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U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation
The Journal of Clinical Investigation ( IF 13.3 ) Pub Date : 2019-10-29 , DOI: 10.1172/jci126598
Koji Haratani , Kimio Yonesaka , Shiki Takamura , Osamu Maenishi , Ryoji Kato , Naoki Takegawa , Hisato Kawakami , Kaoru Tanaka , Hidetoshi Hayashi , Masayuki Takeda , Naoyuki Maeda , Takashi Kagari , Kenji Hirotani , Junji Tsurutani , Kazuto Nishio , Katsumi Doi , Masaaki Miyazawa , Kazuhiko Nakagawa

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:

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。
更新日期:2020-01-04
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