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.

Umbilical cord blood-derived CD11c+ dendritic cells could serve as an alternative allogeneic source of dendritic cells for cancer immunotherapy

“…Thus, UCB could be exploited as an additional source for the generation of allogeneic DCs. UCB-derived DCs have been used in the pilot phase of clinical trials as well, in hematological disorders like AML, as a therapeutic agent to increase the survival of patients [ 29 , 30 ].…”

Dendritic Cells as Pharmacological Tools for Cancer Immunotherapy

“…As discussed above, LCs, presumably via a mechanism that involves IL-15, are far more superior than dermal DCs and moDCs (Romano et al, 2012;Hutten et al, 2014) in terms of their capacity to stimulate antigen-specific CTL immunity. This explains the impetus behind the recent efforts to design new protocols for the generation of DCs with LC-like features (Hutten et al, 2014).…”

“…As discussed above, LCs, presumably via a mechanism that involves IL-15, are far more superior than dermal DCs and moDCs (Romano et al, 2012;Hutten et al, 2014) in terms of their capacity to stimulate antigen-specific CTL immunity. This explains the impetus behind the recent efforts to design new protocols for the generation of DCs with LC-like features (Hutten et al, 2014). Such LC-type, IL-15-expressing DCs can be generated from CD34 + hematopoietic progenitor cells using specific differentiation factors (Romano et al, 2011) or from CD14 + monocytes by replacing IL-4 with IL-15 (Mohamadzadeh et al, 2001;Anguille et al, 2009Anguille et al, , 2013.…”

Umbilical cord blood–derived cellular products for cancer immunotherapy

“…To this end, Hutten et al [40] recently reported a method for the generation of mature CD1a þ mDC and CD207 þ Langerhans cells (LC) from UCBderived CD34 þ HPCs. These cells display potent expansion induction of minor histocompatibility antigen (MiHA)-specific T cells isolated from PB of leukemia patients, as well as priming of naive MiHAspecific T cells.…”