Coley's Toxins - BRUTAL IMMUNOPTHERAPY

thuo hypothesis

Part 1: Introduction

This is a copy of an e-mail I received, with a hypothesis which deserves serious consideration.

Briefly, Coley's Toxins had a very good success rate of about 50%. While that is far, far higher than conventional chemotherapy (about 2.5%), it wasn't 100%. This doctor suggests a reason why.

Hello Barry Groves

Let me start of by introducing myself. My name is Joseph Thuo and I live in Nairobi, Kenya. I recently came across the work of Dr William Coley while researching on obsolete medical therapies. I find it very hard to believe that an effective therapy in the form of Coley's toxins has been ignored by most researchers for many decades. I think the main problem is the fact that many people consider it to be an immunological therapy. However the efforts of cancer immunologists have yet to solve the problem regarding the toxins' unpredictable efficacy. After going through some of the cases of spontaneous remission I have realized that the fever induced by the infectious agents should be the focus of any theory regarding this miraculous phenomenom. Since fever is a metabolic factor, other factors contributing to spontaneous regression should also be primarily metabolic. Anyway, to keep it short I have formulated a theory regarding spontaneous remission which also tries to explain selective efficacy of Coley's toxins.
Introduction

In medical terminology, spontaneous remission of cancer refers to the unexplained and sudden disappearance of all signs and symptoms of cancer. This rare and mysterious phenomenon has been observed physicians for several centuries. Many anecdotal cases have been recorded in modern medical literature.

A number of theories have been proposed to try and explain the obscure mechanisms responsible for spontaneous remission. The most popular theory postulates that the immune system causes spontaneous remission. Another theory suggests that hypothyroidism slows down the growth of cancerous cells. Other researchers think DNA modulation plays a key role in cancer remission. The truth is, no one has come up an undisputable scientific explanation for spontaneous remission of cancer.

Some people may ask why is it important to understand spontaneous remission? The main reason researchers should be interested in spontaneous remission is that it could pave the way for new and more effective therapies to treat cancers. It offers a solid basis of hope and firmly establishes nature's willingness to yield its secrets of cancer healing. Most cases of spontaneous remission are often preceded by acute febrile infections. There are many documented cases of cancer that underwent spontaneous regression after acute bacterial infections e.g. streptococcal or staphylococcal infections. A study carried out by Kleef et al for the office of Complementary and Alternative Medicine [NIH, Bethseda] concluded that the occurrence of fever in childhood protected against the later onset of malignant disease and that spontaneous remission is often preceded by febrile infections.

The incidence of spontaneous remission has been estimated to range from 1:60,000 to 1:100,000. Despite the existence of such an amazing natural phenomenon there is currently very little research focusing on spontaneous remission. The impression I get is that cancer researchers do not consider this topic serious enough to warrant a thorough and conclusive study.
Coley's toxins

One doctor who decided to take the phenomenon of spontaneous remission seriously was Dr. William B. Coley, an eminent New York surgeon. He spent most of his career working at Memorial Hospital [now Memorial Sloan-Keterring Center] He was convinced that there was a more effective way of treating cancer after witnessing the disappointing results of surgery; the standard treatment of solid tumors at the time. He started his search by going through all the records of sarcoma patients at the hospital. To his surprise he came across the case of a German immigrant that had undergone spontaneous remission, after the doctors treating him had declared his cancer terminal. This regression had occurred after a severe attack of erysipelas. Coley searched the east side of New York for the man and found him in apparently good health more than seven years after his "miraculous" healing.

Coley was inspired by this particular case and he decided to experiment with Streptococcus pyogenes the bacterial organism that causes erysipelas. His initial aim was to induce spontaneous remission after inoculating the patient with erysipelas. However, he later decided to use non infectious by products of Streptococcus to minimize the risk of death in his patients. He also discovered that by combining the products of Streptococcus pyogenes with those of Serratia marcesens he could produce a more potent vaccine. The classic Coley's toxins, was a mixed bacterial vaccine containing both endotoxins and exotoxins. Coley's toxins administered in adequate doses caused an acute immune reaction similar to that produced by an acute bacterial infection. The clinical symptoms observed in patients injected with the vaccine were fever, chills, rigors, joint pains and general malaise.

Coley and his colleagues in Europe and America treated thousands of cancer patients.

His daughter Helen Coley-Nauts collected his records and summarized the outcome of 900 microscopically confirmed cases. The five-year survival rate for this particular group of patients was found to be 50%. This proves that Coley's toxins achieved excellent clinical results that exceeded the efficacy of the current treatment modalities. Even staunch critics of the vaccine admitted that a number of hopeless cancer cases were completely cured by Coley's toxins.

However despite these achievements the use of Coley's toxins began to decline after his death in 1936. Eventually the Food and Drug Agency declared that Coley's toxins were ineffective in the treatment of cancer. As a result of the FDA's decision in 1963 it became illegal to use and produce the vaccine in America . This decision was primarily due to the fact that Coley's toxins produced very unpredictable clinical results in cancer patients. Despite the fact that hundreds of patients experienced complete remissions, the vast majority of patients with malignant disease did not respond at all to the toxins. Another factor that contributed to the demise of Coley's toxins is the lack of theoretical basis that could fully explain it's selective efficacy. Since no one knew how it worked no one could improve its efficacy. The discovery of "more effective" therapies in the form of radiotherapy and chemotherapy diverted human and financial resources. These new therapies produced more consistent clinical results and were easier to understand scientifically. Last and not least economic factors also helped to push Coley's toxins out of the list of mainstream medical treatments, into the twilight zone of alternative therapy. This was mainly due to the fact that the various components required to produce Coley's toxins were readily and cheaply available. Therefore most pharmaceutical companies decided to channel their resources into researching and manufacturing chemical compounds that could be patented. This led to the birth of the powerful multibillion dollar chemotherapy industry.

However despite the fact that use of Coley's toxins in cancer treatment is no longer considered to be an effective option, a small number of researchers are still fascinated by the dramatic results achieved in some patients. However one scientific fact that not disputable regarding the positive clinical benefits observed in some patients, is the presence of fever; i.e. the patients who had high fever had significantly higher rates of remission than those who had mild fever or no fever at all.
Current research

Research regarding Coley's toxins focused mainly on the immune system. Immunologists began with the assumption that one of the chemicals produced by the cells of the immune system during an acute immune reaction was responsible for the vaccines efficacy. The race to identify the "active" factor produced in response to Coley's toxins was on. Chemicals produced by the immune system cells to modulate its activity are known as cytokines. Numerous cytokines have been discovered since the 1950s. These include Interleukin-1[IL-1], IL-2, IL-6, IL-8, IL-12, Interferon gamma, macrophage colony stimulating factor and tumor necrosis factor. Some of these cytokines have marked anti-tumor activity, which has been clearly demonstrated in in-vitro studies as well as in laboratory animals. However clinical trials in humans using specific cytokines in combination with chemotherapy or as a monotherapy have produced disappointing results. These poor results have been obtained despite the fact that very high doses of cytokines have been used in these clinical trials when compared to the levels usually produced by the body's natural response. In recent years immunologists have redirected their efforts towards identifying specific antigens produced by malignant cells only. Some of these antigens, which provoke a limited immune response have been well characterized. However despite these promising laboratory studies a crucial clinical breakthrough in cancer vaccination is still missing. In other words the various immuno-therapeutic modalities in use today have not made a significant impact in the lives of most cancer patients. This has not surprised most immunologists since the primary function of the immune system is to protect the body from invasion by foreign organisms; i.e. infectious agents. It is therefore rather obvious that although Coley's toxins cause an immune reaction it is not the immune system that is responsible for the tumor regression. This has convinced another group of researchers to concentrate their efforts on the fever produced by the mixed bacterial vaccine. Scientists have discovered that high temperatures may help shrink tumors. The National Cancer Institute is currently undertaking studies to determine the efficacy of local, regional and whole body hyperthermia in cancer treatment. Local hyperthermia refers to heat application to a small area. This can be done using an implanted microwave antennae or externally using high frequency waves. Regional hyperthermia uses radio frequency waves to heat deeper tissues or limbs. Typically the area to be heated is surrounded by ring of radiating elements. Whole body hyperthermia requires the use of warm water blankets, inductive coils or thermal chambers. This method delivers the thermal energy to the entire body and is frequently used with other systemic therapies e.g. chemotherapy.

It seem as though researchers have completely forgotten the fact the Coley treated his patients with a simple mixed bacterial vaccine. I think that these two groups of researchers should take some time out and review Dr. Coley's seminal work.


Part 2: New hypothesis on spontaneous remission

Since fever has been clearly identified through epidemiological studies as an important factor in cancer remission, any theory regarding this phenomenon must take it into account. Fever is the oldest and most universally known hallmark of disease. It occurs not only in mammals but also in birds, reptiles, amphibians and fish. In acute infections fever, is induced by the toxins produced by bacteria. Endotoxins act on macrophages, monocytes and kupffer cells to produce interleukin-1. IL-1 enters the brain to act on the preoptic area of the hypothalamas. Activation of this area causes the body to raise its temperature set point and the temperature raising mechanisms are activated. The benefits of fever to the organism have not been fully determined. However since fever has persisted as a response to infections and other diseases during the course of evolution, it is presumed to be beneficial.

The main effect of fever on the body cells is an increase in their metabolic rates. It therefore seems logical to think of Coley's toxins as a metabolic therapy rather then an immuno-therapy. However, since fever alone did not result in 100% remission after administration of the toxins it seems reasonable to consider the possibility of another factor [or factors] playing a role in the remissions produced by Coley's toxins. Since fever is a metabolic factor, the search for other factors should start by focusing on any other peculiarities that affected the metabolism of the patients who responded well to the toxins. One factor that comes up again and again when reading the narratives of the cancer patients who responded dramatically to Coley's toxins is starvation. In my view the incidence of undernourishment appears to remarkably high in the anecdotal cases that are frequently touted as proof of the toxins. Indeed Coley's first patient had a sarcoma affecting his neck and tonsils. In fact it is said that the patient was in danger of dying from starvation. After several attempts, Coley succeeded in infecting him with a virulent strain of Streptococcus. He developed severe anorexia, vomiting and a high fever and his tumor began to shrink almost immediately. He went into remission for eight years after just one attack of erysipelas.

Another interesting case was that of a woman from Kentville , Nova Scotia . She was suffering from renal cell carcinoma with peritoneal metastases. The surgeon who operated on her felt that her case was utterly hopeless and he thought that she would not survive the trip back home. In Kentville, her doctor gave her what he thought was a lethal dose of the toxins to end her suffering. That dose caused an almost instant remission of her cancer. Six weeks and 18 intramuscular injections later she was free from all signs of cancer. The patient was traced forty years later still free from cancer.

Another case that points to the fact that excellent results were achieved by the accidental combination of starvation and fever occurred in Costa Rica . In 1902 a young woman with a rapidly growing tumor of the nasopharynx was injected with a high intravenous dose of the toxins. She developed a fever of 105 and all her tumors took on a purple hue. Huge amounts of necrotic tissues formed and they had to be removed with forceps to prevent asphyxia. Within 72 hours of that one injection one tumor the size of an orange was gone and another large tumor was reduced to the size of a small nut. The rapid onset of action in these and other cases clearly prove that the tumors could not have been destroyed by the immune system. The immune system is simply not capable of destroying billions of malignant cells within such a short period of time. What is even more illogical is to claim that the immune system can suddenly attack its own cells that had previously been thriving in the body, after administration of a mixed bacterial vaccine.

I have formulated a theory on spontaneous remission based on the facts mentioned above: the patients who have undergone spontaneous remission of cancer as well as the patients that underwent remission after administration of Coley's toxins did so as a direct result of inadvertently combining starvation with high fever.

Since the main physiological effect of starvation is the mobilization of fatty acids and the formation of ketone bodies by the liver, it is very likely that reduced consumption of glucose and increased utilization of fatty acids derivatives makes malignant cells very susceptible to the increased metabolic rate that occurs during fever.

Cancer researchers have long suspected that cancer cells are susceptible to certain chemical or physical conditions due to their genetic abnormalities. I propose that cancer cells can be killed selectively probably by stimulating apoptosis i.e. programmed cell death. This can be done by reducing glucose as a metabolic substrate and increasing the consumption of ketone bodies. This must then be followed by a sudden increase of the metabolic rate using fever or external thermal sources.

One interesting case that was not preceded by an acute infection has been reported in the current medical literature. This is the case of a patient who had a metastasized lung tumor who also developed myxedema coma. After he was treated for severe hypothyroidism his doctors noted that his lung tumor had undergone spontaneous regression. A novel paradigm was subsequently proposed; the thyroid gland aside from its known physiological activity is also the central modulator of solid neoplasia and therefore functions as an intrinsic biologic response modifier of neoplasia. The proponents of this new theory have carried out several clinical trials in which they induced clinically tolerable hypothyroidism in cancer patients. The results have not been as dramatic as the original case that inspired it.

Regarding this case and the proposed new paradigm I believe the doctors concerned made serious mistakes. First they only took into consideration one clinical aspect of the patient who underwent spontaneous remission i.e. the hypothyroidism. They failed to take into consideration the comatose state of the patient as well as the treatment he received. In other words they did not take into account the possibility that the starvation induced by the coma and the sudden increase in the metabolic rate stimulated by the thyroid hormones used to treat the myxedema coma could have contributed to the remission.

Another thing they failed to do was to compare their particular case of spontaneous remission with the more common cases of fever induced remissions. Had they done so, they would have observed an obvious similarity between these apparently different causes of cancer remission. The only similarity between this case and fever induced remission is and marked increase in the metabolic rate. Thyroid hormones increase the oxygen consumption of most metabolically active tissues in the body. The only exceptions are brain cells, the testis, uterus and lymphatic tissue. The magnitude depends on the metabolic rate prior to giving the hormone. The higher the metabolic rate before the hormone is given the lower the rise in metabolism. Similar changes occur in the rate of metabolism as a result of fever.

It would also be of interest to mention the fact that thyroid hormone is known to cause apoptosis of tadpole tail cells. Zoologists have also noted that that tadpoles tend to starve themselves during this particular phase of their development when they transform into frogs.

In summary I believe that this particular patient with lung cancer underwent spontaneous remission as a result of inadvertently combining the two metabolic factors mentioned above. The starvation induced by the coma and a high metabolic rate stimulated by the thyroid hormone.

The next course of action will involve scientific studies to validate my theory regarding spontaneous remission. This will involve large scale and comprehensive clinical and epidemiological studies.

Epidemiological studies will focus on the metabolic factors and their relationship with spontaneous remission. These retrospective studies will investigate the positive relationship between spontaneous remission of cancer on hand and the presence of both fever and starvation on the other hand. To avoid any controversies the remission cases to be studied should only be of microscopically confirmed cancer. The metabolic factors to be studied will be the presence of fever at least on one occasion as well as starvation prior to or during the febrile reaction. With regard to these metabolic factors both objective and subjective reporting should be accepted as valid. Clinical indicators of starvation include:

* Severe anorexia, especially in bed-ridden patients or those with high tumor loads.
* Recurrent bouts of vomiting e.g. tumors causing gastric or intestinal obstruction.
* The inability to ingest food e.g. in tumors of the palate, pharynx or esophagus.
* Severely debilitated or comatose patients.
* History of rapid weight loss.
* Major depression e.g. pancreatic tumors.

A similar retrospective, study of patients who responded to Coley's toxins needs to be carried out. The main aim of such a study will be to prove that the patients who responded to the treatment did so as a result of the fever induced in patients who were deprived of adequate nutrition. It will also show that those who had only one of these metabolic factors i.e. starvation or fever, did not respond as well as those with both fever and starvation occurring concurrently.

Clinical studies should also be carried out concurrently due to the fact that many cancer patients have already run out of options. Many of these patients who are currently receiving only palliative treatment will make good candidates for the clinical trials. The first step will involve a period of starvation ranging from 7 to 10 days. This period will allow for adequate mobilization of fatty acids and formation of ketone bodies. By the end of this period most non-neural tissues including cancer cells will be utilizing fatty acids and ketone bodies as their major sources of energy. Alternatively a ketogenic diet can be given to those patients who are unable to tolerate starvation or in those who are already undernourished. It may also be interesting to note at this point that some people have advocated for the use of insulin coma therapy as a treatment for cancer. I believe that the few cases of cancer remission that have been recorded as result of insulin therapy have occurred as a result of starvation combined with low-grade fevers. Insulin only augments the natural effect of starvation of lowering the blood sugar.

The second step in the clinical studies will involve suddenly increasing the metabolic rate of the malignant cells. Since most cancers are systemic diseases this will involve increasing the metabolic rate of the whole body. The three basic methods of causing a rapid and sustained increase in the metabolic rate include:

* Intravenous infusion of a mixed bacterial vaccine.
* Whole body hyperthermia using external devices.
* Intravenous thyroid hormone. [Tri-iodothyronine]

The first choice will involve the intravenous administration of a relatively high dose of a standardized mixed bacterial vaccine like Coley's toxins. The sole purpose of this infusion will be to stimulate the immune system cells to produce fever-inducing cytokines to enable the formation of an acute febrile response. High fevers lasting at least ten hours will probably be sufficient to achieve a measurable clinical response. Body temperature, blood pressure, and pulse rate should be closely monitored to enable clinicians to act rapidly in case of adverse reactions. The blood levels of glucose, fatty acids and ketones should also be measured to assess their overall and individual contribution to the efficacy of the treatment. Patients should be given appropriate information regarding the expected side effects. They should be informed that they will have to tolerate the side effects of fever since the analgesics commonly used to treat the generalized body pains tend to lower the fever which required for its direct therapeutic effect on cancer cells. Immediately after the treatment the patients should be assessed to determine the efficacy of the treatment. The final clinical protocol that will be formulated will make room for adjustments to cater for individual treatment. The patient's age, weight, sex, general health, tumor type, tumor size, tumor site and state of the immune system will have to be taken into account.

The second method of increasing the metabolic rate of previously starved cancer patients will involve the use of external heating devices. Since the devices and machines necessary for artificially increasing body temperature are already available in many leading research centers, this method can be quickly evaluated. This method of treatment will be particularly useful in cancers limited to specific organs or limbs.

The third method of increasing the metabolic rate will involve the use of thyroid hormones. The dose to be used should be as high as those used in the treatment of severe hypothyroidism. The only limitation will be the fact that some malignant cells may not respond to treatment because they may lack receptors for thyroid hormone.

Experiments to confirm the role of fever in boosting the immune response should also be carried out. I believe that some of the puzzling behavior observed in sick animals can now be understood. I believe that the reduced food appetite, lethargy and sleepiness observed in animals with acute infections, is a deliberate effort geared towards causing nutritional starvation. The main aim of this starvation is to reduce the glucose consumption of immune cell precursors and increase their use of fatty acid metabolites. This effect is then combined with the hypercatabolic state induced by the fever to stimulate the maturation of the immune cell precursors. Therefore it appears as though fever and anorexia, were invented by evolutionary forces to act primarily on immature immune cells. This activity is probably not confined to immature immune cells, since spontaneous remission proves it also acts other immature cells including undifferentiated malignant cells.

Finally many alternative cancer therapies in use today may have been inspired by actual cases of spontaneous remission caused by the combination of starvation and fever. The doctors who observed them may have considered other more obvious factors leading them to formulate erroneous theories on spontaneous regression. This may include the following:

1. Dr. Josef Issels; whole-body comprehensive immunotherapy.
2. Dr. M. Gerson; combined dietary regime.
3. Dr. Sam Chachoua; induced remission therapy.
4. Dr. Subgis Koroljow; insulin hypoglycemic therapy.
Part 4: Social and economic impact

The news of a real breakthrough in cancer treatment is going to be greeted with great joy and relief. Cancer is one of the most dreaded diseases in the world today. It is responsible for the deaths of millions of people worldwide. In the United States alone it kills 350,000 people annually. However once the general population realizes that the phenomenon of spontaneous remission of cancer has been occurring for hundreds of years they will be shocked by the fact that most cancer researchers had not given it the attention it deserves. The general public will also be informed of the incredible work of William Coley and how it was generally ignored despite some promising results. Most people will soon realize that this breakthrough should have occurred decades ago. Their jubilation will then be replaced anger. Anger due to the unnecessary pain and suffering endured by cancer patients as a result of the disease or the toxic treatments administered.

Most people will find it hard to believe that a treatment so simple could have eluded thousands of brilliant scientists working in the numerous cancer research institutes. But the fact of the matter is very few of these organizations are interested in researching spontaneous remission. Most of these organizations [especially those that are privately funded] have become like the pharmaceutical companies they depend on for financial support. They have become obsessed with the idea of discovering a new molecule that can treat various malignancies. This is mainly due to the perception that only novel molecules can be patented. Therefore most research being carried out today as far as new cancer treatments are concerned is geared towards potentially profitable new molecules. However publicly funded research institutes are supposed to approach cancer with a broader view. Such public institutes should seriously investigate alternative views of cancer treatment as well as apparently strange phenomenon as spontaneous regression. For example, does the National Cancer Institute have any theory regarding spontaneous remission? Does the NCI keep any statistics regarding spontaneous remission? These are the kind of questions that the NCI director might be asked, by a special congressional committee that will be investigating this issue in the near future.

The economic impact will be much more dramatic. The pharmaceutical companies specializing in cancer chemotherapies will be greatly affected by the losses that will definitely incur, as their products will certainly be declared obsolete. Drug regulatory agencies like the FDA will have no choice but to ban the use of most chemicals used in cancer therapy today.

Oncologists and cancer researchers will not be spared. Many researchers will find themselves jobless since most of their funding is obtained from pharmaceutical companies. Most individual donations will probably cease once the general public gets the perception that the war on cancer is finally over. Doctors involved in the diagnosis and treatment of cancer will notice a marked reduction in the demand for their services.
Summary

In conclusion, I believe that the metabolic therapies outlined above will form the basis of a new modality of cancer treatment. A new type of treatment that is exactly what health care providers and consumers had been hoping for, an effective and cheap method of eliminating cancer forever.

In future, the failure by cancer researchers to seriously study spontaneous remission will be regarded as the biggest error in the history of modern medicine. A mistake, that caused a lot of unnecessary suffering and loss of life.
Joseph Thuo — Medical Officer working for the Ministry of Health [ Kenya ].
References

1. Majid Ali
2. Kleef R, Jonas WB, Knogler W, Stenzinger W. Fever, cancer incidence and spontaneous remissions. Neuroimmodulation 2001;9:55-67.
3. Chang WY. Complete spontaneous regression of cancer; four case reports, review of literature, and discussion of possible mechanisms. Hawaii Med J. 2000 Oct;59(10):379-87.
4. Hall, Stephen S. A commotion in the blood: life death and the immune system. New York , Henry Holt, 1997.
5. Kluger MJ, Kozak W, Conn CA, et al. Role of fever in disease. Ann. N Y Acad Sci 1998;856: 224-33.
6. Hercbergs A, Leith JT. Spontaneous remission of metastatic lung cancer following myxedema coma. Journal of the National Cancer Institute. Vol 85(16)(pp 1342-1343),1993.
7. Hercbergs A. Spontaneous remission of cancer-a thyroid hormone phenomenon? Anticancer Res 1999 Nov-Dec;(6A):4839-44.

Last updated 28 August 2005


Coley's Toxins
From Wikipedia, the free encyclopedia

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 and Serratia marcescens, named after William Coley, a surgical oncologist who developed the mixture in the early 20th century as a treatment for cancer.[3]
History

Observations of a relationship between infection and cancer regression date back to at least the 1700s.[4],[5] More specifically, observations of an apparent relationship between erysipelas and remission of cancer predate Coley.[6] For example, Anton Chekhov, in his capacity as a physician, recorded such a relationship in 1884.[7]

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.[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 G.H. Roger indicating that this combination led to greater virulence.[13]

The so-called Coley's Toxins were used against different types of cancer from the year 1893[14] 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 1963, 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.[15] Since then, several small clinical trials have been conducted with mixed results.[16]

Coley's Toxins were also produced by the small German pharmaceutical company Südmedica[17] and sold under the trade name Vaccineurin.[18] However, production ceased by 1990 because of a lack of re-approval by German Federal Institute for Drugs and Medical Devices.
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.[4], [19][20]
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.[21] 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.[22]
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.[23][24] This hypothesis is supported by the fact that streptokinase has been associated with successful treatment of thromboangiitis obliterans.[25]
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.[26], 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, maybe accomplished by a second process, where a possible physical damage of cancer cells leads to a sudden supply of cancer antigens to DC. [4], [27]
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[28]. 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.[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, and was acquired by Pfizer in January 2008.[31] In addition, the Waisbren Clinic in Wisconsin reports they have used Coley's Toxin to treat patients since 1972.[32] 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 - i.e. used by Dr. Josef Issels with Vaccineurin - should not be confused with hyperthermia therapy 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.
* The term toxin is applied as Coley's Toxins contain both endotoxins and exotoxins.

Literature

* Uwe Hobohm: Healing Heat, 2009, ISBN 978-0-557-02885-6
* Uwe Hobohm: Harnessing Infection to Fight Cancer, American Scientist January-February 2009 [5]
* Jessica Marshall: Filthy healthy, New Scientist 12.Jan. 2008 [6]
* Hoption Cann SA, van Netten JP, van Netten C. (2003) "Dr William Coley and tumour regression: a place in history or in the future" Postgrad Med J 79 (938): 672–680 [7] [8] [9]
* Hoption Cann SA, van Netten JP, van Netten C, Glover DW. (2002) "Spontaneous regression: a hidden treasure buried in time" Medical Hypotheses 58 (2): 115-119 [10] [11] [12]
* Hoption Cann SA, Gunn HD, van Netten JP, van Netten C. (2004) "Spontaneous regression of pancreatic cancer" Case Rep Clin Pract Rev 293-296 [13] [14]
* Donald HM. (2003) "Coley" Spontaneous Regression: Cancer and the Immune System Philadelphia: Xlibris. [15]
* Moss RW. (1996) "The Treatment of Cancer with Coley's Toxins" The Cancer Chronicles 7 (3-4) [16]

References

1. ^ Thotathil Z, Jameson MB (2007). "Early experience with novel immunomodulators for cancer treatment". Expert opinion on investigational drugs 16 (9): 1391–403. doi:10.1517/13543784.16.9.1391. PMID 17714025.
2. ^ Taniguchi Y, Nishizawa T, Kouhchi C, et al. (2006). "Identification and characterization of lipopolysaccharide in acetic acid bacteria". Anticancer Res. 26 (6A): 3997–4002. PMID 17195448.
3. ^ Coley Toxins Detailed Scientific Review at mdanderson.org
4. ^ a b c Hobohm, U.: [1] Fever and cancer in perspective, Cancer Immunol Immunother 2001) 50: 391-396 DOI 10.1007/s002620100216
5. ^ Hoption Cann SA, van Netten JP, van Netten C, Glover DW (2002). "Spontaneous regression: a hidden treasure buried in time". Med. Hypotheses 58 (2): 115–9. doi:10.1054/mehy.2001.1469. PMID 11812185.
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http://en.wikipedia.org/wiki/Coley%27s_Toxins