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  • 1
    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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  • 2
    Keywords: EXPRESSION ; CELL ; GENE ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; LINES ; COMPLEX ; COMPLEXES ; ANTIGEN ; CELL-LINES ; treatment ; ASSOCIATION ; polymorphism ; PATTERNS ; PROMOTER ; TUMOR PROGRESSION ; CELL-LINE ; MELANOMA ; DATABASE ; antigen presentation ; MONOCLONAL-ANTIBODIES ; MHC CLASS-I ; IMMUNE-RESPONSE ; INTERFERON-GAMMA ; HUMAN-MALIGNANT MELANOMA ; DR EXPRESSION ; LEVEL ; CIITA ; HLA class II ; RESTRICTED EPITOPES ; TRANSACTIVATOR CIITA
    Abstract: Major histocompatibility complex (MHC) class II proteins (HLA-DR, HLA-DP and HLA-DQ) play a fundamental role in the regulation of the immune response. The level of expression of human leukocyte antigen (HLA) class II antigens is regulated by interferon-gamma (IFN-gamma) and depends on the status of class II trans-activator protein (CIITA), a co-activator of the MHC class II gene promoter. In this study, we measured levels of constitutive and IFN-gamma-induced expression of MHC class II molecules, analysed the expression of CIITA and investigated the association between MHC class II transactivator polymorphism and expression of different MHC class II molecules in a large panel of melanoma cell lines obtained from the European Searchable Tumour Cell Line Database. Many cell lines showed no constitutive expression of HLA-DP, HLA-DQ and HLA-DR and no IFN-gamma-induced increase in HLA class II surface expression. However, in some cases, IFN-gamma treatment led to enhanced surface expression of HLA-DP and HLA-DR. HLA-DQ was less frequently expressed under basal conditions and was less frequently induced by IFN-gamma. In these melanoma cell lines, constitutive surface expression of HLA-DR and HLA-DP was higher than that of HLA-DQ. In addition, high constitutive level of cell surface expression of HLA-DR was correlated with lower inducibility of this expression by IFN-gamma. Finally, substitution A -〉 G in the 5' flanking region of CIITA promoter type III was associated with higher expression of constitutive HLA-DR (p 〈 0.005). This study yielded a panel of melanoma cell lines with different patterns of constitutive and IFN-gamma-induced expression of HLA class II that can be used in future studies of the mechanisms of regulation of HLA class II expression
    Type of Publication: Journal article published
    PubMed ID: 17180681
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  • 3
    Keywords: PEPTIDE ; CANCER ; CELLS ; BLOOD ; CELL ; CLINICAL-TRIAL ; COMBINATION ; NEW-YORK ; DISTINCT ; SAMPLE ; SAMPLES ; RESPONSES ; BASE ; CD8(+) T-CELLS ; T cell ; T cells ; T-CELL ; T-CELLS ; ASSOCIATION ; TRIAL ; TRIALS ; IDENTIFICATION ; ASSAY ; NUMBER ; CLINICAL-TRIALS ; COUNTRIES ; MELANOMA ; LYMPHOCYTES ; VARIABILITY ; PEPTIDES ; NETHERLANDS ; CD8(+) ; ELISPOT ; IMMUNOTHERAPY ; T-LYMPHOCYTES ; T lymphocyte ; sensitivity ; PERIPHERAL-BLOOD ; PROJECT ; INTERFERON-GAMMA ; tetramer ; T lymphocytes ; GUIDELINES ; HETEROGENEITY ; CANCER VACCINES ; ONCOLOGY ; monitoring ; INCREASE ; analysis ; methods ; ASSAYS ; PHASE ; technique ; USA ; RECOMMENDATIONS ; STANDARDIZATION ; VARIABLES ; immunology ; INCREASES ; clinical trial ; CELL RESPONSES ; IMPORTANT DETERMINANT ; CD4+T-CELL IMMUNITY ; CYTOKINE FLOW-CYTOMETRY ; GAMMA ELISPOT ASSAYS ; Interlaboratory testing
    Abstract: The interpretation of the results obtained from immunomonitoring of clinical trials is a difficult task due to the variety of methods and protocols available to detect vaccine-specific T-cell responses. This heterogeneity as well as the lack of standards has led to significant scepticism towards published results. In February 2005, a working group was therefore founded under the aegis of the Association for Immunotherapy of Cancer ("CIMT") in order to compare techniques and protocols applied for the enumeration of antigen-specific T-cell responses. Here we present the results from two consecutive phases of an international inter-laboratory testing project referred to as the "CIMT monitoring panel". A total of 13 centers from six European countries participated in the study in which pre-tested PBMC samples, synthetic peptides and PE-conjugated HLA-tetramers were prepared centrally and distributed to participants. All were asked to determine the number of antigen-specific T-cells in each sample using tetramer staining and one functional assay. The results of the first testing round revealed that the total number of cells analyzed was the most important determinant for the sensitive detection of antigen-specific CD8(+) T-cells by tetramer staining. Analysis by ELISPOT was influenced by a combination of cell number and a resting phase after thawing of peripheral blood mononuclear cells. Therefore, the experiments were repeated in a second phase but now the participants were asked to change their protocols according to the new guidelines distilled from the results of the first phase. The recommendations improved the number of antigen-specific T-cell responses that were detected and decreased the variability between the laboratories. We conclude that a two-step approach in inter-laboratory testing allows the identification of distinct variables that influence the sensitivity of different T-cell assays and to formally show that a defined correction to the protocols successfully increases the sensitivity and reduces the inter-center variability. Such "two-step" inter-laboratory projects could define rational bases for accepted international guidelines and thereby lead to the harmonization of the techniques used for immune monitoring
    Type of Publication: Journal article published
    PubMed ID: 17721783
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  • 4
    Keywords: tumor ; SYSTEM ; ANTIGEN ; METASTATIC MELANOMA ; VACCINE ; PERIPHERAL-BLOOD ; CARCINOMA PATIENTS ; DOSE INTERLEUKIN-2 ; CLINICAL CANCER STAGE ; IV-MELANOMA
    Abstract: PURPOSE: To analyze the prognostic relevance and relative impact of circulating myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) compared with functional tumor antigen-specific T cells in patients with melanoma with distant metastasis. EXPERIMENTAL DESIGN: The percentage of CD14(+)CD11b(+)HLA-DR(-/low) MDSCs, CD4(+)CD25(+)FoxP3(+) Tregs, and the presence of NY-ESO-1- or Melan-A-specific T cells was analyzed in 94 patients and validated in an additional cohort of 39 patients by flow cytometry. Univariate survival differences were calculated according to Kaplan-Meier and log-rank tests. Multivariate analyses were performed using Cox regression models. RESULTS: NY-ESO-1-specific T cells, the M-category, and the frequency of MDSCs were associated with survival. The absence of NY-ESO-1-specific T cells and the M-category M1c independently increased the risk of death. In a second Cox model not considering results on antigen-specific T cells, a frequency of 〉11% MDSCs showed independent impact. Its association with survival was confirmed in the additional patient cohort. Median survival of patients with a lower frequency of MDSCs was 13 months versus 8 months for others (P 〈 0.001, combined cohorts). We observed a strong correlation between high levels of MDSCs and the absence of melanoma antigen-specific T cells implying a causal and clinically relevant interaction. No prognostic impact was observed for Tregs. CONCLUSIONS: Circulating CD14(+)CD11b(+)HLA-DR(-/low) MDSCs have a negative impact on survival and inversely correlate with the presence of functional antigen-specific T cells in patients with advanced melanoma. Our findings provide a rationale to investigate MDSC-depleting strategies in the therapeutic setting especially in combination with vaccination or T-cell transfer approaches. Clin Cancer Res; 20(6); 1601-9. (c)2013 AACR.
    Type of Publication: Journal article published
    PubMed ID: 24323899
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  • 5
    Abstract: PURPOSE: To identify baseline peripheral blood biomarkers associated with clinical outcome following ipilimumab treatment in advanced melanoma patients. EXPERIMENTAL DESIGN: Frequencies of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood counts, and clinical characteristics were assessed in 209 patients. Endpoints were overall survival (OS) and best overall response. Statistical calculations were done by Kaplan-Meier and Cox regression analysis, including calibration and discrimination by C-statistics. RESULTS: Low baseline LDH, absolute monocyte counts (AMC), Lin(-)CD14(+)HLA-DR(-/low)-MDSC frequencies, and high absolute eosinophil counts (AEC), relative lymphocyte counts (RLC), and CD4(+)CD25(+)FoxP3(+)-Treg frequencies were significantly associated with better survival, and were considered in a combination model. Patients (43.5%) presenting with the best biomarker signature had a 30% response rate and median survival of 16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3% response rate and median survival of 4 months. The occurrence of adverse events correlated with neither baseline biomarker signatures nor the clinical benefit of ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC, and RLC, the number of favorable factors (4 vs. 3 vs. 2-0) was also associated with OS (P 〈 0.001 for all pairwise comparisons) in the main study and additionally in an independent validation cohort. CONCLUSIONS: A baseline signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is associated with favorable outcome following ipilimumab. Prospective investigation of the predictive impact of these markers following ipilimumab and other treatments, e.g., PD-1 antibodies, is warranted. Clin Cancer Res; 22(12); 2908-18. (c)2016 AACR.
    Type of Publication: Journal article published
    PubMed ID: 26787752
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  • 6
    Abstract: Human T cells carrying gammadelta T-cell receptors (TCRs) represent a minor population relative to those with alphabeta TCRs. There has been much interest recently in the possibility of using these gammadelta T-cells in cancer therapy because they can kill tumor cells in vitro in an MHC-unrestricted manner, and possess potential regulatory capability and antigen-presenting capacity. The presence of gammadelta T-cells in late-stage melanoma patients and their relationship with survival has not been extensively explored, although relatively lower percentages of total gammadelta T-cells and Vdelta2+ cells have been reported. Here, we present a detailed analysis of associations of gammadelta T-cell subsets and differentiation stages with survival in Stage IV patients, compared with CD4+ and CD8+ alphabeta T-cells. We found an increased Vdelta1:Vdelta2-ratio and a decreased CD4:CD8-ratio in patients compared to healthy controls, on the basis both of relative frequencies and absolute cell counts per muL blood. Nonetheless, Kaplan-Meier analyses showed that a higher than median frequency of Vdelta1+ cells was negatively associated with survival, whereas there were no positive or negative associations with frequencies of Vdelta2+ cells. Correlations of cell differentiation status with survival revealed a negative association of early-differentiated Vdelta1+ T cells with survival, both on the basis of relative frequencies and absolute counts. There was also a positive correlation between the frequencies of early-differentiated CD8+ alphabeta T-cells and survival. Our findings suggest peripheral blood frequencies of Vdelta1+ T-cells as a potential prognostic marker in melanoma. The mechanisms by which higher abundance of Vdelta1+ cells are associated with poorer survival require determination.
    Type of Publication: Journal article published
    PubMed ID: 26383054
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  • 7
    Abstract: Human gammadelta T-cells possess regulatory and cytotoxic capabilities, and could potentially influence the efficacy of immunotherapies. We analysed the frequencies of peripheral gammadelta T-cells, including their most prominent subsets (Vdelta1+ and Vdelta2+ cells) and differentiation states in 109 melanoma patients and 109 healthy controls. We additionally analysed the impact of gammadelta T-cells on overall survival (OS) calculated from the first dose of ipilimumab in melanoma patients. Higher median frequencies of Vdelta1+ cells and lower median frequencies of Vdelta2+ cells were identified in patients compared to healthy subjects (Vdelta1+: 30% versus 15%, Vdelta2+: 39% versus 64%, both p 〈 0.001). Patients with higher frequencies of Vdelta1+ cells (〉/=30%) had poorer OS (p = 0.043) and a Vdelta1+ differentiation signature dominated by late-differentiated phenotypes. In contrast, higher frequencies of Vdelta2+ cells (〉/=39%) were associated with longer survival (p = 0.031) independent of the M category or lactate dehydrogenase level. Patients with decreasing frequencies of Vdelta2+ cells under ipilimumab treatment had worse OS and a lower rate of clinical benefit than patients without such decreases. Therefore, we suggest frequencies of both Vdelta1+ and Vdelta2+ cells as candidate biomarkers for outcome in melanoma patients following ipilimumab. Further studies are needed to validate these results and to clarify whether they represent prognostic associations or whether gammadelta T-cells are specifically and/or functionally linked to the mode of action of ipilimumab.
    Type of Publication: Journal article published
    PubMed ID: 27400322
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  • 8
    Abstract: PURPOSE: To investigate changes of peripheral blood biomarkers and their impact on clinical outcome following treatment with ipilimumab in advanced melanoma patients. EXPERIMENTAL DESIGN: Changes in blood counts and the frequency of circulating immune cell populations analyzed by flow cytometry were investigated in 82 patients to compare baseline values with different time-points after starting ipilimumab. Endpoints were overall survival (OS) and best clinical response. Statistical calculations were done by Wilcoxon-matched pairs tests, Fisher exact test, Kaplan-Meier analysis, and Cox regression analysis. RESULTS: Increases in absolute lymphocyte counts (ALC) 2 to 8 weeks (P = 0.003) and in percentages of CD4+ and CD8+ T cells 8 to 14 weeks (P = 0.001 and P = 0.02) after the first dose of ipilimumab were correlated with improved survival. These associations did not meet significance criteria, when conservatively adjusted for multiple testing, but were additionally correlated with clinical responses (all P 〈 0.05). However, validation is required. Increases in all three factors were observed in 36% of patients, who had a favorable outcome and survival probabilities of 93.3% and 63.8% at 12 and 24 months, respectively. A partial or complete response was observed in 71% of these patients compared with only 8% in patients with decreases in 〉/=1 of the 3 factors, respectively. Changes of regulatory T cells or myeloid-derived suppressor cells were not associated with OS. CONCLUSIONS: Increases of ALC observed 2 to 8 weeks after initiation of ipilimumab and delayed increases in CD4+ and CD8+ T cells reflect changes associated with positive outcome. These changes represent surrogate marker candidates and warrant further validation. Clin Cancer Res; 22(19); 4848-58. (c)2016 AACR.
    Type of Publication: Journal article published
    PubMed ID: 27169993
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  • 9
    Abstract: The role of the assessment of peripheral T-cell phenotypes in predicting overall survival (OS) after ipilimumab treatment is unclear. Here, we analysed mononuclear cells in the blood before and at different time points during treatment with ipilimumab in 137 late-stage melanoma patients. The proportions of baseline naive and memory T-cells were measured by flow cytometry and correlated with OS, with an emphasis on PD-1 expression. High frequencies (〉13%) of CD8 effector-memory type 1 (EM1) T-cells at baseline correlated with longer OS (p = 0.029) and higher clinical response rates (p = 0.01). The frequency of these EM1 cells and the M category had independent impacts on OS (hazard ratio = 1.5, p = 0.033; and hazard ratio = 1.9, p = 0.007). In contrast, high baseline frequencies of late stage-differentiated effector memory CD8 cells (〉23.8%) were negatively associated with OS (p = 0.034) but did not correlate with clinical response. Following treatment, a decrease of CD8 cells from baseline to the time of the second drug dose and at later time points was strongly and consistently correlated with a high clinical response rate. Our observations thus suggest an important predictive role of baseline CD8 EM1 cells and changes in CD8 cells for clinical response of ipilimumab. Further validation of these biomarker candidates is warranted.
    Type of Publication: Journal article published
    PubMed ID: 28167454
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Immunogenetics 14 (1981), S. 549-552 
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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