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cardial damage, coexistent hypertension, and otherfactors.The latest C.D.P. report is a model of objective and

succinct description of many facts, and the interestedreader will need to dissect these carefully. Some

important areas are not discussed. Little informationis given about the systems used for data collection toallow full appraisal of the significance of the excessof arrhythmias in the clofibrate and nicotinic-acidgroups; or of the increased incidence in the clofi-brate group of such symptoms as claudication andangina, where a break in a double-blind designcould influence the findings. No analysis of theresults has yet been reported using orthodox criteriaof statistical confidence to determine significance,although the overall results are undoubtedly negative;and no account has been given of changes in mortalitywith time. Before the book on the treatment ofestablished ischaemic heart-disease by control of

hyperlipidxmia is closed, a trial of the effectivenessof a drug and dietary regimen designed to producemaximal lowering of plasma-lipids should be con-ducted in those with angina alone. The C.D.P. didnot include such patients, and it was in them that theNewcastle 13 and Scottish 14 trials of clofibrateshowed the most striking reduction of morbidityand mortality. In patients in the C.D.P. with anginapresent for 2 months before the initial myocardialinfarction, there was also a trend in favour of clofi-brate.Some will extend the conclusion of the C.D.P. by

judging that control of plasma-lipids by any meanshas little clinical relevance once infarction hasoccurred. Certainly, the results of formal controlledtrials of dietary reduction of plasma-lipids have beenequivocal in the prevention of recurrence of myo-cardial infarction.15,16 But the findings of the C.D.P.should not be allowed to interrupt the painstakingtesting of the effect of lowering raised plasma-lipidson the incidence of ischaemic heart-disease in other-wise healthy men, where the outcome may be morecheering. There are already marginally positiveand encouraging results from two dietary trials ofprimary prevention,17.18 and the W.H.O. primary-prevention cooperative trial of clofibrate 19 and theN.H.L.I. trial of cholestyramine in individuals withfamilial hyperbetalipoproteinmmia 20 have yet to

report. The C.D.P. findings do not mean that grosshyperlipidasmia should be left untreated. Nor shouldthey inhibit investigations into the pathophysiology oflipid metabolism and its relation to atheroma-the13. Physicians of the Newcastle upon Tyne Region. Br. med. J. 1971,

iv, 767.14. Research Committee of the Scottish Society of Physicians. ibid.

p. 775.15. Research Committee to the M.R.C. Lancet, 1968, ii, 693.16. Leren, P. Circulation, 1970, 42, 935.17. Dayton, S., Pearce, M. L., Hashimoto, S., Dixon, W. J., Tomiyasu,

U. ibid. 1969, 40, suppl. 2.18. Miettinen, M., Turpeinen, O., Karvonen, M. J., Elosuo, R.,

Paavilainen, E. Lancet, 1972, ii, 835.19. Heady, J. A. Bull. Wld Hlth Org. 1973, 48, 243.20. Rifkind, B., Levy, R. I. Cardiovasc. Clins, 1974, 6, issue 2.

parent disorder of ischxmic heart-disease. But theyare depressing for many doctors who hoped that adaily pill would improve prognosis, and discouragingfor the pharmaceutical industries which have doneso much to encourage clinical studies of lipid-loweringdrugs.

Immunological Control of CancerVACCINES can prevent malignant disease. Many

years ago CHARLOTTE FRIEND 1 showed that ad-ministration of Friend leukxmia virus treated withformalin prevented the disease in mice. LaterCHURCHILL and his colleagues 2 showed that a livingattenuated vaccine would prevent Marek’s disease inchickens, and many millions of doses of this vaccinehave now been used throughout the world. More

recently JARRETT and his colleagues 3 have shownthat a vaccine can be prepared against feline leukaemia,and LAUFS and STEINKE 4 have reported that Herpes-virus saimiri vaccine prevents malignant lymphomain cotton-topped marmosets; the cat and marmosetwork is reviewed in the next two editorials. These

discoveries, and the increasing likelihood that somehuman malignant processes are due to viruses

analogous to those discovered in animals, open thepossibility of an immunological approach to the

prevention of cancer in man, although there are

formidable problems in assessing safety and evaluat-ing effectiveness to be overcome.5

In the immediate future, treatment rather thanprevention of cancer is the goal. One immunologicalapproach has been to try and couple chemothera-peutic agents on to specific antisera —a techniquewhich has theoretical attractions. Another is to

increase the immunogenicity of tumours, in the hopeof shifting the advantage to the host response. Thereasons for the general failure of immunologicalmechanisms to deal with tumours are imperfectlyunderstood. It is now recognised that an immuno-logical response is made and that failure of effectiveresponse can come from various blocking mech-anisms-for example, excess antigen combining withcytolytic antibody or the production of enhancingantibody, thereby blocking cell-mediated immunity.WATKINS and CHEN have tried to make weak cellular

antigens stronger by the fusion technique. 8 In this

way, a hybrid cell is formed containing strongly anti-genic foreign components and the weakly antigenictumour antigens, so that the former boosts the latter.So far the results are inconclusive.9 Another methodhas been to try and increase the host response withvarious adjuvants; most of this work has been with

1. Friend, C. J. exp. Med. 1959, 109, 217.2. Churchill, A. E., Payne, L. N., Chubb, R. C. Nature, 1969, 221, 744.3. Jarrett, W., Mackey, L., Jarrett, O., Laird, H., Hood, C. ibid. 1974,

248, 230.4. Laufs, R., Steinke, H. ibid. 1975, 253, 71.5. Hilleman, M. R. Cancer, 1974, 34, 1439.6. Rubens, R. S. Lancet, 1974, i, 498.7. Watkins, J. F., Chen, L. Nature, 1969, 223, 1018.8. Harris, H. Cell Fusion. Oxford, 1970.9. Gowans, J. L. Br. med. J. 1974, i, 557.

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B.C.G. vaccine, but Corynebacterium parvum is gainingground. 10 Results in man are rather confused, al-though MATHE and SOKAL et a1.l! have describedsome good results with B.C.G. and ISRAEL and EDEL-STEIN 12 with C. parvum. B.C.G. has a number ofdrawbacks as an adjuvant for this purpose. It is anunstable living vaccine and its efficacy depends on thenumber of viable organisms. The widely used wetvaccines are particularly variable, and for protectionagainst tuberculosis freeze-dried vaccine has provedto be reproducible, stable, effective, and convenient.As an adjuvant, freeze-dried vaccine is probably lesseffective than wet vaccine, and tests will be needed inanimals so that the best preparation can be evaluatedin man; a better approach would be to isolateactive fractions from B.c.G., and some success hasbeen reported. 13Use of C. parvum as an adjuvant began with the

work of HALPERN.14 In animals it is effective in

preventing tumours.15 ADLAM and SCOTT 16 have

prepared a standardised potent killed C. parvumvaccine which has obvious practical advantages overB.C.G.: it is readily standardised and non-viable, andis generally well tolerated in man and animals in effec-tive doses. When given intravenously or intra-peritoneally in mice, C. parvum stimulates productionof large numbers of macrophages, with an increase inliver, spleen, and lung weight. These activated macro-phages themselves seem to mediate most of the anti-tumour effects of C. parvum by this route. A surpris-ing and worrying observation, in an anti-tumouragent supposed to increase the host response, is thatC. parvum reduces cell-mediated immunity 17 ; appar-ently this is another attribute of the activated macro-phage, both in vivo and in vitro. In mice the depres-sion of cell-mediated immunity depends on thepresence of the spleen, where T cells are probablytrapped and may be destroyed. Cell-mediated

immunity is not depressed when C. parvum is givenlocally. SCOTT 18 has lately clarified the position bywork on mice in which mastocytoma was injectedinto the footpad. This tumour kills mice in about29 days. He found that the effect on the tumour ofC. parvum, given intravenously 2 days after tumourimplantation, increased with dose up to the maxi-mum tolerated (700 .g.). In one experiment themean survival-time was increased from 27 to 49

days. A single dose was as effective as multiple doses,if not more so. The intravenous treatment conferredno systemic anti-tumour immunity and results were

10. Scott, M. Semin. Oncol. 1974, 1, 367.11. Mathé, G. Ciba Fdn Symp. 1973, no. 18, p. 305; Sokal, J. E., Aungst,

G. W., Snyderman, M. New Engl. J. Med. 1971, 291, 1226.12. Israel, L., Edelstein, R. L. in Immunological Aspects of Neoplasia.

Baltimore, 1974.13. Meyer, J. J., et al. J. natn. Cancer Inst. 1974, 52, 103.14. Halpern, B. N., et al. J. reticuloendothel. Soc. 1963, 1, 77.15. Woodruff, M. F. A., Boak, J. L. Br. J. Cancer, 1966, 20, 345.16. Adlam, C., Scott, M. T. J. med. Microbiol. 1973, 6, 261.17. Howard, J. G., Scott, M. T., Christie, G. H. Ciba Fdn Symp.

1974, no. 18, p. 101.18. Scott, M. T. J. natn. Cancer Inst. 1974, 53, 855.

unaffected by severe depletion of T cells. One

consequence of this non-specificity of the anti-tumour effect is that any cells that escape the attack

by activated macrophages will be unhampered sub-sequently. ScoTT 19 later found that C. parvum giveninto the tumour was superior; in particular, it stimu-lated cell-mediated immunity. The optimum dosewas a tenth that used intravenously; moreover,treatment was effective up to 12 days after tumourinjection, although in most of his experime"ts it wasused at 6 days. Not only was survival prolonged, butmany mice survived completely. For example, over-all, 44% of mice survived, and in some experimentstwo-thirds survived. The survivors were immune tochallenge with the same tumour in the other hind-leg.Likewise, irradiated mastocytoma cells given withC. parvum immunised mice against a living-tumourchallenge, whereas irradiated cells on their own wereextremely poor immunogens in the system used.The effect of C. parvum given into the tumour

depended on the host immune response and wasmuch reduced in T-cell-deprived mice. A similar

although much lesser effect was seen when C. parvumwas given subcutaneously within the same lymph-node drainage area, but there was no effect whenC. parvum was given subcutaneously at a distant site.

These results indicate that C. parvum may be morebeneficial given into a tumour than when given intra-venously, although intravenously it may have someeffect on metastases. In any clinical situation multipleapproaches with chemotherapeutic agents and irradia-tion are likely to be tried, and these are known toaffect the response to C. parvum. Thus CURRIE andBAGSHA WE 20 found that a combination of cyclo-phosphamide and C. parvum was more effective thaneither alone against an established murine fibro-sarcoma. The exact timing was important; C. parvumhad to follow cyclophosphamide by 12 days. More

experimental work is required to show how this andother immunopotentiating agents can be best usedin man. There are prospects for improving clinicalresults with C. parvum. Another possible way ofstimulating cell-mediated immunity is with theanthelmintic drug levamisole,21 which is alreadybeing tried in various cancers.22,23

AS IN CATS, SO IN MAN?IN most species of animals leukaemia is caused by a

member of the oncomavirus family and there are

indications that this may also be true for man. 24-26Some workers suspect a relationship between a highlevel of social contact and a high incidence of leuk-

19. Scott, M. T. ibid. p. 861.20. Currie, G. A., Bagshawe, K. D. Br. med. J. 1970, i, 541.21. Lancet, Jan. 18, 1975, p. 151.22. Webster, D. J. T., Hughes, L. E. ibid. Feb. 15, 1975, p. 389.23. Amery, W. ibid.24. Jarrett, W. F. H. Br. J. Hœmat. 1973, 25, 287.25. Sherr, C. J., Todaro, G. J. Proc. natn. Acad. Sci. 1974, 71, 4703.26. Gallagher, R. E., Gallo, R. C. Science, 1975, 187, 350.