Pre-clinical safety testing supporting clinical use of allogeneic multipotent adult progenitor cells
Pre-clinical safety testing supporting clinical use of allogeneic multipotent adult progenitor cells
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DOI：
10.1080/14653240802320245
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发表时间：
2008-01-01
期刊：
影响因子：
4.5
通讯作者：
Van't Hof, W.
中科院分区：
文献类型：
--
作者：
Kovacsovics-Bankowski, M.;Mauch, K.;Van't Hof, W.
背景：新型细胞治疗药物的成功临床开发需要对临床急性毒性终点进行评估，以评估导致剂量限制毒性(DLT)的患者不良事件(AE)，以建立最大耐受剂量(MTD)。然而，在临床前的安全性测试中，许多临床病理参数并不是常规的评估。这项临床前研究的目的是深入研究同种异体多潜能成体干细胞(MultiStem)单次和多次给药的急性毒性。多干细胞是一类具有治疗潜力的基质干细胞。方法在大鼠清髓性造血干细胞移植(HSCT)模型上观察联合应用多干细胞对临床参数、临床化学、血液学、免疫学和组织病理学的影响。在HSCT后第2天，动物接受单次剂量为1250万个/公斤的多干细胞移植，或在第2天、第9天、第16天、第23天和第30天按此剂量输注5次。对照组接受磷酸盐缓冲盐水注射，所有动物在第37天被处死。结果输液后呼吸窘迫的评估、临床评估及血液学、临床化学分析，试验组与对照组比较差异无统计学意义。大体尸检和组织病理学分析显示没有器官轮廓改变。在多干细胞输注中没有明显的同种异体抗体产生或T细胞致敏的证据。讨论这些研究证明了在骨髓移植环境中以重复给药方案给药异基因基质干细胞的安全性，并确定了与使用同种异体贴壁成人干细胞开发细胞疗法相关的临床前安全性测试标准。
Background Successful clinical development of novel cellular therapeutics requires the evaluation of clinical acute toxicity endpoints in scoring patient adverse events (AE) contributing to dose-limiting toxicity (DLT) for establishment of the maximum-tolerated dose (MTD). However, many clinical pathology parameters are not routinely evaluated in pre-clinical safety testing. The objective of this pre-clinical study was to investigate thoroughly the acute toxicity of single- and multiple-dose administrations of allogeneic multipotent adult progenitor cells (MultiStem), which represent a class of stromal stem cells with therapeutic potential. MethodsMultiStem were tested as an adjunct treatment in a rat myeloablative hematopoietic stem cell transplantation (HSCT) model for impact on clinical parameters, clinical chemistry, hematology, immunology and histopathology parameters. Animals received MultiStem in a single dose of 12.5 million cells/kg on day 2 after HSCT or in five infusions at this dose on days 2, 9, 16, 23 and 30. Controls received phosphate-buffered saline injections and all animals were killed on day 37. Results There were no significant differences between tests and controls regarding evaluation of respiratory distress upon infusion, clinical assessment and hematology and clinical chemistry analysis. Gross necropsy and histopathology analysis showed no organ profile alterations. There was no significant evidence for allogeneic antibody production or T-cell sensitization upon MultiStem infusion. Discussion These studies demonstrate the safety of administration of allogeneic stromal stem cells in repeat dosing regimens in bone marrow transplant settings, and define pre-clinical safety testing standards relevant to the development of cellular therapeutics using allogeneic adherent adult stem cells.