Targeting oncogenic TCR signaling in PTCL

靶向 PTCL 中的致癌 TCR 信号传导

基本信息

批准号：
10249203
负责人：
Markus Müschen
金额：
$ 45.62万
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/10249203
关键词：
Ablation Affect Antibody-drug conjugates Binding Biological Assay CD3 Antigens CD94 Antigen Cell Death Cell surface Cells Cetuximab Collaborations Complex Cytoplasmic Tail Disease Drug resistance Endocytosis Engineering Epidermal Growth Factor Receptor Excision FOXP3 gene FYN gene Feedback Genomics Goals Guide RNA Human Human T-lymphotropic virus 1 IL2RA gene Individual Interleukin 2 Receptor Laboratories Lesion Ligation Lymphoma cell Malignant lymphoid neoplasm Manuscripts Mass Spectrum Analysis Mediating Mus NPM1 gene NR0B2 gene Natural Killer Cells Nature Oncogenic Oncoproteins Pathway interactions Patients Peripheral Phosphorylation Protein Tyrosine Kinase Receptor Signaling Recycling Refractory Regulation Regulatory T-Lymphocyte Repression Research Personnel Rest Ribonucleoproteins Role SYK gene Signal Pathway Signal Transduction Surface T Chain T cell regulation T-Cell Activation T-Cell Development T-Cell Lymphoma T-Cell Receptor T-Lymphocyte TP53 gene Testing Time Transcriptional Activation Transplant Recipients Umbilical Cord Blood Validation Viral ZAP-70 Gene anti-tumor immune response base cancer cell chimeric antigen receptor chimeric antigen receptor T cells efficacy evaluation experimental study gene repression inhibitor/antagonist novel preclinical development prevent recruit systemic autoimmunity targeted treatment trafficking

项目摘要

PROJECT SUMMARY CD25 was previously identified as α-chain of the heterotrimeric IL2 receptor (IL2R). High expression levels of CD25 was previously attributed to T-cell activation or transcriptional activation by Foxp3 in regulatory T-cells (Tregs). Our preliminary experiments revealed that CD25 is not only an IL2R chain, but in fact binds the CD3 signal chains of the T-cell receptor (TCR) for feedback control of TCR signaling strength. Reflecting its central role in normal T-cell development, the TCR and its downstream signaling pathway is a target of oncogenic transformation in the majority of peripheral T-cell lymphomas (PTCLs). Oncogenic TCR-mimics promote survival and proliferation even in the absence of a functional TCR. Oncogenic TCR-mimics include activating lesions of the TCR-signaling chain CD3ζ, proximal tyrosine kinases (PTKs; FYN, LCK, ZAP70) and ITK-SYK, NPM1-ALK fusions. In collaboration with other investigators of this P01, our group recently discovered that lymphoid malignancies are uniquely dependent on feedback regulation of PTKs (Chen et al., Nature 2015), PI3K (Shojaee et al., Nature Med 2016; Chan et al., Nature 2017) and ERK (Shojaee et al., Cancer Cell 2015; Xiao et al., Cell 2018). Here we validate the concept that in multiple PTCL subtypes, CD25 orchestrates feedback control of all three pathways (PTKs, PI3K and ERK). The central goal of this project is to deliver a comprehensive strategy to target CD25-mediated feedback control of oncogenic TCR signaling to overcome drug resistance in refractory PTCL. The following three Aims will (1) elucidate the mechanism of CD25-mediated feedback control of oncogenic TCR-signaling in PTCL subtypes, (2) provide a rationale for combining PI3K inhibitors with CD25 antibody-drug conjugates (ADC) and (3) evaluate efficacy of newly developed CD25 chimeric antigen receptors (CARs) engineered in T- and NK-cells and their effects on endogenous anti-tumor immune responses. Aim 1: Mechanisms of CD25-mediated feedback control of oncogenic TCR-signaling in PTCL. Aim 2: CD25-endocytosis and endosomal recycling as dynamic feedback control of oncogenic TCR-signaling Aim 3: Preclinical development and validation of CD25 CAR-T and CAR-NK cells.

项目概要 CD25 先前被鉴定为异三聚体 IL2 受体 (IL2R) 的 α 链高表达水平。 CD25 先前被归因于 T 细胞激活或调节性 T 细胞中 Foxp3 的转录激活 (Tregs)。我们的初步实验表明，CD25 不仅是 IL2R 链，而且实际上与 CD3 结合。 T 细胞受体 (TCR) 的信号链，用于 TCR 信号强度的反馈控制。 TCR 及其下游信号通路反映了其在正常 T 细胞发育中的核心作用大多数外周 T 细胞淋巴瘤 (PTCL) 的致癌转化靶标。即使在没有功能性 TCR 的情况下，TCR 模拟物也能促进存活和增殖。包括 TCR 信号链 CD3 z、近端酪氨酸激酶（PTK；FYN、LCK、ZAP70）的激活损伤和 ITK-SYK、NPM1-ALK 融合，我们小组最近与该 P01 的其他研究人员合作。发现淋巴恶性肿瘤独特地依赖于 PTK 的反馈调节（Chen 等人， Nature 2015）、PI3K（Shojaee 等人，Nature Med 2016；Chan 等人，Nature 2017）和 ERK（Shojaee 等人，Cancer） Cell 2015；Xiao 等人，Cell 2018）在此我们验证了在多种 PTCL 亚型中 CD25 的概念。协调所有三个通路（PTK、PI3K 和 ERK）的反馈控制。该项目的中心目标是提供针对 CD25 介导的反馈的综合策略控制致癌 TCR 信号传导以克服难治性 PTCL 的耐药性如下三种。目标将 (1) 阐明 CD25 介导的 PTCL 中致癌 TCR 信号传导的反馈控制机制亚型，(2) 提供了将 PI3K 抑制剂与 CD25 抗体药物偶联物 (ADC) 组合的基本原理，以及 (3) 评估新开发的 T 细胞和 NK 细胞中工程化的 CD25 嵌合抗原受体 (CAR) 的功效及其对内源性抗肿瘤免疫反应的影响。目标 1：PTCL 中 CD25 介导的致癌 TCR 信号传导反馈控制机制。目标 2：CD25 内吞作用和内体循环作为致癌 TCR 信号传导的动态反馈控制目标 3：CD25 CAR-T 和 CAR-NK 细胞的临床前开发和验证。