EX VIVO EXPANSION OF HEMATOPOIETIC CELLS

申请人的描述（Applicant's Description） 离体产生的造血细胞是否可以提供短的和长的造血细胞。 大剂量清髓性化疗后的长期重建不是 知道的 体外培养的多能造血细胞（HPC） 从少量的干细胞（SC）体内可以有巨大的潜力， 各种临床环境。 体外生成的HPC可支持 多个周期的化疗，为患者提供移植选择 在没有匹配供体的情况下，促进载体转导到未成熟的 细胞进行基因治疗，并提供一种无肿瘤产品， 移植 最后，脐带血细胞的体外扩增 可以消除广泛的中性粒细胞减少症和血小板减少症后， 移植本产品。 拟开展两项I期临床试验和相关实验室研究 为了解决离体产生的细胞是否可以提供短期和长期的h 在接受清髓性治疗的患者中， 化疗 第一次审判将决定是否管理 培养的细胞导致任何额外的输注相关毒性， 将培养的细胞与2.5x106 CD 34阳性细胞/Kg输注相结合 未操作的G-CSF动员产物（G-PBMC）。 如果毒性是 我们将进行第二次试验，其中只有培养的细胞被 在清髓性化疗后输注。 第二次审判将使我们 最终确定我们培养的细胞是否能提供快速的早期 造血恢复，也将提供长期的信息， 由该扩增产物介导的重组。 对于未操作的G-PBMC，CD 34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相关 移植 目前尚不清楚是否注入大量的 这些细胞群与培养细胞的植入率相关。 这种理解对于优化离体细胞生产至关重要 对预测病人的康复情况非常重要 因此，在平行 随着临床试验的广泛的表型和功能分析， 提出了扩展产品。 表型和功能组成 将输注产品与植入率进行比较， 与造血恢复相关的标志物。 总之，两人 临床试验和相关研究将提供重要的初步 进一步评估离体生成的造血干细胞的作用的数据 产品在诊所

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.