EX VIVO EXPANSION OF HEMATOPOIETIC CELLS

描述(申请人的描述) 体外产生的造血细胞是否能同时提供短期和 大剂量清髓化疗后的长期重建不是 为人所知。产生多潜能造血细胞(HPC)EX的能力 来自少量干细胞(SC)的活体可能在 各种临床环境。体外产生的HPC可以支持 多周期化疗，为患者提供移植选择 在没有匹配供体的情况下，促进载体转入未成熟 用于基因治疗的细胞，并为 移植。最后，脐带血细胞的体外扩增 能消除术后延展性中性粒细胞减少症和血小板减少症 使用该产品进行移植。 建议进行两个I期临床试验和相关的实验室研究 为了解决体外产生的细胞是否可以提供短期和长期的 接受清髓剂治疗的患者的局部造血重建 化疗。第一次审判将决定是否对 培养的细胞会导致任何额外的输液相关毒性和 将培养的细胞与2.5×106 CD34阳性细胞/公斤输注相结合 非操作G-CSF动员产物(G-PBMC)。如果毒性是 可以忽略不计，我们将进行第二次试验，只有培养的细胞 在清髓化疗后输注。第二次审判将允许我们 最终确定我们的培养细胞是否能提供快速的早期 还将为造血功能的恢复和远期提供信息 由这一扩展产品所介导的重建。 未处理的G-PBMC，CD34阳性细胞和/或CFU-GM的数量 与术后中性粒细胞和血小板恢复率的关系 移植。目前尚不清楚是否大量输注 这些细胞群与培养细胞的植入率相关。 这一认识对于优化体外细胞生产至关重要。 对于预测病人的康复将是无价的。因此，并行地 随着临床试验的广泛的表型和功能的分析 提出了扩展产品的概念。的表型和功能组成 输液产品将与植入率进行比较，以确定 与造血恢复相关的标记物。总而言之，这两个 临床试验和相关研究将提供重要的初步 进一步评估体外生成的造血细胞的作用的数据 临床上的产品。

DESCRIPTION (Applicant's Description) Whether ex vivo generated hematopoietic cells can provide both short and long-term reconstitution after high dose myeloablative chemotherapy is not known. The ability to generate multipotential hematopoietic cells (HPC) ex vivo from a small number of stem cells (SC) could have enormous potential in a variety of clinical settings. Ex vivo generated HPC could support multiple cycles of chemotherapy, provide a transplant option for patients without matched donors, facilitate transduction of vectors into immature cells for gene therapy, and provide a tumor free product for transplantation. Last, ex vivo expansion of umbilical cord blood cells could abrogate the extended neutropenia and thrombocytopenia after transplantation with this product. Two phase I clinical trials and correlative laboratory studies are proposed to address whether ex vivo generated cells can provide short and long-term h e m a topoietic reconstitution in patients that received myeloablative chemotherapy. The first trial will determine whether the administration of cultured cells results in any additional infusion related toxicity and combines cultured cells with infusion of 2.5x106 CD34 positive cells/Kg non-manipulated G-CSF mobilized product (G-PBMC). If the toxicity is negligible, we will perform a second trial, whereby only cultured cells are infused after myeloablative chemotherapy. This second trial will allow us to conclusively determine whether our cultured cells can provide rapid early hematopoietic recovery and will also provide information on the long-term reconstitution mediated by this expansion product. For non-manipulated G-PBMC, the number of CD34 positive cells and/or CFU-GM correlate to the rate of neutrophil and platelet recovery after transplanta-tion. It is not known whether the infusion of large numbers of these cell populations correlate to the engraftment rate of cultured cells. This understanding is essential for optimizing production of cells ex vivo and will be invaluable for predicting patient recovery. Hence, in parallel with the clinical trials extensive phenotypic and functional analysis of the expansion product is proposed. The phenotypic and functional composition of the infusion product will be compared to the rate of engraftment to identify markers that correlate to hematopoietic recovery. In summary, the two clinical trials and correlative studies will provide important preliminary data to further evaluate the role of ex vivo generated hematopoietic products in the clinic.