Coley's good against Arthritis (LANCET, Klein)

The Lancet, Volume 358, Issue 9276, Pages 155 - 156, 14 July 2001
doi:10.1016/S0140-6736(01)05369-7Cite or Link Using DOI

Infection and cancer

Johan Haux -- jhaux [a} operamail.com

Sir

Fran Balkwill and Alberto Mantovani (Feb 17, p 539),1 I think, should have included the name of William B Coley (1862—1936) in their review of Rudolf Virchow's work.
I will by no means depreciate Virchow, but stress the clinical relevance of Coley's work for the inflammation-cancer connection. Coley translated the observation of tumour regression concomitant with infection into a treatment—the Coley toxins (Coley's mixed toxins or Coley's vaccine) consisting of heat-killed or sterile filtrated cultures of Streptococcus pyogenes and Serratia marcescens. Thus, the toxins contained some of the most potent immune-regulatory substances, such as lipopolysaccharides, exotoxins (also as superantigens), enzymes such as streptokinase, as well as an unimaginable amount of other bacterial antigens.
That the Coley toxins could cure patients with extensive inoperable tumours is documented, but the results were unpredictable, which is not surprising considering where bacteriology and immunology stood at that time.2

Tumour necrosis factor (TNF) was the first discovered molecule that directly linked the Coley toxins to an eventual anticancer effect. Today several new members in the TNF superfamily are under fierce investigation as potential anticancer agents, such as TNF related apoptosis inducing ligand, and the picture becomes increasingly complex. TNF kills tumour cells under certain circumstances, but can also promote the malignant state.1 TNF antagonists were first approved for the treatment of rheumatoid arthritis and are now also assessed in clinical cancer studies.1
Less known today, the Coley toxins were also very effective in relieving the symptoms of arthritis, and arthritis was the sole indication for some doctors to use them. The very pronounced effects on pain and stiffness occurred after 1-2 weeks of treatment.3 This may show that a decrease or blockade of TNF was a major clinical effect of the Coley toxins instead of an increase of TNF as has been proposed for explaining the anticancer effects.4

Another constituent of the Coley toxins, streptokinase, may also have favourable effects in cancer treatment for tumours producing vascular endothelial growth factor (VEGF) leading to extravasation of fibrin and thus possibly shielding the tumour cells from immune attacks.5 It has taken half a century to reveal a few of the molecular mechanisms which may explain the anti-cancer effects of the Coley toxins, but still we are far from the whole scenario.

To scrutinise the original Coley toxin concept in a clinical setting with the knowledge and technology of today is probably the only way to get the final answer concerning their mechanisms of action and effectiveness. Such an approach may be a shortcut to find out how to trigger an immune reaction against malignant tumours.

References

1 Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow?. Lancet 2001; 357: 539-545.


       THE USE OF COLEY'S MIXED TOXINS IN THE
             TREATMENT OF CHRONIC ARTHRITIS.
                         BY THOMAS KLEIN, M.D.,

                             PHILADELPHIA, PA.

      One need not look very far into the endless literature to realize
fully the perfectly hopeless task of finding a suitable classification
of the various forms of chronic arthritis.        It is also not within the
bounds of  this  short paper to  enter  into  any lengthy discussion.
Suffice it  to say that the term chronic arthritis as here employed
embodies those types which are variously classified as:  Chronic non-
suppurative  arthritis;     Rheumatoid  arthritis;      Chronic  infectious
arthritis;  Chronic -osteo  arthritis or arthritis deformans.        Gout or
gouty arthropathies being a purely metabolic disease  is  not here
considered.    The same holds true to the arthropathies of nervous
origin or those occurring in tabes dorsalis        (Charcot joints)  and in
syringomyelia.     The chronic hypertrophic osteo arthropathies occur-
ring in the course of pulmonary tuberculosis, bronchiectasis, chronic
bronchitis, malignant tumors of the lung, and various chronic cardiac
conditions are again distinct and are not included in the above term
chronic arthritis as here used.     Syphilitic arthritis is again a more or
less distant entity and is not here considered.         Villous arthritis  is
probably a stage of chronic osteo arthritis and will be considered as
such.   Fibrositis and panniculitis will be described as a part of the
chronic infectious process so frequently occurring in this type of case.
      Thevast majority of the remaining caseswill fall into that group
in which we are primarily interested.       This group is characterized at
the beginning by swelling of the smaller joints,  both meta-carpo-
phalangel and metatarso-phalangel.         The process may be unilateral
but is more often bilateral.     In the early stages the joints gradually
swell with little or no pain.    This gives them the characteristic fusi-
form appearance.      Upon examination they have a distinct doughy
feeling.   At times there is  a questionable effusion  into the joint.
Pathologically this enlargement is due to swelling and hypertrophy
of  the  synovial membrane and capsular  ligament.             Pain is  only
present upon pressure and active or passive motion.              The disease
progresses with definite periods of acute exacerbations, characterized
by fever and its accompanying symptoms; increased pain and stiff-
ness  in  joints  and surrounding  structures -frequently by  focal
manifestations as increased swelling and redness in the joint struct-
ures themselves.      These periods are also  associated with a  slight
increase in leucocyte count as compared during the stage of quies-
cence.   In all respects it follows clinically the course of an infection.
During this time the disease progresses upward involving the larger
joints, namely the wrist, elbow, shoulders, ankle, knee, hip and the
joints of the spine.
      Soon after the beginning of the process which in itself is essen-
tially  an hypertrophy of the periarticular  structures,  we have an
atrophic process  set  up: -The atrophy involves the muscles,  sub-
cutaneous fat and skin.       These atrophic changes are undoubtedly
due in many instances to a reflex atrophy.          Vulpains idea, namely
that impulses carried from irritated articular nerves alter the trophic
activity of the cells in the anterior horns without causing a lesion,
but sufficient to cause atrophy and weakness, is an extremely good
one and is  the best explanation offered.        It is  the glossy atrophic
condition of the skin, atrophy of the subcutaneous fat and muscles
plus  their  subsequent contractures which gives  the characteristic
deformity.     The extensor groups of muscles always suffer  greater
damage than the flexors.      Hence flexor contractures always predomi-
nate.   This is explained by the fact that the nerves which supply the
extensors also supply the joints themselves, consequently they bear
the blunt of the irritation and the greatest atrophy.
     Associated with this degenerative process is a fibrositis involving
both the aponeurosis and the muscles themselves.          In fleshy individ-
uals the subcutaneous fat is also caught in the process in the form of
a panniculitis.   These two conditions account for a good deal of the
patient's suffering and as wewill see later form a very important part
of the treatment.
      The feeling that this type of case is always due to a chronic
infection is fast gaining ground.  Even though the causative organism
is  not  found, the clinical  course with its     frequent,  regular,  acute 
exacerbation associated with fever, increased swelling, pain and red-
 ness of the joints, increased leucocytes as compared with the quies-
 cent period, is sufficient to establish this fact.     Consequently, when
 such a case presents itself  for treatment we immediately look for a
 focal infection.   Teeth and tonsils correctly occupy the foreground
 as the most frequent sites of focal infection.     Following these are the
 sinuses, gall-bladder, prostrate, infected ingrown toe-nails, ulceration
 along the intestinal tract, mediastinal lymph nodes, etc.        The femal
 pelvis has not been found an important factor in our groups of cases.
 In one case now under treatment the mucous membrane of the mouth
 afforded repeated rich groups of a hemolytic streptococcus; otherwise
 no source of infection could be found.         The prostate and seminal
 vesicles are frequently overlooked and when found as a source are
 too often looked upon as gonorrheal.         The streptococcus may long
 persist  without any gonococci being  found.         Non-surgical  biliary
 drainage, done in an aseptic way offers many opportunities for the
 study of the gall  tract  for  infection.    Too often we overlook the
 bacteriology of  the  feces,  as here is  not  an infrequent source of
 streptococcus infection.
      Again we must remember that in the vast majority of cases, we
 are dealing with not one focus of infection but many.  The eradica-
 tion of a dental abscess or a pair of tonsils does not mean that we
 have removed all  the source of infection.        When one considers a
mediastinal lymph node or an intestinal ulceration as a focus he will
 readily realize the difficulties in their removal.    It is because of this
fact and the repeated failure in not getting good results, that lead us
to the utilization of a streptococcus vaccine.       The vaccine also has
further assets.    It probably stimulates antibody formation to over-
come any focus not eradicated and at the same time seems to aid in
a causation of a retrograde process in  the periarticular  structures
themselves.
      During the past seven years Dr. Robert G. Torrey and myself
have been using Coley's Mixed Toxins (amixture of the streptococ-
cus of erysipelitus and bacillus prodigiosus)  in the treatment of this
type of case with surprisingly good results.     This vaccine was selected
solely because of the potency or virulency of the streptococcus used
 (.01 cc.  of the cultures being sufficient  to kill  a white mouse in 
twenty-four hours).      It is  again easily  obtainable  in the market
 Which is  a distinct  advantage to many men.           The action of  this
 vaccine is undoubtedly that of a high powered foreign protein but on
 the contrary after observing quite a series of cases one cannot help
 but wonder if  it  is  not in  some way a specific.        It  suggests the
 thought that the strain of streptococcus causing this disease is  in
 someway related to the streptococcus of erysipelas.        Thus far I have
 treated a series of  twenty-one cases.       Of these twenty-one cases,
 twelve have been cured, seven are still under treatment with marked
 improvement  (diminution of pain,  swelling of joints,  decrease of
 ankylosis,   acute  exacerbation  being  lessened      in   frequency  and
 severity, and finally abolished, with general improvement in health
 and gain in weight).    Twocases stopped treatment because of severe
 focal and local reactions.   The type of cases treated have been in the
 vast majority of cases far advanced.       The earliest case treated was
 that of  three months duration.        The oldest  case of  fifteen  years
 standing.   The average length of duration previous to treatment was
 31 years.    The length of  treatment varied  equally as well.          The
 earlier the case was started, the shorter was the duration of treat-
ment.    In the earliest case the vaccine was given over a period of
 three months.     In the longest case the vaccine was carried over a
period of fifteen months.

                          MODE OF TREATMENT.
      When the case presents itself the patient is  studied thoroughly
 from all standpoints, especial attention being paid to focal infection,
teeth, tonsils, sinuses, gall-bladder, stools, etc.  If the patient presents
gastro-intestinal symptoms fractional gastric analysis, feces examina-
tion and x-ray studies are made.       The colonic stasis which is  rather
frequent in this type of case is corrected by diet and frequent colonic
irrigation, using large quantities of water.       The patient is  usually
undernourished, especially so in young people and I always encour-
age forced feeding; diets of special food have not proven satisfactory
in any other way.     For the past few years I have been making com-
plete  blood  studies  including  complement fixation  tests  and the
examination of urea, nitrogen, blood sugar, uric acid, creatinin and
the chlorides.    It has proven very discouraging with the exception 
of an occasional high uric acid content.      This I believe is of extreme
 importance in helping to differentiate some of these cases.          One of
 my cases has a combination of a rheumatoid and gouty arthritis.
 She runs a rather persistent high blood uric acid.         When the gall-
 bladder is under question the bacteriology of the bile is studied after
 asceptic  transduodenal lavage.       Surgery is  only employed after  a
 proved focus has been found.        Needless to  say that other various
 x-ray studies are made as indicated, including the joints themsleves.
 These patients are usually placed in hospitals for a short time during
 the starting of the vaccine.    Rest is a very essential element in these
 cases and a few weeks in bed usually affords benefit.          At the same
 time it accustoms the patient to the reaction of the vaccine.
      In starting the vaccine it is very essential to start with a small
 dose, usually i minim in 1 cc. salt solution or sterile water.       This is
 given subcutaneously.     Three types of reaction are experienced, focal,
 local and general.    It has been my practice to tell these people that
 after the vaccine injection they will have pain in joints heretofore
 unknown to  be involved.        The pain  in  the joints  is  invariably
 increased after the first  four or five injections.   This thereafter will
 gradually be diminished and the period of freedom from pain will
 gradually be increased.     At the site of injection a marked erythe-
matous area develops.      The fluid is quite irritating and at times you
will think of abscess formation.       This I have not experienced but
 for  a  week or more the  hard  indurated  nodules persist.           These
patients are very hypersensitive to the vaccine and the dose must be
increased very slowly.       This hypersensitivity persists  surprisingly
throughout the course of treatment and varies with each individual.
The largest dose of vaccine given was 10 minims and that after eight
months treatment.       In the case of fifteen years duration in which
we obtained a beautiful result, I could never give over four minims
without causing a general reaction.       It is to be remembered that in
these  cases  of  long  standing  the  patient  is    usually  anemic and
markedly undernourished.       Thepain has been severe and their nerve
has been broken.      Consequently it  is important to try and avoid a
general reaction.    While this does not do the patient any harm, it is
bad from a psychological standpoint.         In addition they have been
through so many hands and tried so many forms of treatment that
they are always dubious of any new form of treatment and especially
so if they are to have more pain in the beginning.
     The time interval of the injections varies from three to four days
at the beginning, gradually being lengthened to five or six days, as
the symptoms improve.         It has been my rule to gage the time of
injection and the size of the dose entirely upon the local reaction.        If
it be severe the same dose is  repeated.       At times it  is necessary to
repeat the same dose as many as four or five times before increasing
the vaccine.   Especially is this true as the larger doses are used.  The
vaccine is  continued until  the patient is  clinically well.       Unfortu-
nately the time of stopping the vaccine is  entirely emperical as I
know of no way of  telling  when the infection  has been entirely
killed out.
     The benefits derived are a diminution of pain plus a loosening
up of the joints.   The acute exacerbations which are so characteristic
of the disease gradually diminish and are finally obliterated.           It is
remarkable to see the rapidity of diminution in the size of the joint.
The patient through his own efforts will begin to move the joint and
loosen it  up as soon as the pain subsides.        In the febrile cases the
temperature gradually returns to the normal course.            The patient's
general health improves and he soon loses his toxic appearance.           The
gain in weight is quite remarkable.  Onepatient who has been under
treatment for the past seven months has gained forty-two pounds.
     At the beginning of the treatment in addition to clearing up foci
of  infection,  rest  and vaccine therapy, the patient  is  given daily
electric bakes to the joints involved; this quite frequently being a
general body bake.      Care is taken not to massage the joints or the
atrophic surrounding structures until after the acute tenderness and
swelling have subsided to  a great extent.          When the massage is
started it  is of the most gentle character, care being exerted not to
traumatize  an already  diseased  tissue.        Manipulation,  extension,
deep massage and other mechanical devices are only resorted to when
the patient is well  toward recovery.        The fibrositis  in  some cases
persists and occasionally it is necessary to stretch the muscles under
an anesthetic.    Casts are applied but are removed each day for the
bake, massage and manipulation.
      In conclusion it must be said that the treatment of these cases
is as complex as their source of infection.     The more thoroughly they
are  studied  the  more  frequently  I  believe  we will        find  definite
evidence of streptococcus infection.      Unfortunately the streptococcus
does not lend itself  to the formation of agglutinins or precipitins;
consequently serological  tests,  so far have failed  to  give us any
definite information.    Coley's mixed toxins when used cautiously and
over a prolonged period of time have in our hands given us a very
satisfactory and pleasing result.