期刊
CANCER IMMUNOLOGY IMMUNOTHERAPY
卷 61, 期 6, 页码 865-879出版社
SPRINGER
DOI: 10.1007/s00262-011-1149-5
关键词
CLL; Dendritic cells; Immunotherapy; Cyclophosphamide; Regulatory T cells; GM-CSF
资金
- Swedish Cancer Society
- Cancer Society in Stockholm
- King Gustav V Jubilee Fund
- Cancer and Allergy Foundation
- Karolinska Institutet Foundations
- EU [LSHB-CT-2004-512074]
- DC-THERA
- Stockholm County Council
- IMTAC
- Miltenyi Biotec GmbH
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-gamma 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.
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