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

• 批准号: 10227765
• 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
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-28 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227765
• 关键词: Address; Antitumor Response; CD8-Positive T-Lymphocytes; CTLA4 blockade; CXCL10 gene; CXCL9 gene; Cancer Patient; Cells; Epigenetic Process; FDA approved; Gene Mutation; Genes; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Immunologic Surveillance; Immunotherapy; KRAS2 gene; Lung; Lung Adenocarcinoma; Lung Neoplasms; Lymphocyte Function; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Oncology; PD-1 blockade; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Property; Publishing; RANTES; Research Personnel; STK11 gene; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Therapeutic Agents; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Vorinostat; anti-PD-1; base; cancer cell; cell type; checkpoint receptors; chemokine; chemotherapeutic agent; design; immune checkpoint blockade; in vivo; lung cancer cell; lymphocyte trafficking; mouse model; mutant; neoplastic cell; novel; novel strategies; programmed cell death protein 1; response; small molecule; synergism; trafficking; treatment strategy; tumor; tumor microenvironment; unpublished works

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.

尽管过去几十年来治疗方面取得了进展，但肺癌患者的5年总生存率 仍然令人沮丧。在一项重要的突破中，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检查站封锁是一个特别有希望的 方法，但应答率仍然相对较低(肺癌约20%)；因此，新的方法是 需要提高疗效。值得注意的是，免疫治疗的好处，包括T细胞检查点阻断，是 通常与治疗前免疫刺激基因在肿瘤中的表达升高有关，尤其是 T细胞趋化因子包括CCL5、CXCL9和CXCL10。我们假设一个没有偏见的屏幕 识别FDA批准的具有免疫刺激特性的肿瘤学药物将识别 增强对免疫疗法的反应。在我们基于癌细胞的屏幕上，我们设计的目的是识别微小的 诱导T细胞趋化因子表达的分子，我们发现只有一种药物类别，HDAC 抑制物(HDACi)诱导这些趋化因子在小鼠和人肺癌中的表达 细胞。以HDACi-romidessin为研究对象，我们发现该药具有较强的抗肿瘤活性。 对KRAS突变的小鼠非小细胞肺癌肿瘤的抑制作用，这完全依赖于 T细胞的存在。重要的是，罗米非辛联合治疗显著增强了对PD-1的反应 封锁。这些结果支持将HDACi与PD-1阻断联合使用作为一种新的治疗方法 肺癌患者的治疗。然而，HDACi的体内作用和协同作用的关键机制 需要定义抗PD-1，特别是这些药物对肿瘤细胞和肿瘤浸润性T细胞的影响 细胞。这些研究将严格检验以HDAC为目标的假设提供了一种新的战略 创造有利于检查点阻断免疫治疗的肿瘤微环境。三个具体目标 将检验这一假设。目的1：明确趋化因子表达和T细胞转运的体内机制 在非小细胞肺癌肿瘤中。目的2：研究HDACi对TIL功能的刺激作用及与PD-2的协同作用。 1封锁。目的3：新的联合策略增强PD-1阻断反应的有效性 KRAS/TP53和KRAS/STK11原位肺肿瘤模型。