Immunotherapy: natural versus synthetic peptides

COMMENT I M M U N O L O G Y TO D AY

gene families on thyrocytes might be the result of T helper 1 (Th1)-dependent cytokine release, which is thought to be responsible for the inappropriate expression of MHC class II on thyrocytes8. The abnormal expression of these different sets of molecules in HT is ultimately seen in the context of cell death, not protection. Should MHC class II expression on thyrocytes play a protective role in autoimmune thyroid conditions, as suggested by Dyan et al., this role might be played mainly in the earlier stages of the autoimmune process in the presence of an adequate expression of the apoptotic– anti-apoptotic system. Once this system fails, either because of an overwhelming release of proinflammatory cytokines by in-

Immunotherapy: natural versus synthetic peptides Tumor-associated antigens (TAAs) recognized by cytotoxic T lymphocytes (CTLs) have been identified1–2, and vaccination protocols using synthetic peptides that correspond to TAAs have been initiated. However, these protocols have several drawbacks: (1) their feasibility only for selected human tumors and major histocompatibility complex (MHC) HLA alleles; and (2) the potential selection in vivo of antigen-loss tumor-cell variants. Ideally, the TAAs used should be as heterogeneous as possible. An alternative strategy may be the use of natural peptides obtained by elution of live tumor cells (termed mild extracts; ME) or by acid treatment of whole cells (termed strong extracts; SE). This approach has been successfully used by different groups for the induction of tumor-specific CTLs both in vitro and in vivo3–8. We have demonstrated that SEs from the non-immunogenic murine B16F1 melanoma, loaded onto engineered antigen-presenting cells (APCs), efficiently primed CD8⫹ T cells against B16F1 cells4. Furthermore, we and others have reported that APCs pulsed with ME or SE peptides from tumor cells induced tumor rejection in vivo3–6,8,9.

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filtrating lymphomononuclear cells and/or because of deprivation of specific survival factors, HLA-DR products alone do not appear to be able to maintain protection, and thyrocyte death ultimately occurs.

Hanafusa, T. and Feldmann, M. (1983) Lancet ii, 1115–1119 3 Hammond, L.J., Lowdell, M., Cerrano, P. et al. (1997) J. Pathol. 182, 138–144 4 Giordano, C., Stassi, G., Maria, R.D. et al.

Rita Mirakian Linda J. Hammond GianFranco Bottazzo St Bartholomew’s and the Royal London School of Medicine and Dentistry, Dept of Immunology, London, UK E1 2AD.

(1997) Science 275, 960–963 5 Bellgrau, D., Gold, D., Selawry, H., Moore, J., Franzusoff, A. and Duke, R.C. (1995) Nature 377, 630–632 6 Ferguson, T.A. and Griffith, T.S. (1997) Immunol. Rev. 156, 167–184 7 Hammond, L.J., Cerrano, P.G., Torre, G.C., Borgonovo, G., Bottazzo, G.F. and Mirakian, R. (1997) Immunology 92 (Suppl.), OP76

References

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The results obtained in vivo point to the importance of the APC for the efficacy of vaccination with MEs or SEs. Mandelboim et al.5 reported a marginal therapeutic effect in mice carrying the D122 carcinoma, vaccinated with the MHC class I-defective RMA-S cell line pulsed with SE. This marginal effect, although greater than to the antigen used alone, should be ascribed to the limited APC potential of RMA-S cells. A much higher therapeutic potential of ME and SE from non-immunogenic tumors has been reported in studies using as APC either dendritic cells (DCs)6 or RMA-S cells expressing the costimulatory molecule B7.1 (Ref. 8). We have also shown that the therapeutic effect on pre-established B16F1 melanoma was strictly dependent on the dose of tumor cells used for challenge8. The efficacy of SEs to induce specific CTLs has also been demonstrated in vitro in humans. SEs of human melanoma cells were able to prime melanoma-specific CTLs from the blood of healthy donors and melanoma patients 7. In this study, SEs were loaded onto MHC class I molecules of autologous macrophages upon phagocytosis of SE-coated latex beads7. These results are the first demonstration of the potential efficacy of natural peptides in humans. We are currently investigating whether SEs may also be presented, and by what mechanism, by human DCs to be used in clinical protocols.

The data reported above suggest that natural peptides extracted from tumor cells may represent a valid alternative to synthetic peptides corresponding to sequence segments of defined TAAs.

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2 Bottazzo, G.F., Pujol-Borrell, R.,

Maria Pia Protti Matteo Bellone Laboratory of Tumor Immunology, Scientific Institute, H. San Raffaele, 20132 Milano, Italy. References 1 Rosenberg, S.A. (1997) Immunol. Today 18, 175–181 2 Boon, T., Coulie, P.G. and Van den Eynde, B. (1997) Immunol. Today 18, 267–268 3 Franksson, L., Petersson, M., Kiessling, R. and Karre, K. (1993) Eur. J. Immunol. 23, 2606–2613 4 Bellone, M., Iezzi, G., Manfredi, A.A. et al. (1994) Eur. J. Immunol. 24, 2691–2698 5 Mandelboim, O., Berke, G., Fridkin, M., Feldman, M., Eisenstein, M. and Eisenbach, L. (1994) Nature 369, 67–71 6 Zitvogel, L., Mayordomo, J.I., Tjandrawan, T. et al. (1996) J. Exp. Med. 183, 87–97 7 Protti, M.P., Imro, M.A., Manfredi, A.A. et al. (1996) Cancer Res. 56, 1210–1213 8 Bellone, M., Iezzi, G., Martin-Fontecha, A. et al. (1997) J. Immunol. 158, 783–789 9 Nair, S.K., Boczkowski, D., Snyder, D. et al. (1997) Eur. J. Immunol. 27, 589–597