U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation

• Published in: The Journal of clinical investigation Vol. 130; no. 1; pp. 374 - 388
• Main Authors: Haratani, Koji, Yonesaka, Kimio, Takamura, Shiki, Maenishi, Osamu, Kato, Ryoji, Takegawa, Naoki, Kawakami, Hisato, Tanaka, Kaoru, Hayashi, Hidetoshi, Takeda, Masayuki, Maeda, Naoyuki, Kagari, Takashi, Hirotani, Kenji, Tsurutani, Junji, Nishio, Kazuto, Doi, Katsumi, Miyazawa, Masaaki, Nakagawa, Kazuhiko
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.01.2020
• Subjects: Analysis; Antibodies; Apoptosis; Atezolizumab; Avelumab; Biochemistry; Biological products; Cancer; Cell death; Chemotherapy; Chromosomal proteins; Durvalumab; Epidermal growth factors; Health aspects; Immunotherapy; Nivolumab; Pembrolizumab; Tumors; Japan; Cancer immunotherapy; Oncology
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI126598

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.