The biography of the immune system and the control of cancer: from St Peregrine to contemporary vaccination strategies.

BACKGROUND: The historical basis and contemporary evidence for the use of immune strategies for prevention of malignancies are reviewed. Emphasis is focussed on the Febrile Infections and Melanoma (FEBIM) study on melanoma and on malignancies that seem to be related to an overexpression of human endogenous retrovirus K (HERV-K). DISCUSSION: It is claimed that, as a result of recent observational studies, measures for prevention of some malignancies such as melanoma and certain forms of leukaemia are already at hand: vaccination with Bacille Calmette-Guérin (BCG) of new-borns and vaccination with the yellow fever 17D (YFV) vaccine of adults. While the evidence of their benefit for prevention of malignancies requires substantiation, the observations that vaccinations with BCG and/or vaccinia early in life improved the outcome of patients after surgical therapy of melanoma are of practical relevance as the survival advantage conferred by prior vaccination is greater than any contemporary adjuvant therapy. SUMMARY: The reviewed findings open a debate as to whether controlled vaccination studies should be conducted in patients and/or regions for whom/where they are needed most urgently. A study proposal is made and discussed. If protection is confirmed, the development of novel recombinant vaccines with wider ranges of protection based, most likely, on BCG, YFV or vaccinia, could be attempted.

Can prior vaccinations against certain infections confer protection against developing melanoma?

Currently available, relatively safe vaccines may help tackle this serious and increasing public health problem.

Protection against melanoma by vaccination with Bacille Calmette-Guerin (BCG) and/or vaccinia: an epidemiology-based hypothesis on the nature of a melanoma risk factor and its immunological control.

A multicentre case-control study conducted by the FEBrile Infections and Melanoma (FEBIM) group has demonstrated a reduced risk of melanoma associated with Bacille Calmette-Guerin (BCG) and/or vaccinia vaccination in early childhood and/or with infectious diseases later in life. This has led to the recognition of a new risk indicator of melanoma; namely 'not being vaccinated with either with BCG or vaccinia'. On the basis of these findings, we propose a hypothesis of immune surveillance for melanoma induced or enhanced by prior contacts with pathogens unexpectedly cross-reactive to a cellular 'marker of melanoma risk'. The reduced risk of melanoma due to BCG and vaccinia, as well as certain common causes of infectious disease, is shown to be associated with antigenic determinants exhibiting sequence homologies with the HERV-K-MEL-antigen. The latter is a product of a pseudo-gene that is closely associated with the env-gene of the endogenous human retrovirus K (HERV-K). A suppressive immune reaction appears to inhibit the expression of endogenous retroviral genes, such as the HERV-K env-gene, that could otherwise result in malignant transformation years or even decades later. The HERV-K env-protein has homologous amino acid sequences with the human nuclear factor Oxygen Responsive Element Binding Protein (OREBP) that controls the expression of glutathione peroxidase. The formation of this and other redox-enzymes, needed to maintain appropriate levels of the normal intracellular redox potential, seems to be suppressed by the OREBP-homologous protein. The present hypothesis is in accordance with the concept that immune dysregulation due to adverse environmental impacts is a risk factor not only for some autoimmune disorders, as previously described, but also for certain malignancies such as melanoma.

Inverse association between melanoma and previous vaccinations against tuberculosis and smallpox: results of the FEBIM study.

Various forms of immunotherapy utilizing bacille Calmette-Guérin vaccine or vaccinia vaccine have been evaluated in clinical trials on melanoma patients. The effect of the "natural" application of these vaccinations, administered to provide protection against tuberculosis and smallpox, has, however, never been studied in epidemiologic investigations on risk factors for melanoma. In a case-control study comprising 11 institutions in seven countries we recruited 603 incident melanoma cases and 627 population controls frequency matched to the cases with respect to sex, age, and ethnic origin within each center to assess this relationship to obtain insights into the prevention of melanoma. Exposure information, incorporating also detailed ascertainment of potential confounding variables, was obtained in standardized personal interviews at the study subject's home. We found an inverse association between melanoma risk and previous bacille Calmette-Guérin vaccine/vaccinia vaccination depicted by an adjusted odds ratio of 0.44 (95% confidence interval: 0.26-0.72) for those vaccinated against tuberculosis and smallpox compared with subjects without a positive history of either vaccination. A variety of subgroup analyses showing a consistent pattern of results make it unlikely that the observed inverse association is a spurious finding. We conclude that bacille Calmette-Guérin vaccination and vaccinia vaccination may lower melanoma risk. Current immunologic theory of melanoma development provides a sound basis for understanding the biologic plausibility of the findings that have to be confirmed in future studies.