PET Imaging of GVHD and GVL after treatment with Azacitidine

阿扎胞苷治疗后 GVHD 和 GVL 的 PET 成像

• 批准号: 8195498
• 负责人: David Piwnica-Worms
• 金额: $ 11.47万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195498
• 关键词: Adoptive Transfer; Aftercare; Allogenic; Azacitidine; CD34 gene; Cells; Clinical; Clinical Trials; Complication; Development; Donor Lymphocyte Infusion; Genes; Hematological Disease; Hematopoietic Stem Cell Transplantation; Human; Image; Imaging Techniques; Immunosuppression; Immunosuppressive Agents; In Vitro; Instruction; Life; Maintenance; Measures; Modeling; Mus; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Prophylactic treatment; Regulatory T-Lymphocyte; Relapse; Reporting; Self Tolerance; Suicide; T-Lymphocyte; Time; Tracer; Transplantation; Treatment Efficacy; Universities; Washington; Xenograft procedure; graft vs host disease; graft vs leukemia effect; in vivo; leukemia; molecular imaging; reconstitution; suicide gene

Regulatory T cells (Tregs) contribute to the maintenance of self-tolerance and mitigate graft-versus-host disease (GvHD), a major complication of allogeneic hematopoietic stem cell transplantation (HSCT), while preserving the beneficial graft-versus-leukemia (GvL) effect. However, in vitro expansion of the rare Treg cell subset is inefficient, costly, and time-consuming. The locus of Foxp3, the master regulator of Tregs, is unmethylated and expressed only in Tregs. We have recently reported that the hypomethylating agent azacitidine (AzaC) induces Foxp3 expression and increases Tregs in vivo, thereby mitigating GvHD without abrogating GvL in a murine allogeneic transplant model. We have also developed an in vivo imaging technique, [18FJ-FHBG-PET, to track genetically-modified T cells carrying a chimeric suicide gene (CD34- TK75). In this renewal, we will further define the optimal conditions for AzaC-induced immune suppression in murine allogeneic transplant models (Aimi), confirm that similar effects can be demonstrated in human T cells using informative xenograft GvHD/leukemia models developed in our lab (Aim 2), and validate the effects of AzaC in a pilot clinical trial (Aim 3). In the clinical trial proposed in Aim 3, we propose to give patients with relapsed AML or MDS after HSCT a donor lymphocyte infusion containing T cells that are transduced with our CD34-TK75 suicide/imaging gene; half will be treated with AzaC. Our hypothesis is that AzaC will convert the T cells into FoxP3+ Tregs that will control the alloreactive T cells thus mitigating GvHD without abrogating GvL effects. The ability of non-invasive [18F]-FHBG-PET imaging to measure the reconstitution, expansion and persistence of adoptively transferred CD34-TK75+ tracer T cells in patients may have significant clinical utility for providing early predictions of GvHD and AzaC treatment efficacy. RELEVANCE (See instructions): If successful, the observation of a "GvHD profile" by [18FJ-FHBG-PET imaging would herald the onset of severe GvHD and the need for initiation of GvHD prophylaxis. In contrast, observation of a "No GvHD" profile would predict negligible to limited GvHD and permit the continued observation of recipients without immunosuppressive medications, thereby permitting a more sustained GvL effect.

调节性 T 细胞 (Treg) 有助于维持自我耐受并减轻移植物抗宿主反应 疾病（GvHD）是同种异体造血干细胞移植（HSCT）的主要并发症， 保留有益的移植物抗白血病（GvL）效应。然而，稀有 Treg 细胞的体外扩增 子集效率低、成本高且耗时。 Tregs 的主要调节因子 Foxp3 的位点是 未甲基化且仅在 Tregs 中表达。我们最近报道了低甲基化剂 阿扎胞苷 (AzaC) 诱导 Foxp3 表达并增加体内 Tregs，从而减轻 GvHD，且无需 在小鼠同种异体移植模型中废除 GvL。我们还开发了一种体内成像 技术，[18FJ-FHBG-PET，追踪携带嵌合自杀基因（CD34- TK75）。在本次更新中，我们将进一步确定 AzaC 诱导的免疫抑制的最佳条件 鼠同种异体移植模型（Aimi），证实在人类 T 细胞中也能表现出类似的效果 细胞使用我们实验室开发的信息丰富的异种移植 GvHD/白血病模型（目标 2），并验证 AzaC 在试点临床试验中的影响（目标 3）。在目标 3 提出的临床试验中，我们建议给予 HSCT 后复发性 AML 或 MDS 患者输注含有 T 细胞的供体淋巴细胞 用我们的 CD34-TK75 自杀/成像基因转导；一半将接受 AzaC 治疗。我们的假设是 AzaC 会将 T 细胞转化为 FoxP3+ Tregs，从而控制同种异体反应性 T 细胞，从而减轻 GvHD 不消除 GvL 效应。非侵入性 [18F]-FHBG-PET 成像测量 患者体内过继转移的 CD34-TK75+ 示踪 T 细胞的重建、扩增和持久性 可能对于提供 GvHD 和 AzaC 治疗效果的早期预测具有重要的临床实用性。 相关性（参见说明）： 如果成功，通过 [18FJ-FHBG-PET 成像观察到的“GvHD 特征”将预示着 严重的 GvHD 以及需要开始 GvHD 预防。相反，观察到“无 GvHD”概况 将预测有限的 GvHD 可以忽略不计，并允许继续观察接受者，而无需 免疫抑制药物，从而实现更持久的 GvL 效果。