Marrow-Infiltrating Lymphocytes

骨髓浸润淋巴细胞

• 批准号: 8924910
• 负责人: Ivan M. Borrello
• 金额: $ 33.87万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8924910
• 关键词: Active Immunotherapy; Acute Graft Versus Host Disease; Address; Adoptive Immunotherapy; Adoptive Transfer; Allogeneic Bone Marrow Transplantation; Allogenic; Anatomy; Autologous; Blood; Bone Marrow; Bone Marrow Transplantation; CD28 gene; CD3 Antigens; Cell Therapy; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Cyclophosphamide; Data; Development; Disease; Donor Lymphocyte Infusion; Failure; Funding; Grant; Hematologic Neoplasms; Immune; Immunity; Institution; Lymphocyte; Malignant lymphoid neoplasm; Marrow; Measurable; Mediating; Morbidity - disease rate; Multiple Myeloma; Myeloproliferative disease; Patients; Pharmaceutical Preparations; Phase; Prophylactic treatment; Recurrent disease; Refractory; Relapse; Research; Risk; Safety; Signal Transduction; Source; T-Lymphocyte; Techniques; Therapeutic; Transplantation; Treatment Efficacy; Treatment Failure; Vaccines; Work; base; chronic graft versus host disease; experience; graft vs host disease; human disease; improved; inhibitor/antagonist; innovation; lenalidomide; mortality; novel; programs; reconstitution; response; tumor; tumor specificity

Disease relapse is the most common reason for treatment failure of both autologous (auto) and allogeneic (alio) blood and marrow transplantation (BMT). As such, there is the unmet need to augment antitumor immunity in these settings. We propose a novel adoptive cell therapy (ACT) approach to augment antitumor immunity after autoBMT and to treat the post-transplant relapse after alloBMT by exploiting the unique characteristic of the bone marrow as both the primary anatomic site for most hematologic malignancies and a compartment enriched with tumor-reactive marrow infiltrating lymphocytes (MILs). We hypothesize that ex vivo activated tumor-specific MILs can impart measurable and sustainable antitumor immunity upon adoptive transfer. This hypothesis is formulated on the basis of our preliminary data and by bringing together innovative strategies developed during the previous funding cycle. MILs from multiple myeloma patients can be expanded ex vivo with anti-CD3/CD28 stimulation and activated as to significantly Increase their tumor specificity in ACT studies. Similarly, MILs obtained from patients undergoing alloBMT using PTCy-based GVHD prophylaxis can also be expanded, using the same techniques and augment their antitumor reactivity. Accordingly, in Specific Aim #1, we will determine if activated MILs in combination with an allogeneic myeloma cell vaccine or lenalidomide can augment and/or sustain antitumor immunity after autoBMT and assess the impact of activated MILs on immune reconstitution, tumor-specific immunity and correlate these parameters with clinical responses. In Specific Aim #2, we will conduct a phase l/ll clinical trial to evaluate the feasibility/safety of alloMILs obtained from the patient as a more tumor-specific "DLI" in patients with myeloid and lymphoid malignancies relapsing after alloBMT following PTCy and examine the impact of activated alloMILs on immune reconstitution, risk of GVHD, and tumor-specificity. Finally, in Specific Aim #3 we will characterize the effects of lenalidomide on modulating MILs' intrinsic differentiation program, expansion, survival, and extrinsic Inhibitory signals and determine the effects of coinhibitory molecules on the ability of MILs to augment antitumor immunity. In aggregate, the proposed research is significant in addressing an important unmet need of reducing or treating relapsed disease following BMT through clinical studies as well as increasing the overall understanding of mechanisms of antitumor immunity and developing innovative ACT strategies utilizing MILs to augment antitumor immunity posttransplant.

疾病复发是自体（自动）和同种异体治疗失败的最常见原因 （ALIO）血液和骨髓移植（BMT）。因此，没有必要增加抗肿瘤 在这些环境中的免疫力。我们提出了一种新颖的收养细胞疗法（ACT）的方法来增强 AutoBMT后的抗肿瘤免疫力，并通过利用AlloBMT治疗后移植后复发 骨髓的独特特征是大多数血液学的主要解剖部位 恶性肿瘤和一个充满肿瘤反应性骨髓浸润淋巴细胞（MILS）的室。我们 假设离体激活的肿瘤特异性MIL可以赋予可衡量的可持续抗肿瘤 收养后的免疫力。该假设是根据我们的初步数据提出的 将创新策略汇总在上一个融资周期中制定的创新策略。来自多个的米尔 可以用抗CD3/CD28刺激将骨髓瘤患者离体扩展，并显着激活 在ACT研究中提高其肿瘤特异性。同样，从接受同倍体的患者获得的MILS 也可以使用相同的技术和增强来扩展基于PTCY的GVHD预防 他们的抗肿瘤反应性。因此，在特定的目标＃1中，我们将确定是否合并激活MILS 使用同种异体骨髓瘤细胞疫苗或列纳莱度胺可以增强和/或维持抗肿瘤免疫力 AutoBMT并评估活化MILS对免疫重建的影响，肿瘤特异性免疫力 并将这些参数与临床反应相关联。在特定的目标＃2中，我们将进行L/LL相 临床试验评估从患者获得的同种异体的可行性/安全性作为肿瘤特异性 PTCY和 检查活化的同种异体对免疫重建，GVHD风险和肿瘤特异性的影响。 最后，在特定的目标＃3中，我们将表征Lenalidomide对调节MILS内在的影响 分化程序，扩展，生存和外部抑制信号，并确定 共抑制分子对MIL增强抗肿瘤免疫力的能力。总共提议 研究对于解决减少或治疗复发疾病的重要未满足的需求很重要 通过临床研究进行BMT，并提高了对机制的总体理解 抗肿瘤的免疫力和开发创新的行为策略利用MIL来增强抗肿瘤免疫力 移植后。