Autografting for Lymphoma

自体造血细胞移植是治疗多发性骨髓瘤的标准方法。 常见类型的非霍奇金淋巴瘤，弥漫性大B细胞(DLBCL)，复发或主要难治性 AHCT在套细胞淋巴瘤诱导治疗中的应用 (MCL)已被证明可以延长疾病的缓解时间。尽管细胞减少率很高，但复发还是会发生 在MCL和约一半的DLBCL病例中持续存在。每种B细胞淋巴瘤独有的独特型是 我们已经成功地实现了疫苗接种的具体目标。在目标1中，我们计划接种疫苗 MCL AHCT后独特型冲击树突状细胞的开发和使用经验 移植后的这些细胞(IND#11227)，以及注射预置的T细胞，以便 优化有效、持久的免疫反应的可能性。我们将测量接种疫苗的效果 通过外周血中肿瘤负荷的分子评估和免疫测定 回应。在目标2中，我们将利用FDG-PET在功能成像方面的进展，使 标准AHCT后复发率极高的DLBCL患者的鉴别。利用现有系统 对于斯坦福大学的中央PET审查，我们将根据以下因素来定义极高风险的DLBCL患者 抢救化疗后的PET阳性疾病和计划AHCT后的免疫治疗 遗传随机化。在高危DLBCL患者中，有匹配的HLA捐赠者(目标2.1)，我们将追求非 应用一种新的包括全淋巴照射的预适应方案的清髓性异基因红细胞移植 (TLI)和抗胸腺细胞球蛋白(ATG)在项目4中开发，并在本计划的项目1中翻译 格兰特项目。我们使用该方案的经验表明，移植物抗肿瘤效果得到保留，但 急性移植物抗宿主病(GVHD)的发生率和与治疗相关的死亡率降低。对于那些 没有可用供体的PET阳性患者(AIM 2.2)，我们计划研究细胞因子诱导的杀伤细胞(CIK) 细胞作为AHCT后的免疫疗法，基于我们之前在项目3中使用CIK细胞的经验，该项目 已在本项目的自体环境中翻译。项目2中的统一假设是 在细胞减少和肿瘤控制建立后应用淋巴瘤特异性免疫治疗 传统的AHCT将提高复发风险较高的淋巴瘤患者的无事件存活率。我们的 目标是开发这种基于免疫的策略，以降低AHCT后疾病复发的风险 可广泛应用于非霍奇金淋巴瘤患者。项目2与项目1、3、4、6、 和8，并得到本计划项目赠款所有核心的支持。

Autologous hematopoietic cell transplantation (AHCT) is the standard treatment for the most common type of non-Hodgkin's lymphoma, diffuse large B-cell (DLBCL), that recurs or is primarily refractory to induction therapy, and the application of AHCT following induction therapy for mantle cell lymphoma (MCL) has been shown to prolong diseas'e remission. Despite excellent cytoreduction, relapse occurs continuously in MCL and in about half of DLBCL cases. The idiotype unique to each B-cell lymphoma is a specific target that we have successfully pursued for vaccination. In Aim 1, we plan to vaccinate with idiotype-pulsed dendritic cells after AHCT in MCL, building upon our experience in developing and using these cells after transplantation (IND #11227), together with administration of primed T-cells, in order to optimize the likelihood of an effective, durable immune response. We will measure the effects of vaccination by molecular assessment of tumor burden in the peripheral blood and by determination of the immune response. In Aim 2, we will take advantage of advances in functional imaging with FDG-PET that allow the distinction of DLBCL patients with a very high rate of relapse after standard AHCT. Utilizing existing systems for central PET review at Stanford University, we will define very high risk DLBCL patients on the basis of PET-positive disease after salvage chemotherapy and plan post-AHCT immunotherapy on the basis of genetic randomization. In high risk DLBCL patients with HLA matched donors (Aim 2.1), we will pursue non- myeloablative allogeneic HCT utilizing a novel conditioning regimen consisting of total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) developed in Project 4 and translated in Project 1 of this Program Project Grant. Our experience with this regimen suggests that graft versus tumor effects are retained but the incidence of acute graft versus host disease (GVHD) and treatment-related mortality is reduced. For those PET-positive patients without an available donor (Aim 2.2), we plan to study cytokine-induced killer (CIK) cells as a post-AHCT immunotherapy, building on our previous experience with CIK cells in Project 3, which has been translated in the autologous setting in this Project. The unifying hypothesis in Project 2 is that lymphoma-specific immunotherapy applied after cytoreduction and tumor control is established with conventional AHCT will improve event-free survival in patients with lymphoma at high risk of recurrence. Our goals are to develop such immune-based strategies to reduce the risk of disease relapse after AHCT that could be broadly applied to non-Hodgkin's lymphoma patients. Project 2 interacts with Projects 1, 3, 4, 6, and 8 and is supported by all of the Cores of this Program Project Grant.