Phase I/II study of vaccination with dendritic‐like leukaemia cells for the immunotherapy of acute myeloid leukaemia

Abstract

Summary Twenty‐two patients with acute myeloid leukaemia were recruited into a phase I/II clinical trial investigating the vaccination of patients in complete remission (CR) with autologous dendritic‐like leukaemia cells (DLLC). At trial entry, leukaemia cells were harvested and tested for their ability to undergo cytokine‐induced dendritic cell differentiation. Patients were then treated with intensive chemotherapy. Five patients achieved both CR and had leukaemia cells that successfully underwent differentiation and therefore proceeded to vaccination. Four escalating doses of DLLC were administered weekly by subcutaneous injection. Vaccination was generally well tolerated although one patient developed extensive eczema and an increased antinuclear factor titre possibly indicating induction of autoimmunity. Development of anti‐leukaemic T‐cell responses was assessed by enzyme‐linked immunospot analysis of gamma‐interferon secreting T lymphocytes and by human leucocyte antigen tetramer analysis for WT1‐specific T cells. Increases in anti‐leukaemic T‐cell responses were demonstrated in four patients, but only two of the five remained in remission more than 12 months postvaccination. The study has demonstrated that generation of DLLC is feasible in only a subgroup of patients and is currently neither broadly applicable or clinically effective.

Quantification of ex vivo generated dendritic cells (DC) and leukemia-derived DC contributes to estimate the quality of DC, to detect optimal DC-generating methods or to optimize DC-mediated T-cell-activation-procedures ex vivo or in vivo

“…In both cases with the mutation, most of fluorescent intensity at codon 617 was V617F and the wild type was only faintly visible, suggesting that most of the leukemic cells expressed V617F. A previous study found a high occurrence of the JAK2 V617F mutation in RA with ringed sideroblasts associated with marked thrombocytosis (71%), 7 and this mutation has also been detected in MDS with myelofibrosis (33%). 8 In our two cases with the mutation, neither thrombocytosis nor myelofibrosis was detected (Table 2).…”

“…4 Overall results of Phase I/II clinical trials with autologous DC in AML patients were that vaccination with DC is feasible and safe, although not clinically effective in every patient. 7,8 Obstacles of these clinical approaches are that clinically relevant numbers of efficient DC and CTL have to be prepared or a monitoring of the specificity of CTLs is necessary. So far, a quantification of DC was performed by microscopical counting of cells exhibiting DC characteristics (cell shape, dendrites), although differentiation of DC from cells with similar morphology (e.g.…”

An ex vivo readout for evaluation of dendritic cell-induced autologous cytotoxic T lymphocyte responses against esophageal cancer

“…So far, only a limited rate of objective tumor regressions has been observed in clinical studies [3,5,9,14,25,27,44]. One reason for the discrepancy between the outcomes as seen in the pre-clinical feasibility assays with respect to the true clinical responses could be that most pre-clinical in vitro tumor models that evaluate direct cytotoxicity of DCs have been performed on either cancer cell lines or mice models [22,30,31,41,52].…”

Cytokine Release Patterns in Mixed Lymphocyte Culture (MLC) of T-Cells with Dendritic Cells (DC) Generated from AML Blasts Contribute to Predict anti-Leukaemic T-Cell Reactions and Patients’ Response to Immunotherapy

“…Cytotoxic T-cells have been detected as crucial mediators of the graft-versusleukaemia (GVL) reaction after SCT, although relapses occur (Kolb et al 2004). DLIs can be applied therapeutically for treatment of relapse after SCT or prophylactically in order to stabilize remissions -indicating again the central role of T-cells (Roddie et al 2006;Barrett & Savani 2006;Schmid et al 2007). For an improvement of therapy of AML-/MDS-pts at relapse after SCT GM-CSF might be applied in the context of DLI in order to facilitate the generation of APC from leukaemic blasts and thereby to increase antileukaemic activities of donor T-cells against myeloid blasts, as already shown by others and us in ex vivo settings (Kufner et al 2005;Kremser et al 2010;Schmid et al 2011;Dreyßig et al 2011).…”

“…An interesting immunotherapeutic option to treat cancer and leukaemia are dendritic cell (DC) based strategies (Claxton et al 2001;Roddie et al 2006). DCs are antigen presenting cells (APC) that stimulate a variety of cells both of the innate and adaptive immune systems (e.g.…”