Allo Stem Cell Transplant as Immunotherapy for Melanoma

描述(由申请人提供)：目前转移性黑色素瘤的治疗方法并不令人满意，因为很少有患者获得持久的完全缓解。 该项目探索了一种提供免疫治疗的新概念，通过 非清髓性异基因干细胞移植(Allo SCT)。我们 假设供者造血嵌合体的建立将导致 移植物抗肿瘤(GVT)效应。越来越多的抗原清单已经被 在黑色素瘤细胞上鉴定，可能诱导I类或II类T细胞 回应。异基因SCT后GVT效应的机制 仔细检查，可能涉及T细胞对次要组织相容的反应性 抗原，以及肿瘤特异性抗原。这样做的具体目的是 建议包括： 1.完成Allo的第二阶段试验(FHCRC协议1462)的第一阶段 螺旋CT在转移性黑色素瘤患者中的临床疗效 (根据客观应答率和存活率进行评估)和毒性 (包括移植物抗宿主病)。多达15名转移性患者 获得部分缓解、轻微缓解或稳定的黑色素瘤 疾病经过初步的系统治疗后，才会得到治疗。符合条件的患者将 接受低剂量全身照射(200cGy.)和氟达拉滨，随后 输注来自人类白细胞抗原相合的同胞捐献者的外周血干细胞， 移植后环孢素和霉酚酸酯。随后，选择 患者将接受供者淋巴细胞以增强GVT效应。 2.评估接受异基因干细胞移植患者的免疫反应，以了解 黑色素瘤抗原、新的肿瘤特异性抗原、组织特异性抗原和 次要的组织相容性抗原。CD_4~+和CD_8~+T细胞对 确定的多肽将通过四聚体分析进行评估，细胞溶解效应 功能和增殖反应性。 评价异基因干细胞移植的潜在反应和安全性，并阐明 这些T细胞反应将促进未来研究的发展 操纵转移性黑色素瘤患者的GVT效应。

DESCRIPTION (Provided by applicant): Current treatments for metastatic melanoma are unsatisfactory, as very few patients achieve durable complete remissions. This project explores a novel concept for delivering immunotherapy, via nonmyeloablative allogeneic stem cell transplantation (Allo SCT). We hypothesize that the establishment of donor hematopoietic chimerism will induce a graft-versus-tumor (GVT) effect. A growing list of antigens have been identified on melanoma cells, which may elicit Class I or Class II T cell responses. The mechanism of GVT effect after Allo SCT is under intense scrutiny, and may involve T cell reactivity to minor histocompatibility antigens, as well as to tumor specific antigens. The Specific Aims of this proposal are: 1. Complete the first stage of a Phase II trial (FHCRC protocol 1462) of Allo SCT in patients with metastatic melanoma, to determine the clinical efficacy (as assessed by the objective response rate and survival) and toxicity (including graft-versus-host disease). Up to 15 patients with metastatic melanoma, who have achieved partial remission, minor remission, or stable disease after initial systemic therapy, will be treated. Eligible patients will receive low-dose total body irradiation (200cGy), and fludarabine, followed by infusion of peripheral blood stem cells from a HLA matched sibling donor, with post-transplant cyclosporine and mycophenylate mofetil. Subsequently, selected patients will receive donor lymphocytes to augment the GVT effect. 2. Evaluate immune responses, in patients undergoing Allo SCT, to known melanoma antigens, novel tumor-specific antigens, tissue-specific antigens, and minor histocompatibility antigens. The CD4+ and CD8+ T cell responses to defined peptides will be assessed by tetramer analysis, cytolytic effector function, and proliferative reactivity. Evaluation of the potential response, safety of Allo SCT, and elucidation of these T-cell responses will facilitate the development of future studies to manipulate GVT effect in patients with metastatic melanoma.