Allo Stem Cell Transplant as Immunotherapy for Melanoma

描述（由申请人提供）：转移性黑色素瘤的当前治疗 但是，这些治疗并不令人满意，因为很少有患者能够达到持久的完全缓解。 这个项目探索了一个新的概念，通过提供免疫治疗， 非清髓性异基因造血干细胞移植（Allo SCT）。我们 假设供体造血嵌合体的建立将诱导 移植物抗肿瘤（GVT）效应。越来越多的抗原已经 在黑色素瘤细胞上鉴定，其可以引发I类或II类T细胞 应答Allo SCT后GVT效应的机制尚不清楚 仔细检查，并可能涉及T细胞对轻微组织相容性的反应性 抗原以及肿瘤特异性抗原。具体目标是 建议如下： 1.完成Allo II期试验（FHCRC方案1462）的第一阶段 转移性黑色素瘤患者的SCT，以确定临床疗效 (as通过客观缓解率和生存率评估）和毒性 （包括移植物抗宿主病）。最多15例转移性患者 已达到部分缓解、轻微缓解或稳定的黑色素瘤患者 疾病后，初步系统治疗，将得到治疗。合格患者将 接受低剂量全身照射（200 cGy），氟达拉滨，然后 输注来自HLA匹配的同胞供体的外周血干细胞， 移植后环孢霉素和吗替麦考酚酯。随后，选定 患者将接受供体淋巴细胞以增强GVT效应。 2.在接受Allo SCT的患者中，评价已知 黑色素瘤抗原、新的肿瘤特异性抗原、组织特异性抗原，和 次要组织相容性抗原CD4+和CD8 + T细胞对 将通过四聚体分析、细胞溶解效应物 功能和增殖反应性。 评价Allo SCT的潜在缓解、安全性和阐明 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.