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).
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-positiveStreptococcus pyogenesand
gram-negativeSerratia marcescensbacteria (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 byHelen Coley Nauts & John R McLaren,
and a link to a scientific publication of ananimal 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.
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.
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:
Acute microbial infections
Heart and circulatory insufficiency
Condition after heart attack or pulmonary embolism
Cardiac arrhythmias, hypertension
Severe hepatic parenchymal disease
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)
Hemorrhagic diathesis (an unusual susceptibility to
bleeding)
Gastric or duodenal ulcers
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 Toxinclinical 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.
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 byStreptococcus 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
A severe and aggressive bout of erysipelas can induce dramatic and complete tumor remission.
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
It is quite difficult to intentionally induce a full erysipelas attack with Streptococci
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-negativeSerratia
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 myterms &
conditions.
Many clinics seem to be manufacturing their own.
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