349
inally used as an anthelmintic, is complex and not entirely understood; the main target may well be the macrophage, although the first effects described were in the restoration of previously depressed cell-
THE LANCET
mediated immune responses. A third class of immunopotentiators is more specific and they prob"THERE is at bottom only one genuinely scienably always potentiate rather than suppress. They tific treatment for all diseases, and that is to stimuinclude transfer factor and immune R.N.A., late the phagocytes. Stimulate the phagocytes: they which may be given as extracts or by infusion devour the disease; and the patient recovers-unof intact foreign lymphocytes which might be supless of course he’s too far gone." The almost-tooposed to be reactive to the antigens of the tumour.7 memorable words of the plausible Bloomfield This approach is inevitably more laborious and can are once from the Bonnington’ re-echoing again be used less often; thus, though there may have many meetings where the anthem of cancer imbeen occasional successes in the past, attention is can be heard. The reasons munotherapy currently now firmly turned to B.c.G., C. parvum, and for this wave of enthusiasm are easy to understand. levamisole, used with or without added tumour First of all, there is an appreciation that many cells or their antigens. human tumours may, indeed, carry antigens that The claims for B.c.G. extend back to a group of could provoke a therapeutic immune response; 50 lymphoma patients, half of whom were given there are available several secondly, immunopoten- B.c.G. in 1965-67;8 rather fewer patients relapsed tiators which are relatively easy to administer and and they did so at a mean time of 25.9 months which do not carry the same toxic risks as other compared with 10.6 months for controls. MATHÉ’S forms of cancer therapy. Of these, B.C.G.,2or the claim for B.C.G. and/or leukæmic cells in acute lymof has Freund’s adjuvant, mycobacterial component phoblastic leukæmia9 has been extensively cited but been with us for many years and has had the lonthe results have not been confirmed and the run in diseases; gest Corynebactreating malignant apparent benefit may well have been due to the terium parvum3 is more recent but increasingly exceptionally poor performance of a small group of popular; while other bacterial products such as control patients. The rather better established endotoxins and lipopolysaccharides have limited claims for immunotherapy in acute myeloid leukaeimmunopotentiating activity in certain experimen- mia 10 11 may now fail for the same reason-i.e., tal circumstances and have not been much used in that the non-immunotherapy controls had fortuiclinical immunotherapy. tously short remissions-but the claim for longer The mechanism of action of these materials is survival, which implies more frequent and betterextremely complex since the effects are mediated maintained second remissions, may yet be valid. If the of B interactions through macrophages, lym- so, however, the reasons may have nothing to do T and phocytes, lymphocytes, the last category in- with the enhancement of specific immunity. Other trials in A.M.L. may have been methodologically cluding subpopulations of cytotoxic, helper, and For cells.2-4 the effects of C. vulnerable.12 Of those trials which cannot yet be suppressor example, parvum include an increase in the production of assessed, one using neuraminidase-treated cells and stimulation of chemomethanol-extracted residue of B.C.G.(M.E.R.),is likemacrophages, macrophage increased taxis, phagocytic activity, amplification ly to be of great interest 13.. of lymphocyte trapping, increased differentiation Elsewhere B.c.G. has been extensively used in the and proliferation of antigen-triggered lymphocytes, treatment of melanoma, either by direct injection and also sometimes suppression of T-cell function. into cutaneous metastases14 15 or by distant intracuThe balance of these effects may be profoundly taneous inoculation. Direct injection is effective affected by the dose, timing, and route of adminisagainst the injected nodule but rarely influences tration : indeed, it is probably the case that all 7. Neidhart, J. A., Lobuglio, A. F. Semin. Oncol. 1974, 1, 379. general immunostimulators can also act as im-
Immunostimulation
,
’
_________________________________________________________
8.
munosuppressors. This is certainly true of the chemically defined compounds, tetramisole and levamisole,5 since too high a dose may diminish rather than augment an immune response.6 The action of levamisole, origG B. The Doctor’s Dilemma. 1906. R C., Zbar, B., Borsos, T., Rapp, H. J. New Engl. J. Med. 1974, 291, 1413. 3 Wollmark, N., Fisher, B. Cancer Res. 1974, 34, 2869. unopotentiation. Ciba Foundation Symposium, 1973. 5 Symeons. J, Brugmans, J. in Fogarty International Center Proceedings, No. 28 U. S Government Printing Office (in the press). 6 Sampson, D , Lui, A. Cancer Res. 1976, 36, 952.
1 Shaw,
2 Bast,
4 Imm
Sokal, J. E., Aungst, C. W., Snyderman, M. New Engl. J. Med. 1974, 291, 1226.
Mathé, G., Amiel, J. L., Schwarzenberg, L., Schneider, M., Cattan, A., Schlumberger, J. R., Hayat, M., DeVassal, F. Lancet, 1969, i, 697. 10. Powles, R. L., Crowther, D., Bateman, C. J., Beard, M. E. J., McElwain, T. J., Russell, J., Lister, T. A., Whitehouse, J. M. A., Wrigley, P. F. M., Pike, M., Alexander, P., Hamilton-Fairley, G. Br. J. Cancer, 1973, 28, 9.
365. 11. Vogler, W. R., Chan, Y. K. Lancet, 1974, ii, 128. 12. Gutterman, J. U., Rodriguez, V., Mavligit, G., Burgess, M. A., Gehan, E., Hersh, E. M., McCredie, K. B., Reed, R., Smith, T., Bodey, G. P., Freireich, E. J. ibid. 1974, ii, 1405. 13. Cuttner, J., Holland, J. F., Bekesi, J. B., Ramachandar, K., Donovan, O. Proc. Am. Ass. Cancer Res. 1975, 16, 264. 14. Morton, D. L., Eilber, F. R., Joseph, W. L., Wood, W. C. Surgery, 1970,
68, 158. 15.
Mastrangelo, M. J., Sulit, H. L., Prehn, L. (Melartin), Bornstein, R. S., Yarbro, J. W., Prehn, R. T. Cancer, 1976, 37, 684.
350
the metastases; it may cause serious; even fatal, bacteraemic shock and should be compared with other local forms of treatment. More interesting is the apparent benefit gained by distant intracutaneous inoculation, particularly in the inhibition of metastases. Many trials are in progress to determine this point: unfortunately the only large study so far published’6 is invalidated by the selection of controls not comparable for age and with internal inconsistencies relating to the site of the primary. The data for lung carcinoma are more convincing, since the trials have in general been well conducted with proper controls. 17-19 They suggest that B.C.G., intracutaneous or intrapleural, may well prevent the establishment or growth of distant metastases. A similar effect is also suggested by the early but encouraging results of a trial using levamisole in lung carcinoma. 20 These are the forerunners of a tide of immunotherapy trials most of which, including all C. parvum studies and all breast-carcinoma trials, are still too young to be evaluated. How are they to be assessed? It is important to recall that experimental immunotherapy is only successful in circumstances where there is a reasonably strong tumour-associated antigen, a small tumour load (e.g.,
inally used as an anthelmintic, is complex and not entirely understood; the main target may well be the macrophage, although the first effects described were in the restoration of previously depressed cell-
THE LANCET
mediated immune responses. A third class of immunopotentiators is more specific and they prob"THERE is at bottom only one genuinely scienably always potentiate rather than suppress. They tific treatment for all diseases, and that is to stimuinclude transfer factor and immune R.N.A., late the phagocytes. Stimulate the phagocytes: they which may be given as extracts or by infusion devour the disease; and the patient recovers-unof intact foreign lymphocytes which might be supless of course he’s too far gone." The almost-tooposed to be reactive to the antigens of the tumour.7 memorable words of the plausible Bloomfield This approach is inevitably more laborious and can are once from the Bonnington’ re-echoing again be used less often; thus, though there may have many meetings where the anthem of cancer imbeen occasional successes in the past, attention is can be heard. The reasons munotherapy currently now firmly turned to B.c.G., C. parvum, and for this wave of enthusiasm are easy to understand. levamisole, used with or without added tumour First of all, there is an appreciation that many cells or their antigens. human tumours may, indeed, carry antigens that The claims for B.c.G. extend back to a group of could provoke a therapeutic immune response; 50 lymphoma patients, half of whom were given there are available several secondly, immunopoten- B.c.G. in 1965-67;8 rather fewer patients relapsed tiators which are relatively easy to administer and and they did so at a mean time of 25.9 months which do not carry the same toxic risks as other compared with 10.6 months for controls. MATHÉ’S forms of cancer therapy. Of these, B.C.G.,2or the claim for B.C.G. and/or leukæmic cells in acute lymof has Freund’s adjuvant, mycobacterial component phoblastic leukæmia9 has been extensively cited but been with us for many years and has had the lonthe results have not been confirmed and the run in diseases; gest Corynebactreating malignant apparent benefit may well have been due to the terium parvum3 is more recent but increasingly exceptionally poor performance of a small group of popular; while other bacterial products such as control patients. The rather better established endotoxins and lipopolysaccharides have limited claims for immunotherapy in acute myeloid leukaeimmunopotentiating activity in certain experimen- mia 10 11 may now fail for the same reason-i.e., tal circumstances and have not been much used in that the non-immunotherapy controls had fortuiclinical immunotherapy. tously short remissions-but the claim for longer The mechanism of action of these materials is survival, which implies more frequent and betterextremely complex since the effects are mediated maintained second remissions, may yet be valid. If the of B interactions through macrophages, lym- so, however, the reasons may have nothing to do T and phocytes, lymphocytes, the last category in- with the enhancement of specific immunity. Other trials in A.M.L. may have been methodologically cluding subpopulations of cytotoxic, helper, and For cells.2-4 the effects of C. vulnerable.12 Of those trials which cannot yet be suppressor example, parvum include an increase in the production of assessed, one using neuraminidase-treated cells and stimulation of chemomethanol-extracted residue of B.C.G.(M.E.R.),is likemacrophages, macrophage increased taxis, phagocytic activity, amplification ly to be of great interest 13.. of lymphocyte trapping, increased differentiation Elsewhere B.c.G. has been extensively used in the and proliferation of antigen-triggered lymphocytes, treatment of melanoma, either by direct injection and also sometimes suppression of T-cell function. into cutaneous metastases14 15 or by distant intracuThe balance of these effects may be profoundly taneous inoculation. Direct injection is effective affected by the dose, timing, and route of adminisagainst the injected nodule but rarely influences tration : indeed, it is probably the case that all 7. Neidhart, J. A., Lobuglio, A. F. Semin. Oncol. 1974, 1, 379. general immunostimulators can also act as im-
Immunostimulation
,
’
_________________________________________________________
8.
munosuppressors. This is certainly true of the chemically defined compounds, tetramisole and levamisole,5 since too high a dose may diminish rather than augment an immune response.6 The action of levamisole, origG B. The Doctor’s Dilemma. 1906. R C., Zbar, B., Borsos, T., Rapp, H. J. New Engl. J. Med. 1974, 291, 1413. 3 Wollmark, N., Fisher, B. Cancer Res. 1974, 34, 2869. unopotentiation. Ciba Foundation Symposium, 1973. 5 Symeons. J, Brugmans, J. in Fogarty International Center Proceedings, No. 28 U. S Government Printing Office (in the press). 6 Sampson, D , Lui, A. Cancer Res. 1976, 36, 952.
1 Shaw,
2 Bast,
4 Imm
Sokal, J. E., Aungst, C. W., Snyderman, M. New Engl. J. Med. 1974, 291, 1226.
Mathé, G., Amiel, J. L., Schwarzenberg, L., Schneider, M., Cattan, A., Schlumberger, J. R., Hayat, M., DeVassal, F. Lancet, 1969, i, 697. 10. Powles, R. L., Crowther, D., Bateman, C. J., Beard, M. E. J., McElwain, T. J., Russell, J., Lister, T. A., Whitehouse, J. M. A., Wrigley, P. F. M., Pike, M., Alexander, P., Hamilton-Fairley, G. Br. J. Cancer, 1973, 28, 9.
365. 11. Vogler, W. R., Chan, Y. K. Lancet, 1974, ii, 128. 12. Gutterman, J. U., Rodriguez, V., Mavligit, G., Burgess, M. A., Gehan, E., Hersh, E. M., McCredie, K. B., Reed, R., Smith, T., Bodey, G. P., Freireich, E. J. ibid. 1974, ii, 1405. 13. Cuttner, J., Holland, J. F., Bekesi, J. B., Ramachandar, K., Donovan, O. Proc. Am. Ass. Cancer Res. 1975, 16, 264. 14. Morton, D. L., Eilber, F. R., Joseph, W. L., Wood, W. C. Surgery, 1970,
68, 158. 15.
Mastrangelo, M. J., Sulit, H. L., Prehn, L. (Melartin), Bornstein, R. S., Yarbro, J. W., Prehn, R. T. Cancer, 1976, 37, 684.
350
the metastases; it may cause serious; even fatal, bacteraemic shock and should be compared with other local forms of treatment. More interesting is the apparent benefit gained by distant intracutaneous inoculation, particularly in the inhibition of metastases. Many trials are in progress to determine this point: unfortunately the only large study so far published’6 is invalidated by the selection of controls not comparable for age and with internal inconsistencies relating to the site of the primary. The data for lung carcinoma are more convincing, since the trials have in general been well conducted with proper controls. 17-19 They suggest that B.C.G., intracutaneous or intrapleural, may well prevent the establishment or growth of distant metastases. A similar effect is also suggested by the early but encouraging results of a trial using levamisole in lung carcinoma. 20 These are the forerunners of a tide of immunotherapy trials most of which, including all C. parvum studies and all breast-carcinoma trials, are still too young to be evaluated. How are they to be assessed? It is important to recall that experimental immunotherapy is only successful in circumstances where there is a reasonably strong tumour-associated antigen, a small tumour load (e.g.,
