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: 9750072
• 负责人: Amer Aziz Beg
• 金额: $ 38.16万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750072
• 关键词: Address; Antitumor Response; CD8-Positive T-Lymphocytes; CTLA4 gene; 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; PD-1 blockade; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Property; Publishing; RANTES; Research Personnel; SLEB2 gene; 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; mouse model; mutant; neoplastic cell; novel; novel strategies; oncology; response; small molecule; synergism; trafficking; treatment strategy; tumor; tumor microenvironment; unpublished works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.

尽管在过去的几十年里治疗取得了进展，但肺癌患者的5年总生存率 仍然令人沮丧。在一个重要的突破中，最近的研究表明免疫疗法在治疗糖尿病中的疗效。 肺癌和其他恶性肿瘤的治疗。PD-1检查站封锁是一项特别有希望的措施 方法，但反应率仍然相对较低（约20%的肺癌）;因此，新的方法， 需要提高效率。值得注意的是，从免疫治疗中获益，包括T细胞检查点阻断， 通常与肿瘤中免疫刺激基因的治疗前表达升高有关， T细胞趋化因子包括CCL5、CXCL9和CXCL10。我们假设，一个公正的筛选， 鉴定FDA批准的具有免疫刺激特性的肿瘤药物将鉴定出 增强对免疫疗法的反应。在我们基于癌细胞的筛选中， 诱导T细胞趋化因子表达的分子，我们发现只有一个单一的代理类别，HDAC， 抑制剂（HDACi）诱导这些趋化因子在小鼠和人肺癌中的表达。 细胞聚焦于HDACi罗米地辛，我们发现该药剂诱导了强烈的抗肿瘤反应。 针对小鼠中KRAS突变型非小细胞肺癌肿瘤，并且这完全依赖于 T细胞的存在。重要的是，罗米地辛联合治疗显著增强了对PD-1的应答 封锁这些结果支持使用HDACi联合PD-1阻断作为治疗PD-1的新方法。 肺癌患者的治疗然而，HDACi的关键体内作用机制和与HDACi的协同作用机制是不确定的。 需要确定抗PD-1，特别是这些药物对肿瘤细胞和肿瘤浸润性T细胞的作用， 细胞这些研究将严格检验靶向HDAC提供了一种新策略的假设， 产生有利于检查点阻断免疫疗法的肿瘤微环境。三个具体目标 将检验这个假设。目的1：确定趋化因子表达和T细胞运输的体内机制 在NSCLC肿瘤中。目的2：研究HDACi对TIL功能的刺激作用以及与PD-1的协同作用。 1封锁。目的3：新的组合策略在增强PD-1阻断应答中的功效 KRAS/TP53和KRAS/STK11自体肺肿瘤模型。