Autografting for Lymphoma

自体移植治疗淋巴瘤

• 批准号: 7615603
• 负责人: SANDRA J. HORNING
• 金额: $ 37.36万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7615603
• 关键词: Acute Graft Versus Host Disease; Allogenic; Antithymoglobulin; Autologous; Autologous Transplantation; B-Cell Lymphomas; B-Lymphocytes; Biology; Cell Transplantation; Cells; Clinic; Clinical Investigator; Dendritic Cells; Development; Diffuse; Diffuse Lymphoma; 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; Pulse taking; Randomized; Rate; Recurrence; Recurrent disease; Refractory; Relapse; Residual Tumors; Risk; Standards of Weights and Measures; System; T-Lymphocyte; Toxic effect; Translating; Transplantation; Treatment Protocols; Tumor Burden; Universities; Vaccinated; Vaccination; Vaccines; base; chemotherapy; conditioning; cytokine; disorder control; disorder risk; experience; fluorodeoxyglucose positron emission tomography; graft vs host disease; improved; mortality; novel; novel therapeutics; older patient; peripheral blood; rituximab; 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）是最多的标准治疗方法 非霍奇金淋巴瘤的常见类型，弥漫性大B细胞（DLBCL），它重现或主要是难治性的 诱导疗法以及诱导治疗后AHCT的应用 （MCL）已显示可延长疾病的缓解。尽管有出色的细胞减少，但发生复发 在MCL和大约一半的DLBCL病例中连续连续。每个B细胞淋巴瘤独有的白痴是A 我们成功追求疫苗接种的具体目标。在AIM 1中，我们计划接种疫苗 在MCL中AHCT之后的白痴型树突状细胞，基于我们在开发和使用方面的经验 移植后这些细胞（IND＃11227），以及启动T细胞的给药，以便 优化有效，耐用的免疫反应的可能性。我们将测量疫苗接种的影响 通过分子评估外周血中的肿瘤负担并确定免疫 回复。在AIM 2中，我们将利用FDG-PET的功能成像进步，允许 标准AHCT后复发率很高的DLBCL患者的区别。利用现有系统 对于斯坦福大学的中央宠物评论，我们将根据 挽救化疗后的宠物阳性疾病并根据 遗传随机化。在具有HLA匹配捐助者的高风险DLBCL患者中（AIM 2.1），我们将追求非 - 脊髓含量的同种异体HCT利用一种由总淋巴照射组成的新型调节方案 （TLI）和抗胸腺细胞球蛋白（ATG）在项目4中开发并在该计划的项目1中翻译 项目赠款。我们对该方案的经验表明，移植物与肿瘤作用被保留，但 急性移植与宿主疾病（GVHD）的发生率和与治疗相关的死亡率降低。对于那些 没有可用供体的宠物阳性患者（AIM 2.2），我们计划研究细胞因子诱导的杀手（CIK） 细胞作为AHCT后免疫疗法，基于我们先前在项目3中对CIK细胞的经验，该经验 在该项目的自体设置中已翻译。项目2中的统一假设是 细胞减少和肿瘤控制后应用的淋巴瘤特异性免疫疗法与 常规AHCT将改善高淋巴瘤患者的无事件生存期，重复发生。我们的 目标是制定这种基于免疫的策略，以降低AHCT之后疾病复发的风险 可以广泛应用于非霍奇金的淋巴瘤患者。项目2与项目1、3、4、6， 和8，并得到该计划项目赠款的所有核心的支持。