Lazarus Hillard M, Koc Omer N, Devine Steven M, Curtin Peter, Maziarz Richard T, Holland H Kent, Shpall Elizabeth J, McCarthy Philip, Atkinson Kerry, Cooper Brenda W, Gerson Stanton L, Laughlin Mary J, Loberiza Fausto R, Moseley Annemarie B, Bacigalupo Andrea
Department of Medicine, The University Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA.
Biol Blood Marrow Transplant. 2005 May;11(5):389-98. doi: 10.1016/j.bbmt.2005.02.001.
Mesenchymal stem cells (MSCs) are found in a variety of tissues, including human bone marrow; secrete hematopoietic cytokines; support hematopoietic progenitors in vitro; and possess potent immunosuppressive properties. We hypothesized that cotransplantation of culture-expanded MSCs and hematopoietic stem cells (HSCs) from HLA-identical sibling donors after myeloablative therapy could facilitate engraftment and lessen graft-versus-host disease (GVHD); however, the safety and feasibility of this approach needed to be established. In an open-label, multicenter trial, we coadministered culture-expanded MSCs with HLA-identical sibling-matched HSCs in hematologic malignancy patients. Patients received either bone marrow or peripheral blood stem cells as the HSC source. Patients received 1 of 4 study-specified transplant conditioning regimens and methotrexate (days 1, 3, and 6) and cyclosporine as GVHD prophylaxis. On day 0, patients were given culture-expanded MSCs intravenously (1.0-5.0 x 10(6)/kg) 4 hours before infusion of either bone marrow or peripheral blood stem cells. Forty-six patients (median age, 44.5 years; range, 19-61 years) received MSCs and HLA-matched sibling allografts. MSC infusions were well tolerated, without any infusion-related adverse events. The median times to neutrophil (absolute neutrophil count > or = 0.500 x 10(9)/L) and platelet (platelet count > or = 20 x 10(9)/L) engraftment were 14.0 days (range, 11.0-26.0 days) and 20 days (range, 15.0-36.0 days), respectively. Grade II to IV acute GVHD was observed in 13 (28%) of 46 patients. Chronic GVHD was observed in 22 (61%) of 36 patients who survived at least 90 days; it was extensive in 8 patients. Eleven patients (24%) experienced relapse at a median time to progression of 213.5 days (range, 14-688 days). The probability of patients attaining disease- or progression-free survival at 2 years after MSC infusion was 53%. Cotransplantation of HLA-identical sibling culture-expanded MSCs with an HLA-identical sibling HSC transplant is feasible and seems to be safe, without immediate infusional or late MSC-associated toxicities. The optimal MSC dose and frequency of administration to prevent or treat GVHD during allogeneic HSC transplantation should be evaluated further in phase II clinical trials.
间充质干细胞（MSCs）存在于多种组织中，包括人类骨髓；能分泌造血细胞因子；在体外支持造血祖细胞；并具有强大的免疫抑制特性。我们推测，在清髓性治疗后，将培养扩增的MSCs与来自HLA相合同胞供体的造血干细胞（HSCs）共同移植，可能会促进植入并减轻移植物抗宿主病（GVHD）；然而，这种方法的安全性和可行性需要确定。在一项开放标签、多中心试验中，我们在血液系统恶性肿瘤患者中，将培养扩增的MSCs与HLA相合同胞匹配的HSCs联合给药。患者接受骨髓或外周血干细胞作为HSC来源。患者接受4种研究指定的移植预处理方案中的1种，以及甲氨蝶呤（第1、3和6天）和环孢素作为GVHD预防用药。在第0天，患者在输注骨髓或外周血干细胞前4小时静脉注射培养扩增的MSCs（1.0 - 5.0×10⁶/kg）。46例患者（中位年龄44.5岁；范围19 - 61岁）接受了MSCs和HLA匹配的同胞同种异体移植物。MSCs输注耐受性良好，无任何与输注相关的不良事件。中性粒细胞（绝对中性粒细胞计数≥0.500×10⁹/L）和血小板（血小板计数≥20×10⁹/L）植入的中位时间分别为14.0天（范围11.0 - 26.0天）和20天（范围15.0 - 36.0天）。46例患者中有13例（28%）发生了II至IV级急性GVHD。36例存活至少90天的患者中有22例（61%）发生了慢性GVHD；其中8例为广泛性慢性GVHD。11例患者（24%）复发，进展的中位时间为213.5天（范围14 - 688天）。在输注MSCs后2年，患者达到无病或无进展生存的概率为53%。将HLA相合同胞培养扩增的MSCs与HLA相合同胞HSC移植共同移植是可行的，且似乎是安全的，无即刻输注相关或晚期MSCs相关毒性。在II期临床试验中应进一步评估预防或治疗异基因HSC移植期间GVHD的最佳MSCs剂量和给药频率。
