title: 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.
authors.affiliation: Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marzia
authors.initials: M
authors.lastname: Palma
authors.forename: Lotta
authors.initials: L
authors.lastname: Hansson
authors.forename: Aniruddha
authors.initials: A
authors.lastname: Choudhury
authors.forename: Barbro
authors.initials: B
authors.lastname: Näsman-Glaser
authors.forename: Ingrid
authors.initials: I
authors.lastname: Eriksson
authors.forename: Lars
authors.initials: L
authors.lastname: Adamson
authors.forename: Eva
authors.initials: E
authors.lastname: Rossmann
authors.forename: Karin
authors.initials: K
authors.lastname: Widén
authors.forename: Rudolf
authors.initials: R
authors.lastname: Horváth
authors.forename: Parviz
authors.initials: P
authors.lastname: Kokhaei
authors.forename: Simona
authors.initials: S
authors.lastname: Vertuani
authors.forename: Håkan
authors.initials: H
authors.lastname: Mellstedt
authors.forename: Anders
authors.initials: A
authors.lastname: Osterborg
mesh_terms: D000276:Adjuvants, Immunologic; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D055252:Cell-Derived Microparticles / Q000276:immunology*; D003520:Cyclophosphamide / Q000276:immunology / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide
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