TY - JOUR AU - Haratani, Koji AU - Yonesaka, Kimio AU - Takamura, Shiki AU - Maenishi, Osamu AU - Kato, Ryoji AU - Takegawa, Naoki AU - Kawakami, Hisato AU - Tanaka, Kaoru AU - Hayashi, Hidetoshi AU - Takeda, Masayuki AU - Maeda, Naoyuki AU - Kagari, Takashi AU - Hirotani, Kenji AU - Tsurutani, Junji AU - Nishio, Kazuto AU - Doi, Katsumi AU - Miyazawa, Masaaki AU - Nakagawa, Kazuhiko T1 - U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation PY - 2020/01/02/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI126598 VL - 130 IS - 1 UR - https://doi.org/10.1172/JCI126598 SP - 374 EP - 388 PB - The American Society for Clinical Investigation ER -