Characterization of CD34+ progenitor-derived dendritic cells pulsed with tumor cell lysate for a vaccination strategy in children with malignant solid tumors and a poor prognosis
ABSTRACT
BACKGROUND: Children and adolescents with primary multifocal, refractory or relapsed malignant extracranial solid tumors still have a poor prognosis inspite of intensive standard radio-/chemotherapy. Here complementary immunomodulatory treatment modalities may prove beneficial as consolidation therapy following cytoreduction. Neuroblastoma, Ewing tumor and soft tissue sarcoma cells have principally been shown to be susceptible towards both cytotoxic and humoral effector mechanisms. Yet in vivo they are not capable of inducing an effective antitumor response which has been attributed to low level MHC expression and lack of costimulatory surface molecules. Professional antigen – presenting cells such as dendritic cells (DCs) in contrast are capable of activating unprimed T cells and are therefore ideal tools for vaccine generation.
RESULTS: Here we demonstrate that DCs may be generated from CD34+ progenitor cells to clinical scale in a three to four week cell culture process including an initial expansion and subsequent differentiation and maturation steps. DCs derived from CD34+ progenitors express the expected marker profile and are highly effective in stimulating allogeneic T cell effectors. We also demonstrate that they effectively take up fluorescence-labelled tumor cell lysate.
DISCUSSION: Having established a cell culture process for clinical scale DC production utilizing CD34+ progenitors as the cellular source we discuss the role of CD34+ derived DCs in clinical vaccination protocols. The rationale for a phase I/II DC dose escalation study for high risk pediatric patients with extracranial solid tumors assessing safety, immunological and clinical efficacy of serial combined intranodal and subcutaneous injections of tumor cell lysate-pulsed autologous DCs is delineated.