Ascentage Pharma (Suzhou) Co, Ltd, 218 Xinghu Street, Suzhou, Jiangsu Province, China.
Oncology & Immunology Unit, WuXi Apptec (Suzhou) Co, Ltd, 1318 Wuzhong Avenue, Suzhou, Jiangsu Province, China.
J Immunother Cancer. 2019 Nov 28;7(1):327. doi: 10.1186/s40425-019-0750-6.
Programmed death-1 (PD-1) immune checkpoint blockade has achieved clinical successes in cancer therapy. However, the response rate of anti-PD-1 agents remains low. Additionally, a subpopulation of patients developed hyperprogressive disease upon PD-1 blockade therapy. Combination therapy with targeted agents may improve immunotherapy. Recent studies show that p53 activation in the myeloid linage suppresses alternative (M2) macrophage polarization, and attenuates tumor development and invasion, leading to the hypothesis that p53 activation may augment antitumor immunity elicited by anti-PD-1 therapy.
Using APG-115 that is a MDM2 antagonist in clinical development as a pharmacological p53 activator, we investigated the role of p53 in immune modulation and combination therapy with PD-1 blockade.
In vitro treatment of bone marrow-derived macrophages with APG-115 resulted in activation of p53 and p21, and a decrease in immunosuppressive M2 macrophage population through downregulation of c-Myc and c-Maf. Increased proinflammatory M1 macrophage polarization was observed in the spleen from mice treated with APG-115. Additionally, APG-115 has co-stimulatory activity in T cells and increases PD-L1 expression in tumor cells. In vivo, APG-115 plus anti-PD-1 combination therapy resulted in enhanced antitumor activity in Trp53, Trp53, and Trp53-deficient (Trp53) syngeneic tumor models. Importantly, such enhanced activity was abolished in a syngeneic tumor model established in Trp53 knockout mice. Despite differential changes in tumor-infiltrating leukocytes (TILs), including the increases in infiltrated cytotoxic CD8 T cells in Trp53 tumors and M1 macrophages in Trp53 tumors, a decrease in the proportion of M2 macrophages consistently occurred in both Trp53 and Trp53 tumors upon combination treatment.
Our results demonstrate that p53 activation mediated by APG-115 promotes antitumor immunity in the tumor microenvironment (TME) regardless of the Trp53 status of tumors per se. Instead, such an effect depends on p53 activation in Trp53 wild-type immune cells in the TME. Based on the data, a phase 1b clinical trial has been launched for the evaluation of APG-115 in combination with pembrolizumab in solid tumor patients including those with TP53 tumors.
程序性死亡受体-1（PD-1）免疫检查点阻断在癌症治疗中取得了临床成功。然而，抗 PD-1 药物的反应率仍然较低。此外，一部分患者在 PD-1 阻断治疗后出现超进展性疾病。联合靶向药物治疗可能会改善免疫治疗。最近的研究表明，髓系细胞中 p53 的激活抑制了替代（M2）巨噬细胞极化，并减弱了肿瘤的发展和侵袭，这导致了这样一种假设，即 p53 的激活可能增强抗 PD-1 治疗引起的抗肿瘤免疫。
我们使用临床开发中的 APG-115 作为一种 MDM2 拮抗剂作为药理学 p53 激活剂，研究了 p53 在免疫调节和 PD-1 阻断联合治疗中的作用。
APG-115 体外处理骨髓来源的巨噬细胞可激活 p53 和 p21，并通过下调 c-Myc 和 c-Maf 减少抑制性 M2 巨噬细胞群。在接受 APG-115 治疗的小鼠脾脏中观察到促炎 M1 巨噬细胞极化增加。此外，APG-115 在 T 细胞中有共刺激活性，并增加肿瘤细胞中 PD-L1 的表达。在体内，APG-115 加抗 PD-1 联合治疗在 Trp53、Trp53 和 Trp53 缺陷型（Trp53）同基因肿瘤模型中增强了抗肿瘤活性。重要的是，在 Trp53 基因敲除小鼠建立的同基因肿瘤模型中，这种增强的活性被消除。尽管肿瘤浸润白细胞（TILs）的变化不同，包括 Trp53 肿瘤中浸润的细胞毒性 CD8 T 细胞增加和 Trp53 肿瘤中 M1 巨噬细胞增加，但在联合治疗时，Trp53 和 Trp53 肿瘤中 M2 巨噬细胞的比例都持续下降。
我们的结果表明，APG-115 介导的 p53 激活促进了肿瘤微环境（TME）中的抗肿瘤免疫，而与肿瘤本身的 Trp53 状态无关。相反，这种作用取决于 TME 中 Trp53 野生型免疫细胞中的 p53 激活。基于这些数据，一项评估 APG-115 联合 pembrolizumab 在包括 TP53 肿瘤在内的实体瘤患者中的 1b 期临床试验已经启动。
