Author:

Keywords:

dendritic cell, interferon alpha-2b, trimix, immunotherapy, melanoma, high-dose interferon-alpha-2b, stage-iv melanoma, cd8(+) t-cells, metastatic melanoma, activation, antigen, interleukin-12, metaanalysis, guidelines, Science & Technology, Life Sciences & Biomedicine, Oncology, Immunology, Medicine, Research & Experimental, Research & Experimental Medicine, TriMix, HIGH-DOSE INTERFERON-ALPHA-2B, STAGE-IV MELANOMA, CD8(+) T-CELLS, METASTATIC MELANOMA, IMMUNOTHERAPY, ACTIVATION, ANTIGEN, INTERLEUKIN-12, METAANALYSIS, GUIDELINES, Adult, Aged, Antigens, Neoplasm, CD27 Ligand, CD40 Antigens, Cancer Vaccines, Dendritic Cells, Drug Therapy, Combination, Electroporation, Female, Histocompatibility Antigens Class II, Humans, Hypersensitivity, Delayed, Interferon alpha-2, Interferon-alpha, Male, Melanoma, Middle Aged, Neoplasm Staging, RNA, Messenger, Recombinant Proteins, Skin Neoplasms, Survival Analysis, Toll-Like Receptor 4, Vaccination, 1107 Immunology, 3204 Immunology, 3211 Oncology and carcinogenesis

Abstract:

The immunostimulatory capacity of dendritic cells is improved by co-electroporation with mRNA encoding CD40 ligand, constitutively active toll-like receptor 4, and CD70 (TriMix-DC). This pilot clinical trial evaluated the feasibility, safety, and immunogenicity of a therapeutic vaccination containing autologous TriMix-DC co-electroporated with mRNA encoding a human leukocyte antigen class II-targeting signal linked to 1 of 4 melanoma-associated antigens (MAGE-A3, MAGE-C2, tyrosinase, and gp100) in patients with advanced melanoma. Thirty-five American Joint Committee on Cancer stage III/IV melanoma patients received autologous TriMix-DC (4 administrations 2 weeks apart). Immune monitoring was performed by evaluating skin biopsies of delayed type IV hypersensitivity (DTH) reactions for presence of vaccinal antigen-specific DTH-infiltrating lymphocytes (DIL). Thereafter, patients could receive interferon-alpha-2b (IFN-alpha-2b) 5 MU subcutaneously 3 times weekly and additional TriMix-DC every 8 weeks. TriMix-DC-related adverse events comprised grade 2 local injection site reactions (all patients), and grade 2 fever and lethargy (2 patients). Vaccinal antigen-specific DIL were found in 0/6 patients tested at vaccine initiation and in 12/21 (57.1%) assessed after the fourth vaccine. A positive post-vaccination DTH test correlated with IL-12p70 secretion capacity of TriMix-DC. No objective responses to TriMix-DC alone were seen according to RECIST. Twenty-nine patients received IFN-alpha-2b after the fourth vaccine without unexpected adverse events. During TriMix-DC/IFN-alpha-2b combination therapy, 1 partial response and 5 stable disease (disease control of > 6 months with regression of metastases) were observed in 17 patients with evaluable disease at baseline. In conclusion, this study demonstrated that therapeutic vaccination with autologous TriMix-DC is feasible, safe, and immunogenic and can be combined with sequential IFN-alpha-2b.