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

HCT 后免疫调节治疗后免疫反应的抗原基础

基本信息

批准号：
10218090
负责人：
Catherine Ju-Ying Wu
金额：
$ 57.67万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-14 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218090
关键词：
Acute Myelocytic Leukemia Algorithms Allogenic Antibodies Antibody Therapy Antigen Presentation Pathway Antigens Bar Codes Blood Bone Marrow Transplantation CD8-Positive T-Lymphocytes Cell Communication Cell Shape Cell Therapy Cells Chronic Myeloid Leukemia Clinical Clinical Trials Clonal Evolution Clone Cells Combined Modality Therapy Cytometry Data Detection Disease remission Dissection Donor Lymphocyte Infusion Elements Engineering Evolution Exposure to Failure Future Gene Expression Profile Genetic Transcription Genomics Heart Neoplasms Hematopoietic Stem Cell Transplantation Immune Immune response Immunocompetence Immunogenomics Immunologics Immunooncology Immunotherapy Intervention Leukemic Cell Link Lymphoid Malignant Neoplasms Maps Marrow Minor Histocompatibility Antigens Modality Modernization Mutation Myelogenous Outcome Patients Population Property Recurrent disease Reporting Research Personnel Resistance Sampling Shapes Somatic Mutation Specificity Specimen T-Lymphocyte Therapeutic Therapeutic Intervention Time Toxic effect Transplantation Tumor Antigens Tumor-infiltrating immune cells Vaccine Therapy Vaccines acute myeloid leukemia cell antigen-specific T cells base cancer cell cohort combinatorial design exhaustion graft vs leukemia effect host neoplasm interaction immune checkpoint blockade immunomodulatory therapies immunoregulation innovation insight leukemia leukemia relapse neoantigens neoplastic cell novel novel therapeutics phase 1 study post-transplant pressure reconstitution responders and non-responders response success tool transcriptome tumor tumor eradication tumor-immune system interactions

项目摘要

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).

项目概要异基因造血干细胞移植（HCT）是一种基于免疫疗法的急性白血病治疗方法。骨髓性白血病 (AML)，并提供了剖析反应和免疫基础的环境抵抗免疫选择压力。特别是HCT为后续的研究提供了有效的平台。免疫调节以增强移植物抗白血病（GvL）效应，因此是开发的机会组合疗法。在 DFCI，我们推进了 HCT 与其他免疫组合的工程设计二十多年来的模式，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）疗法，我们通过这些疗法评估了这些联合疗法的各个组成部分的影响。例如，我们之前报道过 HCT 后产生可检测到的骨髓浸润 CD8+ T 细胞的慢性粒细胞白血病患者更有可能对 DLI 产生持久缓解，并且 DLI 反应与逆转 T 细胞耗竭的转录特征，与提供“免疫帮助”一致（Bachireddy 血2014）。我们假设解剖白血病细胞及其周围的免疫细胞是如何与异体 HCT 课程相关的群体共同进化将为开展这项工作提供重要的见解合理设计有效的联合治疗。我们专注于 HCT 后 AML 的研究，如 DFCI 最近完成了多项信息丰富的临床试验（项目 1）。使用现代免疫基因组工具（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 细胞的免疫基因组特征（即新抗原和次要组织相容性抗原）约 200 例 HCT 前白血病的 (mHAg) 负载、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 后或 HCT 后的后续结果相关疫苗、DLI 或 CPB（核心 1），并整合来自匹配的预和转录的遗传和转录信息移植后复发性白血病样本以确定暴露后免疫逃逸的基础基于免疫的选择压力（目标 1）。同时，我们将确定成分的变化和 HCT后单细胞免疫调节后骨髓浸润免疫细胞的功能状态对从具有明确反应特征的患者收集的样本进行转录组表征（目标 2）。最后，我们将追踪与移植后反应相关的不断变化的抗原-T 细胞相互作用免疫调节，其中我们将链接抗原特异性（即预测的个人新抗原、白血病- 相关抗原，mHAgs）到发现的TCR序列，并确定抗原的细胞状态随着时间的推移，特定的 T 细胞克隆（目标 3）。