomide was introduced as a sedative drug in the late 1950s that was typically used to cure morning sickness. In 1961, it was withdrawn due to teratogenicity and neuropathy. There is now a growing clinical interest in thalidomide, and it is introduced as an immunomodulatory agent used...
controversy and the Kefauver Harris Amendment
Kefauver Harris Amendment
The U.S. Kefauver Harris Amendment or "Drug Efficacy Amendment" is a 1962 amendment to the Federal Food, Drug, and Cosmetic Act.It introduced a requirement for drug manufacturers to provide proof of the effectiveness and safety of their drugs before approval...
of 1962, Coley's Toxins were assigned "new drug" status by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA), making it illegal to prescribe them outside of clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s. Since then, several small clinical trials have been conducted with mixed results.
Coley's Toxins were also produced by the small German pharmaceutical company Südmedica and sold under the trade name Vaccineurin. However, production ceased by 1990 because of a lack of re-approval by German Federal Institute for Drugs and Medical Devices
Federal Institute for Drugs and Medical Devices
The Federal Institute for Drugs and Medical Devices is a medical regulatory body in Germany.It operates under the Federal Ministry of Health.It is headquartered in Bonn....
.
Macrophages
One rationale argues that macrophageMacrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s are either in "repair mode", furthering the growing of cancer, or in "defense mode", destroying cancer. However, macrophages are in "defense mode" only if there is some recognized enemy. As cancer tissue is not recognized as enemy (but as normal body tissue), there is a need to bring more macrophages into "defense mode" by simulating an infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
. The simulated infection results in a real fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
. Unlike hyperthermia
Hyperthermia
Hyperthermia is an elevated body temperature due to failed thermoregulation. Hyperthermia occurs when the body produces or absorbs more heat than it can dissipate...
, real fever not only means heating of the body but also higher activity of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. Thus, fever is seen as a precondition for a therapy using Coley's Toxins to succeed.
Tumor Necrosis Factor and Interleukin
One of the agents in Coley's Toxin that is thought to be biologically active is a lipopolysaccharideLipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
which causes fever. The resulting fever from the lipopolysaccaride is thought to increase lymphocyte activity and boosts tumor necrosis factor (TNF). Tsung and Norton in Surgical Oncology reported that the active agent was thought to be interleukin-12, rather than TNF.
Streptokinase
Another hypothesis argues that streptokinaseStreptokinase
Streptokinase , a protein secreted by several species of streptococci can bind and activate human plasminogen. SK is used as an effective and inexpensive thrombolysis medication in some cases of myocardial infarction and pulmonary embolism...
(produced by bacteria of type "streptococcus" together with plasminogen from the patient) is the active agent of Coley's toxins. This hypothesis is supported by the fact that streptokinase has been associated with successful treatment of thromboangiitis obliterans.
Anti-angiogenesis
In addition to the mechanisms above, Coley's toxins might be antiangiogenic – suppressing the formation of new blood vessels which are vital to the growth of tumors., however, angiogenesis is not a biochemical cause by itself but needs external triggers.Dendritic cells
A robust fever, which occurs in response to Coley fluid, generates inflammatory factors with co-stimulatory activity, which activate resting dendritic cellDendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
s (DC), leading to the activation of anergic T cells, maybe accomplished by a second process, where a possible physical damage of cancer cells leads to a sudden supply of cancer antigens to DC.,
PAMP
Recently (2008), an immunological explanation binding together immunological data with findings about spontaneous regression and epidemiological data indicating a lowered risk to develop cancer later after common infections, has been published. According to this hypothesis, pathogenic substances produced by bacteria, viruses, infectious fungi and other pathogens, but not human tissue, called 'pathogen associated molecular pattern' (PAMP) lead to activation and maturation of tumor-antigen loaded dendritic cells. One PAMP thought to play a major role is the unmethlyated CpG motifCpG Oligodeoxynucleotide
CpG oligodeoxynucleotides are short single-stranded synthetic DNA molecules that contain a cytosine "C" followed by a guanine "G". The "p" refers to the phosphodiester backbone of DNA, however some ODN have a modified phosphorothioate backbone. When these CpG motifs are unmethlyated, they act as...
found in bacterial DNA. The CpG motif is recognized by toll like receptor 9 (TLR9
TLR9
Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene. TLR9 has also been designated as CD289 .- Function :...
) and can induce a strong TH1
T helper cell
T helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...
response.
Availability
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 PfizerPfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
in January 2008. In addition, the Waisbren Clinic in Wisconsin reports they have used Coley's toxin to treat patients since 1972. Coley's toxins are generally not available where approval or licence is required (in particular in the United States and Germany).
Drug makers including Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
and Sanofi-Aventis
Sanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...
are interested in modern versions of Coley's toxins; Pfizer has acquired the Coley Pharmaceutical Group, set up in 1997
Germany
Some specialized medical doctors in Germany apply Coley's toxins to patients. They can do so legally because, in Germany, unapproved medications may be produced, although they may not be sold or given away. Physicians can go to special laboratories and produce Coley's toxins there using their own hands. Coley's toxins may still be applied by a licensed medical doctor, because in Germany there is "Therapiefreiheit" ("therapy freedomTherapy freedom
Therapy freedom is the freedom of a physician to apply whichever therapy he or she believes to be appropriate, considering all his or her medical knowledge...
"), the legal right to apply whichever therapy a physician considers to be appropriate in the light of their medical knowledge. For example, Dr Josef Issels
Josef Issels
Josef M. Issels was a German physician known for promoting an alternative cancer therapy regimen, the Issels treatment. He claimed to cure cancer patients who had been declared incurable by conventional cancer treatments...
used several unconventional and controversial treatments, including Coley's toxins, for cancer patients in the second half of the 20th century.
This kind of therapy is offered as "Fiebertherapie" (fever therapy). Hyperthermia therapy
Hyperthermia therapy
Hyperthermia therapy is a type of medical treatment in which body tissue is exposed to slightly higher temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anti-cancer drugs...
or thermotherapy is not the same type of treatment, although sometimes incorrectly called "fever therapy".
Name
There are several names for Coley's toxins or Coley's vaccine. The reason may lie in the difficulty of classifying such a substance under the view of the established medicine:- Coley's vaccine is not a vaccineVaccineA vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
in the usual sense, namely that it prevents an infection. Rather than that, it triggers infection-like reactions. However, Coley's vaccine may work like many ordinary vaccineVaccineA vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
s: it induces an immune response, in this case against the cancer. In this sense, it predates current attempts to develop cancer vaccineCancer vaccineThe term cancer vaccine refers to a vaccine that either prevents infections with cancer-causing viruses, treats existing cancer or prevents the development of cancer in certain high risk individuals...
s. - The term toxinToxinA toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...
is applied as Coley's toxins contain both endotoxinEndotoxinEndotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
s and exotoxinExotoxinAn exotoxin is a toxin excreted by a microorganism, like bacteria, fungi, algae, and protozoa. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host...
s.
Politics
According to an article in the Iowa Orthopedic Journal, Coley's toxins were opposed by the medical establishment despite his reports of good results, because his reports were not believed to be credible.Companies
Scientific reviews
- Coley toxins, from the American Cancer SocietyAmerican Cancer SocietyThe American Cancer Society is the "nationwide community-based voluntary health organization" dedicated, in their own words, "to eliminating cancer as a major health problem by preventing cancer, saving lives, and diminishing suffering from cancer, through research, education, advocacy, and...
- Coley Toxins, from the M. D. Anderson Cancer Center