Blackwell Publishing Journal Backfiles 1879-2005
Immunotherapy represents an attractive fourth-modality therapeutic approach, especially in the light of the shortcomings of conventional surgery, radiation and chemotherapies in the management of metastatic cancer. To this end, a large number of peptide antigens derived from TAA have been applied in immunotherapeutic trials for the treatment of various malignancies, e.g. cancers of the breast, prostate and kidney, in addition to haematological cancers. In some cases the response rates have been impressive and no adverse autoimmunity have been observed. A major strategic difficulty associated with these trials relates to the choice of best-suited peptide antigens. The vast majority of the antigens described thus far is not vital for survival and growth of the tumour cells, and immunoselection of antigen-loss variants may therefore prove to be an additional obstacle for the clinical applicability of most of the known peptide epitopes. In this respect, the development of acquired antigen loss during immunotherapy has been demonstrated in several cases. Obviously, the development of loss-variant tumour cells implies that these cells acquire a pronounced growth advantage and are left unaffected by further treatment. Ideally, target antigens should be derived from proteins required for survival and growth of tumour cells, as antigens with these characteristics would not be inflicted by the development of loss-variant tumour cells. In this respect, several inhibitors of apoptosis proteins (IAPs) are universally expressed among tumours and play an important role in tumour cell escape from apoptosis. We have characterized spontaneous T-cell reactivity against IAP-derived peptides in cancer patients. From the IAP survivin, we have characterized peptides restricted to the Class I molecules HLA-A1, A2, A3, A11, B7 and B35. Furthermore, we have demonstrated that survivin-specific T cells infiltrate metastatic lesions and that isolated survivin-specific CTLs are capable of killing HLA-matched tumour cells. Survivin-derived peptides are now in clinical trial, and continued work in our lab has demonstrated that other IAPs are targets for spontaneous T-cell reactivity in cancer patients.
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