Th1 Th2 Autoimmune Disease Cancer Immunomodulation
Dr. O'Donnell started by citing the some history relating to immunotherapy and cancer. He stated that in 1891 Coley first injected cancers with bacterial toxins and saw tumor shrinkage. In 1929 Pearl noted that lower cancer rates in tuberculosis patients by autopsy series. In 1976 Morales used intravesical BCG in bladder cancer patients. Use of BGC resulted in decreased tumor cells in cytology specimens, but more neutrophils, suggesting an immune response.
Cytokine production of interleukins is central to the immune response. T cells are stimulated to the bladder after BCG therapy and are present for months thereafter. Interferon-gamma (IFN-gamma) is upregulated and participates in cellular immunity. IFN-gamma is always the last cytokine to come up and may be influenced by more proximal cytokines in the pathway. IL-10 knockout experiments showed that IFN-gamma is critical to the response.
IFN-gamma production is from BCG-stimulated human peripheral blood mononuclearcytes. Cox-2 inhibitors or indocin also inhibit IFN-gamma expression. BCG + IFN-gamma accentuates a type I cytokine response, suggesting that IFN-gamma may suppress IL-10. Response to BCG was increased if IFN-gamma was added. In fact, adding IFN-gamma and decreasing BCG maintains effectiveness.
TRAIL, an apoptosis inducing ligand was found to have higher urine levels in BCG responders vs. non-responders. TRAIL is strongly associated with neutrophils and is increased by IFN-gamma and alpha. BCG promoted cleavage of soluble TRAIL: from neutrophils and a Phase II trial using BCG + IFN-alpha. However, for those who have failed BCG twice, there does not seem to be benefit using the BCG-IFN-alpha. Other trials underway include adenoviral cytokine gene therapy and new gene polymorphisms that affect BCG anti-tumor response are being identified. Useful markers of BCG response are needed to help stratify patients and the basis for BCG failure needs to be better identified. This is an exciting area of research that will improve outcomes for patients in the future.
BCG: The Current Treatment of Choice for Bladder Cancer
Max Sherman, BSPharm
Published Online: September 1, 2007 - 12:00:00 AM (CDT)
After a recent physical examination, 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 is then taken at timed intervals. The resulting films allow the radiologist to view the entire urinary tract. Unfortunately, the diagnosis revealed that my wife had bladder cancer, a well-differentiated papillary tumor, which fortunately 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 Bacille Calmette-Gu?rin (BCG) vaccine instillations?-a treatment that controls superficial bladder cancer, particularly carcinoma in situ. I was surprised to learn that an ancient vaccine, originally designed to prevent tuberculosis (TB), is employed for a completely unrelated indication and is the current treatment of choice for bladder cancer. I thought that other pharmacists might be as curious as I was to learn more about the drug, its discovery, and its alternative use.
History 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 TB in cattle. The culture was highly virulent for many types of animals, and probably for humans, but it became progressively weakened while being cultivated in the test tube by French bacteriologists Albert Calmette and Camille Gu?rin.1
This cultivation 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 in honor of 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 into tuberculous families.4 At first, the vaccine was administered by mouth and only to newborn infants.1 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 TB for a duration of 15 years. One third of clinical trials have shown no protective effect, however.5
Despite the questions about its efficacy, only a few countries do not use BCG for routine vaccination. This situation may change in the future, however, with recent evidence that older versions of the vaccine may be more effective than some of the more recent strains.6 In the United States, 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.5
History 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 Raymond Pearl at Johns Hopkins Hospital in 1929 was one of the first reports that documented a lower frequency of cancer in patients with TB.3 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.7
In 1976, Morales, Eidinger, and Bruce were the first to report on successful treatment of superficial bladder cancer with intravesical (within the bladder) BCG.8 They were able to demonstrate a remarkable decrease in the rates of recurrence in 9 patients. A randomized prospective trial by Donald Lamm and associates in 1980 confirmed these earlier observations.9
BCG is now regarded as the most successful urologic 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 of approximately 1 million doses.2
Mechanism of Action
The initial crucial step in BCG therapy seems to be the binding of mycobacteria to the urothelial 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 the activation of urothelial and antigen-presenting cells.2 This action 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, as well as macrophages.3
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 fact may explain why live attenuated BCG is necessary for successful intravesical BCG therapy.3
It is important to note that this activity in patients? bladders can persist for more than 1 year after the initial 6-week therapeutic induction course, but it commonly begins to wane after 3 to 6 months. This result provides the rationale for maintenance therapy.
Treatment Regimen
Standard treatment consists of a once-weekly instillation of BCG for 6 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 on each side for 15 minutes. Alternatively, some urologists recommend that the instillation be retained in the bladder for 2 hours. This duration ensures that all of the bladder mucosa comes into contact with the BCG.
Caution is suggested in handling the BCG because of a small risk of TB 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 materials.
Patients should be advised to pour 2 cups of household bleach into their toilets after urinating to neutralize any BCG that may be found in the urine. The medication and bleach should remain in the toilet for 15 to 20 minutes before flushing. Patients should be advised to wash their hands and genital areas thoroughly after urinating and to drink plenty of fluids after each instillation to flush the bladder.
At the conclusion of the 6-week course, the patient undergoes a cystoscopy. If the bladder is free of tumor recurrence, then the patient is entered into a program of regular cystoscopic follow- up. If the tumor recurs, then the patient can, after resection, have a further course of BCG.3
Side Effects and Contraindications
Specific side effects are common. The most frequent are abacterial cystitis and dysuria, hematuria, and a 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 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 positive HIV serology.
References
1. Dubos R, Dubos J. The White Plague. New Brunswick, NJ: Rutgers University Press; 1952.
2. Bohle A, Sven B. Immune mechanisms in Bacillus Calmette Guerin immunotherapy for superficial bladder cancer. J Urol. 2003;170:964-969.
3. Meyer JP, Persad R, Gillatt DA. Use of bacille Calmette-Guerin in superficial bladder cancer. Postgrad Med J. 2002;78:449-454.
4. Fine PEM, Carneiro IAM, Milstien JB, Clements CJ. Issues relating to the use of BCG in immunization programmes. Geneva, Switzerland: World Health Organization; 1999.
5. http://en.wikipedia.org. Accessed January 18, 2007.
6. Brosch R, Gordon SV, Garnier T, et al. Genome plasticity of BCG and impact on vaccine efficacy. Proc Natl Acad Sci USA. 2007;104:5596-5601.
7. Coe JE, Feldman JD. Extracutaneous delayed hypersensitivity, particularly in guinea pig bladder. Immunology. 1966;10:127-136.
8. Morales A, Eidinger D, Bruce AW. Intracavity Bacille Calmette-Guerin in the treatment of superficial bladder tumors. J Urol.1976; 116:180-183.
9. Lamm DL, Thor DE, Harris SC, Reyna JA, Stogdill VD, Radwin HM. Bacille Calmette-Guerin immunotherapy of superficial bladder cancer. J Urol. 1980;124:38-40.
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