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)是一种公认的基于免疫的治疗急性白血病的方法。 髓系白血病(AML)，并提供了一个解剖免疫基础的反应和 对免疫选择性压力的抵抗。特别是，HCT为后续工作提供了一个有效的平台 免疫调节增强移植物抗白血病(GVL)效应，因此是发展的机会 综合疗法。在DFCI，我们已经推进了HCT和其他免疫组合的工程 20年来的模式，包括通过HCT后供者淋巴细胞输注(DLI)的第一阶段研究， 全肿瘤细胞疫苗和检查点阻断抗体(CPB)疗法，我们通过这些疗法评估了 这些综合疗法的不同组成部分的影响。例如，我们之前曾报道过 HCT后产生可检测到的骨髓浸润性CD8 T细胞的慢性髓系白血病患者 更有可能发展为DLI的持久缓解，DLI的反应与逆转 T细胞耗尽的转录特征，与提供‘免疫帮助’相一致(巴基雷迪 《血色2014》。我们假设，对白血病细胞及其周围免疫细胞的解剖 与allo-HCT课程相关的种群共同进化将为开展 合理设计有效的综合疗法。我们的重点是研究急性髓系白血病后的HCT，AS DFCI(项目1)最近完成了几项信息丰富的临床试验。使用现代的 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 供者免疫细胞在HCT后共同进化，以便更好地为未来研究的设计制定战略 血细胞移植后免疫调节治疗。我们将利用我们在克隆进化研究中的专业知识 研究急性髓系白血病细胞(新抗原和次要组织相容性抗原)的免疫基因组学特征 约200例血细胞移植前白血病的(Mhag)负载，抗原处理/提呈机制中的体细胞突变 (样本由核心2提供)与单独进行HCT或HCT后的后续结局相关 疫苗，DLI或CPB(核心1)，并集成来自匹配的Pre和 移植后复发白血病样本确定暴露于病毒后免疫逃避的基础 基于免疫的选择性压力(目标1)。同时，我们将确定组成和 HCT后单细胞免疫调节后骨髓浸润性免疫细胞的功能状态 从具有明确反应特征的患者收集的样本的转录组特征(目标2)。 最后，我们将跟踪与移植后反应相关的抗原-T细胞的进化相互作用 免疫调节，其中我们将把抗原特异性(即预测的个人新抗原、白血病- 相关抗原，mHAgs)与发现的TCR序列结合，并确定抗原的细胞状态 随着时间推移，特定的T细胞克隆(目标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).