Inhibition of PGE2 for mobilization of autologous peripheral blood stem cells

描述(申请人提供)：动员的自体外周血干细胞(PBSC)已经取代骨髓成为造血干细胞的来源，因为中性粒细胞和血小板恢复得更快，主要是由于PBSC移植物中CD34+细胞的产量更高。使用髓系生长因子的各种动员策略，特别是G-CSF(非格列格替姆)，已经单独使用或与化疗联合使用。然而，多达40%的患者将无法动员“最佳”CD34细胞剂量(定义为e5x106/kg)。小分子CXCR4拮抗剂plerixafor联合G-CSF动员的CD34+细胞总数已被证明比单独使用G-CSF更多，并已被美国食品和药物管理局批准用于多发性骨髓瘤(MM)和非霍奇金淋巴瘤(NHL)患者的PBSC动员。然而，plerixafor的一个显著缺点是成本；在最近的一项经济分析中，与在NHL患者中单独使用G-CSF相比，每个患者增加了25,567美元。此外，在大型试验中，接受Plerixafor加G-CSF治疗的MM和NHL患者中，14-24%的患者在4天内仍未能收集到e2x106 CD34+细胞/公斤。前列腺素E_2(PGE_2)和环氧合酶(COX)途径在造血和HSC及HPC转运中的作用一直是我们研究组关注的焦点，我们最近定义了PGE_2在造血生态位中的新作用，并发现抑制负责合成PGE_2的COX酶的非类固醇抗炎药(NSAID)显著增加了外周血中HSC和HPC的数量，并与G-CSF协同作用动员具有优越植入潜力的PBSC。这项建议旨在将我们的临床前发现转化为一种新颖、廉价和更有效的PBSC动员方案。具体地说，我们建议：1进行一项II期临床试验，评估美洛昔康和非霍奇金联合动员多发性骨髓瘤和非霍奇金淋巴瘤患者自体PBSC的安全性和有效性，假设FDA批准的非甾体抗炎药、美洛昔康和非格司汀联合使用将增加接受ASCT的非霍奇金淋巴瘤和多发性骨髓瘤患者收集的CD34+细胞的数量，目的2利用分子、表型和功能的方法更好地了解非类固醇抗炎药对移植物内容和功能的作用机制，评估动员的CD34+细胞移植物及其CX4表达、增殖状态和免疫细胞含量(AIM 2A)，以及对CD34+细胞/HPC亚群进行基因表达微阵列和基因本体浓缩分析，以确定与NSAID介导的HPC增殖潜力变化(AIM 2B)相关的基因/生物途径。从长远来看，了解这些变化将使我们能够更有效地弥合移植后的分化差距，并开发新的、可能更有效和更具成本效益的动员方案和策略。

DESCRIPTION (provided by applicant): Mobilized autologous peripheral blood stem cells (PBSC) have replaced bone marrow as the source of hematopoietic stem cells because of more rapid neutrophil and platelet recovery, largely due to a higher yield of CD34+ cells in PBSC grafts. Various mobilization strategies using myeloid growth factors, particularly G-CSF (filgrastim), have been used either alone or in combination with chemotherapy. However, up to 40% of patients will fail to mobilize an "optimal" CD34 cell dose (defined as e5x106/kg). Plerixafor, a small molecule CXCR4 antagonist, in combination with G-CSF has been shown to increase total CD34+ cells mobilized compared to G-CSF alone, and is approved by the Food and Drug Administration for PBSC mobilization in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). However, a significant disadvantage of plerixafor is cost; adding $25,567 per patient compared to G-CSF alone in NHL patients in a recent economic analysis. Furthermore, 14-24% of MM and NHL patients receiving plerixafor plus G-CSF still failed to collect e2x106 CD34+ cells/kg in four days of apheresis in large trials. Our group has a long standing interest in the roles of prostaglandin E2 (PGE2) and the cyclooxygenase (COX) pathway on hematopoiesis and HSC and HPC trafficking, We have recently defined a new role for PGE2 in the hematopoietic niche and shown that non- steroidal anti-inflammatory drugs (NSAID) that inhibit COX enzymes responsible for PGE2 synthesis significantly enhance the number of HSC and HPC in peripheral blood, and act synergistically with G-CSF to mobilize PBSC with superior engraftment potential. This proposal seeks to translate our preclinical findings to develop a novel, inexpensive and more efficacious PBSC mobilizing regimen. Specifically, we propose to: Aim 1 Conduct a phase II clinical trial to assess the safety and efficacy of the combination of meloxicam and filgrastim for mobilizing autologous PBSC in patients with MM and NHL, hypothesizing that the combination of the FDA approved NSAID, meloxicam, and filgrastim will enhance the number of CD34+ cells collected in NHL and MM patients undergoing ASCT, and Aim 2 Utilize a molecular, phenotypic and functional approach to better understand the mechanism of action of NSAID on PBSC graft content and function, assessing the mobilized graft for CD34+ cells and their expression of CXCR4, and proliferation status, and immune cell content (Aim 2A), and performing gene expression microarrays and gene ontology enrichment analysis on CD34+ cells/HPC subsets to identify genes/biological pathways associated with NSAID-mediated change in HPC proliferative potential (Aim 2B). In the long-term, understanding these changes will allow us to more effectively bridge the differentiation gap post-transplant, and develop novel and potentially more efficacious and cost-effective mobilization regimens and strategies.