Enhancing Treg Immune Reconstitution After Stem Cell Transplant

增强干细胞移植后 Treg 免疫重建

• 批准号: 8330787
• 负责人: Catherine M. Bollard
• 金额: $ 31.17万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-09 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8330787
• 关键词: Acute Graft Versus Host Disease; Adenoviruses; Adoptive Transfer; Adverse effects; Affect; Affinity; Allogenic; Allografting; Antibody Formation; Antigens; Bacteria; Biological Assay; Biological Phenomena; Blood specimen; Caring; Cell Separation; Cells; Cellular Immunity; Clinical; Clinical Data; Clinical Research; Clinical Trials; Complication; Cytomegalovirus; Data; Development; Disease; Dose; Engraftment; Excision; Flow Cytometry; Frequencies; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hereditary Disease; High Dose Chemotherapy; Human; IL2 gene; IL2RA gene; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunization; Immunosuppressive Agents; Impact evaluation; In Vitro; Incidence; Infection; Infectious Agent; Infusion procedures; Institutes; Interleukin 2 Receptor; Interleukin-2; Lead; Leukemic Cell; Life; Link; Malignant - descriptor; Malignant Neoplasms; Measures; Modeling; Morbidity - disease rate; Mus; Organ; Organism; Patients; Pharmaceutical Preparations; Phase; Population; Prevention; Procedures; Property; Recovery; Regimen; Regulatory T-Lymphocyte; Relapse; Residual state; Risk; Stem cell transplant; System; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tetanus Toxoid; Time; Transplantation; Viral; Virus; WT1 gene; adverse outcome; base; cell mediated immune response; cost; cytokine; design; graft vs host disease; high risk; in vivo; interest; irradiation; leukemia; leukemia virus; microbial; mortality; novel; novel strategies; pathogen; peripheral blood; phase 2 study; pre-clinical; prevent; prophylactic; reconstitution; response

DESCRIPTION (provided by applicant): We propose using ultra low dose Interleukin 2 (ULD-IL2) to reduce the risk of Graft versus host disease after allogeneic hematopoietic stem cell transplantation (Allo SCT) by increasing levels of endogenous T regulatory cells. AlloSCT) is recognized as the treatment of choice for several hematologic malignancies, as well as for selected immunologic and genetic diseases. However, graft-versus-host disease (GvHD) is one of the major adverse consequences of the procedure. GvHD occurs in approximately 30 to 70% of patients undergoing alloSCT increasing morbidity and mortality, as well as the cost of care. Standard prophylactic therapies are often ineffective and may lead to significant complications. Including organ damage and impaired immune recovery with resultant life-threatening infections and an increased risk of relapse. Thus, more effective and less toxic therapies are needed to prevent GvHD post transplant, while still allowing for immune reconstitution post SCT. There has been increasing interest in the ability of regulatory T cells (Tregs) to modulate GvHD. Evidence suggests that alloSCT recipients with GvHD have lower absolute numbers of Tregs, while murine models have shown that infusion of donor Tregs post SCT prevents GvHD while maintaining the graft-versus- leukemia (GvL) effect. Although ex vivo expansion of T regs and subsequent infusion may be possible, cost and complexity are high. Moreover, one of the most specific markers for Treg is FoxP3, a transcriptional regulator that cannot be used as a basis for separating viable T regs from within the CD25 population. Furthermore, it is unclear whether natural Tregs expanded in vitro will have the same in vivo immunological properties as thymic-derived regulatory T cells. We propose a novel strategy to prevent GvHD by expanding donor-derived Tregs in vivo using ULD IL-2 in patients after alloSCT. Our underlying hypotheses are that (i) regulatory T cells can be preferentially expanded in vivo following alloSCT by the administration of ULD IL-2 to recipients early post SCT, as a strategy to prevent GvHD while (ii) preserving humoral, innate and cell mediated immunity to microbial pathogens and to residual malignancy. These hypotheses, formulated from extensive preclinical data and pilot clinical observations will be tested in two specific aims: (1) In a phase I/II clinical trial, we will determine whether the administration of ULD IL-2 in patients post allogeneic stem cell transplantation is safe and increases Tregs in vivo; and (2) Whether IL-2 induced Tregs affect cellular and humoral immune responses against leukemia, viruses and bacteria as a marker for their effect on post transplant relapse and infection.

描述（由申请人提供）：我们建议使用超剂量白细胞介素2（ULD-IL2）通过增加内源性T调节细胞的水平来降低同种异性造血干细胞移植（Allo SCT）后移植与宿主疾病的风险。 AlloSCT被认为是几种血液学恶性肿瘤以及选定的免疫和遗传疾病的选择治疗方法。然而，移植物与宿主病（GVHD）是该手术的主要不利后果之一。 GVHD发生在大约30％至70％的患者中，患者增加了发病率和死亡率以及护理成本。标准预防性疗法通常无效，可能导致重大并发症。包括器官损伤和免疫恢复受损，导致威胁生命的感染和复发风险增加。因此，需要更有效和更小的毒性疗法来防止GVHD移植后移植，同时仍允许SCT后进行免疫结构。调节T细胞（TREG）调节GVHD的能力一直在增加兴趣。有证据表明，具有GVHD的AlloSCT受体的绝对数量较低，而鼠模型表明，SCT后的供体Tregs的输注可以阻止GVHD，同时保持移植物抗血症（GVL）效应。尽管可能有可能进行T Regs的体内扩展和随后的输注，但成本和复杂性很高。此外，Treg最具体的标记之一是Foxp3，Foxp3是一种转录调节器，无法用作将可行的T regs与CD25人群内部分开的基础。此外，尚不清楚自然treg在体外扩展是否与胸腺衍生的调节性T细胞具有相同的体内免疫学特性。我们提出了一种新的策略，以防止GVHD通过在AlloSCT后使用ULD IL-2在体内扩展供体衍生的Tregs。我们的基本假设是（i）通过将ULD IL-2施用给受体早期SCT后，可以在体内优先扩展体内的调节T细胞，作为预防GVHD的一种策略（ii）（ii）保存体液，先天和细胞对微生物病原体和残留物质的免疫。这些假设由广泛的临床前数据和试点临床观察提出，将在两个具体的目的中进行检验：（1）在I/II期临床试验中，我们将确定同种异体干细胞移植后患者的ULD IL-2是否安全，并且在体内增加Tregs； （2）IL-2诱导的Treg是否影响针对白血病，病毒和细菌的细胞和体液免疫反应，是它们对移植后复发和感染的影响的标志物。

项目成果

Enhancing immune reconstitution: from bench to bedside.

• DOI: 10.1016/j.bbmt.2012.09.016
• 发表时间: 2013
• 期刊: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
• 作者: M. V. D. van den Brink;A. Leen;K. Baird;M. Merchant;C. Mackall;C. Bollard

Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory T cells without diminishing antiviral and antileukemic activity.

• DOI: 10.1158/1078-0432.ccr-13-3205
• 发表时间: 2014-04-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Kennedy-Nasser AA;Ku S;Castillo-Caro P;Hazrat Y;Wu MF;Liu H;Melenhorst J;Barrett AJ;Ito S;Foster A;Savoldo B;Yvon E;Carrum G;Ramos CA;Krance RA;Leung K;Heslop HE;Brenner MK;Bollard CM
• 通讯作者: Bollard CM

Generation of multi-leukemia antigen-specific T cells to enhance the graft-versus-leukemia effect after allogeneic stem cell transplant.

• DOI: 10.1038/leu.2013.66
• 发表时间: 2013-07
• 期刊: Leukemia
• 影响因子: 11.4