Defining the determinants of response and resistance to therapy for Richter's Syndrome

定义里氏综合症治疗反应和耐药的决定因素

基本信息

批准号：
10270038
负责人：
Catherine Ju-Ying Wu
金额：
$ 37.35万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10270038
关键词：
Address Allogenic American Society of Clinical Oncology Animal Model Antigens BCL2 gene CRISPR/Cas technology Cell Shape Cells Cessation of life Characteristics Chronic Lymphocytic Leukemia Clinical Clinical Investigator Clinical Trials Complication DNA sequencing Data Detection Development Disease Disease remission Dissection Engineering Enrollment Evolution Flow Cytometry Funding Genetic Genetically Engineered Mouse Genome Genomics Hematopoietic Stem Cell Transplantation Immune Immunity Immunogenomics Immunohistochemistry Incidence Individual Lead Link Logistics Lymphoma Malignant Neoplasms Marrow Mediating Modeling Molecular Mus Mutation Outcome Pathway interactions Patient-Focused Outcomes Patients Phenotype Population Proteins Regimen Research Personnel Resistance Richter&apos s Syndrome Role Sampling Specificity Specimen Statistical Data Interpretation T-Lymphocyte T-cell receptor repertoire TP53 gene Therapeutic Therapeutic Agents Therapeutic Trials Time Tissue Microarray Tissues Tumor-infiltrating immune cells Validation analytical tool base chemotherapy clinical investigation curative treatments disorder control exome experience human disease immune checkpoint blockade improved in vivo inhibitor/antagonist innovation insight longitudinal analysis loss of function lymph nodes molecular phenotype neoplastic cell novel novel therapeutic intervention novel therapeutics patient response phenome predicting response programmed cell death protein 1 response single-cell RNA sequencing therapeutic development therapy resistant tool transcriptome transcriptome sequencing treatment response tumor tumor-immune system interactions

项目摘要

Abstract Richter's Syndrome (RS) arises from chronic lymphocytic leukemia (CLL) and has long been acknowledged as presenting a bleak clinical outlook for CLL patients. New treatment combinations, however, incorporating novel agents suggest the feasibility of achieving deeper and longer-lasting remissions in patients with RS. These include treatment with immune checkpoint blockade (ICB; -PD1 therapy) together with ibrutinib, and combination of the BCL2 inhibitor venetoclax with chemotherapy. These experiences provide encouraging developments for an entity hitherto considered a death sentence for CLL patients. Despite these promising therapeutic developments, little information is available regarding the determinants of clinical response to these therapies. The recent increase in clinical investigation of novel therapeutic agents for RS now provides an opportunity to more consistently collect biospecimens. Moreover, the recent availability of novel sequencing capabilities, analytic tools and animal models (generated by our efforts over this past funding period) now enable us to maximally extract information about the diverse molecular and phenotypic features of RS from primary patient material. We hypothesize that therapeutic response and resistance to RS therapy are shaped by both tumor-intrinsic and -extrinsic features, and that these features underlie the differential sensitivity to novel agents between RS and CLL. Herein, we will undertake in-depth analysis of specimens collected on therapeutic trials, focusing on longitudinal analyses of both RS specimens and their microenvironment, and also functional validation of these findings in a novel animal model. These studies are supported by strong interactions with Projects 1 and 3, and each of the individual Cores. Our aims are thus to: (i) Define the RS-intrinsic features that govern responses to RS therapies. We will evaluate the molecular characteristics of serially collected RS specimens from patients treated with: (i) BCL2 inhibitor-based and (ii) ICB-based therapy, and link these attributes with clinical features to identify markers/pathways predictive of response or resistance to therapy. (ii) Delineate the key components of the RS immune microenvironment impacting therapeutic response. New immunogenomic approaches enable us to gain fresh mechanistic insights directly from analyzing patient samples. We will perform scRNA-seq profiling of marrow or lymph node-infiltrating immune cells from RS responders and nonresponders per therapy (enrolled on the aforementioned trials) to systematically characterize the composition and functional state of cellular populations participating in response or resistance to novel RS therapeutic combinations. Finally, we will: (iii) Model differential therapeutic sensitivity of RS to -PD1 therapy compared to CLL. Using novel genetically engineered mouse models that reflect CLL or RS disease, we will perform in vivo treatment studies and functional/phenotypic analyses of immune cells to determine the genetic and microenvironmental basis of RS response to ICB compared to CLL.

抽象的里氏综合症 (RS) 源自慢性淋巴细胞白血病 (CLL)，长期以来被认为是一种然而，新的治疗组合给 CLL 患者带来了黯淡的临床前景。药物表明了 RS 患者实现更深入和更持久的缓解的可行性。包括免疫检查点阻断治疗（ICB；α-PD1 疗法）与依鲁替尼一起治疗，以及 BCL2 抑制剂 Venetoclax 与化疗相结合的这些经验令人鼓舞。尽管有这些希望，但迄今为止，实体的发展仍被认为是对 CLL 患者的死刑。治疗进展，但关于这些临床反应的决定因素的信息很少最近对 RS 新型治疗药物的临床研究的增加现在提供了一种新的治疗方法。此外，最近出现了新型测序技术。能力、分析工具和动物模型（由我们在过去的资助期间的努力产生）现在使我们最大程度地从原代细胞中提取有关RS不同分子和表型特征的信息我们追求的是，RS 疗法的治疗反应和耐药性是由患者材料决定的。肿瘤内在和外在特征，并且这些特征是差异敏感性的基础在此，我们将对 RS 和 CLL 之间收集的标本进行深入分析。治疗试验，重点关注 RS 标本及其微环境的纵向分析，以及这些研究结果得到了强有力的相互作用的支持。因此，项目 1 和 3 以及每个核心的目标是： (i) 定义 RS 内在特征。我们将评估连续收集的 RS 的分子特征。来自接受以下治疗的患者的样本：(i) 基于 BCL2 抑制剂的治疗和 (ii) 基于 ICB 的治疗，并将这些治疗联系起来 (ii) 具有临床特征的属性，用于识别预测治疗反应或耐药性的标记物/途径。描述影响治疗反应的 RS 免疫微环境的关键组成部分。免疫基因组方法使我们能够直接从分析患者中获得新的机制见解我们将对来自 RS 的骨髓或淋巴结浸润免疫细胞进行 scRNA-seq 分析。每种治疗有反应者和无反应者（参加上述试验）以系统地表征参与对新型RS的反应或抵抗的细胞群的组成和功能状态最后，我们将： (iii) 建立 RS 对 α-PD1 疗法的差异治疗敏感性模型。与 CLL 相比，我们将使用反映 CLL 或 RS 疾病的新型基因工程小鼠模型。进行体内治疗研究和免疫细胞的功能/表型分析，以确定遗传与 CLL 相比，RS 对 ICB 反应的微环境基础。