Marrow-Infiltrating Lymphocytes

项目2 项目摘要 骨髓浸润性淋巴细胞(MIL)最初是过继T细胞治疗(ACT)的一种方法 开发用于从血液系统恶性肿瘤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渗透的内在特征 淋巴细胞决定了它们的疗效。增强其抗肿瘤疗效的策略将集中在克服 其预扩张功能障碍，最大限度地减少了体内耐受的诱导。这些假设将是 在正在进行的或新的针对复发恶性肿瘤患者的MILS临床试验中进行的临床测试 在异基因骨髓移植和难治性骨髓瘤以及临床前体外和小鼠模型中。 因此，在具体目标1中，我们将调查是否可以通过以下方式增强AutoMILs的效力 增加其抗原特异性或通过检查点封锁。作为这一目标的一部分，我们将：i) 对复发性多发性骨髓瘤(MM)进行一项试验性随机I/II期临床试验，以评估PD-1 BLOCKADE可提高自体MILS作为ACT治疗复发性多发性骨髓瘤患者的疗效；ii)量化 肿瘤特异性免疫和全球免疫反应性来评估总体疗效。在具体目标2中，我们 将确定激活的患者来源的异基因(Allo)MIL的疗效和机制 增强异基因骨髓移植后复发患者的抗肿瘤免疫。在这一目标中，我们将：i) 确定异体骨髓移植后复发患者的临床疗效，以及II)表征 复发性恶性肿瘤患者接受异体骨髓移植治疗后成功和失败的机制。 最后，在特定的目标3中，我们将检验MILS抗肿瘤活性可以通过以下方式增强的假设 克服抑制检查点，利用共刺激的激动剂，并通过激活 刺痛路径。总体而言，拟议的研究对于解决一个重要的未得到满足的需求具有重要意义 通过临床研究减少或治疗骨髓移植后复发的疾病，以及增加 全面了解抗肿瘤免疫机制并开发创新的ACT策略 利用MILs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.