Download Bacillus Calmette-Guerin— Another Surprise!

Bacillus Calmette-Guerin—
Another Surprise!
By Max Sherman
After a physical several years ago, my wife learned that red and white blood cells were
detected in her urine. The doctor ordered an intravenous pyelogram to determine the
cause. In this test, an iodine-containing contrast material is injected into the bloodstream
and a series of X-rays are then taken at timed intervals. The resulting films allow the radiologist to view the entire urinary tract.
Unfortunately, the diagnosis revealed evidence of bladder cancer, a well-differentiated papillary tumor. However, the tumor could be completely removed by transurethral
resection and fulguration. The urologist told us that a high-grade transitional type of
tumor would require the instillation of chemotherapeutic drugs such as mitomycin C or
doxorubicin.
Another option would be to use Bacillus Calmette-Guerin (BCG) vaccine instillations,
a treatment that controls superficial bladder cancer, particularly carcinoma in situ. I was
surprised to learn an ancient vaccine originally designed to prevent tuberculosis is the
current treatment of choice for bladder cancer and employed for a completely unrelated
indication.
I thought other healthcare workers might be as curious as I was to learn more about
the drug, its history, mechanism of action, treatment regimen, side effects and a surprising possible new use.
History of Tuberculosis
Live attenuated BCG vaccine is indicated for the prevention of disease associated with
Mycobacterium tuberculosis. In 1904, the organism destined to be used for the vaccine
was isolated from a case of tuberculosis in cattle. The culture was highly virulent for many
types of animals, and probably for man, but it became progressively weakened while being
cultivated in the test tube by French bacteriologists Calmette and Guerin.1
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This required 231 passages through the laboratory over a period of 13 years. Because
of the inability to preserve viable bacteria (by freezing), this live vaccine required continued
passage, eventually resulting in a profusion of phenotypically different daughter strains.2
This special Mycobacterium bovis strain was named to honor the researchers.3 Once
they were convinced of the safety and immunizing power of BCG in animals, Calmette and
his collaborators conducted a large program of vaccination of children born in tuberculosis
families.4
At first, the vaccine was administered by mouth and only to newborn infants.5 Now, the
method most commonly used consists of injecting the vaccine into the superficial layers
of the skin or depositing a drop of it on the skin and pricking with a sharp needle as is
done in smallpox vaccinations.
At best, the vaccine is 80% effective in preventing tuberculosis for 15 years. However,
one-third of clinical trials have shown no protective effect.6
Despite the questions about efficacy, only a few countries do not use BCG for routine
vaccination. This may change in the future, however, with evidence that older versions of
the vaccine may be more effective than some of the more recent strains.7
In the US, BCG generally is not administered to adults because it is felt that having a
reliable Mantoux test, and being able to accurately detect active disease, is more beneficial to society than vaccinating against a relatively rare condition.8
History of Bladder Cancer
At the beginning of the 20th century, it became known that TB patients were less likely to
contract cancer. Apparently, the disease had an antitumor effect.
An autopsy series by Dr. Raymond Pearl at Johns Hopkins Hospital in 1929 was one
of the first reports that documented a lower frequency of cancer in patients with tuberculosis.9 The mechanism is unclear.
In the 1930s, the use of BCG as a cancer therapy was first raised, but there was
little attention or enthusiasm during the 1950s and 1960s. Further research by Coe and
Feldman rekindled interest with the demonstration of a strong delayed hypersensitivity
reaction to BCG in the guinea pig bladder.10
In 1976, Morales, Eidinger and Bruce were the first to report on successful treatment
of superficial bladder cancer with intravesical (within the bladder) BCG.11 They were able to
demonstrate a remarkable decrease in the rates of recurrence in nine patients.
A randomized prospective trial by Donald Lamm and associates in 1980 confirmed
earlier observations.12 BCG now is regarded as the most successful urological immunotherapy for treating cancer. It has become the treatment of choice for high-risk, superficial
bladder cancer in most countries and it is given at an increasing annual rate.13
Mechanism of Action
The initial crucial step in BCG therapy seems to be the binding of mycobacteria to the urethelial lining, which depends on the interaction of a fibronectin attachment protein on the
bacterial surface with the fibronectin in the bladder wall. The presence of BCG then leads
to activation of urothelial and antigen presenting cells.14
This results in a massive local immune response (immunotherapy) characterized by
induced expression of cytokines in the urine and bladder tissue, and an influx of granulocytes as well as mononuclear cells into the bladder wall. After these events, a massive
cellular infiltration is seen and this local inflammatory reaction in the bladder mucosa is
characterized by large numbers of T cells, both CD4 and CD8, and macrophages.15
The contribution of CD4 T cells also is marked by the secretion of cytokines leading to
the maturation of cytotoxic T cells or possibly specific BCG-activated killer cells. The latter
are capable of differentiating between normal and tumor cells.
Only viable BCG organisms can induce the activity of the killer cells. This may explain
why live attenuated BCG is necessary for successful intravesical BCG therapy.16 It is important to note this activity in patient’s bladders can persist for more than one year after the
initial six-week therapeutic induction course, but they commonly begin to wane after three
to six months. This result provides the rationale for maintenance therapy.
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Treatment Regimen
Standard treatment consists of a once-weekly instillation of BCG for six weeks. Patients
are given live attenuated BCG mixed in 50 mL of normal saline instilled into the bladder
via a urethral catheter. The patient retains the fluid within the bladder for an hour, and
during this period the patient lies prone for 15 minutes, supine for 15 minutes and 15
minutes on each side. This ensures that all of the bladder mucosa comes into contact
with the BCG.
Caution is suggested in handling the BCG as there is a small risk of tuberculosis
infection. The staff administering the BCG should be suitably protected with masks,
goggles, gloves and gowns to avoid inhalation and contact of BCG with broken skin. All
equipment, supplies and receptacles in contact with BCG should be handled and disposed
of as biohazardous. Patients should be advised to bleach their toilets after urinating to
neutralize any BCG that may be found in the urine.
At the conclusion of the six-week course, the patient undergoes a cystoscopy. If the
bladder is free of tumor recurrence, the patient is entered into a program of regular cystoscopic follow-up. If the tumor recurs, the patient can, after resection, have a further
course of BCG.17
Side Effects, Contraindications
Specific side effects are common. The most frequent are abacterial cystitis and dysuria,
hematuria and low-grade pyrexia. These side effects usually subside within a 48-hour
period and require little more than an analgesic for treatment. In these cases, BCG treatment can continue, but if the side effects are more troublesome, increasing the time
between treatments or reducing the dose should be considered.
Contraindications include an impaired immune response caused by disease, drugs or
other therapy, pregnancy and lactation and in patients with a positive HIV serology.
Another Surprise
Recently, a number of investigators from Massachusetts General Hospital and Harvard
Medical School were involved in a trial using BCG for treating long-term type I diabetes.18
Heretofore, there had been no known drugs available that could reverse this serious and
now more prevalent disease.
Type 1 diabetes results from a genetically susceptible, immune-mediated selective
destruction of insulin-secreting beta cells and is on the rise worldwide. In the clinical trial,
the researchers in Boston were able to cure type 1 diabetes in mice, and the results in a
small number of human patients also were promising.19
According to the investigators, BCG ameliorates the advanced autoimmune process
underlying type 1 diabetes by stimulating tumor necrosis factor (TNF), which selectively
kills only disease-causing cells and further permits pancreas regeneration.20,21 Moreover,
the repeated BCG vaccinations at low doses were safe and well-tolerated.22
Final Thoughts
The more I read the current literature, the more I am amazed by the state of clinical
research here and abroad. Much of it comes from unexpected sources, such as using
fatty acids from python’s blood to treat heart disease23 or a peptide from tarantula venom
to inhibit atrial fibrillation or reduce neuropathic pain.24
Who would have guessed that BCG vaccine would be the drug of choice for bladder cancer? As therapeutically beneficial as the vaccine is for bladder cancer, its application could
be far surpassed should it be approved for new onset or long existing type 1 diabetes.
References
1. Dubos R, Dubos J. The White Plague. Rutgers University Press. New Brunswick, NJ. 1952.
2. Bohle A, Sven B. “Immune mechanisms in Bacillus Calmette Guerin immunotherapy for superficial bladder cancer.” Journal
of Urology. 2003; Vol 170:964-969.
3. Meyer JP et al. “Use of Bacille Calmette Guerin in superficial bladder cancer.” Postgraduate Medical Journal.
2002;78:449-454
4. Fine PEM et al. “Issues relating to the use of BCG in immunization programs 1999” World Health Organization.
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5. Op cit 1.
6. “Bacillus Calmette-Guerin.” Wikipedia.org. en.wikipedia.org/wiki/Bacillus_Calmette%E2%80%93Gu%C3%A9rin. Accessed 17
September 2012.
7. Brosch R et al. “Genome plasticity of BCG and impact on vaccine efficacy.” Proceedings of the National Academy of Sciences.
2007;104:5596-5601.
8. Op cit 6.
9. Op cit 3.
10. Coe JE, Feldman JD. “Extracutaneous delayed hypersensitivity, particularly in guinea pig bladder.” Immunology. 1966;
10:127-136.
11. Morales A et al. “Intracavity BCG in the treatment of superficial bladder tumors.” Journal of Urology. 1976; 116:180-183.
12. Lamm DL et al. “BCG immunotherapy of superficial bladder cancer.” Journal of Urology. 1980;124:38-40.
13. Op cit 2.
14.Ibid.
15. Op cit 3.
16.Ibid.
17.Ibid.
18. Faustman DL et al. “Proof-of-concept, randomized controlled clinical trial of Bacillus-Calmette-Guerin for the treatment of
long-term type 1 diabetes.” PLos One. 2012; Vol 7, Issue 8:e4 1756.
19. Sinha V. “BCG vaccine may reverse type 1 diabetes.” Voice of America. 11 August 2012.
20. Ryu S et al. “Reversal of established autoimmune diabetes by restoration of endogenous beta cell function.” Journal of
Clinical Investigation. 2001; 108:63-72.
21. Kodama S et al. “Islet regeneration during the reversal of autoimmune diabetes in NOD mice.” Science. 2003; 302:1223-7
22. Op cit 18.
23. Sherman M: “Pythons: Model to Study Human Heart Disease?” Regulatory Focus. www.raps.org/focus-online/science-andtechnology/science-and-technology-article/article/1775/pythons%E2%80%94a%20model%20to%20study%20human%20
heart%20disease/.aspx.aspx . Accessed 17 September 2012.
24. Sherman M. “Tarantulas: Possible Lifesavers?” Regulatory Focus. www.raps.org/focus-online/science-and-technology/
science-and-technology-article/article/2047/tarantulas-possible-lifesavers.aspx. Accessed 17 September 2012.
Author
Max Sherman is president of Sherman Consulting Services in Warsaw, IN. RAPS recently published a collection of
Sherman’s work, From Alzheimer’s to Zebrafish: Eclectic Science and Regulatory Stories. He can be reached by email by
contacting [email protected].
© 2012 by the Regulatory Affairs Professionals Society. All rights reserved.
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