Marrow-Infiltrating Lymphocytes

骨髓浸润淋巴细胞

基本信息

批准号：
8291667
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
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-12-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8291667
关键词：
Active Immunotherapy Acute Graft Versus Host Disease Adoptive Transfer Allogeneic Bone Marrow Transplantation Allogenic Anatomic Sites Autologous Blood Bone Marrow Bone Marrow Transplantation CD28 gene CD3 Antigens Cell Therapy Cells Characteristics Clinical Clinical Research Clinical Trials Cyclophosphamide Data Disease Failure Funding Grant Hematologic Neoplasms Immune Immunity Lymphocyte Marrow Measurable Mediating Morbidity - disease rate Multiple Myeloma Patients Pharmaceutical Preparations Phase Prophylactic treatment Recurrent disease Refractory Relapse Research Safety Source T-Lymphocyte Techniques Therapeutic Transplantation Treatment Efficacy Treatment Failure Vaccines base chronic graft versus host disease graft vs host disease human disease improved inhibitor/antagonist innovation lenalidomide mortality novel reconstitution response tumor tumor specificity

项目摘要

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

疾病复发是自体和异体治疗失败的最常见原因（alio）血液和骨髓移植（BMT）。因此，增强抗肿瘤的需求尚未得到满足在这些环境中具有免疫力。我们提出了一种新的过继细胞疗法（ACT）方法来增强 autoBMT 后的抗肿瘤免疫，并通过利用 aloBMT 治疗移植后复发骨髓作为大多数血液学的主要解剖部位的独特特征恶性肿瘤和富含肿瘤反应性骨髓浸润淋巴细胞（MIL）的隔室。我们假设离体激活的肿瘤特异性 MIL 可以赋予可测量且可持续的抗肿瘤作用收养转移后的豁免权。这个假设是根据我们的初步数据提出的汇集上一个融资周期中制定的创新战略。来自多个的 MIL 骨髓瘤患者可以通过抗 CD3/CD28 刺激进行体外扩增，并显着激活提高 ACT 研究中的肿瘤特异性。同样，从接受 alloBMT 的患者身上获得的 MIL 使用基于 PTCy 的 GVHD 预防也可以扩展，使用相同的技术和增强他们的抗肿瘤反应性。因此，在具体目标 #1 中，我们将确定是否结合激活的 MIL 与同种异体骨髓瘤细胞疫苗或来那度胺一起使用可以增强和/或维持抗肿瘤免疫力 autoBMT 后并评估激活的 MIL 对免疫重建、肿瘤特异性免疫的影响并将这些参数与临床反应相关联。在具体目标 #2 中，我们将进行阶段 l/ll 评估从患者身上获得的 alloMIL 作为更具肿瘤特异性的药物的可行性/安全性的临床试验