title: Ex vivo generation of interstitial and Langerhans cell-like dendritic cell subset-based vaccines for hematological malignancies.
abstract: Autologous, patient-specific, monocyte-derived dendritic cell (MoDC) vaccines have been successfully applied in the clinical studies so far. However, the routine application of this strategy has been hampered by the difficulties in generating sufficient numbers of DC and the poor DC vaccine quality because of pathology or prior treatment received by the patients. The immunotherapeutic potential of other subsets of DC has not been thoroughly investigated because of their rarity in tissues and difficulties associated with their ex vivo generation. The high expansion and differentiation potential of CD34 hematopoietic progenitor cells (HPC), isolated from umbilical cord blood (UCB), into different DC subsets make them an attractive alternative DC source for cancer immunotherapy. Therefore, the aim of this study was to generate a large number of different DC subsets from CD34 HPC and evaluate their functionality in comparison with MoDC. Our culture protocol generated a clinically relevant number of mature CD1a myeloid DC and CD207 Langerhans cells (LC)-like DC subsets from CD34 HPC with >95% purity. Both DC subsets exhibited a cytokine profile that favors cytotoxic T-cell responses. Furthermore, UCB-DC and UCB-LC demonstrated superior induction of proliferation of both allogeneic as well as viral antigen-specific CD8 T cells, both in vitro and in vivo. Additional studies revealed that UCC-DC and UCB-LC can efficiently expand minor histocompatibility antigen (MiHA) HA-1-specific cytotoxic T cells in the peripheral blood of leukemia patients and prime MiHA HA-1-specific and HA-2-specific cytotoxic T cells in vitro. These preclinical findings support the pharmaceutical development of the described culture protocol for clinical evaluation.
authors.affiliation: Laboratory of Hematology, Department of Laboratory Medicine, Radboud University Medical Centre and Nijmegen Centre for Molecular Life Sciences, Nijmegen, the Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Hutten
authors.forename: Soley
authors.initials: S
authors.lastname: Thordardottir
authors.forename: Willemijn
authors.initials: W
authors.lastname: Hobo
authors.forename: Jessica
authors.initials: J
authors.lastname: Hübel
authors.forename: Anniek B
authors.initials: AB
authors.lastname: van der Waart
authors.forename: Jeannette
authors.initials: J
authors.lastname: Cany
authors.forename: Harry
authors.initials: H
authors.lastname: Dolstra
authors.forename: Basav N
authors.initials: BN
authors.lastname: Hangalapura
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D019496:Cancer Vaccines; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000502:physiology* / Q000637:transplantation; D019337:Hematologic Neoplasms / Q000276:immunology / Q000628:therapy*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008213:Lymphocyte Activation; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D009000:Monocytes / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D019496:Cancer Vaccines; D016207:Cytokines; D015778:Minor Histocompatibility Antigens