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The Journal of clinical investigation
01 02, 2020;130 (1): 374-388.

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

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
Author Information
  1. Koji Haratani: Department of Medical Oncology.
  2. Kimio Yonesaka: Department of Medical Oncology.
  3. Shiki Takamura: Department of Immunology, and.
  4. Osamu Maenishi: Department of Pathology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
  5. Ryoji Kato: Department of Medical Oncology.
  6. Naoki Takegawa: Department of Medical Oncology.
  7. Hisato Kawakami: Department of Medical Oncology.
  8. Kaoru Tanaka: Department of Medical Oncology.
  9. Hidetoshi Hayashi: Department of Medical Oncology.
  10. Masayuki Takeda: Department of Medical Oncology.
  11. Naoyuki Maeda: Biomarker Department.
  12. Takashi Kagari: Oncology Research Laboratories I, and.
  13. Kenji Hirotani: Oncology Clinical Development Department, Daiichi-Sankyo, Tokyo, Japan.
  14. Junji Tsurutani: Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan.
  15. Kazuto Nishio: Department of Genome Biology and.
  16. Katsumi Doi: Department of Otolaryngology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
  17. Masaaki Miyazawa: Department of Immunology, and.
  18. Kazuhiko Nakagawa: Department of Medical Oncology.
PMID: 31661465 DOI: 10.1172/JCI126598

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.

Keywords

Cancer immunotherapy Oncology

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MeSH Term

Animals
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic
Humans
Immunoconjugates
Mice
Neoplasms, Experimental
Programmed Cell Death 1 Receptor
Receptor, ErbB-3
Xenograft Model Antitumor Assays

Chemicals

Immunoconjugates
PDCD1 protein, human
Programmed Cell Death 1 Receptor
ERBB3 protein, human
Receptor, ErbB-3
Journal Article Research Support, Non-U.S. Gov't

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