Medical Archaeology
Coley's toxin: Historical Perspective
Jacob Bickels MD, Yehuda Kollender MD, Ofer Merinsky MD
and Isaac Meller MD
National Unit of Orthopedic Oncology, Tel Aviv Sourasky
Medical Center, Tel Aviv, Israel
Keywords: Coley's toxin, soft tissue sarcoma,
erysipelas, Serratia marcescens
IMAJ 2002;4:471±472
The fact that an acute bacterial infection can induce a
regression in a concurrent malignant tumor has been
known for hundreds of years. However, only in 1868 ±
when Busch intentionally infected a patient with a soft
tissue sarcoma of the neck with erysipelas, hoping that
it will cause a tumor regression ± was it implemented.
Since the causative agent of erysipelas was not known
at that time, the patient was placed in a hospital bed
notoriously known for the frequency with which patients
in it became infected with erysipelas. After being
infected with erysipelas, rapid tumor shrinkage was
observed [1]. This response was only partial and tumor
recurrence subsequently occurred [1]. Only 13 years
later, in 1881, was Streptococcus identified as the
causative agent of erysipelas. In 1891, Dr. William B.
Coley, a New York surgeon just beginning his career,
treated a young patient with a soft tissue sarcoma of
the arm. Although a radical excision of the tumor was
performed, the patient developed metastatic disease and
died. Frustrated by the inability of surgery to achieve
cure and being unaware of Busch's work, Dr. Coley
searched the medical records of the hospital and
located a 7 year old record of a patient with an
inoperable sarcoma that persistently recurred after
repeated resection attempts. That patient ultimately
became infected with erysipelas. Following the
patient's recovery from that infection, a regression of
the malignancy was documented. Coley located the
patient and found him to be free of disease. Stunned by
that finding, he further searched the medical
literature and found a substantial number of
publications documenting the same observation; namely,
that a concurrent infection may lead to regression, and
even cure, of an underlying malignancy.
Coley speculated that the infection around the tumor
site induced a direct cytotoxic reaction, and in May
1891 he conducted the first treatment of an inoperable
tumor with local injections of streptococcal cultures.
His patient had an extensive lymphoma of the neck that
recurred after two excisions and caused severe
difficulty in swallowing, weight loss, and cachexia.
Injections of streptococci were given to the patient
at 3±4 day intervals over a few weeks. Following a
severe attack of erysipelas, the tumor underwent
extensive necrosis and the patient remained
disease-free for 8 years [2]. Encouraged by this
outcome, Coley used injections of streptococci to
treat other patients with a variety of malignant
tumors. The clinical results were variable. The rate
and extent of response differed from patient to
patient; in some the rate of tumor response was rapid
and in some very slow. It was attributed to the
different tumor types in that series of patients but
also to differences in the severity of infection among
these patients. Coley noticed a clear correlation
between the severity of patients' response to the
injection and the tumor response. On the basis of
other observations that the presence of Serratia
marcescens can enhance the virulence of streptococci,
Coley incorporated that bacterium into the
streptococcal vaccine. It was the combined injection
of these two heat-killed bacteria that would
eventually be referred to as ``Coley's toxin.'' [3].
Coley noted that even an injection in a remote
anatomic site could result in impressive tumor
response. This phenomenon, combined with his previous
finding that tumor response was related to the
severity of infection, led him to conclude that the
infection evoked a systemic response, the nature of
which was unclear at that time, and resulted in tumor
destruction.
Administration of the toxin was a complex procedure
that when performed inadequately may result in
significant morbidity and even mortality. Most
patients were injected every other day for a few
weeks. Special attention had to be given to the dose
of the toxin, the site and depth of injection,
frequency of injections, and length of treatment. The
intravenous route was found to be the most effective,
and a dose of the toxin was considered sufficient only
when its injection was accompanied by high fever. The
aim was to produce a rise of temperature to 40±40.58C
accompanied by a chill [4,5].
Over the next 45 years, until the end of Coley's
medical career in 1936, thousands of patients were
treated with Coley's toxin. Coley gained extensive
experience in the treatment of a large variety of
malignant diseases, including soft tissue sarcomas,
lymphomas, osteosarcomas, Ewing's sarcomas, and
malignant melanomas. He also treated cervical,
ovarian, testicular, renal, breast, and colorectal
carcinomas. The best response by far was achieved in
patients with inoperable soft tissue sarcomas;
long-term (more than 5 years) disease-free survival
was achieved in approximately 50% of these patients.
Carcinomas, on the other hand, responded poorly to the
treatment, and Coley concluded that the use of the
toxin should be limited to sarcomas.
Coley's fascinating observations and vast clinical
experience led to the understanding that the
immunologic host response may influence the biologic
behavior of some malignant tumors, and that
manipulation of that balance might therefore result in
recognition of the tumor by the immune system,
initiation of immune response, and tumor kill.
Activation of the immune system, either by making it
respond to an iatrogenic infection as Coley did, or by
treating the patient with a cytokine that is part of
the immune cascade (i.e., interleukin-2, interferon,
or tumor necrosis factor), is the principle underlying
contemporary cancer immunotherapy. Coley's toxin has
been cited as a promising treatment that may have been
prematurely abandoned with the advent of modern
chemotherapy, radiotherapy, and improvement in
surgical techniques.
References 1. Busch W. Verhandlungen artzlicher
gesellschaften. Berlin Klinische Wochenschriften
1868;5:137-8.
2. 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.
3. Coley WB. The treatment of inoperable sarcoma with
the mixed toxins of erysipelas and bacillus prodigiosus
± immediate and final results in one hundred and forty
cases. JAMA 1898;31:389±421.
4. Coley WB. Sarcoma of long bones. The diagnosis,
treatment and prognosis, with a report of sixty-nine
cases. Ann Surg 1907;45:356±82.
5. Coley WB. End results in Hodgkin's disease and
lymphosarcoma treated by the mixed toxins of erysipelas
and bacillus prodigiosus, alone or combined with
radiation. Ann Surg 1928;88:655±6.
Correspondence: Dr. I. Meller, National Unit of
Orthopedic Oncology,
Tel Aviv Sourasky Medical Center, 6 Weizmann St., Tel
Aviv 64239, Israel.
Phone: (972-3) 687-4688 Fax: (972-3) 697-4690
email: imortonc@tasmc.health.gov.il
The fear of hell is hell itself, and the longing for
paradise is paradise itself.
Khalil Jibran (1883±1931), Lebanese writer and
philosopher
In matters of principle, stand like a rock; in matters
of taste, swim with the current.
Thomas Jefferson (1745-1826), Third President of the
United States and founder of the Democratic Party, was
largely responsible for the drafting of the Declaration
of Independence.
Science 2002;295:2460
Capsule
Matrix metalloproteinases and multiple sclerosis
Multiple sclerosis (MS), the most common disabling
neurologic disorder among young adults, is
pathologically characterized by T cell and macrophage
infiltration into the central nervous system (CNS),
demyelination and associated secondary axonal injury.
Proteases, such as matrix metalloproteinases (MMPs),
play a crucial role in these processes, as indicated by
the elevated expression of MMP-2, MMP-7, and MMP-9 in
the CNS, cerebrospinal fluid, and peripheral blood of
MS patients. Galboiz and colleagues have extended these
observations by showing that relapsing-remitting MS
patients treated with interferon (REBIF) have reduced
levels of MMPs mRNA expressed in peripheral blood
leukocytes compared to the levels prior to treatment.
The study has shown that among the mechanisms of action
of IFN in MS is the reduction of MMPs expression at the
transcription level. This study, together with earlier
ones, raise the possibility of using MMPs as surrogate
markers of disease activity and response to
immunomodulatory therapy, and also propose the
potential use of MMP-inhibitors as therapeutic
strategies in MS.
Neurons switch their preferences
When we are awake, our eyes perform small rapid
movements and jump from one fixation point to another.
These saccades occur several times a second. Thiele et
al. compared neuronal activity in two
movement-specialized brain areas, area MT and area MST,
during saccade-induced image motion and during passive
viewing. Some cells suppress their response selectively
during saccades while still being sensitive to such
speed in passive conditions. More remarkably, they
describe a neuron that shows an inversion of its
direction preference during saccades. These changes in
tuning, which seem to occur very rapidly, do not have a
retinal origin but are mediated by an internal signal.
Ann Neurol 2001;51:443 (and 431 for editorial)
472 J. Bickels et al. IMA . Vol 4 . June 2002
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