Coley's toxins

Coley's toxins (also called Coley's toxin,^[1] Coley's vaccine,^[2] Coley vaccine, Coley's fluid or mixed bacterial vaccine) is a mixture consisting of killed bacteria of species Streptococcus pyogenes and Serratia marcescens, named after William Coley, a surgical oncologist at the Hospital for Special Surgery who developed the mixture in the late 19th century as a treatment for cancer.^[3]

History

Bacterial immunotherapy for the treatment of cancer has been utilized throughout history, with the earliest report in 2600 BC, by Egyptian pharaoh Imhotep who had a poultice, followed by incision, to facilitate the development of infection in the desired location and cause regression of the tumour. In 13th century, St. Peregrine experienced spontaneous regression of tumor, after the tumor became infected. In the 18th and 19th centuries, deliberate infection of tumors were a standard treatment, where surgical wounds were left open to facilitate the development of infection. Throughout the time period, physicians reported successful treatment of cancer by exposing the tumor to infection including the report of French physician Dussosoy who covered an ulcerated breast carcinoma with gangrenous discharge soaked clothe, resulting in disappearance of tumor.^[4][5][6] Observations of a relationship between infection and cancer regression date back to at least the 18th century.^[7][8][9] More specifically, observations of an apparent relationship between erysipelas and remission of cancer predate Coley.^[10] For example, Anton Chekhov, in his capacity as a physician, recorded such a relationship in 1884.^[11]

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.^[12][13]

Frustrated by this case, Coley's subsequent research led him to announce evidence of the apparent relationship between infection and cancer regression, which he published in 1891.^[14] His initial attempts at deliberate infection were mixed,^[15] 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.^[16]

Coley published the results of his work as a case series, making it difficult to interpret them with confidence. According to the American Cancer Society, "more research would be needed to determine what benefit, if any, this therapy might have for people with cancer".^[17]

The so-called Coley's Toxins were used against different types of cancer from the year 1893^[18] 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 trials.^[19] Since then, several small clinical trials have been conducted with mixed results.^[20]

Coley's Toxins were also produced by the small German pharmaceutical company Südmedica^[21] and sold under the trade name Vaccineurin.^[22] However, production ceased by 1990 because of a lack of re-approval by German Federal Institute for Drugs and Medical Devices.

According to Cancer Research UK, "available scientific evidence does not currently support claims that Coley's toxins can treat or prevent cancer".^[23] People with cancer who take Coley's toxins alongside conventional cancer treatments, or who use it as a substitute for those treatments, risk seriously harming their health.^[23]

From 2009, research has been conducted in Australia and the United States which indicates the presence of an immune cycle.^[24]

Rationale

There are multiple rationales proposed for how Coley's toxins affect the patient.

Macrophages

One rationale argues that macrophages 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.^[7][25][26]

Tumor necrosis factor and interleukin

One of the agents in Coley's Toxin that is thought to be biologically active is a lipopolysaccharide which causes fever.^[27] 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.^[28]

Streptokinase

Another hypothesis argues that streptokinase (produced by bacteria of type "streptococcus" together with plasminogen from the patient) is the active agent of Coley's toxins.^[29][30] This hypothesis is supported by the fact that streptokinase has been associated with successful treatment of thromboangiitis obliterans.^[31]

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.,^[32] 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 cells (DC), leading to the activation of anergic T cells, possibly accomplished through a second process, where physical damage to cancer cells leads to a sudden supply of cancer antigens to the dendritic cell population.^[7][25]

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.^[33] 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 motif found in bacterial DNA. The CpG motif is recognized by toll like receptor 9 (TLR9) and can induce a strong TH1 response.

Availability

MBVax Bioscience, a Canadian Biotech company, produces Coley Fluid for research and clinical study.^[34][35] 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 Pfizer in January 2008.^[36] In addition, the Waisbren Clinic in Wisconsin reports they have used Coley's toxin to treat patients since 1972.^[37] 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;^[38] Pfizer has acquired the Coley Pharmaceutical Group, set up in 1997^[39]

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 freedom"), 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) or better "Aktive Fiebertherapie" (active fever therapy). This term was introduced by E. Göhring in 1985.^[40] Hyperthermia therapy 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 vaccine 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 vaccines: it induces an immune response, in this case against the cancer. In this sense, it predates current attempts to develop cancer vaccines.
• The term toxin is applied as Coley's toxins contain both endotoxins and exotoxins.

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.^[41]

See also

• Immunotherapy
• Cancer immunotherapy
• Cancer vaccine
• Immune cycle

References

External links

Hospitals

• Hospital for Special Surgery, William B. Coley, Surgeon-in-Chief, 1925-1933

Companies

• MBVax Bioscience Inc
• Coley Pharmaceutical Group

Scientific reviews

• Coley toxins, from the American Cancer Society