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ABSTRACT: Leukemia-associated antigens such as proteinase-3 (PR3) and Wilms´ tumor protein-1 (WT-1) are potential targets of T-cell responses, which can be monitored by T-cell assays within vaccination trials and after allogeneic stem cell transplantation (SCT). In chronic myeloid leukemia (CML) an aberrant cytokine profile of antigen-specific T-cells with predominant TNF-a secretion has previously been described. The aim of this study was to investigate whether these TNF-a (+) /IFN-g (-) CD8 (+) T-cells can also be observed in AML patients after SCT. Eight HLA-A2 (+) AML patients at different time points after SCT were evaluated for HLA-A2-restricted CD8 (+) T-cell responses against PR3, WT-1 and influenza-A using pentamer staining and different cytokine-based T-cell assays. Antigen-specific T-cell immune responses against influenza-A and PR3 were observed in 4/8 patients, WT-1-specific T-cells could be detected in in 3/8 patients. Interestingly, four different cytokine secretion profiles of antigen-specific T-cells were detected: (1) IFN-g (+) /TNF-a (+) , (2) IFN-g (+) /TNF-a (-) , (3) TNF-a (+) / IFN-g (- ) and (4) IFN-g (-) /TNF-a (-) . TNF-a (+) / IFN-g (- ) CD8 (+) T-cells are an interesting biological phenomenon which can obviously be observed also in AML patients. This finding has important implications for both T-cell biology and monitoring within immunotherapy trials. The functional characterization of these TNF-a (+) / IFN-g (- ) CD8 (+) T-cells needs further investigations.
Human vaccines & immunotherapeutics. 04/2013; 9(7).
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Anne Flörcken,
Joachim Kopp, Antje van Lessen,
Kamran Movassaghi,
Anna Takvorian,
Korinna Jöhrens,
Markus Möbs,
Constanze Schönemann,
Birgit Sawitzki,
Karl Egerer,
Bernd Dörken,
Antonio Pezzutto,
Jörg Westermann
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ABSTRACT: Multi-kinase inhibitors have been established for the treatment of advanced renal cell cancer (RCC), but long-term results are still disappointing and immunotherapeutic approaches remain an interesting experimental option particularly in patients with a low tumor burden. DC are crucial for antigen-specific MHC-restricted T cell immunity. Furthermore, allogeneic HLA-molecules pose a strong immunogenic signal and may help to induce tumor-specific T cell responses. In this phase I/II trial, 7 patients with histologically confirmed progressive metastatic RCC were immunized repetitively with 1 × 10 ( 7) allogeneic partially HLA-matched DC pulsed with autologous tumor lysate following a schedule of 8 vaccinations over 20 weeks. Patients also received 3 Mio IE IL-2 sec.c. once daily starting in week 4. Primary endpoints of the study were feasibility and safety. Secondary endpoints were immunological and clinical responses. Vaccination was feasible and safe with no severe toxicity being observed. No objective response could be documented. However, while all patients had documented progress at study entry, 29% of the patients showed SD throughout the study with a mean TTP of 24.6 weeks (range 5 to 96 weeks). In 3/7 patients, TH1-polarized immune responses against RCC-associated antigens were observed. In one patient showing a minimal clinical response and a TTP of 96 weeks, clonally proliferated T cells against yet undefined antigens were induced by the vaccine. Vaccination with tumor antigen loaded DC remains an interesting experimental approach, but should rather be applied in the situation of minimal residual disease after systemic therapy. Additional depletion of regulatory cells might be a promising strategy.
Human vaccines & immunotherapeutics. 03/2013; 9(7).
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ABSTRACT: Induction of regulatory T cells (Treg) is an important mechanism leading to tolerance against tumors. Increased levels of Treg have been described in renal cell carcinoma (RCC) patients and seem to correlate with an adverse outcome. Our study aimed to analyze the influence of sorafenib and sunitinib on the frequency of Treg in patients with metastatic RCC (mRCC). Treg were analyzed by flow cytometry in the peripheral blood (PB) of patients (n=19) with histologically confirmed mRCC under treatment with either sunitinib (50 mg/d, n=11) or sorafenib (800 mg/d, n=8). Blood samples were taken before treatment and during the first, second, and third months of therapy. Flow cytometric analysis of PB mononuclear cells was performed using fluorochrome-labeled antibodies against CD3, CD4, CD25, and FOXp3. During the first month of therapy, patients treated with sorafenib showed a significant increase in FOXp3CD3CD4CD25 Treg (13.5 vs. 36.3% of gated cells, P=0.02, or 0.35 vs. 0.49% of total cells) and the ratio FOXp3 T cells/FOXp3 T cells (0.16 vs. 0.56 of gated cells, P=0.02). These elevated levels persisted throughout the treatment period. There was no influence of sunitinib on the frequency of Treg in our cohort of patients. Sorafenib, but not sunitinib, leads to an early and sustained increase in Treg in PB of mRCC patients. In immunoresponsive tumors such as RCC, immunological effects of kinase inhibitors are particularly relevant for the design of combination trials with immunotherapeutic agents. Our study suggests that sorafenib should be avoided in such a therapeutic setting.
Anti-cancer drugs 12/2011; · 2.23 Impact Factor
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ABSTRACT: In 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 alpha-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 x 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.
British Journal of Haematology 06/2007; 137(4):297-306. · 4.94 Impact Factor
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ABSTRACT: The aim of our study was to evaluate CD52 as a target molecule for antibody therapy for multiple myeloma. Twenty consecutive bone marrow samples from myeloma patients were studied by flow cytometry using antibodies against CD45, CD38, CD138, CD3, CD19, and CD52. Most myeloma cells did not express CD52; CD52 expression was found only in a small subpopulation of plasma cells with a CD45+CD38++ phenotype. In contrast, the major fraction of myeloma cells (CD45-CD38++) was CD52-. Treatment of myeloma patients with anti-CD52 antibodies with the aim to reduce the number of myeloma cells in the CD45+CD38++ subfraction, which possibly contains a proliferative progenitor cell pool, would be at best a highly experimental approach. We conclude that CD52 is not a promising target for antibody-based therapies for most patients with multiple myeloma.
International Journal of Hematology 11/2005; 82(3):248-50. · 1.27 Impact Factor
