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  • Title: Targeting CD4(+) T-helper cells improves the induction of antitumor responses in dendritic cell-based vaccination.
    Author: Aarntzen EH, De Vries IJ, Lesterhuis WJ, Schuurhuis D, Jacobs JF, Bol K, Schreibelt G, Mus R, De Wilt JH, Haanen JB, Schadendorf D, Croockewit A, Blokx WA, Van Rossum MM, Kwok WW, Adema GJ, Punt CJ, Figdor CG.
    Journal: Cancer Res; 2013 Jan 01; 73(1):19-29. PubMed ID: 23087058.
    Abstract:
    To evaluate the relevance of directing antigen-specific CD4(+) T helper cells as part of effective anticancer immunotherapy, we investigated the immunologic and clinical responses to vaccination with dendritic cells (DC) pulsed with either MHC class I (MHC-I)-restricted epitopes alone or both MHC class I and II (MHC-I/II)-restricted epitopes. We enrolled 33 stage III and IV HLA-A*02:01-positive patients with melanoma in this study, of whom 29 were evaluable for immunologic response. Patients received intranodal vaccinations with cytokine-matured DCs loaded with keyhole limpet hemocyanin and MHC-I alone or MHC-I/II-restricted tumor-associated antigens (TAA) of tyrosinase and gp100, depending on their HLA-DR4 status. In 4 of 15 patients vaccinated with MHC-I/II-loaded DCs and 1 of 14 patients vaccinated with MHC-I-loaded DCs, we detected TAA-specific CD8(+) T cells with maintained IFN-γ production in skin test infiltrating lymphocyte (SKIL) cultures and circulating TAA-specific CD8(+) T cells. If TAA-specific CD4(+) T-cell responses were detected in SKIL cultures, it coincided with TAA-specific CD8(+) T-cell responses. In 3 of 13 patients tested, we detected TAA-specific CD4(+)CD25(+)FoxP3(-) T cells with high proliferative capacity and IFN-γ production, indicating that these were not regulatory T cells. Vaccination with MHC-I/II-loaded DCs resulted in improved clinical outcome compared with matched control patients treated with dacarbazine (DTIC), median overall survival of 15.0 versus 8.3 months (P = 0.089), and median progression-free survival of 5.0 versus 2.8 months (P = 0.0089). In conclusion, coactivating TAA-specific CD4(+) T-helper cells with DCs pulsed with both MHC class I and II-restricted epitopes augments TAA-specific CD8(+) T-cell responses, contributing to improved clinical responses.
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