Smac Mimetic APG-1387 Has Synergistic Effect with anti-PD1 Antibody via Increasing NK Cells Recruitment by Inducing Multiple Cytokines from Tumor Cells

Abstract

Background: Immune checkpoint inhibitor has got indication in various tumors, but the response rate was not satisfying. Identification of predictive biomarkers and novel combinations may enhance the response rate. Inhibitor of apoptosis proteins (IAP) ubiquitin-E3 ligase activity is involved in the regulation of immune responses mediated through NF-κB signaling. APG-1387 is a novel Smac-mimetic, which is quite safe and will not cause cytokine storm reaction in human. Based on these findings, we suspect that previous synergistic effect with checkpoint inhibitors of other IAPi may not suitable for APG-1387. In this study, we aim to explore the synergetic effect of APG-1387 with anti-PD1 antibody in preclinical setting. Methods: We utilized syngeneic mouse models of ovarian cancer(ID8), colon cancer(MC38), melanoma(B16) and liver cancer(Hepa1-6) and assessed immune correlates, tumor growth, and survival following treatment with APG-1387 (0.2mg/kg, iv.) and anti-PD-1 antibody (5 mg/kg, ip.). In-vitro and in vivo cytokines release was measured by MSD V-PLEX. Findings: The synergistic effect of APG-1387 with anti-PD1 antibody was found in ID8 ovary and MC38 colon cancer models. APG-1387 combined with anti-PD-1 antibody significantly inhibited tumor growth and enhanced the survival rate of tumor-bearing animals. Moreover, we found that APG-1387 up-regulated tumor-infiltrating NK cells through IL-12 induced from tumor cells. Blocking IL-12p70 could abrogate the synergistic effect of APG1387 and anti-PD1 antibody in MC38 and ID8 models. Interpretation: APG-1387 has potential to turn the cold tumor into hot one and recruited more NK cells in certain tumors. Funding Statement: This study was supported by National Natural Science Foundation of China (NSFC: 81602066 and 81772587); Natural Science Foundation of Guangdong Province (2016A030313280 and 2018A030310260); The Sci-Tech Foundation of Guangdong Province (2018YJ021); The Medical Science Foundation of Guangdong Province (A2016023 and 2018102516469945). Natural Science Foundation of Guangdong Province (grant numbers 2014A030312015), Science and Technology Program of Guangdong (grant numbers 2015B020232008), Science and Technology Program of Guangzhou (grant numbers 15570006, 201508020250, 201510161726583, 201604020003), Guangdong Esophageal Cancer Institute Science and Technology Program (grant number M201809), CSCO-HengRui Oncology Research Fund (grant number Y-HR2018-184), the third outstanding young talents training plan and Medical Scientist program of Sun Yat-sen University cancer center, Medical Science and Technology Research Fund Project of Guangdong Province (grant number A2015003). Declaration of Interests: Da-Jun Yang and Yifan Zhai have ownership interest (including patents) in Ascentage Pharma Group Corp. Limited. Wentao Pan, Douglas D. Fang, Guangfeng Wang and Mengxian Pan are employees of Ascentage Pharma Group Corp. Limited. No potential conflicts of interest were disclosed by the other authors. Ethics Approval Statement: All experiments were performed with Animal Ethics Approval and conformed to regulatory standards set by the Sun Yat-Sen University Animal Ethics Committee.