ABSTRACT
Vaccination with tumor antigen-loaded dendritic cells has been one of the most frequently applied immunotherapeutic strategies in prostate cancer. Immunological effects have been observed in a majority of patients, while clinical effects have been modest and transient. Advances in the understanding of the interplay between cancer and the immune system have generated new concepts in tumor immunology and immunotherapy that might aid in the improvement of vaccine effectiveness. The combination of immunotherapy with conventional treatment modalities and targeting of immunosuppressive mechanisms has demonstrated improved immunological and clinical results that warrant further investigation.
Subject(s)
Cancer Vaccines , Dendritic Cells/metabolism , Immunotherapy, Adoptive , Prostatic Neoplasms/immunology , Prostatic Neoplasms/therapy , Animals , Antigens, Neoplasm/immunology , Clinical Trials as Topic , Combined Modality Therapy , Dendritic Cells/immunology , Dendritic Cells/pathology , Humans , Male , Prostatic Neoplasms/pathology , Tumor Escape , VaccinationABSTRACT
Radical prostatectomy for prostate cancer is followed by PSA recurrence in up to 40% of patients. One third of patients with biochemical relapse progress to uncurable metastatic disease. Therefore, alternative treatment modalities are needed both in the situation of PSA recurrence and in hormone-refractory disease. Dendritic cells (DC) are the most powerful antigen-presenting cells, able to prime naïve T-cells and to break peripheral tolerance and thus induce tumor immune responses. More than 400 prostate cancer patients have been treated with DC-based immunotherapy to date, and immune responses have been reported in two-thirds of these, resulting in clinical responses in almost half of the patients treated. Most responses, however, were modest and transient. Therefore, mechanisms of treatment failure and possibilities to improve vaccination efficacy are being discussed.
Subject(s)
Cancer Vaccines/therapeutic use , Dendritic Cells/immunology , Prostatic Neoplasms/therapy , Antigens, Neoplasm , Cancer Vaccines/adverse effects , Clinical Trials as Topic , Humans , Male , Monitoring, Immunologic , Prostate-Specific Antigen/analysisABSTRACT
BACKGROUND: The therapeutic value of donor lymphocyte infusions in patients who relapse with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT) is limited by a low efficacy and the risk of graft-versus-host disease. We aimed at generating leukemia-reactive donor T cells for patients with AML. METHODS: Peripheral blood mononuclear cells of the donor were stimulated with mature donor dendritic cells, pulsed with irradiated patient leukemic blasts (LB), or directly with cytokine-treated LB. After 3 weekly stimulations, donor cells were tested for anti-leukemic reactivity in an IFNgamma Elispot. RESULTS: In 5 of 6 donors, cells with reactivity against patient LB with low or absent reactivity against non-leukemic cells could be generated. T cell subset analyses in 2 donors indicated that specific anti-leukemic reactivity was mainly mediated by CD4+ T cells, which were also the predominant cell fraction in 4 of 6 donors. One leukemia-reactive donor T cell line was expanded with a recently developed system. One week of expansion resulted in a 10-fold increase in reactivity with sustained specificity of the resulting T cell line. CONCLUSIONS: Our results show the feasibility of the in vitro generation of leukemia-reactive donor lymphocytes, rendering this method a promising tool for post-HSCT immunotherapy.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Dendritic Cells/transplantation , Histocompatibility Testing , Leukemia/therapy , Lymphocytes/immunology , Adult , Aged , Cell Division , Cell Line, Tumor , Female , Humans , Immunophenotyping , Interferon-gamma/metabolism , Leukemia/immunology , Leukemia/metabolism , Lymphocytes/cytology , Male , Microscopy, Confocal , Middle Aged , Transplantation, HomologousABSTRACT
BACKGROUND: In thrombocytopenic conditions of unknown origin, quantification of reticulated platelets (RP) in the peripheral blood by flow cytometry has been shown to differentiate increased platelet (Plt) turnover from insufficient Plt production. METHODS: We used a whole blood flow cytometry method combining thiazole orange and anti-CD41a-staining to assess RP in 71 healthy subjects, six with thrombocytopenic myelodysplastic syndrome (MDS), nine with liver cirrhosis, 14 patients with idiopathic thrombocytopenic purpura (ITP), and 12 patients who had undergone hematopoietic stem cell transplantation (HSCT). RESULTS: Patients with MDS had normal, patients with liver cirrhosis had slightly elevated RP counts compared to healthy subjects. ITP patients had elevated RP counts, and RP >15% were associated with treatment response (P = 0.015). In 7/10 patients after HSCT, an increase of RP preceded Plt recovery, whereas in patients with secondary thrombocytopenia after normal regeneration, the assessment of RP allowed the differentiation between conditions with high Plt turnover, such as GvHD and microangiopathy, indicated by high RP counts, and graft failure, indicated by low RP counts. CONCLUSIONS: Our data provide the rationale for prospective studies on the diagnostic and prognostic value of RP counts in larger patient populations with ITP and after HSCT.
