U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation
Koji Haratani, … , Masaaki Miyazawa, Kazuhiko Nakagawa
Koji Haratani, … , Masaaki Miyazawa, Kazuhiko Nakagawa
Published January 2, 2020; First published October 29, 2019
Citation Information: J Clin Invest. 2020;130(1):374-388. https://doi.org/10.1172/JCI126598.
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Research Article Oncology

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

Abstract

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.

Authors

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

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Figure 6

DXd causes HMGB-1 release and immune activation with damaged cancer cells.

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DXd causes HMGB-1 release and immune activation with damaged cancer cell...
(A) Left: tumor volume curve of subcutaneous CM-3 tumors. Mice were vaccinated as indicated. Right: tumor volume 21 days after treatment initiation. Each dot represents 1 tumor. n = 10 for each arm. Data are representative of 2 independent experiments. (B) ELISA of extracellular HMGB-1. Data represent mean ± SEM of 3 replicates and are representative of 2 independent experiments. (C) Flow cytometry analysis of TLR4-expressing myeloid cells in tumors. Each dot represents 1 tumor. n = 6–7 for each arm. (D) Left: flow cytometry analysis of the indicated cell types. Each dot represents 1 tumor. n = 6–7 for each arm. Right: representative flow cytometric plots of SCARA5-expressing TLR4+ myeloid cells in tumors. A negative control using isotype control antibody is shown as a reference on the left side. Each value in the figures indicates the frequency of each cell type. (E) Left: flow cytometry analysis of the indicated cell types. Each dot represents 1 tumor. n = 6–7 for each arm. Right: Representative flow cytometric plots of TNF-α–producing myeloid cells in tumors. Each value in the figures indicates the frequency of each cell type. P values in A, C, D, and E are shown on the horizontal lines. Data were assessed by unpaired t test.