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  • 1
    Keywords: CANCER ; CELL ; Germany ; KINASE ; GENE ; PATIENT ; RESPONSES ; primary ; DOMAIN ; ANTIGEN ; T cell ; T-CELL ; MR ; IDENTIFICATION ; PROGRESSION ; MUTATION ; MELANOMA ; METASTATIC MELANOMA ; LYMPHOCYTES ; MUTATIONS ; IMMUNITY ; CANCER-RESEARCH ; SELECTION ; MELANOMA PATIENTS ; CTL ; BRAF ; CANCER VACCINES ; T-CELL EPITOPES
    Abstract: Activating BRAF somatic missense mutations within the kinase domain are present in 60-66% of melanomas. The vast majority of these represent a single substitution of glutamate for valine (V599E). Here, we demonstrate spontaneous HLA-B*2705-restrieted cytotoxic T-cell responses against an epitope derived from (V599E)BRaf. These T-cell responses were mutation specific as the corresponding epitope derived from wildtype BRaf was not recognized. The loss of the (V599E)BRAF genotype during progression from primary to metastatic melanoma in patients with (V599E)BRaf specific T-cell responses suggests an active immune selection of nonmutated melanoma clones by the tumor-bearing host
    Type of Publication: Journal article published
    PubMed ID: 15289355
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  • 2
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Allogeneic bone marrow transplantation (BMT) is a potentially curative therapy for patients with haematologic malignancies. Several lines of evidence demonstrate that donor T cells are involved in the antitumour effects observed after BMT. Thus, patients receiving T-cell-depleted BMT have a higher risk of leukaemia relapse compared to patients receiving nonmanipulated BMT, and patients experiencing graft-versus-host disease (GVHD) have a lower risk of disease relapse than patients who do not experience GVHD. Although the importance of donor T cells for the curative action of BMT has been established, the exact mechanisms and molecules involved in this graft-versus-tumour effect remain largely unknown. In a recently initiated project, we have conducted a longitudinal study of T-cell clonotypes in patients who received peripheral blood stem cell grafts after nonmyeloablative conditioning. Peripheral blood samples were obtained sequentially after transplant, and the mononuclear cells (MNCs) were isolated and cryopreserved. CD8+ T cells were isolated from the MNCs by use of immunomagnetic beads or FACS and analysed for the presence of clonally expanded cells by T-cell receptor clonotype mapping based on RT-PCR and denaturing gradient gel electrophoresis (DGGE). Using this gel-based methodology, clonally expanded T cells were monitored after transplant and compared to the clinical data of the patients. The preliminary results demonstrates the presence of clonally expanded CD8+ T cells at all time points analysed. Furthermore, a number of clonotypes persisted for more than 6 months, and other clonotypes emerged during this period. The appearance of newly emerged clonotypes which coincided with clinical GVHD could indicate a role for these T cells in the pathogenesis of GVHD.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
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