CTLA-4 Blockade in Allo Stem Cell Transplantation

描述（由申请人提供）：异基因造血干细胞移植（allo-HCT）是一种已确立的治疗几种恶性血液病的方法。有大量证据表明，供体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。最近，非清髓性异基因移植（NHCT）已被用作限制常规allo-HCT毒性的手段，从而增加过继免疫治疗对癌症患者的可及性。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细胞表面上的CTLA-4分子与其配体的相互作用用于下调特异性细胞介导的免疫应答。来自几个临床前模型的数据表明，抑制CTLA-4功能可以增强抗肿瘤免疫应答。该提案旨在评估延迟CTLA-4阻断作为allo-HCT后持续或进行性恶性肿瘤患者增强GVM的一种手段。具体而言，将进行三阶段临床试验以确定在allo-HCT后单独施用和与供体淋巴细胞输注（DLI）联合施用的延迟CTLA-4阻断是否可行而不诱导严重的移植物抗宿主病（GVHD）或移植物排斥，以及是否可以记录GVM增强的初步证据。体内CTLA-4阻断将通过使用新开发的抗CTLA-4的中和人单克隆抗体（MDX-CTLA-4）实现，该抗体将在NHCT后+100天至+370天之间以单一、固定、生物学确定的剂量给药。评价的主要终点将是CTLA-4阻断后90天内发生的3/4级急性GVHD的发生率。其他终点将包括广泛期慢性GVHD的发生率、移植物排斥的发生率、疾病反应、无进展生存期和总生存期。还将通过体外分析CTLA-4阻断之前和之后从患者分离的T细胞对来源于受体的恶性和非恶性刺激细胞的反应性来评估抗体的功效。

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.