Informed Combination Strategies for Peripheral T-cell Lymphomas

外周 T 细胞淋巴瘤的明智联合策略

基本信息

批准号：
10005201
负责人：
David Marc Weinstock
金额：
$ 173.52万
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：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005201
关键词：
Achyrocline Address Apoptosis Apoptotic Area B-Cell Lymphomas BCL2 gene Biological Models Biological Response Modifier Therapy Biological Testing Biology Biometry Budgets Buffers Cell Line Cell Therapy Cells Cellular Assay Clinical Clinical Trials Clinical Trials Network Communication Computational Biology Dependence Disease remission Ensure FDA approved Feedback Funding Mechanisms Generations Genomics Government regulations Hematologic Neoplasms Hyperactive behavior IL2RA gene Immune Evasion Immunocompetent Immunology In Situ In Vitro In complete remission Incidence JAK1 gene JAK2 gene Laboratories Lead Left Lymphoma Lymphoma cell Lymphomagenesis MCL1 gene MDM2 gene Mediating Medical Minority Modeling Molecular Mus Mutation Natural Killer Cells New Agents Non-Malignant Outcome Pathology Patient-Focused Outcomes Patients Peripheral Phenotype Pre-Clinical Model Program Research Project Grants Progression-Free Survivals Proteins Receptor Cell Receptor Signaling Recurrence Refractory Regulation Relapse Research Research Personnel Resources Sampling Sea Signal Transduction T-Cell Lymphoma T-Cell Receptor T-Lymphocyte Talents Therapeutic Therapeutic Index Time Transgenic Model Translations United States National Institutes of Health Xenograft Model Xenograft procedure biomarker-driven cellular imaging chimeric antigen receptor T cells clinical translation data resource design drug relapse epigenome experience improved outcome in vivo inhibitor/antagonist novel open source overtreatment partial response prevent programs repository resistance mechanism response single-cell RNA sequencing small molecule success treatment response willingness γδ T cells

项目摘要

PROJECT SUMMARY Despite advances in the treatment of many hematologic malignancies, patients with peripheral T-cell lymphomas (PTCLs) continue to have poor outcomes. Except for the small minority with ALK rearrangements, over 75% of PTCLs fail to respond or rapidly relapse after first-line therapy. FDA-approved drugs for relapsed/refractory PTCL have response rates <30% and median progression-free survival <4 months. Thus, there is an urgent unmet medical need for better therapeutics to treat patients with PTCL. Our central focus is the rational translation of molecular discoveries into informed therapeutic strategies for PTCL. This approach has been very successful for B-cell lymphomas but the low incidence of each PTCL subtype and lack of faithful model systems for in vitro and in vivo studies have prevented similar success for PTCLs. Through concerted effort to overcome these roadblocks, the last 3 years has seen remarkable advances in the understanding and modeling of PTCLs. Our P01 program represents a group of talented, productive and experienced investigators who will attack this daunting clinical problem. The central scientific theme that characterizes all four projects is rapid identification of combination strategies that target PTCL-specific vulnerabilities with non-overlapping mechanisms of resistance, including targeted small molecules and cellular therapies. These strategies will be defined and validated in preclinical models to inform biomarker-driven clinical trials in patients with PTCL. A cornerstone of this P01 program is the shared willingness to make data and resources available open-source. We will address four central, hypothesis-driven Aims. In Aim 1, we hypothesize that targeting of CD25 will overcome buffering of hyperactive T-cell receptor signaling within PTCL cells. In Aim 2, we hypothesize that closely-related but phenotypically-distinct γδ T-cell lymphomas have unique cells-of-origin that confer targetable vulnerabilities. In Aim 3, we hypothesize that agents capable of directly inducing apoptosis can increase therapeutic index in combination with small molecules and CAR T cells directed against PTCL. Many of the proposed studies would not be possible through a single-laboratory funding mechanism, as they rely on cross-disciplinary expertise (e.g. basic T-cell immunology and PTCL therapeutics) and resources (e.g. genomics, noninvasive CAR T cell imaging and in situ assessment of signaling within the PTCL microenvironment) available from the Projects and Cores. The collaborative efforts are supported by an Administrative Core that oversees the budget, communication across the P01 and with the Scientific Advisory Board, fiscal oversight, interactions with the NIH, compliance with institutional and government regulations, biostatistical design and analysis, and general scientific direction. Through this carefully-designed P01 program, we will define a new generation of therapeutic strategies, using combinations with non-overlapping resistance mechanisms, to markedly improve outcomes for patients with PTCL.

项目概要尽管许多血液系统恶性肿瘤的治疗取得了进展，但外周 T 细胞淋巴瘤患者 (PTCL) 的结果仍然很差，除了少数有 ALK 重排的患者外，超过 75% 的患者有 ALK 重排。 FDA 批准的治疗复发/难治性药物后，PTCL 未能做出反应或迅速复发。 PTCL 的缓解率<30%，中位无进展生存期<4 个月，因此存在紧迫性。对治疗 PTCL 患者的更好疗法的未满足的医疗需求是合理的。将分子发现转化为 PTCL 的知情治疗策略。对 B 细胞淋巴瘤取得成功，但每种 PTCL 亚型的发病率较低且缺乏可靠的模型系统通过共同努力，体外和体内研究阻止了 PTCL 的类似成功。克服这些障碍，过去 3 年在对 PTCL 的理解和建模方面取得了显着进展。我们的 P01 计划代表了一群才华横溢、富有成效且经验丰富的调查人员，他们将攻克这一难题所有四个项目的核心科学主题是快速识别。针对 PTCL 特定漏洞与不重叠的抵抗机制的组合策略，包括靶向小分子和细胞疗法将在中定义和验证。临床前模型为 PTCL 患者的生物标志物驱动的临床试验提供信息这是 P01 的基石。计划是开放数据和资源的共同意愿，我们将解决四个问题。中心的、假设驱动的目标在目标 1 中，我们勇敢地认为 CD25 的靶向将克服缓冲。在目标 2 中，我们寻找密切相关但又密切相关的 PTCL 细胞内 T 细胞受体信号传导。表型不同的 γδ T 细胞淋巴瘤具有独特的细胞来源，具有可靶向的脆弱性。目标3，我们追求能够直接诱导细胞凋亡的药物可以提高治疗指数许多拟议的研究将与小分子和针对 PTCL 的 CAR T 细胞相结合。通过单一实验室资助机制是不可能的，因为它们依赖于跨学科的专业知识（例如，基础 T 细胞免疫学和 PTCL 疗法）和资源（例如基因组学、非侵入性 CAR T 细胞成像以及 PTCL 微环境内信号传导的原位评估）可从项目和核心获得。协作工作得到行政核心的支持，该核心负责监督预算、沟通整个 P01 以及与科学咨询委员会、财政监督、与 NIH 的互动、合规性具有机构和政府法规、生物统计设计和分析以及一般科学方向。通过这个精心设计的P01计划，我们将定义新一代的治疗策略，使用与非重叠抵抗机制的组合，显着改善结果 PTCL 患者。