Marrow-Infiltrating Lymphocytes

疾病复发是自体和异体移植治疗失败的最常见原因。 （alio）血液和骨髓移植（BMT）。因此，存在未满足的增加抗肿瘤活性的需求。 在这种情况下的免疫力。我们提出了一种新的过继细胞治疗（ACT）方法， 自体BMT后的抗肿瘤免疫，并通过开发抗肿瘤免疫系统治疗同种异体BMT后的移植后复发。 骨髓作为大多数血液病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）的区室。我们 假设离体活化肿瘤特异性MIL可赋予可测量和可持续的抗肿瘤活性 收养转移时的豁免权。这一假设是在我们的初步数据的基础上提出的， 汇集上一个供资周期制定的创新战略。来自多个 骨髓瘤患者可以用抗-CD 3/CD 28刺激离体扩增，并显著激活 在ACT研究中增加其肿瘤特异性。同样，从接受alloBMT的患者中获得的MIL 使用基于PTCy的GVHD预防也可以扩展，使用相同的技术和增加 它们的抗肿瘤活性。因此，在具体目标#1中，我们将确定激活的MIL 同种异体骨髓瘤细胞疫苗或来那度胺可以增强和/或维持抗肿瘤免疫 并评估活化的MIL对免疫重建、肿瘤特异性免疫 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I/II阶段 临床试验，以评估从患者获得的alloMIL作为更具肿瘤特异性的抗肿瘤药物的可行性/安全性。 PTCy后alloBMT后复发的骨髓和淋巴恶性肿瘤患者的“DLI”， 检查活化的alloMIL对免疫重建、GVHD风险和肿瘤特异性的影响。 最后，在具体目标#3中，我们将描述来那度胺对调节MIL的内在 分化程序，扩增，存活和外在抑制信号，并确定 共抑制分子对MIL增强抗肿瘤免疫能力的影响。总体而言，拟议的 研究在解决减少或治疗复发性疾病的重要未满足需求方面具有重要意义 通过临床研究跟踪BMT，并增加对 抗肿瘤免疫和开发利用MIL增强抗肿瘤免疫的创新ACT策略 移植后

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.