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PET Imaging of GVHD and GVL after treatment with Azacitidine

阿扎胞苷治疗后 GVHD 和 GVL 的 PET 成像

基本信息

批准号：
8658382
负责人：
David Piwnica-Worms
金额：
$ 15.43万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8658382
关键词：
Adoptive Transfer Aftercare Allogenic Amendment Azacitidine CD34 gene Cell surface Cells Chimeric Proteins Clinical Clinical Trials Complication DNA Methylation Development Diffuse Donor Lymphocyte Infusion Dose Engraftment Extracellular Domain Flow Cytometry Future Ganciclovir Genes Hematologic Neoplasms Hematological Disease Hematopoietic Stem Cell Transplantation Human Image Imaging Techniques Immunosuppression Immunosuppressive Agents In Vitro Interleukin-2 Knockout Mice Life Maintenance Measures Mediating Modeling Mus Patients Pharmaceutical Preparations Positron-Emission Tomography Production Prophylactic treatment Regulatory T-Lymphocyte Relapse Reporting Self Tolerance Simplexvirus Stem cell transplant Suicide System T-Lymphocyte Thymidine Kinase Time Toxic effect Tracer Transmembrane Domain Transplantation Treatment Efficacy University of Texas M D Anderson Cancer Center Variant Xenograft procedure disorder control graft vs host disease graft vs leukemia effect in vivo in vivo imaging killings leukemia loss of function lymph nodes molecular imaging mouse model reconstitution safety testing suicide gene trafficking

项目摘要

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 (Aim 1), 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.

调节性T细胞（Tregs）有助于维持自身耐受性和减轻移植物抗宿主