Informed Combination Strategies for Peripheral T-cell Lymphomas

项目摘要 尽管许多血液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ALK重排患者外，超过75%的 PTCL在一线治疗后不能应答或迅速复发。FDA批准的复发性/难治性药物 PTCL有效率<30%，中位无进展生存期<4个月。因此，迫切需要 对更好的治疗PTCL患者的医疗需求未得到满足。我们的中心焦点是理性 将分子发现转化为PTCL的知情治疗策略。这种做法非常 对于B细胞淋巴瘤是成功的，但是每个PTCL亚型的发生率低，并且缺乏可靠的模型系统 体外和体内研究阻碍了PTCL取得类似的成功。通过共同努力克服 尽管存在这些障碍，但在过去的3年里，我们在对PTCL的理解和建模方面取得了显著的进步。 我们的P01计划代表了一群才华横溢，富有成效和经验丰富的调查人员，他们将攻击这一点 令人生畏的临床问题。所有四个项目的中心科学主题是快速识别 针对PTCL特定脆弱性的组合策略，具有非重叠的抗性机制， 包括靶向小分子和细胞疗法。这些战略将在 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。P01的基石 计划是共享的意愿，使数据和资源开放源代码。我们将解决四个 核心假设驱动的目标在目标1中，我们假设靶向CD 25将克服CD 25的缓冲。 PTCL细胞内的过度活跃的T细胞受体信号传导。在目标2中，我们假设密切相关，但 表型不同的γδ T细胞淋巴瘤具有赋予可靶向的脆弱性的独特的起源细胞。在 目的3，我们假设能够直接诱导细胞凋亡的药物可以增加治疗指数， 与针对PTCL的小分子和CAR T细胞组合。许多拟议的研究将 不可能通过单一实验室供资机制，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微环境内信号的原位评估）。 这些合作努力得到了一个行政核心的支持，该核心负责监督预算、通信和信息技术。 整个P01和科学顾问委员会，财政监督，与NIH的互动，合规性 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项目，我们将定义新一代的治疗策略， 使用与非重叠耐药机制的组合，以显著改善 PTCL患者。

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.