Antigenic basis of immune responses after immune modulatory therapies post-HCT

项目摘要 异基因造血干细胞移植（HCT）是一种已建立的基于免疫的急性造血干细胞移植治疗方法。 骨髓性白血病（AML），并提供了一个设置解剖的免疫基础的反应， 抵抗免疫选择压力。特别是，HCT提供了一个有效的平台， 免疫调节，以增强移植物抗白血病（GvL）的作用，因此是一个机会， 组合疗法在DFCI，我们已经推进了HCT与其他免疫组合的工程化， 二十多年来的模式，包括通过HCT后供体淋巴细胞输注（DLI）的I期研究， 全肿瘤细胞疫苗和检查点阻断抗体（CPB）治疗，我们已经评估了 这些联合疗法的各种成分的影响。例如，我们之前报道过， HCT后产生可检测骨髓浸润性CD 8 + T细胞的慢性髓性白血病患者 更有可能发展为DLI的持久缓解，DLI反应与DLI逆转相关。 T细胞耗竭的转录特征，与“免疫帮助”的提供一致（Bachireddy Blood 2014）。我们假设白血病细胞及其周围免疫细胞 人群与allo-HCT课程的关系共同发展将为开展 合理设计有效的联合治疗方案。我们专注于HCT后AML的研究， DFCI最近完成了几项信息丰富的临床试验（项目1）。利用现代 免疫基因组学工具（核心3）和临床因素关联分析（核心1），我们将绘制白血病和 供体免疫细胞在HCT后共同进化，以便更好地制定未来研究的设计策略。 HCT后免疫调节治疗。我们将利用我们在克隆进化研究方面的专业知识， 研究AML细胞的免疫基因组学特征（即新抗原和次要组织相容性抗原 （mHAg）载量，抗原加工/呈递机制中的体细胞突变） （核心2提供的样本）与单独HCT或与HCT后的后续结局相关 疫苗，DLI或CPB（核心1），并整合遗传和转录信息，从匹配的前， 移植后复发白血病样本，以确定暴露于 基于免疫的选择性压力（目标1）。同时，我们将确定组成的变化， HCT后通过单细胞免疫调节后骨髓浸润免疫细胞的功能状态 从具有确定的应答谱的患者收集的样品的转录组表征（目的2）。 最后，我们将跟踪与移植后应答相关的抗原-T细胞相互作用的演变。 免疫调节，其中我们将抗原特异性（即预测的个人新抗原，白血病- 相关抗原，mHAg）与所发现的TCR序列相关联，并确定抗原- 特异性T细胞克隆随时间的变化（目的3）。

Project Summary Allogeneic hematopoietic stem cell transplantation (HCT) is an established immune-based therapy for acute myelogenous leukemia (AML), and provides a setting for dissecting the immune basis of response and resistance to immunologic selective pressure. In particular, HCT provides an effective platform for subsequent immunomodulation to enhance graft-versus-leukemia (GvL) effects, and is thus an opportunity to develop combinatorial therapy. At DFCI, we have advanced the engineering of combinations of HCT with other immune modalities over two decades, including through phase I studies of post-HCT donor lymphocyte infusion (DLI), whole tumor cell vaccines, and checkpoint blockade antibody (CPB) therapy, by which we have evaluated the impact of the various components of these combined therapies. For example, we previously reported that patients with chronic myeloid leukemia who generated detectable marrow-infiltrating CD8+ T cells after HCT were more likely to develop durable remission to DLI, and that DLI response was associated with reversal of transcriptional signatures of T cell exhaustion, consistent with the provision of `immunologic help' (Bachireddy Blood 2014). We hypothesize that dissection of how leukemia cells and their surrounding immune cell populations co-evolve in relationship to allo-HCT course will provide essential insights for undertaking the rational design of effective combination therapy. We focus on studies of AML following HCT, as several informative clinical trials have been recently completed at DFCI (Project 1). Using modern immunogenomic tools (Core 3) and clinical factor association analysis (Core 1), we will map how leukemia and donor immune cells co-evolve following HCT in order to better strategize about the design of future studies of post-HCT immunomodulatory therapy. We will leverage our expertise in the study of clonal evolution to investigate the immunogenomic features of AML cells (i.e. neoantigen and minor histocompatibility antigen (mHAg) load, somatic mutations in antigen processing/presentation machinery) of ~200 pre-HCT leukemias (samples provided by Core 2) in relation to subsequent outcome following HCT alone, or with post-HCT vaccines, DLI or CPB (Core 1), and integrate genetic and transcriptional information from matched pre- and post-transplant relapse leukemia samples to identify the basis of immunologic escape following exposure to immune-based selective pressure (Aim 1). In parallel, we will determine the changes in the composition and functional state of marrow-infiltrating immune cells following post-HCT immunomodulation through single cell transcriptome characterization of samples collected from patients with defined response profiles (Aim 2). Finally, we will track evolving antigen-T cell interactions in association with response to post-transplant immunomodulation in which we will link the antigen specificity (i.e. predicted personal neoantigens, leukemia- associated antigens, mHAgs) to the discovered TCR sequences, and determine the cellular state of antigen- specific T cell clones over time (Aim 3).