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Hemapoietic stem cells in cancer therapyC. C. Stella |
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Carmelo C.Stella, A. M. Gianni
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N.M.A. transplant
as a novel immune
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A. Capaldi, D. Caravelli,
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Reduced intensity
allogeneic hematopoietic stem cell transplantation
for hematological
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Lambertenghi Deliliers G.,
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Dysregulated apoptosis mechanisms play key roles in the pathogenesis and progression of tumors, allowing neoplastic cells to survive beyond their normal life-span, and to eventually acquire chemo-radioresistance. Thus, apoptotic pathways represent attractive therapeutic targets for restoring apoptosis sensitivity of malignant cells or activating agonists of apoptosis. In order to modulate apoptotic genes and proteins, several strategies can be envisaged which target either the intrinsic (Bcl-2, Bcl-XL), extrinsic (DR4, DR5, FLIP), or the convergence (cIAP2) pathways of apoptosis. The use of recombinant molecules for targeting apoptotic pathways might be hampered by several limitations, including systemic toxicity, short-half life, and tumor resistance. In order to overcome such limitations and specifically target tumor cells, adenoviral-mediated gene transfer approaches are currently being exploited. However, effective adenovector-based gene therapy largely depends on the efficient infection of target tumor cells, as well as the ability to escape immune clearance. In addition, several safety and toxicity issues concerning systemic injection of adenoviral vectors still remain to be addressed. To overcome drawbacks inherent the systemic administration of therapeutic adenoviral vectors, one can hypothesize to package adenovectors within cells that serve as primary delivery vehicles. These cells would not only protect adenovectors until they reach the sites of tumor growth, but would also allow vector targeting at high efficiency. Various cell types home preferentially to tumors and can be loaded with constructs producing anticancer molecules. Due to their homing characteristics, CD34+ cells, natural killer cells as well as mesenchymal stem cells are attractive candidates as delivery vehicles for anticancer molecules. Following intravenous infusion, each cell type display distinct homing properties (e.g., the capacity of CD34+ cells to permanently colonize the bone marrow). These homing properties are strictly related to the expression of adhesion receptors which interact with specific ligands expressed on stromal cells residing within the bone marrow microenvironment as well as the tumor microenvironment. In vitro and in vivo models used for evaluating the potential of different cell types as targeted-delivery vehicles for anticancer agents will be discussed. 
The existence of a graft versus tumor effect (GVT) of donor derived T-cells after allogeneic hematopoietic stem cell transplantation (HCT) is well established as a critical component for the success of the procedure in several hematological malignancies. Although
it was suggested that a GVT effect might also be generated in patients affected by refractory solid tumors, the morbidity of conventional allogeneic HCT limited its investigation in these diseases. Recently introduced allogeneic non-myeloablative regimens have shown they greatly decrease morbidity and mortality related to transplants still retaining a powerful GVT. On this basis, it became possible to explore in detail the existence of alloreactivity also in solid tumors. This approach has been used in several solid tumors confirming the existence of a graft versus solid tumor effect. On these basis will be important to optimize the procedure to further reduce the morbidity and to guide more specifically the allogeneic T-cell activity.
Allogeneic hematopoietic stem cell transplantation is a potential curative treatment for hematological and non-hematological malignancies but it may be associated with high rates of transplant-related mortality (TRM), especially in older patients or those affected by other concurrent medical conditions. Since the median age at diagnosis for patients with acute and chronic leukemias, lymphomas, multiple myeloma or myelodysplastic syndromes, ranges from 65 to 70 years, reduced-intensity conditioning (RIC) regimens have been developed with the aim to reduce TRM, obtain donor engraftment and use graft-versus-tumor (GVT) to eradicate disease. 
transplant might be a promising approach for older patients with advanced CLL because the kinetics of tumor-cell growth provides enough time for the graft to exert a GVT effect. Larger trials are in progress to determine the optimal time of this procedure in the course of the disease, and to evaluate also in younger patients the impact of biological and clinical risk factors on the outcome. Similarly, the results are particularly promising in patients with low-grade non-Hodgkin lymphomas who have significant disease or relapsing after high-dose autograft, as the GVT effect appears sufficient to overcome the slow tumor growth particularly in patients with chemosensitive disease. In contrast, for aggressive high-grade non-Hodgkin lymphomas, RIC transplant is only indicated for patients with minimal disease, as regimens are unable to control rapidly proliferating or resistant disease. In the advanced stages tandem high-dose autologous followed by RIC allograft may augment response and delay or prevent relapse.