Immunotherapy to cure cancer; perhaps a missed opportunity called Coley’s Toxin?

Why Coley's Toxin cure (Mixed Bacterial Vaccine) is not used in mainstream cancer care

As mentioned in one of my previous blog posts, this year 8 million people will die of cancer (see WHO World Cancer Report 2014). What if, approximately 40% of these people could attain a durable remission (no detectable cancer in your body) with a little known immunotherapy that cannot be patented?

Cancer immunotherapy: Coley's Toxin therapy diagram showing how 

primary tumor in metastatic cancer is injected with Mixed Bacterial 

Vaccine (MBV) and the percentage chance of durable remission
when a patient suffers from inoperable or end-stage colon cancer
(CRC) or terminal kidney / renal cancer.

The often heard claim "that for various plausible reasons of vested interests, politicians and lawmakers will not allow this treatment (immunotherapy) to be legally available", is treating the absence of this particular therapy superficially. It would be shortsighted to simply lay the blame at the feet of pharmaceutical companies, politicians, or well-intended rules and regulations that govern quality control of pharmaceutical products. 

So why is it not pro-actively pursued by the vast majority of oncologists, clinicians or physicians in mainstream medicine or currently terminally ill cancer patients, even though the American Cancer Society have taken this form of therapy off their quack list? 

There are several reasons:

The only countries where this form of cancer treatment is legally available are Germany, Japan, South Africa, China and Mexico (mainly through private clinics). As such, access to this form of therapy is severely restricted and limited to financially secure people that know about it. (If you represent a clinic that provides proper medical care alongside appropriately managed Coley Toxin therapy then please get in touch if you would like to have your contact details listed on this page). 

Cancer immunotherapy: 5-year survival of 896 Coley Toxin 

treated cancer patients with microscopically confirmed 

cancers - modified fromMonograph 18 by Helen Coley Nauts

Another issue relates to GMP certified manufacturing of this therapy and the import and distribution challenges faced in countries where this form of therapy is not legally allowed. For example, as a scientist with a background in immunology, cancer research and virology, I have the know how and capacity to physically produce large amounts of quality controlled and potent Coley’s Toxin in a standard P2 / P3 molecular biosafety level laboratory. Yet, because of strict laws, rules and regulations in relation to pharmaceutical drug manufacturing, I would not be allowed to supply this to anyone.

Initial estimates suggest that it would cost approximately 5 – 6 million USD or Euros to set up a facility that would be GMP certified and legally allowed to supply this product for use in clinical trials. 

However, a fundraising effort in Canada to set up such a GMP certified production facility failed to generate sufficient public interest. As such, it clearly shows a lack of public support for potentially lifesaving therapies that are not mainstream. Put another way, if every terminally ill cancer patient (that will die this year) donated less than a dollar (0.70 USD), they'd be funding the efforts of a small group of academics (e.g. in Germany) to make this potential cure available. 
Put another way; isn't it terribly shortsighted to solely blame the pharmaceutical industry for lack of treatment options and their unwillingness to invest in unpatentable technology, when patients themselves are unwilling to invest the equivalent of a Mars bar in saving their own skin? Pharmaceutical and / or biotech companies will not invest in Coley’s Toxin vaccine as they have no financial incentive to do so (this technology cannot be patented and as such profits for shareholders are likely to be non-existent). 

Interestingly, there are a growing number of clinicians / investigators (medical doctors that run clinical trials) in Europe and North America that would be eager to conduct a clinical trial with Coley’s Toxin. However, as long as there isn’t a reliable, regular, consistent supply of potent, quality controlled, GMP certified Coley’s Toxin, these clinical trials are unlikely to take place and as such the status quo of limited access to this therapy will be maintained. Hence, if you would like to see this therapy being made available to terminally ill cancer patients (at perhaps a low cost) then my advice would be to donate to those charities or academic institutions that are eager to support clinical trials with, or investigate molecular aspects of this therapy (e.g. a German research group led by Professor Bernd Kreikemeyer, based at the University of Rostock's medical faculty).  

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What is Coley’s Toxin?

Coley’s Toxin is also known as Coley Vaccine, Mixed Bacterial Vaccine, Coley Fluid (CF), Issel’s therapy, and active fever therapy.

For info about Biozantium by Paeon Laboratories:  http://www.biozantium.com

Coley’s toxin is a form of immunotherapy. In other words it is a method of treatment in which a person receives substances designed to boost the immune system and help the body fight off an illness such as cancer (which is why it is sometimes called a mixed bacterial vaccine). 

The use of Coley’s Toxins, as a therapy for treating cancer, essentially involves injecting the break down products of heat killed (and / or filter sterilised) bacterial cultures (Streptococcus pyogenes and Serratia marcescens (previously classified as B. prodigiosus) directly into your tumour, bloodstream, muscle or skin (sub cutaneously). Best results are likely to be obtained by injecting directly into or close to the tumour (if accessible) and by adhering to a schedule of 5 injections per week for the first 3 months. 

Many researchers around the world are looking into various types of immunotherapy (which includes promising pre-clinical research, as well as some early phase clinical trials). Investigations into attenuated Salmonella bacteria is an example of another type of immunotherapy to treat cancer. I will publish a blog post about this in the future (follow me @PvanUden on twitter to get notified on the day it is published). 

Coley’s Toxin was originally developed by a surgeon named Dr William Coley (which is why it bears his name). The treatment consisted of a mixture of gram-positive Streptococcus pyogenes and gram-negative Serratia marcescens bacteria (the two major classes of bacteria). Using this killed bacterial suspension, Dr Coley was able to mimic an infection (producing chills and fever) and in doing so, induce an immune response that targeted cancer cells for destruction, without incurring the risks of an actual infection.

T-cells target cancer cells for destruction as seen in this micrograph, where four 

T-cells (red) attack a cancer cell – Modified from  Dr Alice Roberts, “The Complete 

Human Body: The Definitive Visual Guide”

Some organisations state that immunotherapies that have been developed in more recent years are more effective. However, a comprehensive and detailed analysis of scientific and medical research publications demonstrates that properly administered and manufactured Coley’s Toxins used in the treatment of certain cancers actually achieves better and more durable results (long term durable remissions) than many other therapies currently available, including chemotherapy, radiation, and targeted therapies. As such, the following link to a review of 20th century clinical use by Helen Coley Nauts & John R McLaren, and a link to a scientific publication of an animal study by Donnelly, Havas and Groesbeck) may be of interest. Although Coley’s Toxin is still recommended and administered by some physicians, most mainstream oncologists look upon Dr William Coley’s therapy as the starting point or foundation of modern cancer immunotherapy while unfortunately not appreciating its true value in the treatment of current end-stage cancer patients.

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How does Coley's Toxin / Mixed Bacterial Vaccine (MBV) work?

Recent advances in the field of immunology would suggest that injection of Coley’s Mixed Toxins, facilitate the ”perfect storm” of Toll Like Receptors (TLR) and other Pathogen Recognition Receptors (PRRs) agonists, which mobilise the forces of both the innate and adaptive immunity in cancer patients. These PRRs are proteins expressed by cells of the innate immune system to identify Pathogen-Associated Molecular Patterns (PAMPs), which are associated with microbial pathogens or cellular stress, as well as Damage-Associated Molecular Patterns (DAMPs), which are associated with cell components released during cell damage (e.g. debris from a tumour as a result of necrosis). These PAMPs can be thought of as red flags or danger signals. Nevertheless, the precise mechanism of Coley’s toxin remains to be elucidated and characterised, despite recent efforts and increased interest in immunology research.

The fact is Coley’s Vaccine contains such a myriad of PRR stimuli, some of which are quite possibly unknown at this time, which makes it difficult to provide an all encompassing explanation of how it orchestrates these durable remissions. However, what we do know is that the vaccine contains some of the most potent immune-regulatory substances, including lipopolysaccharides (LPS), exotoxins (superantigens), enzymes such as streptokinase, as well as an unimaginable amount of other bacterial antigens (PRR agonists). Some of these molecules have been analysed and studied in detail in an effort to characterise, purify, and patent them with a view to create a drug that consists of one purified component for use in mainstream cancer therapies. Examples of such compounds include LPS, and unmethylated CpG bacterial DNA as well as signaling molecules that are part of the elicited host immune response following Coley’s Toxin treatment. Examples of such signaling molecules or chemokines include Tumour Necrosis Factor (TNF), Interleukin-2 (IL-2), Interferon (IFN), etc…. Nonetheless, it would be wishful thinking to expect these single entities (or even a handful of these purified molecules), to have a refined effect on the immune system and instill a lasting tumour response. It’s like using a sledgehammer to unwrap a piece of candy; it will create a lot of mess and it is unlikely to result in the desired outcome (durable remission). Given that many of these modern standalone immunotherapies are based on the products of bacterial antigens, it is not surprising that Coley’s Toxin therapy contains some of the same immune mediators that comprise today’s stand-alone immunotherapies. Nevertheless, the elegance and beauty of Coley’s cure lies in the fact that it exploits all these immunoadjuvants (and a vast array of many other bacterial components) in concert and within the spatial, temporal, and sequential format that is optimised for recognition by the patient’s immune system.

Furthermore, it is thought that the inflammatory cascade induced by the immunoadjuvants, contained in Coley’s Toxin, attracts large numbers of leucocytes to the tumour, leading to white blood cell mediated damage of host tissues. This is known to cause the release of TLR ligands such as Heat Shock Proteins and hyaluronic acid, thereby generating additional inflammatory cascades that result in further leucocyte infiltration and additional dendritic cell chemo attraction. The result of such a positive feedback loop is likely to cause CD4+ T-cell priming and the release of additional inflammatory mediators that will further enhance a cytotoxic response to the tumour.

In addition, it has been found that solid tumors are not just a homogeneous mass of one type of mutant cell. Instead tumours often show a high degree of leukocyte infiltration and a heterogeneous mixture of other cells. Even micrometastasis contain infiltrating leukocytes. These Tumor-Infiltrating Leukocytes (TILs) consist of varying proportions of neutrophils, macrophages, T cells (CD4+ and cytotoxic CD8+), B cells, and natural killer (NK) cells. During expansion and growth of tumours, cytokines are released that signal an increased need for oxygen and nutrients. It is thought that leukocytes, which are also involved in tissue repair, are attracted to malignant lesions because of the presence of these signaling molecules or chemokines, and as such assume roles in repairing and expanding the vascular network as well as stimulating tumour growth. Also, recent evidence supports the notion that tumors grow with the assistance, rather than the antagonism, of the immune system. Hence, treatment with Coley's Toxin is designed to reactivate the defensive activities of these TILs and essentially re-programme these tumour associated immune cells.

In summary, the immunotherapy called Coley’s Toxin is essentially re-programming and boosting your immune system and as such orchestrates the attack on cancer cells using the incredible capacity of your own immune system to target and destroy tumours.

Some more recently developed cancer therapies also work by stimulating the immune system (e.g. at the end of 2013 the FDA approved such a new treatment in the USA for glioblastoma (common agressive form of brain cancer)) and I intend to discuss a selection of these in a future blog post (please follow me @PvanUden on twitter to get notified when I publish these items).

The above outline of how Coley’s Toxin works at a molecular level also provides a reasonable explanation for Dr Coley’s observation and advise that the Coley Vaccine is most effective when administered daily, combined with a repeatedly induced fever, and that the treatment should be continued (at less frequent intervals) well past clinical regression to prevent recurrence. This all makes sense in light of the danger model and the way the immune system is educated through continuous exposure.  

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What to expect during Coley’s Toxin therapy?

Briefly, you should expect to have Coley’s toxins injections either directly into the tumour or into a vein. For optimal effect these should be administered 5 times per week. You should also expect to develop a high temperature of approximately 41°C (104 – 105 degrees Fahrenheit). The initial therapy often takes 3 months followed by a less intensive schedule of 2 - 3 times per week injections for another 6 – 12 months (to reduce the chance of recurrence (cancer coming back)).

Before any therapy is initiated, the physician treating you at the clinic where you receive treatment should conduct a thorough and careful examination to exclude contraindications (i.e. health and safety reasons for not providing this treatment to you).

Contraindications include:

1. Acute microbial infections
2. Heart and circulatory insufficiency
3. Condition after heart attack or pulmonary embolism
4. Cardiac arrhythmias, hypertension
5. Severe hepatic parenchymal disease
6. Adrenal insufficiency (a condition in which the adrenal glands do not produce adequate amounts of cortisol or aldosterone, which regulates sodium conservation, potassium secretion, and water retention)
7. Hemorrhagic diathesis (an unusual susceptibility to bleeding)
8. Gastric or duodenal ulcers
9. Pregnancy

Once you have had an injection it will take approximately 45 to 60 minutes before you experience a chill followed by shaking and a temperature rise that fluctuates (different degrees). These are similar to flue-like symptoms. Temperatures up to 41.7 °C can be reached, but are rare, typically the core temperature (measured rectally) oscillates between 39°C and 40°C (approximately 103° to 105° Fahrenheit), and then gradually goes down to a normal temperature of 37°C after two to three hours (in some cases this may take 6 hours and may still be slightly increased the next day). Vital signs (blood pressure, heart rate, respiratory rate, temperature) should be closely monitored by professional and qualified medical staff.

Some people will also experience nausea, headaches and joint pain (similar to aches and pains experienced during flue). Medications can be taken to relieve those symptoms.

The literature indicates that Coley’s Vaccine has a long and safe history of use. In addition, patients indicate that they experience an improvement in well being after each treatment (including less pain, increased appetite and mobility).

What are the side effects of Coley’s Toxin therapy?

Common side effects that are mild include: head, back or joint pain, nausea, vomiting (this can often be prevented by not eating a few hours before injection), chills, diarrhea, circulatory problems by hypotension, lip and acrocyanosis (blue or cyanotic discoloration of the extremities, occurring in the hands, feet and distal parts of the face (which is transient)).

Rare side effects that require, immediate medical care and treatment include: cardiovascular problems, thrombosis, pulmonary embolism, allergic reactions.

Women who are pregnant or breastfeeding should not use this form of therapy. Also it is very important to let your doctors know if you are thinking of using this type of therapy.

Scientific, and Medical / Clinical evidence for Coley’s Toxin efficacy? 

Scientific evidence suggests Coley toxins or other mixed bacterial vaccines have a role to play in the treatment of end stage cancer patients.

Dr William Coley reported his results as case series (a commonly accepted method of reporting of clinical studies in the earlier part of the twentieth century). You should also keep in mind that up to 15 different preparations of MBV existed at that time, and not all were potent enough to induce high fever and durable remissions (especially the commercially available preparations that were administered by physicians not based in New York). For example, there was one reported case in which Dr Coley was contacted by a colleague who had treated a patient with high doses of a commercial product without being able to elicit any response. However, when this physician used vaccine supplied by Dr Coley (i.e. made by a scientist (called Martha Tracy) in the hospital laboratory), the patient responded immediately to the injection with high fever, chills, and subsequent tumor remission. This patient was disease-free until he died of heart disease 33 years later (see publication by Helen Coley Nauts in 1975).

Although, small studies have been performed subsequently MBV treatment was applied less aggressively, and the vaccines were made less potent (as per oral communication, by H. Coley-Nauts in December 1996). Moreover, it is important to realise that patients, participating in these subsequent studies, were often pre-treated with chemotherapy and / or radiotherapy, which significantly alters a patients’ immune system and as such modifies the response to immunotherapy (often in a negative manner).

In a small clinical trial conducted by Johnston and colleagues into which 34 patients were enrolled, 7 MBV-treated patients with advanced metastatic cancer showed a subjective response while 9 patients were recorded with objective responses (3 of these participants achieved a complete remissions. In contrast, the control group of 37 patients (who were administered typhoid vaccines), only 1 improvement was reported (Johnston et al., 1962). I.e. 47% of patients that received Coley’s Toxin observed either a subjective or objective response, while in the control group less than 3% of patients observed a response.

In another small trial conducted by Kempin and colleagues in 1983, patients with advanced non-Hodgkin's lymphoma who were supplemented with mixed bacterial vaccine (MBV) in addition to chemotherapy showed a much higher response rate than control patients without MBV (complete remissions 85% vs 44%, respectively). Importantly, survival in the MBV arm of the study was significantly longer.

Results of a Chinese study of patients with advanced liver cancer, which was published in 1991, reported a significant benefit for patients with inoperable advanced liver cancer.

A number of other studies on MBV have unfortunately mainly been concerned with immunomodulation (e.g. cytokine induction) and tolerability. A recent example of such a study published in the American Association for Cancer Research journal called Clinical Cancer Research describes a German phase I Coley’s Toxin clinical trial conducted in 2012 by Karbach and colleagues.

However, the participants in this study only received a maximum of 8 injections (with the exception of one patient (patient 11)). These injections were administered subcutaneously (under the skin) instead of intratumorally or intravenously. In addition, these injections were only administered 2 x per week, while temperature increases were not allowed to go beyond 39.5 degrees Celsius (if a dose elicited a higher temperature the participant would get a lower dose subsequently). 

In summary, this phase I clinical trial study was severely limited. 

Interestingly, patient 11 (the participant that received an additional 16 injections following a request for extended use on compassionate grounds), is the only one to have observed objective regression of metastatic cancer (as per CT scans and CEA blood level measurements). In addition, 50% of cancer patients that participated in this study experienced a significantly better survival time than the average survival time for their disease despite the severely limited dosing schedule.

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History of Coley’s Toxin 

Coley’s toxins treatment was developed by a bone surgeon called Dr William Coley in New York City at Memorial Hospital in New York City (now Memorial Sloan-Kettering Cancer Center).

Dr William Coley and vials of Mixed 

Bacterial Vaccines

He embarked on his search for a cure to cancer after his first attempt to save a 17 year-old girl from bone cancer failed. This failed attempt had such an impact on Dr. Coley that he began reviewing bone cancer cases. During his review of cancer cases stored in the archives of Memorial Hospital he observed that cancer patients in whom bacterial infections developed after surgery had better chances of survival than those that did not. 

In one of his searches he came across the record of a 31-year-old male patient (Fred Stein) a German immigrant, who had suffered from a recurrent sarcoma of the neck which was considered inoperable. Mr Stein had contracted a severe erysipelas infection (which was caused by Streptococcus pyogenes) following a failed final surgical attempt. The infection had rapidly spread across his neck and face and was accompanied by a high fever. Within two weeks he had suffered from a second attack. Interestingly, during these attacks, his cancer had disappeared entirely. 

It was seven years later when Dr Coley came across this medical record of Mr Stein and was able to track him down. Mr Stein still enjoyed good health and had only a scar below his ear to remind him of where the sarcoma had been. 

To cut a long story short, throughout the development of Coley’s vaccine a number of lessons were learned. For example

1. A severe and aggressive bout of erysipelas can induce dramatic and complete tumor remission. 
2. An injection of live Streptococcus pyogenes without a full erysipelas can improve the disease and induce some tumor shrinkage but does not lead to complete, durable tumor remission
3. It is quite difficult to intentionally induce a full erysipelas attack with Streptococci
4. Erysipelas is a severe, life-threatening disease.

These difficulties led Dr Coley to the use of sterilized / heat killed bacterial preparations. Unfortunately they had little effect. However, Rogers who was involved in experimental research with bacterial vaccines, mixed his vaccines with toxins of gram-negative Serratia marcescens (i.e. a mixed bacterial vaccine (MBV)) and observed encouraging results. This led Dr Coley to the use of what is now known as Coley’s Toxin. The first patient who was treated with this mixed bacterial vaccine was a 16 year-old with an inoperable spindle cell sarcoma located growing within the abdominal wall, with approximate tumor dimensions of 6.5 × 5.25 × 5 inches. This tumor was also attached to the pelvis and was infiltrating the bladder. Needless to say, the patient was in a bad condition when the MBV treatment was started. The intratumoral injections were followed by a temperature rise, with tachycardia, chill, extreme trembling, and severe headaches. Throughout the boys treatment, the tumor reacted by becoming enlarged on the days following the injection. However, it gradually decreased over the next months and finally disappeared. He regained a good condition and stayed healthy without a recurrence, until he suddenly died of heart attack 26 years later in a subway station. 

Dr Coley published many papers in leading scientific journals based on over a thousand cancer patients that were treated with his mixed bacterial vaccine. Complete details of all the patients that he treated are in these medical journals and can be found at the Yale archive. 

As mentioned earlier, Dr Coley published his research in the format of case reports. Luckily, his daughter Helen Coley Nauts took it upon herself to go through her father’s notebooks and followed up many of the patients that had been treated by Dr Coley as well as patients that had been treated by other physicians using Coley’s Toxin. As such, the long term survival times of these patients were established. 

All this data was published in a series of monographs by the Cancer Research Institute between 1953 and 1979. In other words these cases have been properly analysed and are remarkably accurately documented. 

There have been over 20 formulations of Coley Fluid that have been used since Dr Coley developed the original formulation (together with colleagues such as Buxton and Tracy). Unfortunately, these have varied in efficacy quite considerably. While Dr Coley treated his patients with mixed bacterial vaccines that were made in the hospital laboratory, the commercial versions of Coley Fluid were manufactured in the UK by the Lister Institute and in the USA by Parke Davis. Research suggests that these commercial versions were considerably less effective than the version made for Dr Coley. 

An analysis of 137 inoperable sarcomas showed that the 5 year survival rate was 32% (using the Parke Davis vaccine). Parke Davis was by far the most widely used vaccine. Nevertheless, the 5 year survival rate, using the vaccine made by Martha Tracy (scientist) for Dr Coley was 67%. 

To put this in perspective: In 2013, the 5 year survival rate in the UK of end stage sarcoma (bone cancer) that has metastasised, was approximately 10% (30% in the case of Ewings sarcoma). So the less potent Parke Davis vaccine was probably more effective than current modern therapy for end stage sarcoma, while the vaccine made for Dr Coley (by Martha Tracy) was even more effective. 

Dr. Coley's daughter, Helen Coley Nauts, published several papers documenting her father's results. She also founded the Cancer Research Institute in New York in 1953, which continues to study how immunology can help diagnose and treat cancer. 

Dr. Coley has since been credited with pioneering the field of cancer immunotherapy.

Is Coley’s Toxin available now and where can you get it?

Coley’s toxins treatment is not available as a standard treatment in most countries with the exception of Germany, Japan, South Africa, Mexico and China. Given that all recent manufacturers of Coley’s Toxin have ceased production (the last known manufacturer (MBVax in Canada) stopped production in 2012), it is unclear where these clinics are currently obtaining their Coley’s Toxin.

Please note: Any medical or scientific information published on this website is not intended as a substitute for informed medical advice from a physician and you should not take any action before consulting with a health care professional. For more information, please read my terms & conditions.

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