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  • 1
    Keywords: PEPTIDE ; CELLS ; IN-VITRO ; tumor ; carcinoma ; Germany ; GENERATION ; LINES ; TIME ; PATIENT ; DENDRITIC CELLS ; DOWN-REGULATION ; TRIAL ; NUMBER ; CLINICAL-TRIALS ; LINE ; B-CELLS ; PEPTIDES ; CARCINOMAS ; ANTIGEN-PRESENTING CELLS ; IMMUNOTHERAPY ; vaccination ; TARGETS ; INTERFERON-ALPHA ; RECOMBINANT INTERLEUKIN-2 ; QUANTITIES ; CTL ; renal cell carcinoma ; RE ; TUMOR-ANTIGENS ; PHASE-II TRIAL ; dendritic cell ; CELL-CARCINOMA ; human renal cell carcinoma ; RENAL-CELL-CARCINOMA ; APC ; ADOPTIVE TRANSFER ; antigen-presenting cell ; AUTOLOGOUS DENDRITIC CELLS ; B-LYMPHOCYTES ; peptide-specific cytotoxic T lymphocyte ; cytotoxic T lymphocyte
    Abstract: Renal cell carcinomas (RCCs) are supposed to be immunogenic, and several clinical trials of immunotherapy using tumor lysate-pulsed dendritic cells (DCs) have been performed. We report on the generation of RAGE-1 and MAGE-9 peptide-specific CTL lines. RAGE-1 and MAGE-9 are expressed in 56% and 38% of RCCs. Seven MAGE-9 and 13 RAGE-1-derived peptides were found to be immunogenic in the context of the HLA-A*0201 MHC. CTLs were generated by coculture with peptide-pulsed, activated B cells, which were easily generated in great quantities and displayed functional activity for a prolonged period of time. MAGE-9 and RAGE-1 peptide-specific CTL lines were strictly peptide-specific and displayed high cytotoxic activity not only against peptide-loaded T2 cells but also against HLA-A*0201-positive RCC lines, which naturally express MAGE-9, RAGE-1 or both. Thus, B cells are well suited as APCs for the generation of large numbers of tumor peptide-specific CTLs for adoptive transfer. MAGE-9 as well as RAGE-1 may well provide suitable targets for immunotherapy of RCC. (c) 2005 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 15900605
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  • 2
    Keywords: PEPTIDE ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; TUMOR-CELLS ; BLOOD ; Germany ; IN-VIVO ; VITRO ; POPULATION ; TUMORS ; LINES ; PATIENT ; LIGAND ; RESPONSES ; IFN-GAMMA ; ANTIGEN ; DENDRITIC CELLS ; SKIN ; T-CELL ; T-CELLS ; RECOGNITION ; IDENTIFICATION ; LINE ; MELANOMA ; LYMPHOCYTES ; REGION ; LIGANDS ; EPITOPES ; IMMUNOTHERAPY ; vaccination ; PERIPHERAL-BLOOD ; RE ; MELANOMA-CELLS ; TYROSINASE-RELATED PROTEIN-2 ; dendritic cell ; T cell epitope ; T-CELL EPITOPE ; VACCINIA VIRUS ANKARA ; tumor antigen ; HOST-RANGE SELECTION ; TRP-2
    Abstract: Tyrosinase-related protein-2 (TRP-2) is a known target antigen of spontaneous cytotoxic T cell responses in melanoma patients. Its frequent expression in metastatic tumors suggests that it might be an ideal candidate antigen for T cell-based immunotherapy. To provide knowledge about TRP-2-derived T cell epitopes useful for immunotherapy we applied a "reverse immunology strategy" based on repeated in vitro peptide stimulation of peripheral blood lymphocytes (PBL) from normal donors with predicted HLA-A*01 ligands. This led to the identification of TRP-2(181-190) as the first HLA-A*01-presented TRP-2-derived epitope. T-cell lines specific for peptide TRP-2(181-190) could be established from PBL of 50% of the normal HLA-A*01(+) donors tested. Such T cells responded specifically to autologous dendritic cells transduced virally with TRP-2, as well as to HLA-A*01(+), TRP-2(+) melanoma cells, although tumor cells had to be pretreated with IFN-gamma to become susceptible to T cell recognition. Interestingly, short-term in vitro peptide stimulation of PBL from HLA-A*01(+) melanoma patients showed the presence of TRP-2(181-190)-reactive CD8(+) T cells in some donors, suggesting their in vivo sensitization. Because TRP-2(181-190) overlaps with the known HLA-A*0201-presented epitope TRP-2(180-188), an 11mer peptide encompassing both epitopes might be of specific value for vaccination of a broad population of melanoma patients. (C) 2005 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 15856458
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  • 3
    Keywords: RECEPTOR ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; IN-VITRO ; BLOOD ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; human ; INHIBITION ; KINASE ; TOXICITY ; PROTEIN ; DONOR ; ANTIGEN ; ASSAY ; PEPTIDES ; VACCINE ; EPITOPE ; IMMUNOTHERAPY ; T-LYMPHOCYTES ; GENE DELIVERY ; CYTOKINE ; ASSAYS ; cytotoxic T lymphocyte ; INHIBITS TUMOR ANGIOGENESIS
    Abstract: Antigen-specific cancer immunotherapy directed toward tumor-nourishing angiogenic blood vessels holds the promise of high efficacy, low toxicity, and ease of application. To evaluate whether the human angiogenic kinase insert domain-containing receptor (KDR) can serve as a target for cellular immunotherapy, 19 peptide sequences with HLA-A*0201 motifs were selected by computer-based algorithms. Five peptides (KDR82-90, KDR288-297, KDR766-774, KDR1093-1101, KDR1035-1044) stimulated specific cytotoxic T lymphocytes (CTLs) from peripheral-blood mono-nuclear cells (PBMCs) of 3 HLA-A*0201 donors. The decapeptide KDR288-297 was efficient in sensitizing target cells for recognition by a CTL clone at a concentration of 10 nM. More important, KDR288-297 specific CTLs lysed target cells transfected with HLA-A2/KDR cDNAs and a range of HLA-matched KDR+ angiogenic endothelial cells (aECs) and also recognized CD34(+) endothelial progenitor cells. The specificity of CTLs was further confirmed by tetramer assay and cold-target inhibition assay. In addition, ex vivo exposure of aECs to the inflammatory cyto-kines enhanced CTL reactivity, which is in keeping with up-regulated KDR and HLA class 1 expression. In Matrigel assays, recognition of aECs by specific CTLs triggered an antivascular effect. These findings provide the first proof of the antigenic property of KDR protein and may be useful for devising new immunotherapeutic approaches to human cancers. (Blood. 2006; 107:1476-1483) (c) 2006 by The American Society of Hematology
    Type of Publication: Journal article published
    PubMed ID: 16234362
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  • 4
    Keywords: PROSTATE-CANCER ; MELANOMA PATIENTS ; COLONY-STIMULATING FACTOR ; RENAL-CELL CARCINOMA ; PULSED DENDRITIC CELLS ; REGULATORY T-CELLS ; tumor-antigen ; HIGH-FREQUENCIES ; MYELOID SUPPRESSOR-CELLS ; Peptide vaccine
    Abstract: IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02(+) subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3)(+) regulatory T (T(reg)) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T(reg) cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing.
    Type of Publication: Journal article published
    PubMed ID: 22842478
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  • 5
    Keywords: PROTEINS ; INFECTION ; CELL-LINES ; EPITOPES ; DETERMINANTS ; ADAPTIVE IMMUNE-RESPONSES ; MEMBRANE ASSOCIATION
    Abstract: Fine mapping of human cytotoxic T lymphocyte (CTL) responses against hepatitis C virus (HCV) is based on external loading of target cells with synthetic peptides which are either derived from prediction algorithms or from overlapping peptide libraries. These strategies do not address putative host and viral mechanisms which may alter processing as well as presentation of CTL epitopes. Therefore, the aim of this proof-of-concept study was to identify naturally processed HCV-derived major histocompatibility complex (MHC) class I ligands. To this end, continuous human cell lines were engineered to inducibly express HCV proteins and to constitutively express high levels of functional HLA-A2. These cell lines were recognized in an HLA-A2-restricted manner by HCV-specific CTLs. Ligands eluted from HLA-A2 molecules isolated from large-scale cultures of these cell lines were separated by high performance liquid chromatography and further analyzed by electrospray ionization quadrupole time of flight mass spectrometry (MS)/tandem MS. These analyses allowed the identification of two HLA-A2-restricted epitopes derived from HCV nonstructural proteins (NS) 3 and 5B (NS3(1)(4)(0)(6)(-)(1)(4)(1)(5) and NS5B(2)(5)(9)(4)(-)(2)(6)(0)(2)). In conclusion, we describe a general strategy that may be useful to investigate HCV pathogenesis and may contribute to the development of preventive and therapeutic vaccines in the future.
    Type of Publication: Journal article published
    PubMed ID: 22235280
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  • 6
    Abstract: Fine mapping of human cytotoxic T lymphocyte (CTL) responses against hepatitis C virus (HCV) is based on external loading of target cells with synthetic peptides which are either derived from prediction algorithms or from overlapping peptide libraries. These strategies do not address putative host and viral mechanisms which may alter processing as well as presentation of CTL epitopes. Therefore, the aim of this proof-of-concept study was to identify naturally processed HCV-derived major histocompatibility complex (MHC) class I ligands. To this end, continuous human cell lines were engineered to inducibly express HCV proteins and to constitutively express high levels of functional HLA-A2. These cell lines were recognized in an HLA-A2-restricted manner by HCV-specific CTLs. Ligands eluted from HLA-A2 molecules isolated from large-scale cultures of these cell lines were separated by high performance liquid chromatography and further analyzed by electrospray ionization quadrupole time of flight mass spectrometry (MS)/tandem MS. These analyses allowed the identification of two HLA-A2-restricted epitopes derived from HCV nonstructural proteins (NS) 3 and 5B (NS3(1)(4)(0)(6)(-)(1)(4)(1)(5) and NS5B(2)(5)(9)(4)(-)(2)(6)(0)(2)). In conclusion, we describe a general strategy that may be useful to investigate HCV pathogenesis and may contribute to the development of preventive and therapeutic vaccines in the future.
    Type of Publication: Journal article published
    PubMed ID: 22235280
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  • 7
    Abstract: T cells have been proven to be therapeutically effective in patients with relapsed leukemias, although target antigens on leukemic cells as well as T-cell receptors (TCRs), potentially recognizing those antigens, are mostly unknown. We have applied an immunopeptidomic approach and isolated human leukocyte antigen (HLA) ligands from primary leukemia cells. We identified a number of ligands derived from different genes that are restrictedly expressed in the hematopoietic system. We exemplarily selected myeloperoxidase (MPO) as a potential target and isolated a high-avidity TCR with specificity for a HLA-B*07:02-(HLA-B7)-restricted epitope of MPO in the single HLA-mismatched setting. T cells transgenic for this TCR demonstrated high peptide and antigen specificity as well as leukemia reactivity in vitro and in vivo. In contrast, no significant on- and off-target toxicity could be observed. In conclusion, we here demonstrate, exemplarily for MPO, that leukemia-derived HLA ligands can be selected for specific effector tool development to redirect T cells to be used for graft manipulation or adoptive T-cell therapies in diverse transplant settings. This approach can be extended to other HLA ligands and HLA molecules in order to provide better treatment options for this life-threatening disease.Leukemia advance online publication, 13 May 2014; doi:10.1038/leu.2014.131.
    Type of Publication: Journal article published
    PubMed ID: 24736212
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  • 8
    Keywords: tumor ; PATIENT ; ANTIGENS ; MEMORY ; VACCINES ; vaccination ; CANCER-IMMUNOTHERAPY ; CD4(+) T-CELLS ; ADVANCED MELANOMA ; IPILIMUMAB
    Abstract: The breakthrough development of clinically effective immune checkpoint inhibitors illustrates the potential of T-cell-based immunotherapy to effectively treat malignancies. A remaining challenge is to increase and guide the specificities of anticancer immune responses, e.g., by therapeutic vaccination or by adoptive T-cell transfer. By analyzing the landscape of naturally presented HLA class I and II ligands of primary chronic lymphocytic leukemia (CLL), we delineated a novel category of tumor-associated T-cell antigens based on their exclusive and frequent representation in the HLA ligandome of leukemic cells. These antigens were validated across different stages and mutational subtypes of CLL and found to be robustly represented in HLA ligandomes of patients undergoing standard chemo-/immunotherapy. We demonstrate specific immune recognition of these antigens exclusively in CLL patients, with the frequencies of representation in CLL ligandomes correlating with the frequencies of immune recognition by patient T cells. Moreover, retrospective survival analysis revealed survival benefits for patients displaying immune responses to these antigens. These results directly imply these nonmutant self-peptides as pathophysiologically relevant tumor antigens and encourages their implementation for cancer immunotherapy.
    Type of Publication: Journal article published
    PubMed ID: 25548167
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  • 9
    Keywords: CANCER ; IFN-GAMMA ; vaccination ; STEM-CELL TRANSPLANTATION ; COMPLETE REMISSION ; MULTIPLE-MYELOMA ; MYELODYSPLASTIC SYNDROME ; CYTOTOXIC T-LYMPHOCYTES ; WT1 PEPTIDE ; TUMOR REJECTION
    Abstract: Identification of physiologically relevant peptide vaccine targets calls for the direct analysis of the entirety of naturally presented human leukocyte antigen (HLA) ligands, termed the HLA ligandome. In this study, we implemented this direct approach using immunoprecipitation and mass spectrometry to define acute myeloid leukemia (AML)-associated peptide vaccine targets. Mapping the HLA class I ligandomes of 15 AML patients and 35 healthy controls, more than 25 000 different naturally presented HLA ligands were identified. Target prioritization based on AML exclusivity and high presentation frequency in the AML cohort identified a panel of 132 LiTAAs (ligandome-derived tumor-associated antigens), and 341 corresponding HLA ligands (LiTAPs (ligandome-derived tumor-associated peptides)) represented subset independently in 〉20% of AML patients. Functional characterization of LiTAPs by interferon-gamma ELISPOT (Enzyme-Linked ImmunoSpot) and intracellular cytokine staining confirmed AML-specific CD8(+) T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4(+) T-cell epitopes and potentially synergistic embedded HLA ligands, allowing for complementation of a multipeptide vaccine for the immunotherapy of AML.
    Type of Publication: Journal article published
    PubMed ID: 25092142
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  • 10
    Keywords: EXPRESSION ; IN-VITRO ; LIGAND ; resistance ; NATURAL-KILLER-CELLS ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; ACUTE MYELOID-LEUKEMIA ; NECROSIS-FACTOR FAMILY ; BAFF ; APRIL
    Abstract: Natural killer (NK) cells are cytotoxic lymphocytes that substantially contribute to the therapeutic benefit of antitumor antibodies like Rituximab, a crucial component in the treatment of B-cell malignancies. In chronic lymphocytic leukemia (CLL), the ability of NK cells to lyse the malignant cells and to mediate antibody-dependent cellular cytotoxicity upon Fc receptor stimulation is compromised, but the underlying mechanisms are largely unclear. We report here that NK-cells activation-dependently produce the tumor necrosis factor family member 'B-cell activating factor' (BAFF) in soluble form with no detectable surface expression, also in response to Fc receptor triggering by therapeutic CD20-antibodies. BAFF in turn enhanced the metabolic activity of primary CLL cells and impaired direct and Rituximab-induced lysis of CLL cells without affecting NK reactivity per se. The neutralizing BAFF antibody Belimumab, which is approved for treatment of systemic lupus erythematosus, prevented the effects of BAFF on the metabolism of CLL cells and restored their susceptibility to direct and Rituximab-induced NK-cell killing in allogeneic and autologous experimental systems. Our findings unravel the involvement of BAFF in the resistance of CLL cells to NK-cell antitumor immunity and Rituximab treatment and point to a benefit of combinatory approaches employing BAFF-neutralizing drugs in B-cell malignancies.
    Type of Publication: Journal article published
    PubMed ID: 25710310
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