Project 3 - Targeting CDK4/6 to modulate immunogenicity in gliomas (Wen/Zhao)

胶质母细胞瘤（GBM）是成人最常见的原发性恶性脑肿瘤，是导致脑胶质瘤的重要原因。 缺乏有效治疗的患者发病率和死亡率。细胞周期蛋白D1依赖性 激酶4/6-视网膜母细胞瘤（cyclinD 1-CDK 4/6-Rb）信号传导轴在大多数GBM中被遗传激活 （~80%）通过CDKN 2A/B的基因组丢失、CDK 4/6的扩增或RB 1的缺失/突变。CDK 4/6具有 基于抑制CDK 4/6对pRB的磷酸化将导致细胞凋亡的观点， 循环停滞除了抑制细胞周期进程外，我们最近发现CDK 4/6拮抗剂还促进了细胞周期进程。 抗肿瘤免疫这背后的分子机制在两个水平上发挥作用：（i）抗原加工和呈递机制的肿瘤细胞自主增强和（ii）Treg/CD 8+比率的非肿瘤细胞自主、系统性降低。总的来说，这些作用促进了细胞毒性T细胞介导的肿瘤细胞清除，这通过添加免疫检查点阻断进一步增强 治疗学值得注意的是，CDK 4/6抑制和检查点阻断的组合的作用是非常显著的。 在我们的临床前模型中，CDK 4/6抑制剂是FDA批准用于治疗以下疾病的药物： 雌激素受体（ER）阳性转移性乳腺癌，他们现在提出了一个良好的耐受性，一线 改善无进展生存期的治疗。其对GBM的功效尚不清楚。然而，早 未发表的临床数据表明，与大多数靶向治疗一样，CDK 4/6抑制剂作为单一药物可能 只有适度的好处。类似地，关于免疫检查点阻断的早期数据并不乐观， 复发性GBM，最近这类药物作为单一药物治疗未能改善生存率。建筑 根据我们最近的发现，我们假设脑渗透性CDK 4/6抑制剂可以增加 用于GBM的免疫治疗方法，包括用于复发性GBM的PD-1检查点抑制剂。这项建议 有三个特定的目的，旨在研究联合CDK 4/6抑制的治疗方法， 在临床前和临床环境中GBM中的免疫检查点阻断（ICB）：（目的1）评估 CDK 4/6抑制对GBM细胞内源性免疫应答的影响（目的2）研究CDK 4/6抑制对GBM细胞内源性免疫应答的影响 在GBM的同基因模型中增强免疫治疗的抑制;以及（目的3）评估 CDK 4/6抑制剂对GBM患者免疫功能和临床结局的影响。通过使用患者源性GBM 肿瘤和GBM的同基因小鼠模型，我们将确定CDK 4/6抑制剂在GBM中的临床前疗效。 与针对GBM的免疫疗法组合，进一步巩固了设计临床 GBM患者的临床试验。

Glioblastoma (GBM), the most common primary malignant brain tumor of adults, is a significant cause of patient morbidity and mortality for which effective treatments are lacking. The cyclin D1-cyclin dependent kinase 4/6-retinoblastoma (cyclinD1-CDK4/6-Rb) signaling axis is genetically activated in majority of GBM (~80%) via genomic loss of CDKN2A/B, amplification of CDK4/6 or deletion/mutation of RB1. CDK4/6 has been targeted based on the notion that suppressing the phosphorylation of pRB by CDK4/6 will lead to cell cycle arrest. Beyond suppressing cell cycle progression, we recently found that CDK4/6 antagonists promote anti-tumor immunity. The molecular mechanisms underlying this are exerted at two levels: (i) a tumor cell-autonomous enhancement of the antigen processing and presentation machinery and (ii) a non-tumor cell-autonomous, systemic decrease of the Treg/CD8+ ratio. Collectively, these effects promote cytotoxic T cell-mediated clearance of tumor cells, which is further enhanced by the addition of immune checkpoint blockade therapeutics. Notably the actions of the combination of CDK4/6 inhibition and checkpoint blockade was much greater than additive in our preclinical models. CDK4/6 inhibitors are FDA-approved for the treatment of estrogen receptor (ER)-positive metastatic breast cancer, where they now present a well-tolerated, first-line therapy that improves progression-free survival. Their efficacy against GBM is unknown. However, early unpublished clinical data suggest that, like most targeted therapies, CDK4/6 inhibitors as single agents may have only modest benefit. Similarly, early data on immune checkpoint blockade have not been promising in recurrent GBM in which recently this class of drug failed to improve survival as single agent therapy. Building upon our recent findings, we hypothesize that brain penetrant CDK4/6 inhibitors could augment immunotherapy approaches for GBM including PD-1 checkpoint inhibitors for recurrent GBM. This proposal has three specific aims designed to investigate the therapeutic approach of combined CDK4/6 inhibition and immune checkpoint blockade (ICB) in GBM in both preclinical and clinical settings: (Aim 1) To assess the effects of CDK4/6 inhibition on GBM cell-intrinsic immune response; (Aim 2) To assess the effects of CDK4/6 inhibition on enhancing immunotherapy in syngeneic models of GBM; and (Aim 3) To evaluate the impact of CDK4/6 inhibitors on immune function and clinical outcome for GBM patients. By using patient-derived GBM tumors and syngeneic mouse models of GBM, we will determine the preclinical efficacy of CDK4/6 inhibitors in combination with immunotherapy against GBM, further solidifying the preclinical rationale to design clinical trials for patients with GBM.