Vaccination with mRNA-Electroporated Dendritic Cells Induces Robust Tumor Antigen-Specific CD4+ and CD8+ T Cells Responses in Stage III and IV Melanoma Patients
SourceClinical Cancer Research, 18, 19, (2012), pp. 5460-5470
Article / Letter to editor
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Laboratory of Medical Immunology
Paediatrics - OUD tm 2017
Clinical Cancer Research
SubjectN4i 2: Invasive mycoses and compromised host ONCOL 3: Translational research; N4i 4: Auto-immunity, transplantation and immunotherapy NCMLS 2: Immune Regulation; N4i 4: Auto-immunity, transplantation and immunotherapy ONCOL 1: Hereditary cancer and cancer-related syndromes; NCMLS 2: Immune Regulation; NCMLS 2: Immune Regulation ONCOL 3: Translational research; ONCOL 2: Age-related aspects of cancer; ONCOL 3: Translational research; ONCOL 3: Translational research NCMLS 2: Immune Regulation; ONCOL 4: Quality of Care; ONCOL 5: Aetiology, screening and detection
PURPOSE: Electroporation of dendritic cells (DC) with mRNA encoding tumor-associated antigens (TAA) has multiple advantages compared to peptide loading. We investigated the immunologic and clinical responses to vaccination with mRNA-electroporated DC in stage III and IV melanoma patients. Experimental design: Twenty-six stage III HLA*02:01 melanoma patients scheduled for radical lymph node dissection (stage III) and 19 melanoma patients with irresectable locoregional or distant metastatic disease (referred to as stage IV) were included. Monocyte-derived DC, electroporated with mRNA encoding gp100 and tyrosinase, were pulsed with keyhole limpet hemocyanin and administered intranodally. TAA-specific T-cell responses were monitored in blood and skin-test infiltrating lymphocyte (SKIL) cultures. RESULTS: Comparable numbers of vaccine-induced CD8(+) and/or CD4(+) TAA-specific T-cell responses were detected in SKIL cultures; 17/26 stage III patients and 11/19 stage IV patients. Strikingly, in this population, TAA-specific CD8(+) T cells that recognize multiple epitopes and produce elevated levels of IFNgamma upon antigenic challenge in vitro, were significantly more often observed in stage III patients; 15/17 versus 3/11 stage IV patients, P = 0.0033. In stage IV patients, one mixed and one partial response were documented. The presence or absence of IFNgamma-producing TAA-specific CD8(+) T cells in stage IV patients was associated with marked difference in median overall survival of 24.1 months versus 11.0 months, respectively. CONCLUSION: Vaccination with mRNA-electroporated DC induces a broad repertoire of IFNgamma producing TAA-specific CD8(+) and CD4(+) T-cell responses, particularly in stage III melanoma patients. Clin Cancer Res; 18(19); 5460-70. (c)2012 AACR.
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