Abstract
BackgroundActive dendritic cell (DC) immunization protocols are rapidly gaining interest as therapeutic options in patients with acute myeloid leukemia (AML). Here we present for the first time a GMP-compliant 3-day protocol for generation of monocyte-derived DCs using different synthetic Toll-like receptor (TLR) agonists in intensively pretreated patients with AML.MethodsFour different maturation cocktails were compared for their impact on cell recovery, phenotype, cytokine secretion, migration, and lymphocyte activation in 20 AML patients and 25 healthy controls.ResultsMaturation cocktails containing the TLR7/8 agonists R848 or CL075, with and without the addition of the TLR3 agonist poly(I:C), induced DCs that had a positive costimulatory profile, secreted high levels of IL-12(p70), showed chemotaxis to CCR7 ligands, had the ability to activate NK cells, and efficiently stimulated antigen-specific CD8+ T cells.ConclusionsOur results demonstrate that this approach translates into biologically improved DCs, not only in healthy controls but also in AML patients. This data supports the clinical application of TLR-matured DCs in patients with AML for activation of innate and adaptive immune responses.
Highlights
Active dendritic cell (DC) immunization protocols are rapidly gaining interest as therapeutic options in patients with acute myeloid leukemia (AML)
No significant differences in recovery rates were observed between patients and healthy controls, irrespective of the maturation cocktail used (Table 3)
DC-based immunotherapies have induced immunologic responses in the majority of trials, far only a limited number of clinical responses have been observed. It remains unclear why some patients respond to DC-based immunotherapy and others do not, but it has been suggested that the current protocols used to generate mature DCs may not result in optimal T helper 1 (TH1) and NK cell responses
Summary
Active dendritic cell (DC) immunization protocols are rapidly gaining interest as therapeutic options in patients with acute myeloid leukemia (AML). Allogeneic HSCT was shown to provide a potent immunological anti-leukemic effect, with the lowest rate of relapse and a relevant benefit for overall survival in certain age groups [3]. This approach is restricted to a subset of patients due to patient-associated morbidity and mortality, donor availability, recipient comorbidities, or age. Clinical vaccination trials with peptides derived from leukemiaassociated antigens like proteinase 3 (PR1), Wilm’s tumor gene product 1 (WT-1), and the receptor for hyaluronic acid-mediated motility (RHAMM or CD168) have tried to stimulate autologous anti-leukemic T cell responses and have shown promising results regarding immunogenicity and clinical efficacy [4,5,6,7,8]
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