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In the past two decades, the most successful immunotherapy in man probably consisted of non-specific immunotherapy with BCG for superficial bladder cancer. This intravesical therapy was first introduced by Morales in 1976 [1].

Superficial papillary bladder cancer is not, in most cases, a lethal disease but it is characterized by a high percentage of recurrences (60–80%) and a much lower percentage of progression to invasive, potentially lethal bladder cancer (15%) [2]. The initial therapy for this disease is surgery, and adjuvant intravesical chemotherapy has been used to reduce recurrences and prevent progression. The latter, however, has not been successful, as shown in multiple randomized clinical trials [3].

Zbar et al. formulated the conditions for which BCG in an optimal situation could work against malignant tumours [4]. These meant that: (i) direct contact between tumour cells and BCG is mandatory; (ii) an adequate dose of BCG is necessary; (iii) BCG will work only when the tumour burden is limited; (iv) not only the tumour but also lymph node metastases draining from the parent organ may disappear.

Morales projected the conditions of Zbar et al. to superficial bladder cancer, where it was easy to bring BCG in a watery solution through the urethra into the bladder, directly in contact with tumour cells. BCG turned out to be superior to any of the known chemotherapeutic drugs. In some selected series, it seems that BCG is able to prevent progression to invasive bladder cancer [5]. However, a number of problems remain despite intensive research during the past 20 years.

Urologists still do not know whether there is an optimal strain of BCG. All the known BCG strains are derived from the original strain found by Calmette and Guérin. This product was the result of an attempt to find an attenuated strain of a highly virulent bovine tuberculosis strain that was to serve as a vaccine against human tuberculosis. By prolonged culture the bovine tubercular strain lost its virulence and its pathogenic characteristics but its immunogenic properties remained unaffected [6].

It took Calmette and Guérin 13 years of culture with 230 consecutive transplants to tame the bacterium. During this period mutation and genetic drift had taken place. After exporting the strain all over the world the genetic drift must have gone further, resulting in different therapeutic results and immunogenic properties [7]. In relation to bladder cancer, few studies have been performed to compare the effects of different strains [8]. Aside from the question as to which strain is superior, the optimal dose and instillation regimen of BCG are also still unknown.

However, the most intriguing problem that remains is that we do not know exactly how BCG works. There is a cascade of immunological events which depends upon the host, dose and regimen and which can lead to immunostimulation, as well as to inhibition, of immune reactions [9]. In the case of superficial bladder cancer, the immune response is translated into the urinary secretion of cytokines such as interferon-alpha (IFN-α), IFN-γ and IL-2. Although not yet tested in large series of patients, the level of cytokines secreted seems to be related to the clinical outcome for patients with superficial bladder tumours [10].

The authors Luo et al. in this issue of Clinical and Experimental Immunology[11] take a major step forwards in the use and understanding of how BCG works in human bladder cancer. As Calmette and Guérin had done, they altered the genetic properties of tubercle bacilli but this time by using recombinant BCG (rb-BCG) and incorporating the human IFNα 2B gene. Such genetic modification may lead to a greater clinical efficacy and fewer side-effects of BCG immunotherapy, although this has yet to be established. Luo et al. then elegantly showed that this rb-BCG incorporating the human IFNα 2B gene induced increased production of both recombinant human IFN-α (rh-IFN-α) and IFN-γ, compared with wild-type BCG. This production was inhibited upon antibody neutralization of rh-IFN-α, indicating that the genetic alteration was responsible for the increased immunostimulation. Both in vitro and with peripheral blood mononuclear cells from 10 patients, the authors showed an immune response to rb-BCG which was also more rapid than that to wild-type BCG.

This work is important for two reasons. First, it may lead to a better understanding of how BCG exerts its anti-tumour effect in bladder cancer, and second, it may be a step towards developing a BCG product with higher efficacy and lower toxicity for patients than the wild types of BCG. Further work is required to translate Luo et al.'s studies to a clinical setting.

References

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  2. References
  • 1
    Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette–Guerin in the treatment of superficial bladder tumours. J Urol 1976; 116:180 3.
  • 2
    Lamm DJ, Van Der Meijden APM, Akaza H et al. Intravesical chemotherapy and immunotherapy: how do we assess their effectiveness and what are their limitations and uses. Int J Urol 1995; Suppl. 2:22 25.
  • 3
    Pawinsky A, Sylvester R, Kurth K-H et al. A combined analysis of European Organization for Research and Treatment of Cancer and Medical Research Council randomized clinical trials for the prophylactic treatment of Stage Ta Tl bladder cancer. J Urol 1996; 156:1934 40.
  • 4
    Zbar B, Bernstein ID, Bartlett GL, Hanna MG Jr, Rapp HJ. Immunotherapy of cancer: regression of intradermal tumours and prevention of growth of lymph node metastases after intralessional injection of living Mycobacterium bovis. J Natl Cancer Inst 1972; 49:119 30.
  • 5
    Herr HW. Tumour progression and survival in patients with T1G3 bladder tumours: fifteen year outcome. Br J Urol 1997; 80:762 8.
  • 6
    Guerin C. The history of BCG. In: RosenthalSR, ed. BCG vaccine: tuberculosis-cancer. Littleton, MA: PSG Publishing Co. Inc., 37.
  • 7
    Mackaness GB, Auclair DJ, Iagrange PH. Immunopotentiation with BCG immune response to different strains and preparations. J Natl Cancer Inst 1973; 5:1655.
  • 8
    Witjes JA, Van Der Meijden APM, Witjes WP. A randomized prospective study comparing intravesical instillations of Mitomycin-C, BCG-Tice and BCG-Rivm in pTa-pTl tumours and primary carcinomas in situ of the urinary bladder. Eur J Urol 1993; 12:1672.
  • 9
    De Boer EC, De Jong WH, Steerenberg PA et al. Induction of urinary IL-1, IL-2, IL-6 and IFN during intravesical immunotherapy with BCG in superficial bladder cancer. Cancer Immunol Immunother 1992; 34:306 12.
  • 10
    Reijke TM, De Boer LC, De Kurt K-H, Schamhart DHJ. Urinary cytokines during intravesical Bacillus Calmette–Guerin therapy for superficial bladder cancer. Processing stability and prognostic value. J Urol 1996; 155:477 82.
  • 11
    Luo Y, Chen X, Han R, O'Donnell MA. Recombinant bacille Calmette-Guerin (BCG) expressing human interferon-alpha 2B demonstrates enhanced immunogenicity. Clin Exp Immunol 2001; 123 :264 270.