CTLA-4 Blockade in Allo Stem Cell Transplantation

同种异体干细胞移植中的 CTLA-4 阻断

• 批准号: 6942568
• 负责人: EDWARD David BALL
• 金额: $ 28.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6942568
• 关键词: CD28 molecule; T lymphocyte; antigen presenting cell; antineoplastics; cellular immunity; clinical research; clinical trials; flow cytometry; graft versus host disease; hematopoietic stem cells; hematopoietic tissue transplantation; homologous transplantation; human subject; human therapy evaluation; leukocyte activation /transformation; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer relapse /recurrence; neoplastic cell; neoplastic process; neutralizing antibody; stem cell transplantation; transplant rejection

DESCRIPTION (provided by applicant): Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an established therapy for several hematologic malignancies. There exists considerable evidence that adoptive immunotherapy in the form of a donor T-cell mediated graft-versus-malignancy (GVM) is an important component of the curative potential of allo-HCT. Recently, non-myeloablative allogeneic transplantation (NHCT) has been utilized as a means of limiting the toxicity of conventional allo-HCT, thus increasing the accessibility of adoptive immunotherapy to cancer patients. However, cancer relapse remains an important cause of treatment failure and death following allo-HCT, and may be an even more significant hurdle following NHCT. Interaction of the CTLA-4 molecule on the T-cell surface with its ligands serves to down-regulate specific cell-mediated immune responses. Data from several pre-clinical models suggests that inhibition of CTLA-4 function may enhance anti-tumor immune responses. This proposal aims to assess delayed CTLA-4 blockade as a means of augmenting GVM in patients who have persistent or progressive malignancy following allo-HCT. Specifically, a three stage clinical trial will be performed to determine whether delayed CTLA-4 blockade, administered alone and in conjunction with donor lymphocyte infusion (DLI), is feasible following allo-HCT without induction of severe graft-versus-host disease (GVHD) or graft rejection, and whether preliminary evidence of augmentation of GVM can be documented. In vivo CTLA-4 blockade will be achieved through the use of a newly developed neutralizing human monoclonal antibody against CTLA-4 (MDX-CTLA-4) which will be administered at a single, fixed, biologically determined dose between day +100 and +370 following NHCT. The primary endpoint evaluated will be the incidence of grade 3/4 acute GVHD occurring within 90 days following CTLA-4 blockade. Other endpoints will include incidence of extensive stage chronic GVHD, incidence of graft rejection, disease response, progression-free and overall survival. Efficacy of the antibody will also be assessed by in vitro analysis of the reactivity of T-cells isolated from patients before and after CTLA-4 blockade, to malignant and non-malignant stimulator cells derived from the recipient.

描述(申请人提供)：异基因造血干细胞移植(allo-hct)是一种公认的治疗多种血液系统恶性肿瘤的方法。有大量证据表明，供者T细胞介导的移植物抗恶性肿瘤(GVM)形式的过继免疫治疗是allo-HCT治疗潜力的重要组成部分。近年来，非清髓性异基因移植(NHCT)已被用作限制传统异基因移植毒性的一种手段，从而增加了癌症患者过继免疫治疗的可及性。然而，癌症复发仍然是allo-HCT后治疗失败和死亡的重要原因，并且可能是NHCT后更重要的障碍。T细胞表面的CTLA-4分子与其配体的相互作用有助于下调特定的细胞介导的免疫反应。来自几个临床前模型的数据表明，抑制CTLA-4功能可能会增强抗肿瘤免疫反应。这项建议旨在评估延迟的CTLA-4阻断作为一种手段来增强在allo-HCT后有持续性或进展性恶性肿瘤的患者的GVM。具体地说，将进行一项三阶段的临床试验，以确定单独使用和联合供者淋巴细胞输注(DLI)的延迟CTLA-4阻断在allo-HCT后是否可行，而不会导致严重的移植物抗宿主病(GVHD)或移植物排斥反应，以及是否可以记录GVM增加的初步证据。在体内，CTLA-4的阻断将通过使用一种新开发的中和人抗CTLA-4的单抗(MDX-CTLA-4)来实现，该单抗将在NHCT后+100天至+370天之间以生物确定的单一固定剂量给予。评估的主要终点是CTLA-4阻断后90天内发生的3/4级急性移植物抗宿主病的发生率。其他终点将包括广泛期慢性移植物抗宿主病的发生率、移植物排斥反应的发生率、疾病反应、无进展和总存活率。该抗体的有效性还将通过体外分析CTLA-4阻断前后患者分离的T细胞对接受者来源的恶性和非恶性刺激细胞的反应性来评估。

项目成果

CTLA-4 blockade following relapse of malignancy after allogeneic stem cell transplantation is associated with T cell activation but not with increased levels of T regulatory cells.

• DOI: 10.1016/j.bbmt.2010.08.005
• 发表时间: 2011-05
• 期刊: BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
• 影响因子: 4.3
• 作者: Zhou, Jiehua;Bashey, Asad;Zhong, Ruikun;Corringham, Sue;Messer, Karen;Pu, Minya;Ma, Wenxue;Chut, Theresa;Soiffer, Robert;Mitrovich, Rachel C.;Lowy, Israel;Ball, Edward D.
• 通讯作者: Ball, Edward D.