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Multiple myeloma (MM) is a clonal B-cell malignancy characterized by accumulation of malignant plasma cells (PCs) within the bone marrow (BM). The PCs are in close contact with stromal cells, which secrete growth factors and cytokines, promoting tumor cell growth and survival. Despite the availability of new drugs with immunomodulatory properties targeting the neoplastic clone and its microenvironment, MM is still an incurable disease, with patients experiencing subsequent phases of remission and relapse, eventually leading to disease resistance and patient death. It is now well established that the MM BM microenvironment is hypoxic, a condition required for the activation of the hypoxia-inducible factor 1 alpha (HIF-1α). It has been shown that HIF-1α is constitutively expressed in MM even in normoxic conditions, suggesting that HIF-1α suppression might be part of a therapeutic strategy. Constitutively activated HIF-1α enhances neovascularization, increases glucose metabolism, and induces the expression of antiapoptotic proteins. HIF-1α is thought to be one of the most important molecular targets in the treatment of cancer, and a variety of chemical inhibitors for HIF-1α have been developed to date. This review examines the role of HIF-1α in MM and recent developments in harnessing the therapeutic potential of HIF-1α inhibition in MM. [ABSTRACT FROM AUTHOR]

: ObjectiveThe immunogenic role of human CD34+ cells in allogeneic hematopoietic stem cell transplantation is controversial. In this study we tested the role of CD40 and CTLA4 ligands on CD34+ cell costimulation of HLA-mismatched lymphocytes.: Materials and MethodsAn anti-CD40L monoclonal antibody (hu5C8) and/or CTLA4-Ig molecule were used in primary mixed lymphocyte culture (MLC) with irradiated CD34+ blood cells and allogeneic responders. Then, secondary MLC, cytotoxic activity, and effector cytokine expression and production were measured.: ResultsEach reagent was able to reduce anti-CD34+ cell alloreactivity, but only the combination of the anti-CD40L monoclonal antibody and CTLA4-Ig induced greater than 90% inhibition of T-cell response in primary MLC and prevented generation of cytotoxic T cells when priming with purified CD34+ cells. Importantly, responder cells activated by allogeneic CD34+ cells in the presence of anti-CD40L monoclonal antibody and CTLA4-Ig entered a state of antigen-specific unresponsiveness while responding to third party antigen, tetanus toxoid, or phytohemagglutinin, and showed suppression of interferon-γ and increase of interleukin-10 expression and release. Interestingly, addition of interleukin-2 in secondary MLC did not reverse T-cell anergy.: ConclusionsThe results demonstrate that human CD34+ blood progenitors stimulate T-cell responses potently and can induce T-cell unresponsiveness only when both B7:CD28 and CD40:CD40L pathways are blocked, with an increase of interleukin-10–producing cells. Therefore, our data allow design of in vivo studies aimed at achieving T-cell tolerance across HLA barriers by using purified CD34+ cells and costimulatory blockade. [Copyright &y& Elsevier]

Abstract: We assessed the capacity of positively selected autologous CD133+ hematopoietic stem cells (HSCs) to reconstitute lymphomyelopoiesis in chronic lymphocytic leukemia (CLL) patients receiving myeloablative chemotherapy. Ten resistant/relapsed CLL patients underwent HSC mobilization with chemotherapy and granulocyte-colony stimulating factor (G-CSF). Positive selection of circulating CD133+ HSCs was performed by immunomagnetic technique. Highly purified HSCs were reinfused after busulphan/melphalan myeloablative treatment. A median number of 4.2 × 106 CD34+ cells/kg and of 3.14 × 106 CD133+ cells/kg were collected. Immunomagnetic selection resulted in the reinfusion of a median number of 2.45 × 106 CD133+ cells/kg (median purity: 94.8%; median recovery: 84%) and 2.4 × 106 CD34+ cells/kg (median purity: 93%; median recovery: 71%). HSC selection resulted in a median T cell and CD19+/CD5+ cell depletion of 3.85 log and 2.8 log, respectively. At the molecular level, however, 7 of 8 valuable purified HSC fractions were contaminated by leukemic cells. All CLL patients showed rapid and sustained myeloid engraftment after reinfusion of purified CD133+ cells. Immunologic reconstitution was comparable to that routinely observed in patients reinfused with unmanipulated leukapheresis products and no late infectious complications were observed. With a median follow-up of 28 months for transplanted patients, 5 patients are in clinical complete remission, 3 are in partial remission, and 1 is in progression. In conclusion, the reinfusion of highly purified CD133+ HSCs allowed the rapid and sustained recovery of hematopoiesis after myeloablative treatment in resistant/relapsed CLL patients. However, the purging potential of positive selection of CD133+ cells is not adequate to achieve tumor-free autografts. [Copyright &y& Elsevier]

: ObjectiveThe aim of this study was to determine whether expression of the CD86 costimulatory molecule in acute myeloid leukemia (AML) can identify blast cells committed to the monocytic/dendritic lineage.: Material and MethodsOne hundred ten consecutive AML patients observed at diagnosis were studied by flow cytometry. In selected experiments, in vitro cultures with CD34+CD86+ or CD34−CD86+ blasts were performed in the presence of granulocyte-macrophage colony-stimulating actor (GM-CSF) with or without tumor necrosis factor-α (TNF-α) or GM-CSF + interleukin-4 (IL-4), respectively, to induce a dendritic differentiation, documented by morphologic and immunophenotypic assays. T-cell alloreactivity to CD86+ AML cells and leukemic dendritic cells (AML-DC) was tested in mixed leukocyte cultures and anti-leukemic cytotoxic assays.: ResultsCD86 was expressed in 54% AML, whereas CD80 and CD1a were only occasionally positive. CD86+ AML samples included M5 and M4, but also 47% M0-M1 FAB types, and were more frequently CD14+ (p < 0.00001) and CD34− (p = 0.00005) than CD86−AML. Six different patterns of CD86+ AML were identified, according to CD34 or CD14 total or partial coexpression. Four samples enriched in CD34+CD86+ AML cells differentiated into AML-DC CD86+, CD80+, CD40+, CD11c+, HLA-DR+1, CD14+/− that also were CD1a+ or CD83+, after 6 days of in vitro culture with GM-CSF ± TNF-α. CD34−CD86+ AML cells differentiated into AML-DC after 3 to 5 days (n = 5 experiments), and trisomy 8 was found in two AML and AML-DC samples by fluorescence in situ hybridization analysis. Finally, AML-DC induced more potent allo–T-cell proliferation, cytokine release, and anti-leukemic cytotoxicity than CD86+ blasts.: ConclusionsIn AML, CD86 is a marker of monocytic/dendritic lineage. Because CD86+ blasts may differentiate into DC rapidly, CD86+AML patients could be optimal candidates for immunotherapy studies, both in autologous and allogeneic settings. [Copyright &y& Elsevier]