Posted: October 17th, 2013
Coley’s Toxins are the invention of William B. Coley, a bone surgeon at a cancer hospital in New York, who developed a vaccine that he used in cancer treatment after he witnessed a patient of his succumb to sarcoma. The development of the vaccine, Coley’s Toxins, is well mapped out as well as its effectiveness in treating some of the cases that Coley and others handled (Nauts, 1953). The effectiveness of his treatments was critiqued by his peers. The advancement of other methods of cancer treatment like radiotherapy and subsequently chemotherapy continued to undermine the relevance of Coley’s Toxins. The outcome of Coley’s life work is the motivation it inspired to further research in the field of cancer immunotherapy.
Born in 1862, William B. Coley attended college at Yale before being admitted into Harvard Medical School in 1888. He was drawn into cancer treatment by a patient that was referred to him, Bessie Dashiell, who was suffering from bone cancer and eventually succumbed to it despite radical surgery. He trudged through hospital records trying to find cases that had different outcomes to his patient’s case and came across a case study of a patient Fred Stein. This German immigrant’s tumor disappeared after the fever from an erysipelas infection caused by the bacteria Streptococcus pyrogens. His interest sparked, Coley found this patient and verified that his cancer had gone into remission.
Coley knew that anecdotal theories that connected tumor remission with concurrent bacterial infections existed in antiquity. The renowned Egyptian physician Imhotep recommended the treatment of tumors (swellings) as the application of a cataplasm followed by an incision (Ebbell, 1937). Diedier reported in 1725 that patients suffering from syphilis developed few tumors, if any (Diedier, 1725). Sir James also mentioned the same (Hobohm, 2001). Coley did further research and stumbled into other medical pioneers such as Koch and Pastuer, who had made similar observations. He was convinced of this line of thought and decided to act on it.
In 1891, Coley made the courageous move to infect his patients intentionally with live Streptococcus pyrogens bacteria. The first patient to receive this treatment had throat cancer, and the erysipelas infection improved his condition. His findings related to similar ones made by a German physician W. Busch (Busch, 1867). The patient lived for additional eight and a half years without any further recurrence of metastases. Bolstered by his outcome, Coley continued to infect a further nine of his patients with erysipelas. He noted that the results were either an active immune response to the infection or a fatality due to the infection.
History is replete with examples of spontaneous regression of tumors after fever inducing infections. One such example is Peregrine Laziosi (1265-1345), the canon saint of cancer patients. He has a tumor on his tibia that was diagnosed malignant by the best physicians of his time (Pack, 1967). Just before his leg was amputated, the only option available to him, the lesion grew and broke through his skin becoming severely infected. This infection coincided with the spontaneous regression of the cancerous tumor. Such cases reported in literature (Coley, 1893) served to bolster Coley’s research and strengthened his belief in the methods he used, coupled with own findings (Coley, 1906).
Coley’s assessment of the responses was that the live Streptococcus bacteria produced erysipelas but, unfortunately, not on all the patients given the treatment. In some, the administration of the bacteria gave no response due to the patient forming immunity to the bacteria. In other instances, the patient would succumb to the bacterial infection because of his or her own immune system inadequacies (Coley, 1896). His second attempt involved the use of heat sterilized Steptococcus bacteria. The reason is that Coley needed to find a way to control the virulence of the bacteria Streptococcus pyrogens while still maintaining its purpose which was to produce a fever inducing infection but it did not provide the expected results.
He combined the use of the sterilized streptococcal bacteria with a second organism, Serratia marcescens, and this concoction is known as Coley’s Toxins. This proved successful in cancer treatment and documented the cases he had treated using this approach (Coley, 1914). Coley injected his preparation directly into the tumor or in the surrounding area in several doses. These treatment courses would last even for weeks but the outcome was positive. For years to come, physicians used Coley’s Toxins to treat inoperable cases with high success rates. A compiled review to these cases was published by Coley’s daughter, Helen Coley Nauts, where 896 cases were documented (Nauts, 1982).
In spite of Coley’s success rates and high profile as a bone surgeon, he came under great criticism due to various inconsistencies. These included, poorly-documented follow up that was also not well control casting doubts on the supposed success of these treatments; the number of different preparations of Coley’s Toxins and their associated efficiencies; the mode of administration varied from intravenous injections to injections directly in the tumor (McCarthy, 2006). This meant that not every doctor got the same results as Coley did.
The Journal of the American Medical Association (JAMA) issued a stern review of Coley’s Toxins. It held the view that the toxin was a complete failure as a remedy for sarcomas and carcinomas based on the toxins’ failure to produce satisfactory results when used by various oncologists. It disputed Coley’s reported findings ignoring the reports submitted by other physicians using the same regimen on their patients and showing favorable results (JAMA, 1894).
Cancer treatment was not a clearly understood process in the turn of the century, and naturally, some practitioners favored certain modes of treatment to others. Coley’s Toxins were not one of the better-understood treatments available. Furthermore, advances made in radiation therapy provided a better alternative since it was a more predictable regimen. The mode of action of Coley’s Toxins was not, and still is not well understood. This served to marginalize Coley’s Toxins even further despite the fact that some doctors were able to report the successful use of this regimen.
Coley’s Toxins faced further resistance after the establishment of the Bone Sarcoma Registry whose role was to standardize bone cancer therapeutics (McCarthy, 1995). It proved difficult to have some of Coley’s cases accepted by the registry because members of the registry believed that the toxins did not work or claimed that some of the successful cases were misdiagnosed. His work slowly fell out of favor, and the Park Davis Company halted production of Coley’s Toxins. By 1962, the U.S. Food and Drug Administration had accredited Coley’s Toxins as a “new drug” meaning it could no longer be used in cancer treatment (Hoption, 2003).
Although Coley’s ideas were no longer acceptable by most doctors to treat cancer, he continued to believe in his methods until the end of his career. Some doctors were willing to welcome the notion that the toxins may be beneficial after all. In fact, in 1934, JAMA changed its position and acceded that Coley’s Toxins might be valuable. It praised the ingenuity of the combined erysipelas and prodigious toxins (Coley’s Toxins) and retained them in New and Unofficial Remedies with an aim of promoting more research on the toxins (JAMA, 1934).
Additional acceptance of Coley’s research and treatment methods was brought about by his own children. Bradley Coley, an orthopaedic surgeon, succeeded Coley as the head of the Bone Tumor Service at his father’s former residency at Memorial Hospital in New York (now Memorial Sloan Kettering Cancer Center). Bradley published a textbook on bone tumors and reinforced Coley’s Toxins use as auxiliary treatment to prevent micro-metastasis (Coley, 1949). Helen Coley Nauts, a cancer researcher, dedicated her life to studying her father’s work, documenting his cases and publishing them (Coley-Nauts, 1990)
The mechanism of action of Coley’s Toxins has generated great interest leading to research with the aim of identifying the “active” ingredient of the toxins and their role in cancer regression. The increased understanding of the factors involved in an immune response led to suggestions that cytokines like tumor necrosis factor (TNF), interleukins (IL) and interferons played a significant role (Old, 1988; Oettgen,1990; Nethersell,1990). This, supported by the observations, made after treatment of superficial bladder cancer by bacillus Calmette-Guerin (BCG), a bacterial vaccine used in conventional therapy (Hoption, 2003).
A random clinical trial carried out in the late 1980s proposes the mode of action of Coley’s Toxins in the following way: interferons induce augmentation of natural killer cell activity, stimulation of lymphoid tissues, induction of serum factor that causes necrosis of tumors, activation of macrophages, as well as stimulation of interleukin-2. (Tang et al., 1991) Interleukin II, or IL-2, is a well-known conventional immunotherapy and Bacillus Calmette Guerin (BCG), another vaccine, is used in conventional immunotherapy for bladder cancers. (Zlotta et al., 1998).
Some proposals of the immune response elicited by the administration of Coley’s Toxins are that the cell-mediated immune (adaptive) response is the key moderator of cancer regression (Lucey, 1996) although animal studies involved infections that evoke a humoral immune response: aspergillus (Tzankov, 2001), malaria (Nauts, 1980), trichella (Molinari, 1979), and trypanosome (Cabral,2000). Besides, tumor regression occurred within a few hours of injection with Coley’s Toxins while adaptive immune response takes a few days to a week (Medzhitov, 2001). This supports the theory that the immune response elicited in the non-specific innate immune response.
Because of the immune stimulating nature, treatment with Coley’s Toxins induces other conventional regimens that cannot be used simultaneously. Radiotherapy and chemotherapy suppress the immune system, killing the cancerous cells in the process. Coley’s Toxins, on the other hand, trigger an immune response with the macrophages destroying the cancer. An increased vivacity of the immune system and enhancement of lymphocyte activity due to the biologically active lipopolysaccharide result in the high fevers, typical of Coley’s Toxins therapy. Tests conducted on mice showed that mixed bacterial toxins caused regression of tumors with 15% or less lethal effects compared to the use of purified lipopolysaccharide (Havas, 1990).
Non-immune mechanisms have been postulated to be responsible for the mechanism of action of Coley’s Toxins. This has been documented by Helen Coley Nauts as being derived from bacterial enzymes like streptokinase (Nauts, 1953). This theory was further developed, and streptokinase was proposed to act as a bacterial plasminogen to activate the host’s plasminogen. Plasminogen is then converted to the potent enzyme plasmin to initiate protease precipitation reactions capable of breaking down various plasma proteins (Zacharski, 2002; Zacharski, 2005).
The efficacy of Coley’s Toxins is not a blanket treatment as evidenced by the various success and failure cases. It is believed or even extrapolated from a study of the cases documented that different types of cancers respond differently to this mode of treatment. The most successful cases have stemmed from the regimen being administered to patients suffering from sarcomas compared to carcinomas. The difference between a carcinoma and a sarcoma is the tissue showing malignancy. Tissue types of mesenchymal origin like bone, muscular, cartilaginous or adipose tissue, are considered to be sarcomas if they form malignant tumors while those of epithelial cells, such as colon and lung, are carcinomas.
The possibility of toxicity of Coley’s Toxins means that doses should be adjusted and care given to support such patients. This treatment is patient specific but not to be recommended to all, but at the doctor’s own discretion. Some instances require special mention: patients with severe hepatic insufficiency, patients with severe cardiac conditions, or patients near death since the regimen will not help them (Nauts, 1975). The finished product needs to be tested using modern methods to assay the lipopolysaccharide and exotoxins presence and levels.
Since it is evident that tumors secrete proteins that can stimulate an immune response, it is imperative that ways isolate the tumor-reactive T-cells from the tumor-bearing host. Attempts are made to up-regulate the chances of an immune response by modifying tumor cell to exhibit immunoregulatory proteins such as cytokines, interferons, streptokinase, and tumor necrosis factor (TNF) (Chang, 1996). These advancements in the understanding of immunobiology in relation to cancer are stimulating research into vaccines for treatment in different types of cancer, specifically colon cancer and melanoma (Chamberlain, 2004)
The American Cancer Society’s Guide to Complementary Alternative Cancer Methods attests, “Scientific evidence suggests Coley toxins or the mixed bacterial vaccine (MBV) may have a therapeutic role in the treatment of cancer, in a combined treatment approach.” (American Cancer Society, 2000). This is followed by the disclaimer that much has been learned about the science of immunology and practice of immunotherapy since Coley’s time and that modern immunotherapy is likely to be of greater value.
The toxins are used outside the United States, for example, a Canadian company MBVax Bioscience produces Coley’s Fluid for use in clinical trials and research purposes. The biotech company Coley Pharmaceutical Group is involved in research on the DNA sequences that enable Coley’s Toxins to be efficient in producing regression of certain types of cancers. In addition, laws in Germany permit physicians to use any therapy he or she considers most appropriate in light of the patient’s medical condition and their medical knowledge.
By 2006, there had been thirty human studies conducted and published in peer-reviewed literature databases but only two articles were relevant to Coley’s Toxins (Zacharski, 2005; McCarthy, 2006). Case studies involving this cancer-treating regimen have been well documented by Helen Coley Nauts and proved the success rate of her father’s treatment. Still, these cases are not usually cited by modern researches due to the advancement in modern clinical trials methods. The procedures followed now are more rigid and require adequate and consistent follow-up of patients, something Coley’s reports did poorly or lacked entirely.
All this cancer research requires large amounts of resources, and the National Cancer Institute is the main agency that coordinates the national cancer research program. It is also responsible for disbursing funds received from Congress, federal agencies, voluntary organizations private institutions and corporations. Coley’s first patient Bessie Dashiell was reportedly John. D. Rockefeller Jr.’s childhood friend, and her death stimulated his contribution to cancer research funding. Pharmaceutical companies such as Pfizer are involved in research in the hopes of developing their own drugs and vaccines.
The use of Coley’s Toxins has brought to light the significance played by fever-inducing infections (Hoption, 2003). The modern use of antibiotics has suppressed the natural immune mechanisms resulting from evolution, and antipyretic use to manage fever has resulted in the neglect of the significance of fever as the body’s response to an infection. The onset of fever usually accompanies multifarious physiological changes, namely increase in metabolic rates which facilitates leukocyte proliferation, maturation, and activation (Aubert, 1999; Hasday, 2000). Historically, fevers were considered important and even encouraged. Perhaps, a return to these previously held practices may help boost our weakened immune systems, which in turn would fight some of the incurable diseases faced by mankind today (Hoption, 2003).
Coley’s Toxins have a place in the future despite being designated “new drug” status by the U.S. Food and Drug Administration. The successful use of this regimen by Coley and other physicians during his time proves that it is a useful area of research. This widely documented method of treating spontaneously occurring tumors has been instrumental in instigating further investigation into the significance of the role of the innate immune response to cancerous tumors. Modern cancer treatments repress the immune system. Although they are the conventional modes of therapy, they do not provide a definite cure.
The nature of Coley’s work, his dedication, and the extensive case studies documented on the use of the toxins have granted him the epithet “Father of Immunotherapy”. Although he did not discover a new therapeutic method, his research and creation of Coley’s Toxins were not only useful to his patients but stimulated a change in the way that the immune system is viewed. His life’s work brought to light the role immunotherapy can have not only for managing cancer but also for curing it. Using the methods of study including but not limited to extensive clinical studies, the principles of Coley’s Toxins can be established with respect to the exhaustive human data in existence.
Resurgence in interest, in Coley’s Toxins and the mechanism of action, may seem like retrogression in the field of cancer research. Clearly, Coley was a man before his time in terms of finding innovative to tack an ancient scourge that has plagued humanity with more severity in recent times. The slow progression of orthodox cancer therapy has lent a closer look into the medical past to chart the way forward (Hoption, 2003).
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