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...

• Autores: von Euw, E.M.; Barrio, M.M.; Furman, D.; Levy, E.M.; Bianchini, M.; Peguillet, I.; Lantz, O.; Vellice, A.; Kohan, A.; Chacón, M.; Yee, C.; Wainstok, R.; Mordoh, J.
• Año de publicación: 2008
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: J. Transl. Med. 2008;6
• Materia: 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
• Institución: Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales

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.