Augmenting T cell trafficking and functionality through novel combinations of epigenetic agents and PD-1 blockade

通过表观遗传剂和 PD-1 阻断的新型组合增强 T 细胞运输和功能

基本信息

批准号：
9388827
负责人：
Amer Aziz Beg
金额：
$ 39.35万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-28 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9388827
关键词：
Address CD8-Positive T-Lymphocytes CXCL10 gene CXCL9 gene Cancer Patient Cells Cytotoxic T-Lymphocyte-Associated Protein 4 Epigenetic Process FDA approved Gene Mutation Genes Histone Deacetylase Inhibitor Human Immunologic Surveillance Immunotherapy Infiltration KRAS2 gene Lung Lung Adenocarcinoma Lung Neoplasms Lymphocyte Function Malignant Neoplasms Malignant neoplasm of lung Modeling Mus Mutation Non-Small-Cell Lung Carcinoma Pathway interactions Patients Pharmaceutical Preparations Pharmacology Property Publishing RANTES Research Personnel STK11 gene T-Lymphocyte TP53 gene Testing Therapeutic Therapeutic Agents Tumor-Infiltrating Lymphocytes Vorinostat base cancer cell cell type chemokine chemotherapeutic agent design immune checkpoint blockade in vivo mouse model mutant neoplastic cell novel novel strategies oncology receptor response small molecule synergism trafficking treatment strategy tumor tumor microenvironment unpublished works

项目摘要

Despite therapeutic advances over the last decades, the 5-year overall survival of lung cancer patients remains dismal. In an important breakthrough, recent studies have shown efficacy of immunotherapy in the treatment of lung cancer and other malignancies. PD-1 checkpoint blockade is an especially promising approach, yet response rates remain relatively low (~20% in lung cancer); thus, new approaches are needed to enhance efficacy. Notably, benefit from immunotherapy, including T cell checkpoint blockade, is often associated with elevated pre-treatment expression of immuno-stimulatory genes in tumors, especially T cell chemokines including CCL5, CXCL9 and CXCL10. We hypothesized that an unbiased screen to identify FDA-approved oncology agents with immuno-stimulatory properties would identify agents that augment the response to immunotherapy. In our cancer cell-based screens designed to identify small molecules that induce the expression of T cell chemokines, we found that only a single agent class, HDAC inhibitors (HDACi), induced expression of these chemokines in an array of mouse and human lung cancer cells. Focusing on the HDACi romidepsin, we found that this agent induced a strong anti-tumor response against KRAS mutant non-small cell lung cancer tumors in mice, and that this was entirely dependent on the presence of T cells. Importantly, romidepsin co-treatment markedly augmented the response to PD-1 blockade. These results support using HDACi in combination with PD-1 blockade as a new approach for the treatment of lung cancer patients. However, key in vivo mechanisms of action of HDACi and of synergy with anti-PD-1 need to be defined, especially the effect of these agents on tumor cells and tumor-infiltrating T cells. These studies will rigorously test the hypothesis that targeting HDACs provides a new strategy for generating a tumor microenvironment favorable for checkpoint blockade immunotherapy. Three Specific Aims will test this hypothesis. Aim 1: Defining in vivo mechanisms of chemokine expression and T cell trafficking in NSCLC tumors. Aim 2: Investigating stimulatory effects of HDACi on TIL function and synergism with PD- 1 blockade. Aim 3: Efficacy of novel combinatory strategies to augment PD-1 blockade response in KRAS/TP53 and KRAS/STK11 autochthonous lung tumor models.

尽管过去几十年的治疗进展，但肺癌患者的总体生存率为5年仍然很沮丧。在一个重要的突破中，最近的研究表明免疫疗法在治疗肺癌和其他恶性肿瘤。 PD-1检查点封锁是一个特别有希望的方法然而，反应率仍然相对较低（肺癌的20％）；因此，新方法是需要增强功效。值得注意的是，从包括T细胞检查点封锁在内的免疫疗法中受益于通常与肿瘤中免疫刺激基因的预处理前表达升高有关，尤其是 T细胞趋化因子在内，包括CCL5，CXCL9和CXCL10。我们假设一个公正的屏幕识别具有免疫刺激特性的FDA批准的肿瘤学剂，将确定增强对免疫疗法的反应。在我们的基于癌症细胞的屏幕中，旨在识别小的诱导T细胞趋化因子表达的分子，我们发现只有单个药物类别HDAC 抑制剂（HDACI），在小鼠和人肺癌阵列中诱导这些趋化因子的表达细胞。专注于HDACI romidepsin，我们发现该药物引起了强烈的抗肿瘤反应针对小鼠中的KRAS突变体非小细胞肺癌肿瘤，这完全取决于 T细胞的存在。重要的是，romidepsin共同治疗显着增强了对PD-1的反应封锁。这些结果支持使用HDACI与PD-1封锁相结合作为新方法肺癌患者的治疗。但是，关键的HDACI和协同作用的体内机理与需要定义抗PD-1，尤其是这些药物对肿瘤细胞和肿瘤浸润T的影响细胞。这些研究将严格检验以下假设，即针对HDACS为HDAC提供了一种新的策略产生有利于检查点阻滞免疫疗法的肿瘤微环境。三个具体目标将检验这一假设。目标1：定义趋化因子表达和T细胞运输的体内机制在NSCLC肿瘤中。 AIM 2：研究HDACI对TIL功能和与PD的协同作用的刺激作用 1个封锁。目标3：新型组合策略的功效增强PD-1阻断反应 KRAS/TP53和KRAS/STK11自肺肺肿瘤模型。