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

• 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
• 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' 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

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.

摘要 里希特综合征（RS）源于慢性淋巴细胞白血病（CLL），长期以来一直被认为是 对慢性淋巴细胞白血病患者的临床前景暗淡。然而，新的治疗组合， 药物提示RS患者获得更深、更持久缓解的可行性。这些 包括用免疫检查点阻断（ICB; PD-PD 1疗法）与伊曲替尼一起治疗， BCL 2抑制剂venetoclax与化疗的组合。这些经验令人鼓舞 迄今为止被认为是对CLL患者判处死刑的实体的发展。尽管有这些有希望 治疗的发展，很少有信息是关于这些临床反应的决定因素 治疗最近增加的临床研究的新的治疗药物的RS现在提供了一个 有机会更一致地收集生物标本。此外，最近可用的新的测序， 能力、分析工具和动物模型（由我们在过去的资助期内的努力产生）现在使 我们最大限度地提取信息的不同分子和表型特征的RS从小学 病人的材料。我们假设对RS治疗的治疗反应和抵抗是由以下因素形成的： 肿瘤内在和外在特征，这些特征是差异敏感性的基础。 RS和CLL之间的新药物。在此，我们将深入分析 治疗试验，重点是RS标本及其微环境的纵向分析， 在一种新的动物模型中对这些发现进行功能验证。这些研究得到了强相互作用的支持 项目1和项目3，以及每个单独的核心。因此，我们的目标是：（i）定义RS-内在特征 控制对RS疗法的反应。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标本：（i）基于BCL 2的治疗和（ii）基于ICB的治疗，并将这些 具有临床特征的属性，以识别预测对治疗的反应或抗性的标志物/途径。（二） 描述影响治疗反应的RS免疫微环境的关键组分。新 免疫基因组学方法使我们能够直接从分析患者 样品我们将对RS患者的骨髓或淋巴结浸润免疫细胞进行scRNA-seq分析， 每种治疗的应答者和非应答者（入组上述试验），以系统表征 参与对新RS的应答或抗性的细胞群的组成和功能状态 治疗组合。最后，我们将：（iii）RS对PD 1治疗的差异治疗敏感性模型 与CLL相比。使用反映CLL或RS疾病的新型基因工程小鼠模型，我们将 进行免疫细胞的体内治疗研究和功能/表型分析，以确定遗传 以及RS对ICB响应的微环境基础。