ABSTRACT
Imiquimod and resiquimod represent Toll-like receptor (TLR) 7 and 8 agonists, which emerged as attractive candidates for tumor therapy. To elucidate immune cells, which mainly contribute to TLR7/8-mediated antitumoral activity, we investigated the impact of imiquimod and resiquimod on native human 6-sulfo LacNAc (slan) dendritic cells (DCs). We found that both TLR7/8 agonists significantly improve the release of various proinflammatory cytokines by slanDCs and promote their tumor-directed cytotoxic activity. Furthermore, resiquimod efficiently augmented the ability of slanDCs to stimulate T cells and natural killer cells. These results indicate that imiquimod and resiquimod trigger various immunostimulatory properties of slanDCs, which may contribute to their antitumor effects.
Subject(s)
Aminoquinolines/pharmacology , Antineoplastic Agents/pharmacology , Dendritic Cells/drug effects , Imidazoles/pharmacology , Toll-Like Receptor 7/agonists , Toll-Like Receptor 8/agonists , Antigens, CD/metabolism , B7-2 Antigen/metabolism , Cell Proliferation , Coculture Techniques , Cytokines/metabolism , Cytotoxicity, Immunologic/drug effects , Dendritic Cells/immunology , Dendritic Cells/metabolism , Drug Screening Assays, Antitumor , HLA-DR Antigens/metabolism , HT29 Cells , Humans , Imiquimod , Immunoglobulins/metabolism , Immunomodulation/drug effects , Inflammation Mediators/metabolism , K562 Cells , Killer Cells, Natural/immunology , Lymphocyte Activation , Membrane Glycoproteins/metabolism , T-Lymphocytes/immunology , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 8/metabolism , CD83 AntigenABSTRACT
Donor lymphocyte infusions have been effective in patients with chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation, but their use is associated with the risk of graft-versus-host disease. We investigated the effects of prophylactic infusion of in vitro-generated donor T cells reactive against peptides derived from CML-associated antigens. Fourteen CML patients received conditioning therapy followed by CD34(+)-selected peripheral blood stem cells from matched siblings (n = 7) or unrelated (n = 7) donors. Donor-derived mature dendritic cells generated in vitro from CD14(+) monocytes were loaded with human leukocyte Ag-restricted peptides derived from PR1, WT1, and/or B-cell receptor-ABL and used to repetitively stimulate donor CD8(+) T cells in the presence of IL-2 and IL-7. Stimulated T cells were infused 28, 56, and 112 days after transplantation. Thirteen patients are alive and 7 remain in molecular remission (median follow-up, 45 months). Interestingly, all 4 patients receiving CD8(+) T cells displaying marked cytotoxic activity in vitro and detectable peptide-reactive CD8(+) T cells during follow-up have not experienced graft-versus-host disease or relapse. Our study reveals that prophylactic infusion of allogeneic CD8(+) T cells reactive against peptides derived from CML-associated antigens is a safe and promising therapeutic strategy. This trial was registered at www.clinicaltrials.gov as #NCT00460629.
Subject(s)
Antigens, Neoplasm/immunology , CD8-Positive T-Lymphocytes/transplantation , Graft vs Host Disease/prevention & control , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Lymphocyte Depletion , Peptide Fragments/immunology , Peripheral Blood Stem Cell Transplantation/methods , Adult , Aged , Antigens, Neoplasm/metabolism , CD8-Positive T-Lymphocytes/immunology , Cells, Cultured , Coculture Techniques , Cohort Studies , Dendritic Cells/metabolism , Feasibility Studies , Female , Fusion Proteins, bcr-abl/metabolism , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology , Male , Middle Aged , Myeloblastin/metabolism , Peripheral Blood Stem Cell Transplantation/adverse effects , Remission Induction , Survival Analysis , Transplantation, Homologous , WT1 Proteins/metabolism , Young AdultABSTRACT
Dendritic cells (DCs) are professional antigen-presenting cells (APCs), which display an extraordinary capacity to induce, sustain, and regulate T-cell responses providing the opportunity of DC-based cancer vaccination strategies. Thus, clinical trials enrolling prostate cancer patients were conducted, which were based on the administration of DCs loaded with tumor-associated antigens. These clinical trials revealed that DC-based immunotherapeutic strategies represent safe and feasible concepts for the induction of immunological and clinical responses in prostate cancer patients. In this context, the administration of the vaccine sipuleucel-T consisting of autologous peripheral blood mononuclear cells including APCs, which were pre-exposed in vitro to the fusion protein PA2024, resulted in a prolonged overall survival among patients with metastatic castration-resistant prostate cancer. In April 2010, sipuleucel-T was approved by the United States Food and Drug Administration for prostate cancer therapy.
