Autografting for Lymphoma

自体移植治疗淋巴瘤

• 批准号: 8260362
• 负责人: SANDRA J. HORNING
• 金额: $ 35.17万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260362
• 关键词: Acute Graft Versus Host Disease; Allogenic; Antithymoglobulin; Autologous; Autologous Transplantation; B-Cell Lymphomas; B-Lymphocytes; Biology; Bone Marrow Transplantation; Cell Transplantation; Cells; Clinic; Clinical Investigator; Dendritic Cells; Development; Diffuse; Disease; Disease remission; Disease-Free Survival; Exclusion; Functional Imaging; Genetic; Goals; Graft-Versus-Tumor Induction; Hematopoietic; Immune; Immune Targeting; Immune response; Immunoglobulin Idiotypes; Immunotherapy; Incidence; Killer Cells; Laboratories; Lymphatic Irradiation; Lymphoma; Mantle Cell Lymphoma; Measures; Mediating; Molecular; Morbidity - disease rate; Neoadjuvant Therapy; Non-Hodgkin' s Lymphoma; Patients; Physiologic pulse; Positron-Emission Tomography; Pre-Clinical Model; Principal Investigator; Program Research Project Grants; Randomized; Recurrence; Recurrent disease; Refractory; Regimen; Relapse; Residual Tumors; Risk; System; T-Lymphocyte; Toxic effect; Translating; Transplantation; Tumor Burden; Universities; Vaccinated; Vaccination; Vaccines; base; chemotherapy; conditioning; cytokine; disorder control; disorder risk; experience; fluorodeoxyglucose positron emission tomography; high risk; improved; leukemia/lymphoma; mortality; novel; novel therapeutics; older patient; peripheral blood; rituximab; standard care; tositumomab; tumor

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.

自体造血细胞移植（AHCT）是大多数患者的标准治疗方法 非霍奇金淋巴瘤的常见类型，弥漫性大 B 细胞 (DLBCL)，会复发或难治性 套细胞淋巴瘤诱导治疗及AHCT在诱导治疗后的应用 (MCL) 已被证明可以延长疾病缓解时间。尽管细胞减灭术出色，但还是会出现复发 在 MCL 和大约一半的 DLBCL 病例中持续存在。每种 B 细胞淋巴瘤都有独特的独特型 我们成功实现疫苗接种的具体目标。在目标 1 中，我们计划接种疫苗 基于我们开发和使用的经验，在 MCL 中进行 AHCT 后进行独特型脉冲树突状细胞 这些细胞在移植后（IND #11227），并与引发的 T 细胞一起施用，以便 优化有效、持久免疫反应的可能性。我们将衡量疫苗接种的效果 通过对外周血中肿瘤负荷的分子评估以及通过测定免疫 回复。在目标 2 中，我们将利用 FDG-PET 功能成像的进步，使 标准 AHCT 后复发率非常高的 DLBCL 患者的区别。利用现有系统 对于斯坦福大学的中央 PET 审查，我们将根据以下情况定义极高风险的 DLBCL 患者： 挽救性化疗后 PET 阳性疾病，并根据以下情况计划 AHCT 后免疫治疗 遗传随机化。对于具有 HLA 匹配供体的高风险 DLBCL 患者（目标 2.1），我们将追求非 利用由全淋巴照射组成的新型预处理方案进行清髓性同种异体 HCT （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 项目补助金。我们对该方案的经验表明，移植物抗肿瘤作用得以保留，但 急性移植物抗宿主病（GVHD）的发生率和治疗相关死亡率降低。对于那些 PET阳性患者没有可用的供体（目标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 后免疫疗法，基于我们之前在项目 3 中使用 CIK 细胞的经验， 已在该项目中翻译成自体环境。项目 2 中的统一假设是 细胞减灭术和肿瘤控制建立后应用淋巴瘤特异性免疫疗法 传统 AHCT 将提高复发风险高的淋巴瘤患者的无事件生存率。我们的 目标是开发这种基于免疫的策略来降低 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 交互， 8 并得到本计划项目拨款的所有核心项目的支持。