Hexner Elizabeth O, Luger Selina M, Reshef Ran, Jeschke Grace R, Mangan James K, Frey Noelle V, Frank Dale M, Richman Lee P, Vonderheide Robert H, Aqui Nicole A, Rosenbach Misha, Zhang Yi, Chew Anne, Loren Alison W, Stadtmauer Edward A, Levine Bruce L, June Carl H, Emerson Stephen G, Porter David L
Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Am J Hematol. 2016 May;91(5):453-60. doi: 10.1002/ajh.24303. Epub 2016 Apr 4.
Limited cell numbers in umbilical cord blood (UCB) grafts present a major impediment to favorable outcomes in adult transplantation, largely related to delayed or failed engraftment. The advent of UCB transplantation (UCBT) using two grafts successfully circumvents this obstacle, despite the engraftment of only one unit. Preclinical models suggested that the addition of UCB T cells at the time of transplant can enhance engraftment. We tested whether ex vivo activation by CD3/CD28 costimulation and expansion of T cells from a single UCB graft would be safe and feasible in adults with advanced hematologic malignancies, with an overall objective of optimizing engraftment in single unit UCBT. In this phase 1 study, recipients of single UCB units were eligible if the unit was stored in two adequate fractions. Dose limiting toxicity was defined as grade 3 or grade 4 GVHD within 90 days of UCBT. Four patients underwent UCBT; all were treated at the first dose level (10(5) cells/kg). At the 10(5) cells/kg dose level two subjects experienced grade 3 intestinal GVHD, thus meeting stopping criteria. For three subjects, neutrophil engraftment was early (12, 17, and 20 days), while one subject experienced primary graft failure. We observed early donor T cell trafficking and found that expanded T cells produced supraphysiologic levels of cytokines relevant to engraftment and to lymphoid differentiation and function. Taken together, these preliminary data suggest rapid engraftment in recipients of a single UCBT combined with relatively low doses of activated T cells, though potentially complicated by severe GVHD.
脐带血（UCB）移植物中细胞数量有限是成人移植获得良好预后的主要障碍，这在很大程度上与植入延迟或失败有关。使用两份移植物进行UCB移植（UCBT）的出现成功地克服了这一障碍，尽管只有一个单位实现了植入。临床前模型表明，移植时添加UCB T细胞可增强植入。我们测试了通过CD3/CD28共刺激对单个UCB移植物中的T细胞进行体外激活和扩增，对于患有晚期血液系统恶性肿瘤的成人患者是否安全可行，总体目标是优化单单位UCBT中的植入。在这项1期研究中，如果单个UCB单位以两个足够的部分储存，则其接受者符合条件。剂量限制毒性定义为UCBT后90天内出现3级或4级移植物抗宿主病（GVHD）。4例患者接受了UCBT；所有患者均在第一个剂量水平（10⁵细胞/kg）接受治疗。在10⁵细胞/kg剂量水平时，两名受试者出现3级肠道GVHD，因此达到停药标准。对于三名受试者，中性粒细胞植入较早（12、17和20天），而一名受试者出现原发性移植物失败。我们观察到供体T细胞早期迁移，并发现扩增的T细胞产生了与植入以及淋巴细胞分化和功能相关的超生理水平的细胞因子。综上所述，这些初步数据表明，单单位UCBT联合相对低剂量的活化T细胞可使受者快速植入，尽管可能会并发严重的GVHD。
