Marrow-Infiltrating Lymphocytes

计划2 项目摘要 骨髓浸润淋巴细胞（MIL）最初代表了过继性T细胞治疗（ACT）的方法。 开发用于从恶性血液病的肿瘤微环境中富集肿瘤特异性T细胞。 我们的中心假设是激活的肿瘤特异性骨髓浸润的内在特征， 淋巴细胞决定其功效。增强其抗肿瘤疗效的策略将集中于克服 它们的预扩张功能障碍并使体内耐受性的诱导最小化。这些假设将是 在复发性恶性肿瘤患者中正在进行的或新的MIL临床试验的背景下进行临床测试 在alloBMT后和那些患有难治性骨髓瘤的人以及临床前体外和鼠模型中。 因此，在具体目标1中，我们将研究autoMIL的功效是否可以通过以下方式增强： 增加它们的抗原特异性或通过检查点阻断。作为这一目标的一部分，我们将： 在复发性多发性骨髓瘤（MM）中进行一项初步随机I/II期临床试验，以评估PD-1 阻断可以增强autoMILS作为ACT在复发性多发性骨髓瘤患者中的功效; ii）定量 肿瘤特异性免疫和整体免疫应答以评估总体功效。在具体目标2中， 将确定激活的患者来源的同种异体（allo）MIL在 增强同种异体BMT后复发患者的抗肿瘤免疫力。为此，我们将：i） 确定alloMIL在alloBMT后复发的患者中的临床疗效，和ii）表征 在用alloMILs治疗的alloBMT后复发性恶性肿瘤患者的成功和失败机制。 最后，在具体目标3中，我们将测试MIL的抗肿瘤活性可以通过以下方式增强的假设： 克服抑制性检查点，利用共刺激的激动剂，并通过激活 STING途径。总的来说，拟议的研究对解决一个重要的未满足的需求具有重要意义 通过临床研究减少或治疗BMT后复发的疾病， 全面了解抗肿瘤免疫机制，开发创新的ACT策略 利用MIL增强移植后的抗肿瘤免疫。

Project 2 Project Summary Marrow infiltrating lymphocytes (MILs) represent an approach to adoptive T cell therapy (ACT) initially developed to enrich for tumor specific T cells from the tumor microenvironment for hematologic malignancies. Our central hypothesis is that intrinsic characteristics of activated tumor-specific marrow infiltrating lymphocytes determine their efficacy. Strategies to augment their anti-tumor efficacy will focus on overcoming their pre-expansion dysfunction and minimizing the induction of tolerance in vivo. These hypotheses will be tested clinically in the context of ongoing or new clinical trials of MILs in patients with relapsed malignancies after alloBMT and those with refractory myeloma as well in preclinical in vitro and murine models. Accordingly, in Specific Aim 1, we will investigate if the efficacy of autoMILs can be augmented by increasing their antigen-specificity or through checkpoint blockade. As a part of this aim we will: i) conduct a pilot randomized phase I/II clinical trial in relapsed multiple myeloma (MM) to evaluate if PD-1 blockade can augment efficacy of autoMILS as ACT in patients with relapsed multiple myeloma; ii) quantify tumor specific immunity and global immune responsiveness to assess overall efficacy. In Specific Aim 2, we will determine the efficacy and mechanisms of activated patient-derived, allogeneic (allo)MILs in augmenting anti-tumor immunity in patients relapsing post-allogeneic BMT. In this aim we will: i) determine the clinical efficacy of alloMILs in patients relapsing after alloBMT and ii) characterize the mechanisms of success and failure in patients with relapsed malignancy after alloBMT treated with alloMILs. Finally, in Specific Aim 3, we will test the hypothesis that MILs anti-tumor activity can be enhanced by overcoming inhibitory checkpoints, harnessing agonists of co-stimulation, and by activating the STING pathway. 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.