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 - 主宿主 疾病（GVHD），这是同种异性造血干细胞移植（HSCT）的主要并发症，而 保留有益的移植物与白血病（GVL）效应。但是，稀有Treg细胞的体外扩张 子集效率低下，昂贵且耗时。 Tregs的主要监管机构Foxp3的基因座是 未甲基化并仅在Treg中表达。我们最近报道了低甲基化剂 azacitidine（Azac）诱导FOXP3表达并在体内增加Treg，从而减轻GVHD没有 在鼠同种异体移植模型中废除GVL。我们还开发了一个体内成像 技术，[18FJ-FHBG-PET，用于跟踪带有嵌合自杀基因的遗传改性T细胞（CD34-- TK75）。在这种续约中，我们将进一步定义AZAC诱导的免疫抑制的最佳条件 鼠同种异体移植模型（AIMI），证实在人类中可以证明类似的影响 使用内容丰富的异种移植GVHD/白血病模型在我们的实验室中开发的细胞（AIM 2），并验证 AZAC在试验临床试验中的影响（AIM 3）。在AIM 3提出的临床试验中，我们建议给予 HSCT后，患有AML或MDS的患者A供体淋巴细胞输注，其中含有T细胞 用我们的CD34-TK75自杀/成像基因转导；一半将用AZAC处理。我们的假设是 AZAC会将T细胞转换为Foxp3+ Tregs，该细胞将控制同种异体T细胞，从而减轻GVHD 没有废除GVL效果。非侵入性[18F] -FHBG-PET成像的能力测量 患者中采用转移的CD34-TK75+示踪剂T细胞的重构，扩张和持久性 可能具有大量的临床实用性，以提供GVHD和AZAC治疗功效的早期预测。 相关性（请参阅说明）： 如果成功，[18FJ-FHBG-PET成像对“ GVHD概况”的观察将预示 严重的GVHD和需要GVHD预防的必要性。相比之下，观察“无GVHD”轮廓 可以预测被限制的GVHD可以忽略不计，并允许对接收者的持续观察 免疫抑制药物，从而允许更持续的GVL效果。