Coley's Toxins

Coley's Toxins (also called Coley's toxin,^[1] Coley's vaccine^[2], Coley vaccine or Mixed Bacterial Vaccine) is a mixture consisting of killed bacteria of species Streptococcus pyogenes as well as Serratia marcescens,^[3] named after Dr. William Coley, who discovered Coley's Toxins.^[4]

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History

The relationship between infection and cancer regression dates back to at least the 1700s.^[5] More specifically, observations of an apparent relationship between erysipelas and remission of cancer predate Coley,^[6] and was the source of much interest in Europe. For example, Anton Chekhov (in his capacity as a physician) made a record of such a relationship in 1884.^[7]

Coley was apparently unaware of this line of inquiry. His interest in cancer was heightened after observing the death of one of his first patients, Elizabeth Dashiell, from sarcoma. (She was a close childhood friend of John D. Rockefeller, Jr., who later indicated that her death was what first motivated his subsequent work in funding cancer research.)^[8][9]

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.^[10][11] His initial attempts at deliberate infection were mixed,^[12] but in 1893 he began combining Streptococcus pyogenes and Serratia marcescens, based upon research from GH Roger indicating that this combination led to greater virulence.^[13]

Coley's Toxins were used against different types of cancer from the year 1893^[14][15] to the year 1963. In the wake of the thalidomide controversy and the Kefauver Harris Amendment, in 1963, Coley's Toxins were assigned "new drug" status by the Food and Drug Administration (FDA), making it illegal in the U.S. to prescribe this kind of therapy outside of clinical trials.^[16] However, as Coley's Toxins are known and thus not patentable, no clinical trials have been financed since then. The illegalization of Coley's Toxins in the United States has led to a loss of unwritten knowledge of how to exactly create and apply Coley's Toxins. From 1923 on, Parke-Davis was the only source of Coley's Toxins in the United States. However, the Parke-Davis version was much less concentrated than Coley's Toxins mixtures formerly produced by others and thus had to be applied at much higher dose to provoke any effect.^[17]

Coley's Toxins were also produced by the small German pharmaceutical company Südmedica^[18] and was sold under the trade name Vaccineurin.^[19] However, production was ceased by the year 1990 because of a lack of a commission pursuing the re-approval by German authorities. (Coley's Toxins were automatically approved in Germany as a "known drug" up to the year 1990, when re-approval was required for every such drug.)^{[citation needed]}

Coley's Toxins have been subject of about 500 scientific papers.^{[citation needed]}

Some effective treatment against thromboangiitis obliterans as well as osteoarthritis is also reported.^{[citation needed]}

Usage

Coley's Toxins are injected into affected tissue. After an injection, high fever usually develops, but this is intended. The cancer tissue may become necrotic, which then must be removed by drains. The injections are repeated usually after every 2 days.^{[citation needed]} Doses may be increased to compensate for the reticuloendothelial system's increasing capacity to clear the contents of Coley's Toxins.

Newer experiments with Coley's Toxins suggest that Coley's Toxins should be injected into veins rather than into muscle or tumor tissues for greater efficacy. If the reactions are too severe (like heart rate higher than 140 beats per minute or body temperature higher than 40 °C), paracetamol should be given to terminate the reaction.^{[citation needed]}

In many cases, major improvement can be recognized, up to cases where no signs of disease can be found any more.^{[citation needed]}

A 1992 paper suggested that Coley's toxins may be most effective in treating tumors derived from mesoderm.^[20]

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. (However, as the Coley's Toxins consist only of killed bacteria, there is no active infection. This makes Coley's Toxins much safer than a real 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.^[21] Thus, usually, fever induced by treatment with Coley's Toxins should not be treated (e.g. using antipyretics) unless really necessary (for example, if the fever is higher than expected). Rather than that, one should simply wait for the fever to fall.

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.^[22] 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.^[23]

streptokinase

Another rationale argues that streptokinase (produced by bacteria of type "streptococcus" together with plasminogen from the patient) is the active agent of Coley's Toxins.^[24][25] This hypothesis is supported by the fact that streptokinase has been associated with successful treatment of thromboangiitis obliterans.^[26]

fever and starvation

A third rationale from Joseph Thuo argues that high fever together makes the body cells have a higher metabolic rate.^[27] In this condition, the theory proposes, the cancer cells are much more susceptible to a drop of glucose supply than normal cells. Normal cells can consume fatty acids or ketonie bodies (reaction products of fatty acids) for their energy needs much better than cancer cells, the theory proposes. Thus starvation is selectively applied just to cancer cells, but not to other normal body cells.

anti-angiogenesis

In addition to the mechanisms above, Coley's Toxins might be antiangiogenic - suppressing the formation of new blood vessels which are (literally) vital to the growth of tumors.^[28]

Availability

MBVax Bioscience, a Canadian Biotech company, produces Coley Fluid for research and clinical study.^[29][30] A private biotech company, Coley Pharmaceutical Group, has conducted clinical trials using genetic sequences which may have contributed to Coley's Toxin's effectiveness.^{[citation needed]} In addition, the Waisbren Clinic in Wisconsin reports they have used Coley's Toxin to treat patients since 1972.^[31] Coley's Toxins are generally not available where approval or licence is required. (In particular, this is the case at least in the United States as well as in Germany.)

Germany

However, there are some specialized medical doctors at least in Germany, who still apply Coley's Toxins to patients. They can do so legally, because in Germany, unapproved medications may not be given away (or sold), but they may still be produced. Thus, these medical doctors 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 the "Therapiefreiheit" ("therapy freedom"), the legal right of a physician to apply whichever therapy he/she believes to be appropriate, considering all his/her medical knowledge.

This kind of therapy is offered as "Fiebertherapie" (fever therapy). However, a fever therapy using Coley's Toxins should not be confused with a "fever therapy" of Dr. Josef Issels or with hyperthermia or thermotherapy, sometimes (falsely) denominated as "fever therapy" as well.

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.
• Although Coley's Toxins contain both endotoxins and exotoxins, Coley's Toxins are not toxins in the usual sense, namely that they are used to cause death. Rather than that, Coley's Toxins are used to heal and they have - correctly applied - nearly no persistent negative impact.

References

See also

• Coley Fluid