ABSTRACT
Based on the practive of traditional allogeneic hematopoietic stem-cell transplantation therapy allo-HSCT and the development of nonmyeloablative conditioning, a new immunotherapy for solid tumor nonmyeloablative allo-HSCT, has been initiated. The nonmyeloablative,preparative regimens are associated with the use of lower dose of drugs,and less treatment-related toxicities. Instead of achieving maximal tumor reduction, the regimens are disigned to induce adequate immunosuppression to permit the engraftment of donor hematopoietic stem cells and serve as the platform for the administration of donor T cell in adoptive cell therapy. Donor's T-cell mediates a graft-versus-tumor(GVT)effect. This response is effective for the eradication of acceptor's tumor cell. This article reviews the concept, rationale, early clinical results, and limitation of nonmyeloablative allo-HSCT as a novel immunotherapy in solid tumors.
ABSTRACT
BACKGROUND: Nitric oxide (NO) synthesis by inducible nitric oxide synthase (iNOS) is induced during graft-versus-host disease (GVHD). It is yet unknown whether NO has any roles in graft-versus-tumor effect (GVT) which is often associated with GVHD. The present study was performed to test the role of NO in GVT. METHODS: GVT was induced by tail vein injection of C57BL/6J (H-2b) mouse splenocytes (10(8)cells/mouse) to [C57BL/6J (H-2(b))XBALB/c (H-2(d))] F1 mice bearing Meth-A (H-2d) ascites tumors. RESULTS: Induction of GVT increased nitrite production (21.0+/-4.1 M) and expression of iNOS protein and mRNA by cells derived from ascites. The increased nitrite production was inhibited by NG-monomethyl-L-arginine (MLA). Immunomagnetic depletion of Mac-1+ cells from ascites cells of GVT mice resulted in a 70% decrease in the nitrite production, indicating that macrophages were implicated as a major cellular source of the nitrite production. Interferon-gamma (IFNgamma) levels in both serum and ascites fluid were markedly increased during GVT. Induction of GVT in ascites tumor-bearing mice prolonged survival from 9.5+/-2.2days to 17.6+/-1.2 days (P<0.001), and increased urinary nitrate excretion up to threefold. MLA administration effectively inhibited the GVT-induced urinary nitrate excretion and further prolonged the GVT-induced increase in survival from 17.6+/-1.2days to 23.6+/-1.9days (P<0.001). CONCLUSION: These results indicate that NO synthesis by iNOS is induced in tumor tissues during GVT, and the NO acts as an inhibitor mechanism of GVT.
Subject(s)
Mice , AnimalsABSTRACT
Allogenic hematopoietic stem cell transplantation is one of the effective therapy for several hematologic malignancies. Transplantation preparative regimen is designed to eradicate the patient's underlying disease and immunosuppress the patient adequately to prevent rejection of donor's hematopoietic stem cells. so, Conventional myeloablative preparative regimens with high-dose chemotherapy or radiotherapy are related to high rate of morbidity and mortality. however, It has become clear that the high-dose therapy dose not eradicate the malignancy in some patients, and that the therapeutic benefit of allogenic transplantation is largely related to graft-versus-leukemia/graft-versus-tumor (GVL/GVT) effect. An new approach is to utilize less toxic, nonmyeloablative preparative regimens to achieve engraftment and allow GVL/GVT effects to developed. This strategy reduces the risk of treatment-related mortality and allows transplantation for elderly and those with comorbidities that preclude high-dose chemoradiotherapy.
Subject(s)
Aged , Humans , Chemoradiotherapy , Comorbidity , Drug Therapy , Hematologic Neoplasms , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells , Mortality , Radiotherapy , Stem Cell Transplantation , Stem CellsABSTRACT
Allogenic hematopoietic stem cell transplantation is one of the effective therapy for several hematologic malignancies. Transplantation preparative regimen is designed to eradicate the patient's underlying disease and immunosuppress the patient adequately to prevent rejection of donor's hematopoietic stem cells. so, Conventional myeloablative preparative regimens with high-dose chemotherapy or radiotherapy are related to high rate of morbidity and mortality. however, It has become clear that the high-dose therapy dose not eradicate the malignancy in some patients, and that the therapeutic benefit of allogenic transplantation is largely related to graft-versus-leukemia/graft-versus-tumor (GVL/GVT) effect. An new approach is to utilize less toxic, nonmyeloablative preparative regimens to achieve engraftment and allow GVL/GVT effects to developed. This strategy reduces the risk of treatment-related mortality and allows transplantation for elderly and those with comorbidities that preclude high-dose chemoradiotherapy.