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恶性脑肿瘤，是引起脑部肿瘤的重要原因。 缺乏有效治疗的患者发病率和死亡率。细胞周期蛋白D1-细胞周期蛋白依赖性 蛋白激酶4/6-视网膜母细胞瘤(CyclinD1-CDK4/6-Rb)信号轴在大多数GBM中处于基因激活状态 (~80%)是由于CDKN2A/B基因缺失、CDK4/6扩增或RB1基因缺失/突变所致。CDK4/6有 基于这样一个概念，即抑制CDK4/6对pRb的磷酸化将导致细胞 周期拘禁。除了抑制细胞周期进程，我们最近发现CDK4/6拮抗剂促进 抗肿瘤免疫。其背后的分子机制在两个水平上发挥作用：(I)肿瘤细胞自主性 加强抗原处理和递送机制，以及(Ii)非肿瘤细胞自主性， 全身性Treg/CD8+比值下降。总而言之，这些效应促进了细胞毒T细胞介导的 清除肿瘤细胞，通过增加免疫检查点阻断进一步增强 治疗学。值得注意的是，CDK4/6抑制和检查点阻断相结合的作用 在我们的临床前模型中比加法更有效。CDK4/6抑制剂被FDA批准用于治疗 雌激素受体(ER)阳性的转移性乳腺癌，目前呈现耐受性良好的第一线 提高无进展存活率的疗法。它们对GBM的疗效尚不清楚。然而，早些时候 未发表的临床数据表明，像大多数靶向治疗一样，CDK4/6抑制剂作为单一药物可能 只会带来不大的好处。同样，关于免疫检查点封锁的早期数据在 复发的基底膜，最近这类药物作为单一药物治疗未能提高生存率。建房 根据我们最近的发现，我们假设大脑穿透性CDK4/6抑制剂可以增强 GBM的免疫治疗方法包括PD-1检查点抑制剂对复发的GBM。这项建议 有三个具体目的旨在研究联合抑制CDK4/6和 临床前和临床环境下GBM的免疫检查点阻断(ICB)：(目标1)评估 抑制CDK4/6对GBM细胞内源性免疫应答的影响(目的2)评价CDK4/6的作用 抑制同基因GBM模型中加强免疫治疗；以及(目标3)评估 CDK4/6抑制剂对GBM患者免疫功能和临床转归的影响通过使用患者来源的GBM 肿瘤和同基因小鼠GBM模型，我们将确定CDK4/6抑制剂的临床前疗效。 与针对GBM的免疫治疗相结合，进一步巩固临床前设计临床的理论基础 针对GBM患者的试验。

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 cellautonomous enhancement of the antigen processing and presentation machinery and (ii) a non-tumor cellautonomous, systemic decrease of the Treg/CD8+ ratio. Collectively, these effects promote cytotoxic T cellmediated 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 However, early unpublished clinical data suggest that, like most targeted therapies, CDK4/6 inhibitors as single agents may have only modest benefit.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.