Vaccination with dendritic cells loaded with tumor apoptotic bodies (Apo-DC) in patients with chronic lymphocytic leukemia: effects of various adjuvants and definition of immune response criteria

Abstract

We previously demonstrated that autologous dendritic cells that have endocytosed apoptotic bodies of chronic lymphocytic leukemia (CLL) cells (Apo-DC) can stimulate antileukemic T cell responses in vitro. In this phase I study, we vaccinated 15 asymptomatic CLL patients at five time points with Apo-DC administered intradermally either alone (cohort I), or in combination with subcutaneous granulocyte-macrophage-colony-stimulating-factor (GM-CSF) (cohort II) or with GM-CSF and intravenous low-dose cyclophosphamide (cohort III). Aim of the study was to evaluate the safety and immunogenicity of Apo-DC alone or in combination with GM-CSF and low-dose cyclophosphamide in CLL patients. All patients completed the vaccination schedule without dose-limiting toxicity. No objective clinical responses were seen. Vaccine-induced leukemia-specific immune responses were evaluated by IFN-γ ELISpot and proliferation assays over a 52 weeks observation period and immune response criteria were defined. According to these criteria, 10/15 patients were defined as immune responders. The frequency of immune-responding patients was higher in cohorts II (3/5) and III (5/5) than in cohort I (2/5). In order to further characterize the induced immune response, estimation of secreted cytokines and CD107-degranulation assay were performed. Clustering of T and CLL cells was observed in CD107-degranulation assay and visualized by confocal microscopy. Additionally, assessment of regulatory T cells (T(regs)) revealed their significantly lower frequencies in immune responders versus non-responders (P < 0.0001). Cyclophosphamide did not reduce T(regs) frequency. In conclusion, vaccination with Apo-DC + GM-CSF and cyclophosphamide was safe and elicited anti-CLL immune responses that correlated inversely with T(regs) levels. Lack of clinical responses highlights the necessity to develop more potent vaccine strategies in B cell malignancies.

A phase I clinical trial combining dendritic cell vaccination with adoptive T cell transfer in patients with stage IV melanoma

“…The standard operating procedure (SOP) used for DC generation has, with minor modifications, already been applied in a number of clinical trials [23,24]. This 7-day protocol resulted in high numbers of mature antigen-loaded DC in all cases.…”

Multicomponent mannose-containing liposomes efficiently deliver RNA in murine immature dendritic cells and provide productive anti-tumour response in murine melanoma model

“…DCs can be loaded with tumour antigens in the form of peptides [6], proteins [7], tumour cell lysates [8], apoptotic [9,10] or live [11] tumour cells, as well as viral vectors [12,13,14] and nucleic acids (NA) encoding TAA [15]. Nowadays, there is a range of techniques available to deliver NA-encoding tumour antigens into DCs, such as electroporation [16,17], and viral [18][19][20] and non-viral vectors [21][22][23].…”

Dendritic cell subsets in neoplastic tissue and peripheral blood of laryngeal cancer patients: relation with grade and stage of the disease

“…DCs have been analyzed for their biology (5,6), the role they play in the pathogenesis of diseases in humans (7)(8)(9), their protective function against cancers, their anticancer activity (10) and their application in therapy (11)(12)(13)(14). The progress in research on DCs, which has been motivated by hope that these cells may be used in therapies for human diseases, has resulted in a relatively wide knowledge of DCs.…”