Enhancing Engraftment of Cord Blood by CD26 Inhibition

描述（由申请人提供）：脐带血（CB）移植极大地扩展了造血细胞移植（HCT）的可用性，使原本不会接受这种治愈性治疗的患者能够获得这种造血细胞移植。与骨髓（BM）和动员的外周血（mPB）相比，CB具有几个优点，包括收集的容易性和安全性、容易获得性以及减轻急性和慢性移植物抗宿主病（GVHD）。然而，与BM或mPB相比，CB的缺点是有核细胞、造血祖细胞（HPC）和可能的干细胞（HSC）的数量低，这已经转化为移植失败、延迟植入和延迟免疫重建的风险增加。基于我们已发表的实验室和临床前动物模型研究、初步临床数据以及本文报告的CD 26/二肽基肽酶（DPP）IV活性的机制研究，我们认为抑制CD 26/DPPIV将显著增强限制人CB细胞数量的植入能力，并加速单个CB单位的植入时间。这项多PI资助提出了以下具体目标：目标1：进行一项多中心II期临床试验，以评估使用西格列汀全身抑制CD 26/DPPIV的疗效和安全性，以增强血液系统癌症成人中单个CB单位的植入。假设：通过全身给予CD 26抑制剂西格列汀来抑制CD 26/DPPIV将增强植入，而不会对与单次CB移植相关的相对较低水平的GVHD产生负面影响。主要目的：评价移植后第+30天中性粒细胞恢复的患者比例，作为植入速度的指标。使用最佳两阶段设计，在第+30天植入<50%的患者将被认为是不可接受的（零假设; H 0：p0<0.5），而70%或更多的植入将被认为值得进一步研究（备择假设：H1：p1e0.7）。Subaims是：a）评估血小板植入时间、患者存活、移植失败、复发率、急性和慢性GVHD水平; B）使用相关测定通过表型和功能分析评估免疫细胞的恢复;和c）评估CD 26/DPPIV和造血相关细胞因子的血液水平。目标二：使用小鼠和人细胞因子的细胞培养和生物化学研究以及小鼠BM和人CB细胞，评价CD 26/DPPIV如何机械调节造血。假设：CD 26/DPPIV通过以下方式调节造血：其特异性酶促能力截短和抑制不同的造血活性细胞因子。我们将比较目标1中的临床研究结果，以更好地理解和利用这种新的治疗方式。Subaims包括：a）评估与全长形式相比，被CD 26/DPPIV截短的GM-CSF、G-CSF、IL-3和EPO如何在细胞内发出信号; B）确定向小鼠全身施用西格列汀是否增强HSC的归巢并影响细胞因子产生;和c）研究其他分子的CD 26/DPPIV截短和活性。 公共卫生相关性：脐带血移植是一种可行的治疗方法，但一个缺点是单个脐带血采集中细胞数量有限，特别是对于成年受者。通过了解细胞表面酶CD 26如何调节血细胞生成，并通过特异性抑制这种酶在脐带血移植受体中的全身作用，我们相信供体细胞植入将大大增强成人受体。

DESCRIPTION (provided by applicant): Cord blood (CB) transplantation has greatly extended availability of a hematopoietic cell transplant (HCT) to patients who would not otherwise have received this curative treatment. CB has several advantages over bone marrow (BM) and mobilized peripheral blood (mPB), including ease and safety of collection, ready availability, and lessened acute and chronic graft vs. host disease (GVHD). However, a disadvantage with CB is low numbers of nucleated cells, hematopoietic progenitors (HPC), and likely stem cells (HSC), compared with BM or mPB, which has translated into increase risk of graft failure, delayed engraftment, and delayed immune reconstitution. Based on our published laboratory and preclinical animal model studies, preliminary clinical data, and mechanistic studies on CD26/Dipeptidylpeptidase (DPP) IV activities reported herein, we believe that inhibition of CD26/DPPIV will significantly enhance engraftment capability of limiting numbers of human CB cells, and accelerate time to engraftment of single CB units. This multi-PI grant proposes the following specific aims: Aim 1: Conduct a multicenter phase II clinical trial to assess efficacy and safety of systemic inhibition of CD26/DPPIV using sitagliptin, to enhance engraftment of single CB units in adults with hematological cancers. Hypothesis: Inhibition of CD26/DPPIV by systemic administration of CD26 inhibitor sitagliptin will enhance engraftment, without negatively impacting relatively lower levels of GVHD associated with single CB transplantation. Primary Objective: Evaluate proportion of patients with neutrophil recovery by day +30 after transplant as a measure of speed of engraftment. Using an optimal two-stage design, <50% of patients engrafting by day +30 will be considered unacceptable (null hypothesis; H0: p0<0.5), while 70% or more engrafting will be considered worthy of further study (alternate hypothesis: H1: p1e0.7). Subaims are: a) Evaluate time to platelet engraftment, patient survival, graft failure, relapse rate, acute and chronic GVHD levels; b) Use correlative assays to assess recovery of immune cells through phenotypic and functional analysis; and c) Assess blood levels of CD26/DPPIV, and hematopoietically relevant cytokines. Aim 2: Evaluate how CD26/DPPIV mechanistically regulates hematopoiesis, using cell culture and biochemical studies on mouse and human cytokines and with cells from mouse BM and human CB. Hypothesis: CD26/DPPIV regulates hematopoiesis through: its specific enzymatic capability to truncate and inactivate different hematopoietically active cytokines. We will compare results to clinical study in Aim 1 to better understand and utilize this new treatment modality. Subaims include: a) Evaluate how GM-CSF, G-CSF, IL-3 and EPO truncated by CD26/DPPIV, compared to full length form, signal intracellularly; b) Determine if systemic administration of sitagliptin to mice enhances homing of HSC and influences cytokine production; and c) Study other molecules for CD26/DPPIV truncation and activity. PUBLIC HEALTH RELEVANCE: Cord blood transplantation is a viable treatment, but one disadvantage is the limiting number of cells in single cord blood collections, especially for adult recipients. By understanding how a cell surface enzyme, CD26, regulates blood cell production, and by specifically inhibiting this enzyme systemically in recipients of cord blood transplantation, we believe that donor cell engraftment will be greatly enhanced in adult recipients.