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（TCRs）有助于维持自身耐受和减轻移植物抗宿主 疾病（GvHD），异基因造血干细胞移植（HSCT）的主要并发症，而 保留有益的移植物抗白血病（GvL）效应。然而，罕见的Treg细胞的体外扩增， 子集是低效、昂贵且耗时的。Foxp 3基因座是TcR的主要调节因子， 未甲基化的，仅在TcB中表达。我们最近报道了低甲基化剂 阿扎胞苷（AzaC）在体内诱导Foxp 3表达并增加TcR，从而减轻GvHD，而不 在鼠同种异体移植模型中消除GvL。我们还开发了一种体内成像技术， 技术，[18FJ-FHBG-PET]，以追踪携带嵌合自杀基因（CD 34-CD 36）的遗传修饰的T细胞。 TK 75）。在这次更新中，我们将进一步确定AzaC诱导的免疫抑制的最佳条件， 小鼠同种异体移植模型（Aimi）证实了在人T细胞中可以证明类似的作用， 细胞使用我们实验室开发的信息性异种移植物GvHD/白血病模型（Aim 2），并验证 AzaC在先导性临床试验中的作用（目的3）。在目标3中提出的临床试验中，我们建议给予 HSCT后复发的AML或MDS患者接受含有T细胞的供体淋巴细胞输注， 用我们的CD 34-TK 75自杀/成像基因转导;一半将用AzaC治疗。我们的假设是 AzaC将T细胞转化为FoxP 3 + T细胞，FoxP 3 + T细胞将控制同种异体反应性T细胞，从而减轻GvHD 而不消除GvL效应。非侵入性[18F]-FHBG-PET成像测量 患者中过继转移的CD 34-TK 75+示踪T细胞的重建、扩增和持久性 可能具有提供GvHD和AzaC治疗功效的早期预测的显著临床效用。 相关性（参见说明）： 如果成功，通过[18FJ-FHBG-PET成像观察到“GvHD特征”将预示着GvHD的发生。 严重GvHD和需要启动GvHD预防。相比之下，“无GvHD”概况的观察 将预测可忽略到有限的GvHD，并允许继续观察接受者， 免疫抑制药物，从而允许更持续的GvL效应。