Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient reinvigoration of antitumor immunity with the drug alone; therefore, rational therapeutic combinations are required to improve its efficacy. In our preclinical study, we evaluated the antitumor effect of U3-1402, a human epidermal growth factor receptor 3–targeting (HER3–targeting) antibody-drug conjugate, and its potential synergism with PD-1 inhibition. Using a syngeneic mouse tumor model that is refractory to anti–PD-1 therapy, we found that treatment with U3-1402 exhibited an obvious antitumor effect via direct lysis of tumor cells. Disruption of tumor cells by U3-1402 enhanced the infiltration of innate and adaptive immune cells. Chemotherapy with exatecan derivative (Dxd, the drug payload of U3-1402) revealed that the enhanced antitumor immunity produced by U3-1402 was associated with the induction of alarmins, including high-mobility group box-1 (HMGB-1), via tumor-specific cytotoxicity. Notably, U3-1402 significantly sensitized the tumor to PD-1 blockade, as a combination of U3-1402 and the PD-1 inhibitor significantly enhanced antitumor immunity. Further, clinical analyses indicated that tumor-specific HER3 expression was frequently observed in patients with PD-1 inhibitor–resistant solid tumors. Overall, U3-1402 is a promising candidate as a partner of immunotherapy for such patients.

中文翻译：

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U3-1402通过免疫激活使表达HER3的肿瘤对PD-1阻断敏感

靶向程序性细胞死亡1（PD-1）的免疫疗法可在多种类型的癌症中产生持久的抗肿瘤功效。但是，由于仅用这种药物不足以增强抗肿瘤免疫力，因此这种临床益处有限。因此，需要合理的治疗组合以提高其功效。在我们的临床前研究中，我们评估了U3-1402（一种人类表皮生长因子受体3靶向（HER3靶向）抗体-药物偶联物）的抗肿瘤作用，及其与PD-1抑制作用的潜在协同作用。使用抗PD-1治疗难治的同基因小鼠肿瘤模型，我们发现U3-1402的治疗通过直接裂解肿瘤细胞表现出明显的抗肿瘤作用。U3-1402对肿瘤细胞的破坏增强了先天性和适应性免疫细胞的浸润。用Exatecan衍生物（U3-1402的药物有效载荷Dxd）进行化学疗法后发现，U3-1402产生的增强的抗肿瘤免疫力与通过肿瘤诱导警报素有关，包括高迁移率的box-1（HMGB-1）。特异性细胞毒性。值得注意的是，U3-1402显着使肿瘤对PD-1阻断敏感，因为U3-1402和PD-1抑制剂的组合显着增强了抗肿瘤免疫力。此外，临床分析表明，在PD-1抑制剂耐药实体瘤患者中经常观察到肿瘤特异性HER3表达。总体而言，U3-1402是此类患者免疫疗法合作伙伴的有希望的候选人。包括高迁移率的box-1（HMGB-1），通过肿瘤特异性细胞毒性作用。值得注意的是，U3-1402显着使肿瘤对PD-1阻断敏感，因为U3-1402和PD-1抑制剂的组合显着增强了抗肿瘤免疫力。此外，临床分析表明，在PD-1抑制剂耐药实体瘤患者中经常观察到肿瘤特异性HER3表达。总体而言，U3-1402是此类患者免疫疗法合作伙伴的有希望的候选人。包括高迁移率的box-1（HMGB-1），通过肿瘤特异性细胞毒性作用。值得注意的是，U3-1402显着使肿瘤对PD-1阻断敏感，因为U3-1402和PD-1抑制剂的组合显着增强了抗肿瘤免疫力。此外，临床分析表明，在PD-1抑制剂耐药实体瘤患者中经常观察到肿瘤特异性HER3表达。总体而言，U3-1402是此类患者免疫疗法合作伙伴的有希望的候选人。