A phase I clinical study of vaccination of melanoma patients with dendritic cells loaded with allogeneic apoptotic/necrotic melanoma cells. Analysis of toxicity and immune response to the vaccine and of IL-10-1082 promoter genotype as predictor of disease progression
Background: Sixteen melanoma patients (1 stage IIC, 8 stage III, and 7 stage IV) were treated in a Phase I study with a vaccine (DC/Apo-Nec) composed of autologous dendritic cells (DCs) loaded with a mixture of apoptotic/necrotic allogeneic melanoma cell lines (Apo-Nec), to evaluate toxicity and imm...
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2008
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_14795876_v6_n_p_vonEuw http://hdl.handle.net/20.500.12110/paper_14795876_v6_n_p_vonEuw |
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paper:paper_14795876_v6_n_p_vonEuw |
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dspace |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
alpha interferon B7 antigen CD8 antigen CD83 antigen CD86 antigen chemokine receptor CCR7 dendritic cell vaccine dextran fluorescein isothiocyanate glycoprotein gp 100 granulocyte macrophage colony stimulating factor HLA A antigen HLA antigen class 1 HLA antigen class 2 interleukin 10 interleukin 4 macrophage inflammatory protein 3beta melan A melanoma antigen tetramer cancer vaccine interleukin 10 abdominal cramp abdominal pain adolescent adult anorexia antigen expression apoptosis article asthenia cancer staging CD8+ T lymphocyte cell culture cell death cell maturation cell migration cell stimulation chill clinical trial controlled clinical trial controlled study correlation analysis culture medium cytokine production dendritic cell diarrhea disease course drug safety drug tolerability endocytosis enzyme linked immunospot assay fatigue female follow up gamma radiation genetic polymorphism genotype headache human human cell humoral immunity immune response in vitro study injection site reaction leukapheresis liver dysfunction lymph node dissection lymphocyte proliferation male melanoma melanoma cell monocyte myalgia nausea peripheral blood mononuclear cell phagocytosis phase 1 clinical trial polymerase chain reaction prediction prognosis promoter region treatment outcome tumor immunity upregulation vomiting autotransplantation delayed hypersensitivity dendritic cell genetics immunology lymphocyte activation melanoma middle aged necrosis pathology patient selection prediction and forecasting transplantation Adolescent Adult Apoptosis Cancer Vaccines Dendritic Cells Disease Progression Female Genotype Humans Hypersensitivity, Delayed Interleukin-10 Lymphocyte Activation Male Melanoma Middle Aged Necrosis Neoplasm Staging Patient Selection Phagocytosis Polymorphism, Genetic Predictive Value of Tests Promoter Regions (Genetics) Transplantation, Autologous |
| spellingShingle |
alpha interferon B7 antigen CD8 antigen CD83 antigen CD86 antigen chemokine receptor CCR7 dendritic cell vaccine dextran fluorescein isothiocyanate glycoprotein gp 100 granulocyte macrophage colony stimulating factor HLA A antigen HLA antigen class 1 HLA antigen class 2 interleukin 10 interleukin 4 macrophage inflammatory protein 3beta melan A melanoma antigen tetramer cancer vaccine interleukin 10 abdominal cramp abdominal pain adolescent adult anorexia antigen expression apoptosis article asthenia cancer staging CD8+ T lymphocyte cell culture cell death cell maturation cell migration cell stimulation chill clinical trial controlled clinical trial controlled study correlation analysis culture medium cytokine production dendritic cell diarrhea disease course drug safety drug tolerability endocytosis enzyme linked immunospot assay fatigue female follow up gamma radiation genetic polymorphism genotype headache human human cell humoral immunity immune response in vitro study injection site reaction leukapheresis liver dysfunction lymph node dissection lymphocyte proliferation male melanoma melanoma cell monocyte myalgia nausea peripheral blood mononuclear cell phagocytosis phase 1 clinical trial polymerase chain reaction prediction prognosis promoter region treatment outcome tumor immunity upregulation vomiting autotransplantation delayed hypersensitivity dendritic cell genetics immunology lymphocyte activation melanoma middle aged necrosis pathology patient selection prediction and forecasting transplantation Adolescent Adult Apoptosis Cancer Vaccines Dendritic Cells Disease Progression Female Genotype Humans Hypersensitivity, Delayed Interleukin-10 Lymphocyte Activation Male Melanoma Middle Aged Necrosis Neoplasm Staging Patient Selection Phagocytosis Polymorphism, Genetic Predictive Value of Tests Promoter Regions (Genetics) Transplantation, Autologous von Euw, Erika María Barrio, María Marcela Levy, Estrella Mariel A phase I clinical study of vaccination of melanoma patients with dendritic cells loaded with allogeneic apoptotic/necrotic melanoma cells. Analysis of toxicity and immune response to the vaccine and of IL-10-1082 promoter genotype as predictor of disease progression |
| topic_facet |
alpha interferon B7 antigen CD8 antigen CD83 antigen CD86 antigen chemokine receptor CCR7 dendritic cell vaccine dextran fluorescein isothiocyanate glycoprotein gp 100 granulocyte macrophage colony stimulating factor HLA A antigen HLA antigen class 1 HLA antigen class 2 interleukin 10 interleukin 4 macrophage inflammatory protein 3beta melan A melanoma antigen tetramer cancer vaccine interleukin 10 abdominal cramp abdominal pain adolescent adult anorexia antigen expression apoptosis article asthenia cancer staging CD8+ T lymphocyte cell culture cell death cell maturation cell migration cell stimulation chill clinical trial controlled clinical trial controlled study correlation analysis culture medium cytokine production dendritic cell diarrhea disease course drug safety drug tolerability endocytosis enzyme linked immunospot assay fatigue female follow up gamma radiation genetic polymorphism genotype headache human human cell humoral immunity immune response in vitro study injection site reaction leukapheresis liver dysfunction lymph node dissection lymphocyte proliferation male melanoma melanoma cell monocyte myalgia nausea peripheral blood mononuclear cell phagocytosis phase 1 clinical trial polymerase chain reaction prediction prognosis promoter region treatment outcome tumor immunity upregulation vomiting autotransplantation delayed hypersensitivity dendritic cell genetics immunology lymphocyte activation melanoma middle aged necrosis pathology patient selection prediction and forecasting transplantation Adolescent Adult Apoptosis Cancer Vaccines Dendritic Cells Disease Progression Female Genotype Humans Hypersensitivity, Delayed Interleukin-10 Lymphocyte Activation Male Melanoma Middle Aged Necrosis Neoplasm Staging Patient Selection Phagocytosis Polymorphism, Genetic Predictive Value of Tests Promoter Regions (Genetics) Transplantation, Autologous |
| description |
Background: Sixteen melanoma patients (1 stage IIC, 8 stage III, and 7 stage IV) were treated in a Phase I study with a vaccine (DC/Apo-Nec) composed of autologous dendritic cells (DCs) loaded with a mixture of apoptotic/necrotic allogeneic melanoma cell lines (Apo-Nec), to evaluate toxicity and immune responses. Also, IL-10 1082 genotype was analyzed in an effort to predict disease progression. Methods: PBMC were obtained after leukapheresis and DCs were generated from monocytes cultured in the presence of GM-CSF and IL-4 in serum-free medium. Immature DCs were loaded with gamma-irradiated Apo-Nec cells and injected id without adjuvant. Cohorts of four patients were given four vaccines each with 5, 10, 15, or 20 × 106 DC/Apo-Nec cell per vaccine, two weeks apart. Immune responses were measured by ELISpot and tetramer analysis. Il-10 genotype was measured by PCR and corroborated by IL-10 production by stimulated PBMC. Results: Immature DCs efficiently phagocytosed melanoma Apo-Nec cells and matured after phagocytosis as evidenced by increased expression of CD83, CD80, CD86, HLA class I and II, and 75.2 ± 16% reduction in Dextran-FITC endocytosis. CCR7 was also up-regulated upon Apo-Nec uptake in DCs from all patients, and accordingly DC/Apo-Nec cells were able to migrate in vitro toward MIP-3 beta. The vaccine was well tolerated in all patients. The DTH score increased significantly in all patients after the first vaccination (Mann-Whitney Test, p < 0.05). The presence of CD8+T lymphocytes specific to gp100 and Melan A/ MART-1 Ags was determined by ELISpot and tetramer analysis in five HLA-A*0201 patients before and after vaccination; one patient had stable elevated levels before and after vaccination; two increased their CD8 + levels, one had stable moderate and one had negligible levels. The analysis of IL-10 promoter -1082 polymorphism in the sixteen patients showed a positive correlation between AA genotype, accompanied by lower in vitro IL-10 production by stimulated PBMC, and faster melanoma progression after lymph nodes surgery (p = 0.04). With a mean follow-up of 49.5 months post-surgery, one stage IIC patient and 7/8 stage III patients remain NED but 7/7 stage IV patients have progressed. Conclusion: We conclude that DC/Apo-Nec vaccine is safe, well tolerated and it may induce specific immunity against melanoma Ags. Patients with a low-producing IL-10 polymorphism appear to have a worst prognosis. © 2008 von Euw et al; licensee BioMed Central Ltd. |
| author |
von Euw, Erika María Barrio, María Marcela Levy, Estrella Mariel |
| author_facet |
von Euw, Erika María Barrio, María Marcela Levy, Estrella Mariel |
| author_sort |
von Euw, Erika María |
| title |
A phase I clinical study of vaccination of melanoma patients with dendritic cells loaded with allogeneic apoptotic/necrotic melanoma cells. Analysis of toxicity and immune response to the vaccine and of IL-10-1082 promoter genotype as predictor of disease progression |
| title_short |
A phase I clinical study of vaccination of melanoma patients with dendritic cells loaded with allogeneic apoptotic/necrotic melanoma cells. Analysis of toxicity and immune response to the vaccine and of IL-10-1082 promoter genotype as predictor of disease progression |
| title_full |
A phase I clinical study of vaccination of melanoma patients with dendritic cells loaded with allogeneic apoptotic/necrotic melanoma cells. Analysis of toxicity and immune response to the vaccine and of IL-10-1082 promoter genotype as predictor of disease progression |
| title_fullStr |
A phase I clinical study of vaccination of melanoma patients with dendritic cells loaded with allogeneic apoptotic/necrotic melanoma cells. Analysis of toxicity and immune response to the vaccine and of IL-10-1082 promoter genotype as predictor of disease progression |
| title_full_unstemmed |
A phase I clinical study of vaccination of melanoma patients with dendritic cells loaded with allogeneic apoptotic/necrotic melanoma cells. Analysis of toxicity and immune response to the vaccine and of IL-10-1082 promoter genotype as predictor of disease progression |
| title_sort |
phase i clinical study of vaccination of melanoma patients with dendritic cells loaded with allogeneic apoptotic/necrotic melanoma cells. analysis of toxicity and immune response to the vaccine and of il-10-1082 promoter genotype as predictor of disease progression |
| publishDate |
2008 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_14795876_v6_n_p_vonEuw http://hdl.handle.net/20.500.12110/paper_14795876_v6_n_p_vonEuw |
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paper:paper_14795876_v6_n_p_vonEuw2023-06-08T16:18:25Z A phase I clinical study of vaccination of melanoma patients with dendritic cells loaded with allogeneic apoptotic/necrotic melanoma cells. Analysis of toxicity and immune response to the vaccine and of IL-10-1082 promoter genotype as predictor of disease progression von Euw, Erika María Barrio, María Marcela Levy, Estrella Mariel alpha interferon B7 antigen CD8 antigen CD83 antigen CD86 antigen chemokine receptor CCR7 dendritic cell vaccine dextran fluorescein isothiocyanate glycoprotein gp 100 granulocyte macrophage colony stimulating factor HLA A antigen HLA antigen class 1 HLA antigen class 2 interleukin 10 interleukin 4 macrophage inflammatory protein 3beta melan A melanoma antigen tetramer cancer vaccine interleukin 10 abdominal cramp abdominal pain adolescent adult anorexia antigen expression apoptosis article asthenia cancer staging CD8+ T lymphocyte cell culture cell death cell maturation cell migration cell stimulation chill clinical trial controlled clinical trial controlled study correlation analysis culture medium cytokine production dendritic cell diarrhea disease course drug safety drug tolerability endocytosis enzyme linked immunospot assay fatigue female follow up gamma radiation genetic polymorphism genotype headache human human cell humoral immunity immune response in vitro study injection site reaction leukapheresis liver dysfunction lymph node dissection lymphocyte proliferation male melanoma melanoma cell monocyte myalgia nausea peripheral blood mononuclear cell phagocytosis phase 1 clinical trial polymerase chain reaction prediction prognosis promoter region treatment outcome tumor immunity upregulation vomiting autotransplantation delayed hypersensitivity dendritic cell genetics immunology lymphocyte activation melanoma middle aged necrosis pathology patient selection prediction and forecasting transplantation Adolescent Adult Apoptosis Cancer Vaccines Dendritic Cells Disease Progression Female Genotype Humans Hypersensitivity, Delayed Interleukin-10 Lymphocyte Activation Male Melanoma Middle Aged Necrosis Neoplasm Staging Patient Selection Phagocytosis Polymorphism, Genetic Predictive Value of Tests Promoter Regions (Genetics) Transplantation, Autologous Background: Sixteen melanoma patients (1 stage IIC, 8 stage III, and 7 stage IV) were treated in a Phase I study with a vaccine (DC/Apo-Nec) composed of autologous dendritic cells (DCs) loaded with a mixture of apoptotic/necrotic allogeneic melanoma cell lines (Apo-Nec), to evaluate toxicity and immune responses. Also, IL-10 1082 genotype was analyzed in an effort to predict disease progression. Methods: PBMC were obtained after leukapheresis and DCs were generated from monocytes cultured in the presence of GM-CSF and IL-4 in serum-free medium. Immature DCs were loaded with gamma-irradiated Apo-Nec cells and injected id without adjuvant. Cohorts of four patients were given four vaccines each with 5, 10, 15, or 20 × 106 DC/Apo-Nec cell per vaccine, two weeks apart. Immune responses were measured by ELISpot and tetramer analysis. Il-10 genotype was measured by PCR and corroborated by IL-10 production by stimulated PBMC. Results: Immature DCs efficiently phagocytosed melanoma Apo-Nec cells and matured after phagocytosis as evidenced by increased expression of CD83, CD80, CD86, HLA class I and II, and 75.2 ± 16% reduction in Dextran-FITC endocytosis. CCR7 was also up-regulated upon Apo-Nec uptake in DCs from all patients, and accordingly DC/Apo-Nec cells were able to migrate in vitro toward MIP-3 beta. The vaccine was well tolerated in all patients. The DTH score increased significantly in all patients after the first vaccination (Mann-Whitney Test, p < 0.05). The presence of CD8+T lymphocytes specific to gp100 and Melan A/ MART-1 Ags was determined by ELISpot and tetramer analysis in five HLA-A*0201 patients before and after vaccination; one patient had stable elevated levels before and after vaccination; two increased their CD8 + levels, one had stable moderate and one had negligible levels. The analysis of IL-10 promoter -1082 polymorphism in the sixteen patients showed a positive correlation between AA genotype, accompanied by lower in vitro IL-10 production by stimulated PBMC, and faster melanoma progression after lymph nodes surgery (p = 0.04). With a mean follow-up of 49.5 months post-surgery, one stage IIC patient and 7/8 stage III patients remain NED but 7/7 stage IV patients have progressed. Conclusion: We conclude that DC/Apo-Nec vaccine is safe, well tolerated and it may induce specific immunity against melanoma Ags. Patients with a low-producing IL-10 polymorphism appear to have a worst prognosis. © 2008 von Euw et al; licensee BioMed Central Ltd. Fil:von Euw, E.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Barrio, M.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Levy, E.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2008 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_14795876_v6_n_p_vonEuw http://hdl.handle.net/20.500.12110/paper_14795876_v6_n_p_vonEuw |