Harnessing CDK4/6 inhibition to promote T cell-mediated anti-tumor immunity

利用 CDK4/6 抑制促进 T 细胞介导的抗肿瘤免疫

• 批准号: 406316140
• 负责人: Dr. Grit Sophie Herter-Sprie
• 金额: --
• 依托单位: Klinik für Innere Medizin I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/406316140?language=en
• 关键词: Harnessing; CDK4; inhibition; promote; cell

Cancer is the leading cause of death worldwide and its numbers are projected to rise further, resulting in an estimated 12 million deaths in 2030. A significant amount of these cancer-related deaths is attributable to lung cancer. Although targeted therapies for lung adenocarcinomas (approx. 40% of all lung cancers) have been developed (e.g. Erlotinib, Alectinib), aggressive, non-kinase KRAS-driven lung adenocarcinoma remains refractory to targeted treatment strategies until today. Additionally, KRAS mutations are frequently associated with concurrent loss of key tumor suppressor genes, such as TP53 or STK11/LKB1 in this tumor type. Currently, increased response rates of lung cancers are observed when treated with immune checkpoint inhibitors rearousing the patient´s own adaptive anti-tumor immunity. However, only a minority of patients responds yet, and it is highly likely that application of multimodal therapy is required to tackle KRAS-driven lung adenocarcinoma. The overall aim of this study addresses the question whether radiation therapy (RTx) and CDK4/6 inhibitors act synergistically to sensitize Kras-driven lung adenocarcinoma towards immune checkpoint inhibitors (ICIs). Specifically, we aim to define the effects of CDK4/6 inhibition on effector T cells in vitro. Secondly, we will analyse the tumor immune microenvironment upon CDK4/6 inhibition in vivo. Knowledge of altered immune cell populations and functions upon CDK4/6 repression will help us in timing the addition of other anti-cancer compounds. Lastly, we will perform a preclinical study to evaluate whether dual modality therapy (CDK4/6 inhibition + RTx), or triple modality therapy (CDK4/6 inhibition + RTx + immune check point inhibitor) have synergistic anti-tumor efficacy towards Kras-driven lung adenocarcinoma. Ultimately, the findings from this project will help clinicians to design informed patient-tailored clinical studies for rapid translation in the human setting.

癌症是全世界死亡的主要原因，预计其数量将进一步上升，预计到 2030 年将导致 1200 万人死亡。这些与癌症相关的死亡中有很大一部分是由肺癌造成的。尽管针对肺腺癌（约占所有肺癌的 40%）的靶向疗法已经开发出来（例如厄洛替尼、艾乐替尼），但直到今天，侵袭性、非激酶 KRAS 驱动的肺腺癌仍然难以采用靶向治疗策略。此外，KRAS 突变通常与关键肿瘤抑制基因的同时丢失相关，例如该肿瘤类型中的 TP53 或 STK11/LKB1。目前，当用免疫检查点抑制剂治疗时，观察到肺癌的反应率增加，从而重新激发患者自身的适应性抗肿瘤免疫力。然而，只有少数患者有反应，很可能需要应用多模式治疗来解决 KRAS 驱动的肺腺癌。本研究的总体目标是解决放射治疗 (RTx) 和 CDK4/6 抑制剂是否协同作用以使 Kras 驱动的肺腺癌对免疫检查点抑制剂 (ICIs) 敏感的问题。具体来说，我们的目标是在体外确定 CDK4/6 抑制对效应 T 细胞的影响。其次，我们将分析体内CDK4/6抑制后的肿瘤免疫微环境。了解 CDK4/6 抑制后免疫细胞群和功能的改变将有助于我们确定添加其他抗癌化合物的时机。最后，我们将进行临床前研究，以评估双模态治疗（CDK4/6抑制+RTx）或三模态治疗（CDK4/6抑制+RTx+免疫检查点抑制剂）是否对Kras驱动的肺腺癌具有协同抗肿瘤功效。最终，该项目的研究结果将帮助临床医生设计知情的、为患者量身定制的临床研究，以便在人类环境中快速转化。