免疫检查点抑制剂被批准用于治疗多种肿瘤，但对某些恶性肿瘤的缓解率并不令人满意。凋亡蛋白抑制剂 (IAP) 泛素-E3 连接酶活性参与免疫反应的调节。 APG-1387 是一种新型的第二种线粒体衍生的 caspase 激活剂 (Smac) 模拟 IAP 抑制剂。本研究的目的是探讨 APG-1387 与抗 PD-1 抗体在临床前联合使用时的协同效应。我们利用了卵巢癌 (ID8)、结肠癌 (MC38)、恶性黑色素瘤 (MC38) 的同基因小鼠模型。 B16）和肝癌（Hepa1-6）来评估 APG-1387 和抗 PD-1 抗体的联合作用，包括免疫相关因素、肿瘤生长和生存。使用经过 MSD V-PLEX 验证的测定法来测量体外和体内细胞因子释放。 在 ID8 卵巢癌和 MC38 结肠癌模型中，APG-1387 和抗 PD1 抗体具有协同抗肿瘤作用。在MC38模型中，APG-1387与抗PD-1抗体联合显着抑制肿瘤生长（P<0.0001）并提高荷瘤动物的存活率（P<0.001）。此外，我们发现 APG-1387 通过促进肿瘤细胞分泌 IL-12，将肿瘤浸润 CD3  NK1.1 细胞上调近 2 倍。阻断 IL-12 分泌消除了 APG-1387 和抗 PD-1 抗体在 MC38 和 ID8 模型中的协同作用。APG-1387 有潜力通过招募更多 CD3  NK1.1  细胞将“冷肿瘤”变成热肿瘤进入某些肿瘤。基于这些和其他数据，将在晚期实体瘤或血液恶性肿瘤患者的 1/2 期试验中研究该组合的安全性和治疗效果 (NCT03386526)。© 2024。作者。

Immune checkpoint inhibitors are approved for the treatment of various tumors, but the response rate is not satisfactory in certain malignancies. Inhibitor of apoptosis proteins (IAP) ubiquitin-E3 ligase activity is involved in the regulation of immune responses. APG-1387 is a novel second mitochondria-derived activator of caspase (Smac) mimetic IAP inhibitor. The aim of this study was to explore the synergistic effect of APG-1387 when combined with anti-PD-1 antibody in a preclinical setting.We utilized syngeneic mouse models of ovarian cancer (ID8), colon cancer (MC38), malignant melanoma (B16), and liver cancer (Hepa1-6) to assess the combination effect of APG-1387 and anti-PD-1 antibody, including immune-related factors, tumor growth, and survival. MSD V-PLEX validated assays were used to measure in vitro and in vivo cytokine release.In ID8 ovarian cancer and MC38 colon cancer models, APG-1387 and anti-PD1 antibody had synergistic antitumor effects. In the MC38 model, the combination of APG-1387 and anti-PD-1 antibody significantly inhibited tumor growth (P < 0.0001) and increased the survival rate of tumor-bearing animals (P < 0.001). Moreover, we found that APG-1387 upregulated tumor-infiltrating CD3 + NK1.1 + cells by nearly 2-fold, by promoting tumor cell secretion of IL-12. Blocking IL-12 secretion abrogated the synergistic effects of APG-1387 and anti-PD-1 antibody in both MC38 and ID8 models.APG-1387 has the potential to turn "cold tumors" into hot ones by recruiting more CD3 + NK1.1 + cells into certain tumors. Based on these and other data, the safety and therapeutic effect of this combination will be investigated in a phase 1/2 trial in patients with advanced solid tumors or hematologic malignancies (NCT03386526).© 2024. The Author(s).