Vaccination with autologous non‐irradiated dendritic cells in patients with bcr/abl+ chronic myeloid leukaemia

Abstract

SummaryIn chronic myeloid leukaemia (CML), dendritic cells (DC) and leukaemic cells share a common progeny, leading to constitutive expression of putative tumour antigens, such as bcr/abl, in DC. In this phase-I/II study, autologous DC were used as a vaccine in patients with chronic phase bcr/abl+ CML, who had not achieved an adequate cytogenetic response after treatment with a-interferon or imatinib. Ten patients were enrolled, DC were generated from peripheral blood monocytes and vaccination consisted of four subcutaneous injections of increasing numbers of DC (1-50 · 10 6 cells per injection) on days 1, 2, 8 and 21. Vaccination was feasible and safe. Improvement of the cytogenetic/molecular response, as detected by fluorescence in situ hybridization of peripheral blood mononuclear cells (PBMC), was possibly related to vaccination in four of 10 patients. In three of these patients, T cells recognizing leukaemia-associated antigens became detectable. The proliferative capacity of PBMC in response to autologous DC increased after vaccination in all evaluable patients. We conclude that vaccination with autologous, non-irradiated 'leukaemic' DC is feasible, safe and induces anti-leukaemic T-cell responses in some CML patients. DC vaccination might be useful in CML as postremission therapy, i.e. after treatment with tyrosine kinase inhibitors.

Evaluation of monocyte-derived dendritic cells, T regulatory and Th17 cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

“…We confirmed that DC could be efficiently differentiated from peripheral blood monocytes of CML patientxs [9,14]. The yield of generated DC was lower compared to healthy donors, with some differences noted in surficial markers, such as lower percentages of cells with expression of CD1a, CD80 and CD83, CD206 and CD209.…”

“…Eisendle et al showed lower expression of CD80, CD83, CD86 on LPS maturated DC [4], which was improved when IL-1b, TNF-a and PGE2 were used. DC cells maturated with a cytokine cocktail were fully functional in a mixed leukocyte reaction (MLR), something also found in a study by Westermann et al [9]. Dong et al showed high expression of maturation markers (CD80, CD86 HLA-DR) with IL-1b and TNF used for maturation.…”

“…Chronic myeloid leukemia (CML) is a clonal disease, characterized by a reciprocal t (9,22) chromosomal translocation resulting in a chimeric BCR/ABL fusion gene that encodes an abnormal fusion protein (p210) with a tyrosine kinase activity, which probably plays a key role in the pathogenesis of the disease [5]. Imatinib mesylate is a specific inhibitor of of Abl protein tyrosine kinases, which has been shown to induce complete hematologic and cytogenetic responses in a significant proportion of patients [6] and has become the standard first-line treatment for patients with chronic phase CML (CP-CML).…”

“…Initial clinical trials with CML-derived DC (CML-DC) immunotherapy have been reported [7][8][9] and have shown immune and clinical responses in some patients [9]. The optimal vaccination protocol for inducing anti-tumor responses using DC has not yet been established, meaning that further studies into the biology of CML-DC are still required, especially in the context of the influence of TKI therapy on CML-DC.…”

Chronic Myelocytic Leukemia (CML) Patient-Derived Dendritic Cells Transfected with Autologous Total RNA Induces CML-Specific Cytotoxicity

“…Bcr/abl1-presenting DCs can be generated from peripheral blood mononuclear cells (PBMCs) or CD34c progenitor cells of CML patients, and have been shown to have the capacity to capture, process and present bcr/abl1 antigen [5,12]. Active and specific immunotherapy targeting of the bcr/abl1-derived p210 fusion protein improves patient outcome and it has recently been reported that CML patients have similar immunological responses to the e14a2 bcr/abl1 peptide as healthy subjects under the same vaccination schedule [13,14]. Therefore, strategies employing active and specific DC-based vaccination have the potential to eradicate MRD when applied in combination with TKIs, or as an alternative treatment for patients resistant to TKI therapy.…”