Coley's Toxins

Coley's Toxins (also called Coley's toxin,cite journal |author=Thotathil Z, Jameson MB |title=Early experience with novel immunomodulators for cancer treatment |journal=Expert opinion on investigational drugs |volume=16 |issue=9 |pages=1391–403 |year=2007 |pmid=17714025 |doi=10.1517/13543784.16.9.1391] Coley's vaccinecite journal |author=Taniguchi Y, Nishizawa T, Kouhchi C, "et al" |title=Identification and characterization of lipopolysaccharide in acetic acid bacteria |journal=Anticancer Res. |volume=26 |issue=6A |pages=3997–4002 |year=2006 |pmid=17195448 |doi=] , 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. [ [http://www.mdanderson.org/departments/cimer/display.cfm?id=35F66009-F06A-11D4-810200508B603A14&method=displayFull&pn=6EB86A59-EBD9-11D4-810100508B603A14 Coley Toxins Detailed Scientific Review at mdanderson.org] ]

History

Observations of a relationship between infection and cancer regression date back to at least the 1700s.cite journal |author=Hoption Cann SA, van Netten JP, van Netten C, Glover DW |title=Spontaneous regression: a hidden treasure buried in time |journal=Med. Hypotheses |volume=58 |issue=2 |pages=115–9 |year=2002 |pmid=11812185 |doi=10.1054/mehy.2001.1469] More specifically, observations of an apparent relationship between erysipelas and remission of cancer predate Coley. [W. Busch. Einfluβ von Erysipel. Berliner Klin Wschr 1866. 3: 245-246. ] For example, Anton Chekhov, in his capacity as a physician, recorded such a relationship in 1884.cite journal |author=Gresser I |title=A. Chekhov, M.D., and Coley's toxins |journal=N. Engl. J. Med. |volume=317 |issue=7 |pages=457 |year=1987 |pmid=3302707 |doi=]

Coley was apparently unaware of this line of inquiry. His interest in cancer was heightened after observing the death of one of his first patients, Elizabeth Dashiell, from sarcoma. 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. [cite web |url=http://www.nytimes.com/books/first/h/hall-commotion.html |title="A Commotion in the Blood" |accessdate=2007-11-10 |format= |work=] cite book |author=Hall, Stephen K. |title=A commotion in the blood: life, death, and the immune system |publisher=Henry Holt |location=New York |year=1997 |pages= |isbn=0-8050-5841-9 |oclc= |doi=]

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. [ [http://www.ralphmoss.com/html/coley.pdf "The Cancer Chronicles", Ralph W. Moss, PH.D., 1996] ] [Coley WB. Annals of Surgery 1891;14:199-200] His initial attempts at deliberate infection were mixed,cite journal |author=McCarthy EF |title=The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas |journal=The Iowa orthopaedic journal |volume=26 |issue= |pages=154–8 |year=2006 |pmid=16789469 |doi=] 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. [Roger, G.H. Séances et Mém Soc de Biol Paris 1890;2:573-580]

The so-called Coley's Toxins were used against different types of cancer from the year 1893 [Coley WB. The treatment of malignant tumors by repeated inoculations of Erysipelas, with a report of ten original cases. Am J Med Sci 1893;105:487-511.] 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. [cite web |url=http://findarticles.com/p/articles/mi_m0ISW/is_251/ai_n6112670/pg_13 |title=Coley's Toxins - The First Century Townsend Letter for Doctors and Patients - Find Articles |accessdate=2007-11-10 |format= |work=] Since then, several small clinical trials have been conducted with mixed results. [ [http://www.latimes.com/features/health/la-he-labbox18feb18,1,2366354.story Treatment pioneer] , from the "Los Angeles Times", published February 18 2008. Accessed March 26 2008.]

Coley's Toxins were also produced by the small German pharmaceutical company "Südmedica"cite book |author=Hess, J David. |title=Can bacteria cause cancer?: alternative medicine confronts big science |publisher=New York University Press |location=New York |year=1997 |pages=11 |isbn=0-8147-3562-2 |oclc= |doi=] and sold under the trade name "Vaccineurin". [cite web |url=http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.section.59582 |title=History and Background |accessdate=2007-11-10 |format= |work=] 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. [cite journal |author=Hoption Cann S, van Netten J, van Netten C |title=Dr William Coley and tumour regression: a place in history or in the future |journal=Postgrad Med J |volume=79 |issue=938 |pages=672–80 |year=2003 |pmid=14707241 [http://pmj.bmjjournals.com/cgi/content/full/79/938/672 link] ]

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. [cite web |url=http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.section.59631 |title=Proposed Mechanism of Action |accessdate=2007-11-10 |format= |work=] 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. [cite journal |author=Tsung K, Norton JA |title=Lessons from Coley's Toxin |journal=Surgical oncology |volume=15 |issue=1 |pages=25–8 |year=2006 |pmid=16814541 |doi=10.1016/j.suronc.2006.05.002]

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. [cite journal |author=Zacharski L, Sukhatme V |title=Coley's toxin revisited: immunotherapy or plasminogen activator therapy of cancer? |journal=J Thromb Haemost |volume=3 |issue=3 |pages=424–7 |year=2005 |pmid=15748226 |doi=10.1111/j.1538-7836.2005.01110.x] cite journal |author=Haux J |title=Infection and cancer |journal=Lancet |volume=358 |issue=9276 |pages=155–6 |year=2001 |pmid=11469250 |doi=] This hypothesis is supported by the fact that streptokinase has been associated with successful treatment of thromboangiitis obliterans.cite journal |author=Hussein EA, el Dorri A |title=Intra-arterial streptokinase as adjuvant therapy for complicated Buerger's disease: early trials |journal=International surgery |volume=78 |issue=1 |pages=54–8 |year=1993 |pmid=8473086 |doi=]

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. [ [http://download.journals.elsevierhealth.com/pdfs/journals/1359-6101/PIIS1359610102000710.pdf Infection and cancer: the common vein] ]

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. [cite journal |author=Hobohm U |title=Fever and cancer in perspective |journal=Cancer Immunol. Immunother. |volume=50 |issue=8 |pages=391–6 |year=2001 |month=October |pmid=11726133 |doi= |url=]

Availability

MBVax Bioscience, a Canadian Biotech company, produces Coley Fluid for research and clinical study. [cite web |url=http://findarticles.com/p/articles/mi_m0ISW/is_286/ai_n19170440 |title=MBVax Bioscience revives century-old "Coley's Toxins" cancer therapy Townsend Letter for Doctors and Patients - Find Articles |accessdate=2007-11-10 |format= |work=] [cite web |url=http://www.mbvax.com/ |title=MBVax Bioscience |accessdate=2007-11-10 |format= |work=] 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.cite web |url=http://www.latimes.com/features/health/la-he-lab18feb18,1,162154.story?ctrack=1&cset=true |title=Cancer and the bacterial connection |accessdate=2008-02-17 |format= |work=] In addition, the Waisbren Clinic in Wisconsin reports they have used Coley's Toxin to treat patients since 1972. [cite web |url=http://www.waisbrenclinic.com/ |title=Waisbren Clinic - Home Page |accessdate=2007-11-10 |format= |work=] "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 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.

References

External links

Companies

* [http://www.mbvax.com/ MBVax Bioscience Inc]
* [http://www.coleypharma.com/ Coley Pharmaceutical Group]

Scientific reviews

* [http://www.cancer.org/docroot/ETO/content/ETO_5_3X_Coley_Toxins.asp?sitearea=ETO Coley Toxins] , from the American Cancer Society
* [http://www.mdanderson.org/departments/CIMER/display.cfm?id=43EF7F2C-0DAF-11D5-810D00508B603A14&method=displayFull&pn=6EB86A59-EBD9-11D4-810100508B603A14 Coley Toxins] , from the M. D. Anderson Cancer Center