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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

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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 (Tregs) revealed their significantly lower frequencies in immune responders versus non-responders (P < 0.0001). Cyclophosphamide did not reduce Tregs frequency. In conclusion, vaccination with Apo-DC + GM-CSF and cyclophosphamide was safe and elicited anti-CLL immune responses that correlated inversely with Tregs levels. Lack of clinical responses highlights the necessity to develop more potent vaccine strategies in B cell malignancies.

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Acknowledgments

Supported by grants from The Swedish Cancer Society, The Cancer Society in Stockholm, King Gustav V Jubilee Fund, The Cancer and Allergy Foundation, The Karolinska Institutet Foundations, the EU-grant LSHB-CT-2004-512074; DC-THERA, The Stockholm County Council; IMTAC and Miltenyi Biotec GmbH. For excellent secretarial help, we thank Ms. Leila Relander.

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The authors have no conflict of interest to disclose.

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Correspondence to Håkan Mellstedt.

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Marzia Palma and Lotta Hansson contributed equally.

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Palma, M., Hansson, L., Choudhury, A. et al. 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. Cancer Immunol Immunother 61, 865–879 (2012). https://doi.org/10.1007/s00262-011-1149-5

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