Coley's Toxins - S. A. Hoption Cann 2001

Medical Hypotheses (2002) Harcourt Publishers Ltd

Spontaneous regression: a hidden treasure buried in time

S. A. Hoption Cann, 1,2,3 J. P. van Netten, 1,2 C. van Netten, 3 D. W. Glover

Special Development Laboratory, Royal Jubilee Hospital, Victoria, British Columbia, Canada;

Department of Biology, University of Victoria, Victoria,

British Columbia, Canada;

Department of Health Care and Epidemiology, University of British Columbia, Vancouver, British Columbia, Canada

Summary

Spontaneous tumor regression is a phenomenon that has been observed for hundreds, if not thousands
of years. Although the term spontaneous implies `without apparent cause', a review of case reports over the last several
hundred years demonstrates that regression generally coincides with acute infections. Observations of this non-specific
effect led to the emergence of active cancer immunotherapies by the 1700s. By the 1890s, William Coley refined this
approach with a bacterial vaccine which, when administered properly, could induce complete regression of extensive
metastatic disease. Unfortunately, after Coley's death, his vaccine and technique fell into obscurity.
Modern approaches to treatment have reduced the occurrence of spontaneous regressions. Aseptic techniques and
antibiotics significantly reduce postoperative infections, while chemotherapy and radiation impair immune activation even
when an infection does occur.

More than a century after its inception, Coley's vaccine and aggressive approach to treatment may still be
one of most effective immunotherapies for cancer. & 2002 Harcourt Publishers Ltd


INTRODUCTION

In a recent review of current immunotherapy regimens, it
was stated that `immunotherapy applied to patients with
established tumors rarely leads to an objective response'
(1). Yet historically, tumor regression associated with an
immune response was not an unusual phenomenon.Why
is this regression not observed in association with current
immunotherapy regimens?

Although numerous cases of so-called spontaneous
tumor regression have been published over the last sev-
eral hundred years, such reports have become rare in
current medical literature. Virtually all of these reports
note regression concomitant with infections, including
diphtheria, gonorrhea, hepatitis, influenza, malaria, mea-
sles, smallpox, syphilis and tuberculosis, as well as various
other pyogenic and non-pyogenic infections (2). An early
example was a case reported by Le Dran (3) in 1742. A
15-year-old patient had an extensive inoperable cancer of
the left breast. The tumor ulcerated and gangrene devel-
oped. Within 2 days the entire tumor sloughed off with
profuse hemorrhaging and later suppuration. The wound
healed after 5 weeks. However, the disease recurred,
causing death 8 months later. Similarly, Trnka (4) in 1783
described a patient with breast cancer who developed
tertianmalaria (associated with chills, fever and sweating).
The illness was associated with a complete remission after
few weeks. Benefits arising from such intratumoral infec-
tions was not an uncommon observation, as the physician
Quesnay (5) stated of one patient: `thismortification could
have been advantageous to the patient, for it could, as we
have seen sometimes, destroy the whole tumor, procuring
a salutary amputation without pain.'

THE EMERGENCE OF IMMUNOTHERAPY

Coincidental infections were probably the impetus for
the active use of pathogens as a cancer treatment. An
example was reported by White (6) in 1768 as `the
wonderful method of curing cancers by means of toads,'
where he describes a woman from Hungerford, England,
who treated patients with breast cancer. The method
required that a toad be applied to the breast lesion until
its death (7). Reportedly, the dead toad would be allowed
to remain on the breast lesion by the application of a
poultice for several weeks. Pennant (8) provides the
details of one such case, a woman with metastatic breast
cancer who had been `reduced to a meer skeleton.' Her
left side and stomach were swollen and a tumor on her
neckmade swallowing difficult.Without surgery and after
several months of toad treatment, however, her meta-
static lesions abated and shewas able to swallowwith ease.

In 1752, Amoureaux (9) treated a patient with an ulcerated
malignant breast by applying a septic dressing. The pat-
ient developed a fever and severe inflammation with
suppuration; complete regression was noted in 4 weeks.

Similarly, other physicians were known to deliberately
establish multiple `issues' (suppurating sores) following
cancer surgery. These issues were generally situated in
the tumor, its periphery or in the arms (10,11). An analo-
gous method was used by Verneuil (12). After cancer
surgery, he would leave the incision open or loosely
approximated with drainage, where suppuration would
then ensue. A student of Verneuil made the following
observation: `I was often struck by the slowness with
which recurrence developed in such cases . . . I asked
myself if suppuration, in eliminating the traces of cancer
which had escaped the knife, did not play a role in
delaying recurrence, and if therein lay the secret of suc-
cess' (13). In addition to these treatments, some investi-
gators induced tumor regression by injecting patients
with other infectious agents such as malaria (14) and
syphilis (15,16).

These basic `immunotherapies' gained some general
acceptance in the 1800s. In his treatise on breast cancer,
Tanchou (17) commented: `it is remarkable that after
hemlock it is gangrene that caused the largest number
of cures. Gangrene may be considered as a therapeutic
agent, whether it occurs spontaneously or is induced
medically.' Similarly, Walshe (18), in his text on cancer
treatment, viewed such therapy as a practical application
of a phenomenon that had been observed for centuries,
and concluded that `the inoculation of the matter of
common and hospital gangrene has been practiced, with
the design of imitating the natural processes of cure.'
Cruveilhier (19) also promoted these measures, stating
that a beneficial inflammation may be produced spon-
taneously or: `induced by incisions or irritating applica-
tions. There results a melting away or gangrene of the
affected tissues, followed by complete sloughing and a
radical cure.' However, as a result of the growing pop-
ularity of Lister's methods for aseptic surgery in the
late nineteenth and early twentieth century (20), septic
`immunotherapy' soon fell into disfavor among cancer
surgeons who failed to appreciate its therapeutic value.
Thus, as the prevention of postoperative infections gained
further acceptance, the idea that cancer surgery should
be distinct from other types of surgery was lost.

`INFECTION' WITHOUT AN INFECTION

William Coley, a surgeon at New York Memorial (Sloan-
Kettering) Hospital, was the first researcher to make a
systematic study of the entire immunotherapy approach
and would eventually treat the largest series of patients
in this manner. Unaware of the previous work in this area,
Coley noted a coincidental tumor regression in a patient
who developed a streptococcal infection within an ulcer-
ated tumor. Based on this observation, he attempted to
reproduce these results by infecting his cancer patients
with this same bacterium, previously known as erysipelas
(21). Although he achieved some success, in the pre-
antibiotic era problems associated with this approach
soon became apparent. Erysipelas was not easy to con-
trol once it began and, perhaps surprisingly, it was not
all that easy to induce in the first place. Some patients
required repeated injections and others never developed
an infection. Subsequently, Coley developed a vaccine
consisting of extracts of killed Gram-positive Strepto-
coccus pyogenes and Gram-negative Serratia marcescens,
which became known as `Coley's toxins' (22). These toxins
produced many of the symptoms of bacterial infections,
such as fever and chills, without the need to worry about
producing an actual infection.

Throughout his career Coley stressed that the tech-
nique of administration was essential to its curative effect,
while the precise formulation was of secondary impor-
tance ± he used more than 15 different formulations
during his career. Martha Tracy, a researcher who made
many of the vaccine formulations for Coley and who
experimented with a wide range of killed bacterial vac-
cines on animal tumors, observed that the most effective
formulations were those that induced both local and
systemic reactions (23).

A key aspect that Coley found to be necessary for
tumor regression was the induction of a mild to mod-
erate fever. He would thus gauge dosage levels according
to individual patient responses and increase the dose
as necessary to avoid vaccine tolerance. To simulate the
effects of a chronic infection in his patients, he would
inject the tumor vicinity daily or every other day for the
first month or two. Other factors that he found crucial to
a patient's long-term survival included direct vaccine
injection into the tumor or metastases, and a prolonged
follow-up to prevent recurrence (24). Ensuring a pro-
longed follow-up was the most difficult aspect. Due to
space limitations, patients would often be referred to
their personal physician after a week to one month of
treatment. In general, these physicians, and in many cases
the patient, would not fully comprehend the importance
of follow-up treatments or how these treatments should
be carried out.

At present, the only conventional treatment analogous
to Coley's technique is bacillus Calmette±Guerin (BCG)
treatment of bladder cancer. Like Coley's approach, this
treatment uses the whole bacterium, it is applied direc-
tly to the tumor, it produces both a local and systemic
response, its effects persist after administration (because
it is a live bacterium), and prolonged administration
improves recurrence-free survival (25). Yet unlike Coley's
approach, BCG therapy uses a live bacterium and dis-
seminated infections, which can often be serious, occa-
sionally occur.

Other interesting observations by Coley were that
the toxins led to a marked relief of pain, so that patients
could often discontinue using narcotics; and, as these
injections often followed surgery or were injected into
ulcerated tumors, there was an extraordinary enhance-
ment of wound healing and even bone regeneration (22).
Similar observations on infectious amelioration of can-
cer pain and enhancement of wound healing has been
reported by others (5,12,26).

Although Coley is often credited as the father of can-
cer immunotherapy, few modern investigators have ever
closely examined his results. A recent retrospective
analysis compared patients treated with Coley's toxins
(1890±1960) to that of patients from the Surveillance
Epidemiology End Result (SEER) registry (1980s) for can-
cers of the breast, ovaries, kidneys, and soft-tissue sarco-
mas (27). In comparing treatment with Coley's toxins to
the SEER registry, the authors concluded that the risk of
death within 10 years was not significantly different for
any of the cancers studied. These results are rather sur-
prising considering the fact that Coley's vaccine was
developed at only a nominal cost, that most cases were
considered inoperable, and that this experimental work
began over 100 years ago.

SIDE-EFFECT OR IMMUNE RESPONSE?

Use of Coley's toxins is not an easy treatment for the pat-
ient. In addition to the fever and chills, a patient might
experience other symptoms such as loss of appetite, fati-
gue, and depression. In part, these symptoms were due
to the vaccine, and in part to toxemia arising from the
rapid tumor regression, where necrotic tumor consti-
tuents would enter the bloodstream.
The symptoms described above are also known to
occur in conjunction with some current immunothera-
pies (28±31). Unfortunately, modern investigators often
consider such immune responses `side-effects' (28,30,31),
failing to recognize their value in tumor regression and
generally seeking ways to minimize or eliminate these
symptoms. Little consideration is given as to whether
such side-effects improve patient survival.
Decline in the use of Coley's toxins came about after
Coley's death in 1936. By the 1950s, antibiotics came into
general use for surgery, greatly reducing the chance of
infection following tumor excision. Furthermore, radia-
tion and chemotherapy became mainstays of treatment
as they required less individualization and the immedi-
ate results were more predictable, although it soon
became apparent that such treatments often led to cures
of a short duration. Chemotherapy, and to varying degrees
radiation, is highly immunosuppressive, and therefore
infections in the cancer patient cause little immuno-
stimulation, and in any case, are rapidly treated with
antibiotics. Thus, it is not surprising that reports of spon-
taneous regression have become rare. Still, an association
with acute infections prevails in the few recent reports
of this phenomenon (32±34).

THE DUAL ROLE OF THE IMMUNE SYSTEM

In recent years, histological studies have established that
solid tumors and their metastases are infiltrated by large
numbers of immune cells (35±37). Yet, morphological
alterations of tumor cells suggestive of leukocyte-induced
damage are absent or extremely rare ± despite the close
contact generally observed between leukocytes and
tumor cells. Thus, in spite of the innate ability of the
immune system to induce tumor regression, the cytotoxic
activity of these tumor-infiltrating leukocytes (TIL) is
compromised. We have suggested that this is primarily
due to the fact that the immune system has two major
functions: defense and repair (38). The well-studied
defensive role may become active during acute infection,
where cytotoxic cells seek out and destroy invading
pathogens. Although the reparative process following
wounding is also well-known, less emphasis has been
placed on the role the immune system plays in medi-
ating this process (39). In fact, a considerable volume of
research in this area has confirmed that TIL not only fail
to inhibit growth, but also actively aid tumor progres-
sion through their reparative functions (37,40±43).
How can the immune response be so erratic? An
example that highlights this duality in function was dis-
cussed by Williams (44) in 1898. He noted a conspicuous
antagonism between active tuberculosis and cancer, sta-
ting `it is certainly most exceptional to find both diseases
in active progress in the same individual. The outbreak
of cancer often follows or coincides with the healing of
pulmonary tubercle, although, in most cases, the inter-
vening period is fairly protracted.' In an analysis of 11 195
autopsy examinations, Carlson and Bell (45) noted that
Spontaneous regression 117
& 2002 Harcourt Publishers Ltd Medical Hypotheses (2002) 58(2), 115±119tuberculosis was of a similar prevalence in those with
and without cancer. However, in confirming Williams's
observations, they found active tuberculosis to be `strik-
ingly less' in cancerous than non-cancerous subjects. The
preceding example illustrates that the same infection can
stimulate or allow either immune defensive or reparative
responses, which correspondingly may suppress or aug-
ment tumor growth (Fig. 1). Thus, within the confines
of tumorous lesions, an opportunity exists; strategically
located immune cells lie awaiting the appropriate stimuli
necessary for reactivating their defensive capabilities (38).

IMPLICATIONS FOR TREATMENT

Most of the early, yet often successful, forays into cancer
immunotherapy have been forgotten. A recent review
of cancer vaccines described spontaneous regression as
being `often mentioned ± rarely observed' (46). Such
comments illustrate how little is presently known of the
underlying causes of `spontaneous' tumor regression, as
well as those factors which inhibit it ± aseptic surgery,
antibiotic usage, chemotherapy and radiotherapy.
In his published papers, Coley repeatedly emphasized
factors that he found to be vital for successful treatment
(i.e. daily injections, direct tumor injection, and a pro-
longed follow-up) ± points that appear lost to modern
researchers. Despite the `crude' approach taken by Coley,
his vaccine stimulated a complex immune response that
could induce the complete regression of both exten-
sive primary and metastatic lesions. Furthermore, his vac-
cine was universally effective against many types of
malignancies. Tumors that were observed to partially or
completely regress following treatment with Coley's vac-
cine included: lymphomas, melanomas, myelomas, sar-
comas and a wide spectrum of carcinomas (2,22,24).
How is this relevant to modern cancer therapy? Des-
pite the seemingly rudimentary nature of the vaccine, the
immune system has evolved to generate an elaborate
response involving a multitude of factors secreted in
sequentially precise order and concentration following
exposure to infectious agents. Modern investigations
have shown how difficult it is to reproduce this complex
immune response, and correspondingly tumor regression,
when more precise tumor-specific antigens and cytokines
are used (47). In contrast to such immunotherapies,
Coley's vaccine could be produced at a nominal cost, be
used for a wide spectrum of cancers, and still provide a
significant benefit to patients at all stages of disease.
His approach should now become a challenge to mod-
ern immunotherapy investigators. Applying our current
knowledge of the immune system to Coley's approach
will allow the fine tuning, monitoring and careful control
of this procedure, while providing new insights into pain
control, healing, and tumor regression.

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& 2002 Harcourt Publishers Ltd Medical Hypotheses (2002) 58(2), 115±119


Received 12 February 2001
Accepted 5 July 2001
Correspondence to: Stephen A. Hoption Cann, Department of Health
Care and Epidemiology, University of British Columbia, 5804 Fairview
Avenue, Vancouver, BC V6T 1Z3, Canada. Phone: ?1 604 822 5688;
Fax: ?1 604 822 4994; E-mail: shopcann@interchange.ubc.ca