CTLA-4 Blockade in Allo Stem Cell Transplantation

描述（由申请人提供）：同种异体造血干细胞移植（alloo - hct）是几种血液恶性肿瘤的既定治疗方法。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同种异体造血干细胞移植治疗潜力的重要组成部分。最近，非清髓异体移植（non- myeleloative allogeneic transplantation， NHCT）被用作限制传统同种异体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，癌症复发仍然是同种异体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异性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。该提案旨在评估延迟CTLA-4阻断作为增强同种异体hct后持续性或进行性恶性肿瘤患者GVM的手段。具体来说，将进行一项三期临床试验，以确定在不诱导严重移植物抗宿主病（GVHD）或移植物排斥反应的情况下，单独或联合供体淋巴细胞输注（DLI）延迟CTLA-4阻断是否可行，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针对CTLA-4的中和性人单克隆抗体（MDX-CTLA-4）来实现，该抗体将在NHCT后第100天至第370天之间以单一、固定、生物确定的剂量给药。评估的主要终点将是CTLA-4阻断后90天内发生的3/4级急性GVHD的发生率。其他终点包括广泛期慢性GVHD的发生率、移植物排斥反应的发生率、疾病反应、无进展和总生存期。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细胞对来自受体的恶性和非恶性刺激细胞的反应性来评估。

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.