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Background: This randomized phase III trial was designed to demonstrate the superiority of autologous peptide-loaded dendritic cell (DC) vaccination over standard dacarbazine (DTIC) chemotherapy in stage IV melanoma patients. Patients and methods: DTIC 850 mg/m2 intravenously was applied in 4-week intervals. DC vaccines loaded with MHC class I and II-restricted peptides were applied subcutaneously at 2-week intervals for the first five vaccinations and every 4 weeks thereafter. The primary study end point was objective response (OR); secondary end points were toxicity, overall (OS) and progression-free survival (PFS). Results: At the time of the first interim analysis 55 patients had been enrolled into the DTIC and 53 into the DC-arm (ITT). OR was low (DTIC: 5.5%, DC: 3.8%), but not significantly different in the two arms. The Data Safety & Monitoring Board recommended closure of the study. Unscheduled subset analyses revealed that patients with normal serum LDH and/or stage M1a/b survived longer in both arms than those with elevated serum LDH and/or stage M1c. Only in the DC-arm did those patients with (i) an initial unimpaired general health status (Karnofsky = 100) or (ii) an HLA-A2+/HLA-B44− haplotype survive significantly longer than patients with a Karnofsky index <100 (P = 0.007 versus P = 0.057 in the DTIC-arm) or other HLA haplotypes (P = 0.04 versus P = 0.57 in DTIC-treated patients). Conclusions: DC vaccination could not be demonstrated to be more effective than DTIC chemotherapy in stage IV melanoma patients. The observed association of overall performance status and HLA haplotype with overall survival for patients treated by DC vaccination should be tested in future trials employing DC vaccines

Item does not contain fulltext, The induction of antigen-specific T cell tolerance and its maintenance in the periphery are critical for the immune system to prevent autoaggressive immune responses. Our current state of knowledge about the immunoregulatory mechanisms responsible for T cell tolerance in the periphery offers new possibilities for immunomodulation to prevent transplant rejection as well as to diminish autoimmune reaction or chronic allergy. There is growing evidence that dendritic cells, besides their well-known T cell stimulatory functions, also maintain and regulate T cell tolerance in the periphery. This control function is exerted by certain maturation stages and subsets of dendritic cells, and can be further influenced and modulated by immunoregulatory cytokines and drugs. The regulatory functions of dendritic cells include the induction of T cell anergy, of T cells with regulatory properties and of T cells that produce immunosuppressive cytokines such as IL-10 or TGF-beta. Additionally, distinct subsets of resident regulatory T cells generated in the thymus play a central role in maintenance of peripheral tolerance by active suppression of effector T cell populations. These CD4(+)CD25(+) regulatory T cells inhibit a variety of autoimmune and inflammatory diseases and they are also efficient in the suppression of alloantigen responses. This review summarises the current knowledge regarding the immunoregulatory role of dendritic cells and the functional activities of resident regulatory T cells as guardians for peripheral T cell tolerance.

Item does not contain fulltext, The induction of antigen-specific T cell tolerance and its maintenance in the periphery are critical for the immune system to prevent autoaggressive immune responses. Our current state of knowledge about the immunoregulatory mechanisms responsible for T cell tolerance in the periphery offers new possibilities for immunomodulation to prevent transplant rejection as well as to diminish autoimmune reaction or chronic allergy. There is growing evidence that dendritic cells, besides their well-known T cell stimulatory functions, also maintain and regulate T cell tolerance in the periphery. This control function is exerted by certain maturation stages and subsets of dendritic cells, and can be further influenced and modulated by immunoregulatory cytokines and drugs. The regulatory functions of dendritic cells include the induction of T cell anergy, of T cells with regulatory properties and of T cells that produce immunosuppressive cytokines such as IL-10 or TGF-beta. Additionally, distinct subsets of resident regulatory T cells generated in the thymus play a central role in maintenance of peripheral tolerance by active suppression of effector T cell populations. These CD4(+)CD25(+) regulatory T cells inhibit a variety of autoimmune and inflammatory diseases and they are also efficient in the suppression of alloantigen responses. This review summarises the current knowledge regarding the immunoregulatory role of dendritic cells and the functional activities of resident regulatory T cells as guardians for peripheral T cell tolerance.

Item does not contain fulltext, The induction of antigen-specific T cell tolerance and its maintenance in the periphery are critical for the immune system to prevent autoaggressive immune responses. Our current state of knowledge about the immunoregulatory mechanisms responsible for T cell tolerance in the periphery offers new possibilities for immunomodulation to prevent transplant rejection as well as to diminish autoimmune reaction or chronic allergy. There is growing evidence that dendritic cells, besides their well-known T cell stimulatory functions, also maintain and regulate T cell tolerance in the periphery. This control function is exerted by certain maturation stages and subsets of dendritic cells, and can be further influenced and modulated by immunoregulatory cytokines and drugs. The regulatory functions of dendritic cells include the induction of T cell anergy, of T cells with regulatory properties and of T cells that produce immunosuppressive cytokines such as IL-10 or TGF-beta. Additionally, distinct subsets of resident regulatory T cells generated in the thymus play a central role in maintenance of peripheral tolerance by active suppression of effector T cell populations. These CD4(+)CD25(+) regulatory T cells inhibit a variety of autoimmune and inflammatory diseases and they are also efficient in the suppression of alloantigen responses. This review summarises the current knowledge regarding the immunoregulatory role of dendritic cells and the functional activities of resident regulatory T cells as guardians for peripheral T cell tolerance.

Background: This randomized phase III trial was designed to demonstrate the superiority of autologous peptide-loaded dendritic cell (DC) vaccination over standard dacarbazine (DTIC) chemotherapy in stage IV melanoma patients. Patients and methods: DTIC 850 mg/m2 intravenously was applied in 4-week intervals. DC vaccines loaded with MHC class I and II-restricted peptides were applied subcutaneously at 2-week intervals for the first five vaccinations and every 4 weeks thereafter. The primary study end point was objective response (OR); secondary end points were toxicity, overall (OS) and progression-free survival (PFS). Results: At the time of the first interim analysis 55 patients had been enrolled into the DTIC and 53 into the DC-arm (ITT). OR was low (DTIC: 5.5%, DC: 3.8%), but not significantly different in the two arms. The Data Safety & Monitoring Board recommended closure of the study. Unscheduled subset analyses revealed that patients with normal serum LDH and/or stage M1a/b survived longer in both arms than those with elevated serum LDH and/or stage M1c. Only in the DC-arm did those patients with (i) an initial unimpaired general health status (Karnofsky = 100) or (ii) an HLA-A2+/HLA-B44− haplotype survive significantly longer than patients with a Karnofsky index <100 (P = 0.007 versus P = 0.057 in the DTIC-arm) or other HLA haplotypes (P = 0.04 versus P = 0.57 in DTIC-treated patients). Conclusions: DC vaccination could not be demonstrated to be more effective than DTIC chemotherapy in stage IV melanoma patients. The observed association of overall performance status and HLA haplotype with overall survival for patients treated by DC vaccination should be tested in future trials employing DC vaccines