821
EDITORIALS
Topical BCG for recurrent superficial bladder cancer During the period from 1967 to 1976, bacille Calmette-Guerin (BCG) was evaluated as an immune adjuvant for the treatment of virtually all types of cancer. This research was stimulated by results obtained in laboratory animalsl and by preliminary observations in children with acute lymphoblastic leukaemia.2 However, the overall outcome was disappointing: with the exception of bladder cancer, there was no clear evidence of any benefit of these immunological manipulations on survival of cancer patients.3 Furthermore, because animal studies had shown the greatest benefit in small-volume disease, adjuvant BCG was mainly used in patients without
measurable metastases (50% reduction of product of diameters of measurable metastases is the minimum criterion for treatment-induced response in phase 2 studies). Consequently it was far from clear whether this treatment failed because the dose was insufficient antitumour immune response or because that response was irrelevant to cancer resistance in man. Ten years later the durable complete remission achieved after interleukin-2 treatment in melanoma patients with measurable metastases, and the detection of HLA-restricted autologous tumourspecific cytotoxic T lymphocytes (the halhnark of specific antitumour response) among the cells infiltrating tumours, provided the first real indication that augmentation of host immune response could influence survival of cancer patients. These HLArestricted tumour lymphocytes, expanded by IL-2 and labelled with a neomycin resistance gene, were reinjected into the autologous host where they homed to tumour cell masses, which subsequently regressed.4 The results of Nitta et alwho studied T-cell receptors on tumour-infiltrating lymphocytes and found restricted variable region V alpha 7 gene polymorphisms, provided the final link between oligoclonal HLA-restricted T lymphocytes and
to alter
rejection. Although these observations
tumour
enthusiasm
was
were
encouraging,
short lived because there
was
little
evidence that this principle applied to tumours other than melanoma. In this context the focus has switched to superficial bladder cancer, the one exception in the BCG studies of the 1970s. Even in 1976, when interest in BCG was waning fast, the results obtained by Morales and colleagues6 in a mere 9 patients, 8 of whom remained clear of tumour at 12 months, were impressive compared with the outcome of BCG therapy in most other tumour types. However, little notice was taken of these findings for two reasons. First, many treatments had been tried for superficial bladder cancer-from silver nitrate to formalin and including virtually all the direct acting cytotoxic agents-and there was little to choose between them.7 Second, too many urologists, especially in the UK, were familiar with the late effects of urinary tuberculosis, which produces a shrunken bladder and death from ureteric obstruction. Lamm et al8 were the first to confirm Morales’ observation, but interest in this approach remained modest until randomised trials had shown that results with BCG were better than those achieved with chemotherapy such as thiotepa and doxorubicin.9-11 In the USA, the discovery that BCG was equally effective in patients with recurrent papillary and flat in-situ carcinoma12 was another important step in making doctors aware of this treatment, whereas in the UK doubts about chronic fibrosis of the bladder persisted. Publication of 5-year follow-up information on response and toxicity13,14 showed that continuous disease-free survival was 20% better than with intravesical chemotherapy. The most serious sideeffect during the course of treatment was dysuria, which occurred in up to 50% of patients at some stage, was more frequent than with intravesical chemotherapy, but usually resolved within 2-3 days; there was no evidence of later contracted bladder. 15 As a consequence of these studies two strains of BCGConnaught and Tice-have now been licensed for use in superficial bladder cancer in the USA. Quality control of these products before marketing had to be far more stringent than that used for BCG as an anti-tuberculosis vaccine because samples with poor viability produced an inferior tumour
response.16 Studies in the UK are less advanced, although two trials are in progress. In a trial organised by the Medical Research Council, Glaxo/Evans BCG, which has been lyophilised and has a reasonable shelf-life, is being compared with the Pasteur fresh material, which is more difficult to store but produces a stronger immune response. The results of this study could have an important bearing on whether BCG becomes established in routine clinical practice. Ever since the early days of BCG therapy in leukaemia, French and British immunologists have debated whether there is any difference between the two preparations, and the results of this trial (77 of a planned 100 patients have been recruited) are eagerly awaited. In Scotland
822
interest in BCG has been more widespread17 and patients with flat in-situ carcinoma are being recruited for a study of maintenance therapy. The results from studies with BCG world wide provide strong justification for the licensing of these products. However, there is little doubt that toxicity is occasionally very serious-eg, systemic BCG infection including hepatitis15-and there has been some anxiety that there might be an increased frequency of nonurological cancers.18 Although such events occur in less than 5% of patients, they are by no means negligible and overall there has been about 0-5% treatment-related mortality.15 What is the mechanism of the BCG effect? There are some pointers to an HLA-restricted T-cell response. First, there is clear evidence that treatment induces HLA class II antigen expression on tumour cells,19 and second there is direct correlation between the amount of interleukin-2 released into the urine following therapy and response.2° Further studies in this area are required, especially since there are reports of loss of HLA class I antigen expression in bladder cancer1 and the switching on of beta human chronic gonadotropin expression as escape mechanisms for tumours that become invasive and metastasise.22 There is also a need for more serious study of these tumours for papilloma virus antigens in view of case-reports of bladder tumours containing HPV 11I DNA developing in patients taking immuno-
suppressive drugs 23 How about reducing the toxicity of treatment? There has been little progress, although other immunological treatments have been studied, including BRM OK432, which is aT-lymphocyte stimulant produced as an extract from staphylococcal cultures. A drawback of this agent is the need for administration by weekly intradermal injection. The effects resemble those of BCG in respect of preventing recurrence of bladder tumours.24 Preclinical studies of another agent, LS2616 (’Linamide’), which augments immune rejection of tumours when taken orally25 indicate that this option may be worth exploring. 1. Old LJ, Clarke DA, Benacerraf B. Effect of bacillus Calmette-Guérin infection on transplanted tumours in the mouse. Nature 1959; 184: 291-92. 2. Mathé G, Amiel JL, Schwartzenberg L. Active immunotherapy for acute lymphoblastic leukaemia. Lancet 1969; i: 697-99. 3. Oliver RTD. Biology of host/tumour cell interaction. In: Chisholm GD, Williams DI, eds. Scientific foundations of urology. 2nd ed. London: Heinemann, 1982: 624-31. 4. Rosenberg SA, Aebersold P, Cometta K, et al. Gene transfer into
humans-immunotherapy of melanoma using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med 1990; 323: 570-78. 5. Nitta T, Oksenberg JR, Rao NA, Steinman L. Predominant expression of T cell receptor V&agr; 7 in tumor-infiltrating lymphocytes of uveal melanoma. Science 1990; 249: 672-73. 6. Morales A, Eidinger D, Bruce AW. Intracavity bacillus Calmette-Guérin in the treatment of superficial bladder tumors. J Urol 1976; 116: 183. 7. Fitzpatrick JM, Khan O, Oliver RTD, Riddle PR. Long term follow-up in patients with superficial bladder tumours treated with intravesical epodyl. Br J Urol 1979; 51: 545-49. 8. Lamm DL, Thor DE, Harris SC, et al. Bacillus Calmette-Guérin immunotherapy of superficial bladder cancer. J Urol 1980; 124: 28.
9.
Sarosdy MF, Lamm DL. Long term results of intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer. J Urol 1989;
142: 719-22. 10. Martinez-Pineiro
JA, Jimenez-Leon J, et al. Bacillus Calmette-Guérin thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol 1990; 143: 502-06. 11. Jauhiainen K, Rintala E, Alfthan O. Immunotherapy (BCG) versus chemotherapy (MMC) in intravesical treatment of superficial urinary bladder cancer. In: de Kerrion JB, ed. Immunotherapy of urological tumours. Edinburgh: Churchill Livingstone, 1990: 13-26. 12. Herr HW, Pinsky CM, Whitmore WF Jr, Sogani PC, Oettgen HF, Melamed MR. Long term effect of bacillus Calmette-Guérin on flat carcinoma in situ of the bladder. J Urol 1986; 135: 265-71. 13. Sarosdy MF, Lamm DL. Long term results of intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer. J Urol 1989; versus
142: 719-22. 14. Martinez-Pineiro JA. BCG vaccine in superficial bladder tumours: eight years later. Eur Urol 1984; 10: 93-98. 15. Lamm DL. Complications of bacillus Calmette-Guérin immunotherapy in 1278 patients with bladder cancer. J Urol 1986; 135: 272-74.
16. Kelley DR, Ratliff TL, Catalona WJ, et al. Intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer: effect of bacillus Calmette-Guérin viability on treatment results. J Urol 1985; 134: 48-53. 17.
Gumming JA, Hargreave TB, Webb JN, McIntyre MA, Chisholm GD.
Intravesical Evans bacille Calmette-Guérin in the treatment of carcinoma in situ. Br J Urol 1989; 63: 259-63. 18. Khanna OP, Chou RH, Cottone R, et al. Does bacillus Calmette-Guérin immunotherapy accelerate growth and cause metastatic spread of second primary malignancy? Urology 1988; 31: 459-68. 19. Prescott S, James K, Busuttil A, Hargreave TB, Chisholm GD, Smyth JF. HLA DR expression by high grade superficial bladder cancer treated with BCG. Br J Urol 1989; 63: 264-69. 20. Fleischmann JD, Toosi Z, Ellner DB, Wentworth BS, Ratliff TL, Imbembo AL. Urinary interleukins in patients receiving intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer. Cancer 1989; 64: 1447-54. 21. Nouri AME, Smith MEF, Crosby D, Oliver RTD. Selective and non-selective immunoregulatory molecules (HLA-A, B, C antigens and LFA-3) in transitional cell carcinoma. Br JCancer 1990; 62: 603-06. 22. Oliver RTD, Nouri AME, Crosby D, et al. Biological significance of beta hCG, HLA and other membrane antigen expression on bladder tumours and their relationship to tumour infiltrating lymphocytes (TIL). J Immunogenet 1990; 16: 381-90. 23. Querci Della Rovere G, Oliver RTD, McCance DJ, Castro JE. Development of bladder tumour containing HPV type 11 DNA after renal transplantation. Br J Urol 1989; 62: 36-38. 24. Nakagami YJ, Kishimoto T, Matsumoto K. Evaluated study on immunotherapy (BRM. OK432) to prevent postoperative recurrence of superficial bladder cancer. J Cancer Res Clin Oncol 1990; 116 (suppl 1): abstr B4.209.20. 25. Kalland T. Effects of the immunomodulator LS2616 on growth and metastasis of murine B16F10 melanoma. Cancer Res 1986; 46: 3018.
Human rabies: strain identification reveals lengthy incubation Now that differences between strains of street rabies virus can be detected, the origin of a particular rabies virus isolate can be tracked down to its likely animal vector species and geographic location. Virus typing depends on the pattern of reactions with a panel of monoclonal antibodies, and on analysis of viral cDNA with the polymerase chain reaction.1 The source of infection was unknown in four of ten patients who died of rabies in the USA in the 1980s. The infecting rabies viruses of three, all immigrants, were analysed by Smith and her colleagues1 with the new typing techniques. The three strains differed from those of rabid American skunks, foxes, and bats, but were indistinguishable from street viruses originating from or near Mexico, Laos, or the
EDITORIALS
Topical BCG for recurrent superficial bladder cancer During the period from 1967 to 1976, bacille Calmette-Guerin (BCG) was evaluated as an immune adjuvant for the treatment of virtually all types of cancer. This research was stimulated by results obtained in laboratory animalsl and by preliminary observations in children with acute lymphoblastic leukaemia.2 However, the overall outcome was disappointing: with the exception of bladder cancer, there was no clear evidence of any benefit of these immunological manipulations on survival of cancer patients.3 Furthermore, because animal studies had shown the greatest benefit in small-volume disease, adjuvant BCG was mainly used in patients without
measurable metastases (50% reduction of product of diameters of measurable metastases is the minimum criterion for treatment-induced response in phase 2 studies). Consequently it was far from clear whether this treatment failed because the dose was insufficient antitumour immune response or because that response was irrelevant to cancer resistance in man. Ten years later the durable complete remission achieved after interleukin-2 treatment in melanoma patients with measurable metastases, and the detection of HLA-restricted autologous tumourspecific cytotoxic T lymphocytes (the halhnark of specific antitumour response) among the cells infiltrating tumours, provided the first real indication that augmentation of host immune response could influence survival of cancer patients. These HLArestricted tumour lymphocytes, expanded by IL-2 and labelled with a neomycin resistance gene, were reinjected into the autologous host where they homed to tumour cell masses, which subsequently regressed.4 The results of Nitta et alwho studied T-cell receptors on tumour-infiltrating lymphocytes and found restricted variable region V alpha 7 gene polymorphisms, provided the final link between oligoclonal HLA-restricted T lymphocytes and
to alter
rejection. Although these observations
tumour
enthusiasm
was
were
encouraging,
short lived because there
was
little
evidence that this principle applied to tumours other than melanoma. In this context the focus has switched to superficial bladder cancer, the one exception in the BCG studies of the 1970s. Even in 1976, when interest in BCG was waning fast, the results obtained by Morales and colleagues6 in a mere 9 patients, 8 of whom remained clear of tumour at 12 months, were impressive compared with the outcome of BCG therapy in most other tumour types. However, little notice was taken of these findings for two reasons. First, many treatments had been tried for superficial bladder cancer-from silver nitrate to formalin and including virtually all the direct acting cytotoxic agents-and there was little to choose between them.7 Second, too many urologists, especially in the UK, were familiar with the late effects of urinary tuberculosis, which produces a shrunken bladder and death from ureteric obstruction. Lamm et al8 were the first to confirm Morales’ observation, but interest in this approach remained modest until randomised trials had shown that results with BCG were better than those achieved with chemotherapy such as thiotepa and doxorubicin.9-11 In the USA, the discovery that BCG was equally effective in patients with recurrent papillary and flat in-situ carcinoma12 was another important step in making doctors aware of this treatment, whereas in the UK doubts about chronic fibrosis of the bladder persisted. Publication of 5-year follow-up information on response and toxicity13,14 showed that continuous disease-free survival was 20% better than with intravesical chemotherapy. The most serious sideeffect during the course of treatment was dysuria, which occurred in up to 50% of patients at some stage, was more frequent than with intravesical chemotherapy, but usually resolved within 2-3 days; there was no evidence of later contracted bladder. 15 As a consequence of these studies two strains of BCGConnaught and Tice-have now been licensed for use in superficial bladder cancer in the USA. Quality control of these products before marketing had to be far more stringent than that used for BCG as an anti-tuberculosis vaccine because samples with poor viability produced an inferior tumour
response.16 Studies in the UK are less advanced, although two trials are in progress. In a trial organised by the Medical Research Council, Glaxo/Evans BCG, which has been lyophilised and has a reasonable shelf-life, is being compared with the Pasteur fresh material, which is more difficult to store but produces a stronger immune response. The results of this study could have an important bearing on whether BCG becomes established in routine clinical practice. Ever since the early days of BCG therapy in leukaemia, French and British immunologists have debated whether there is any difference between the two preparations, and the results of this trial (77 of a planned 100 patients have been recruited) are eagerly awaited. In Scotland
822
interest in BCG has been more widespread17 and patients with flat in-situ carcinoma are being recruited for a study of maintenance therapy. The results from studies with BCG world wide provide strong justification for the licensing of these products. However, there is little doubt that toxicity is occasionally very serious-eg, systemic BCG infection including hepatitis15-and there has been some anxiety that there might be an increased frequency of nonurological cancers.18 Although such events occur in less than 5% of patients, they are by no means negligible and overall there has been about 0-5% treatment-related mortality.15 What is the mechanism of the BCG effect? There are some pointers to an HLA-restricted T-cell response. First, there is clear evidence that treatment induces HLA class II antigen expression on tumour cells,19 and second there is direct correlation between the amount of interleukin-2 released into the urine following therapy and response.2° Further studies in this area are required, especially since there are reports of loss of HLA class I antigen expression in bladder cancer1 and the switching on of beta human chronic gonadotropin expression as escape mechanisms for tumours that become invasive and metastasise.22 There is also a need for more serious study of these tumours for papilloma virus antigens in view of case-reports of bladder tumours containing HPV 11I DNA developing in patients taking immuno-
suppressive drugs 23 How about reducing the toxicity of treatment? There has been little progress, although other immunological treatments have been studied, including BRM OK432, which is aT-lymphocyte stimulant produced as an extract from staphylococcal cultures. A drawback of this agent is the need for administration by weekly intradermal injection. The effects resemble those of BCG in respect of preventing recurrence of bladder tumours.24 Preclinical studies of another agent, LS2616 (’Linamide’), which augments immune rejection of tumours when taken orally25 indicate that this option may be worth exploring. 1. Old LJ, Clarke DA, Benacerraf B. Effect of bacillus Calmette-Guérin infection on transplanted tumours in the mouse. Nature 1959; 184: 291-92. 2. Mathé G, Amiel JL, Schwartzenberg L. Active immunotherapy for acute lymphoblastic leukaemia. Lancet 1969; i: 697-99. 3. Oliver RTD. Biology of host/tumour cell interaction. In: Chisholm GD, Williams DI, eds. Scientific foundations of urology. 2nd ed. London: Heinemann, 1982: 624-31. 4. Rosenberg SA, Aebersold P, Cometta K, et al. Gene transfer into
humans-immunotherapy of melanoma using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med 1990; 323: 570-78. 5. Nitta T, Oksenberg JR, Rao NA, Steinman L. Predominant expression of T cell receptor V&agr; 7 in tumor-infiltrating lymphocytes of uveal melanoma. Science 1990; 249: 672-73. 6. Morales A, Eidinger D, Bruce AW. Intracavity bacillus Calmette-Guérin in the treatment of superficial bladder tumors. J Urol 1976; 116: 183. 7. Fitzpatrick JM, Khan O, Oliver RTD, Riddle PR. Long term follow-up in patients with superficial bladder tumours treated with intravesical epodyl. Br J Urol 1979; 51: 545-49. 8. Lamm DL, Thor DE, Harris SC, et al. Bacillus Calmette-Guérin immunotherapy of superficial bladder cancer. J Urol 1980; 124: 28.
9.
Sarosdy MF, Lamm DL. Long term results of intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer. J Urol 1989;
142: 719-22. 10. Martinez-Pineiro
JA, Jimenez-Leon J, et al. Bacillus Calmette-Guérin thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol 1990; 143: 502-06. 11. Jauhiainen K, Rintala E, Alfthan O. Immunotherapy (BCG) versus chemotherapy (MMC) in intravesical treatment of superficial urinary bladder cancer. In: de Kerrion JB, ed. Immunotherapy of urological tumours. Edinburgh: Churchill Livingstone, 1990: 13-26. 12. Herr HW, Pinsky CM, Whitmore WF Jr, Sogani PC, Oettgen HF, Melamed MR. Long term effect of bacillus Calmette-Guérin on flat carcinoma in situ of the bladder. J Urol 1986; 135: 265-71. 13. Sarosdy MF, Lamm DL. Long term results of intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer. J Urol 1989; versus
142: 719-22. 14. Martinez-Pineiro JA. BCG vaccine in superficial bladder tumours: eight years later. Eur Urol 1984; 10: 93-98. 15. Lamm DL. Complications of bacillus Calmette-Guérin immunotherapy in 1278 patients with bladder cancer. J Urol 1986; 135: 272-74.
16. Kelley DR, Ratliff TL, Catalona WJ, et al. Intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer: effect of bacillus Calmette-Guérin viability on treatment results. J Urol 1985; 134: 48-53. 17.
Gumming JA, Hargreave TB, Webb JN, McIntyre MA, Chisholm GD.
Intravesical Evans bacille Calmette-Guérin in the treatment of carcinoma in situ. Br J Urol 1989; 63: 259-63. 18. Khanna OP, Chou RH, Cottone R, et al. Does bacillus Calmette-Guérin immunotherapy accelerate growth and cause metastatic spread of second primary malignancy? Urology 1988; 31: 459-68. 19. Prescott S, James K, Busuttil A, Hargreave TB, Chisholm GD, Smyth JF. HLA DR expression by high grade superficial bladder cancer treated with BCG. Br J Urol 1989; 63: 264-69. 20. Fleischmann JD, Toosi Z, Ellner DB, Wentworth BS, Ratliff TL, Imbembo AL. Urinary interleukins in patients receiving intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer. Cancer 1989; 64: 1447-54. 21. Nouri AME, Smith MEF, Crosby D, Oliver RTD. Selective and non-selective immunoregulatory molecules (HLA-A, B, C antigens and LFA-3) in transitional cell carcinoma. Br JCancer 1990; 62: 603-06. 22. Oliver RTD, Nouri AME, Crosby D, et al. Biological significance of beta hCG, HLA and other membrane antigen expression on bladder tumours and their relationship to tumour infiltrating lymphocytes (TIL). J Immunogenet 1990; 16: 381-90. 23. Querci Della Rovere G, Oliver RTD, McCance DJ, Castro JE. Development of bladder tumour containing HPV type 11 DNA after renal transplantation. Br J Urol 1989; 62: 36-38. 24. Nakagami YJ, Kishimoto T, Matsumoto K. Evaluated study on immunotherapy (BRM. OK432) to prevent postoperative recurrence of superficial bladder cancer. J Cancer Res Clin Oncol 1990; 116 (suppl 1): abstr B4.209.20. 25. Kalland T. Effects of the immunomodulator LS2616 on growth and metastasis of murine B16F10 melanoma. Cancer Res 1986; 46: 3018.
Human rabies: strain identification reveals lengthy incubation Now that differences between strains of street rabies virus can be detected, the origin of a particular rabies virus isolate can be tracked down to its likely animal vector species and geographic location. Virus typing depends on the pattern of reactions with a panel of monoclonal antibodies, and on analysis of viral cDNA with the polymerase chain reaction.1 The source of infection was unknown in four of ten patients who died of rabies in the USA in the 1980s. The infecting rabies viruses of three, all immigrants, were analysed by Smith and her colleagues1 with the new typing techniques. The three strains differed from those of rabid American skunks, foxes, and bats, but were indistinguishable from street viruses originating from or near Mexico, Laos, or the
