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 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 1

U3-1402 exhibits HER3-dependent cytotoxicity and improves CD8+ TILs function.

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U3-1402 exhibits HER3-dependent cytotoxicity and improves CD8+ TILs func...
(A) Images of membranous HER3 immunostaining of CM-3 (left), MDA-MB-453 (middle), and CT26 cells (right). Scale bars: 100 mm. (B) Flow cytometry analysis of membranous HER3 expression. Data are representative of 3 independent experiments. (C) Left: in vitro growth inhibition assay for U3-1402 with CM-3 or CT26 cells. Right: in vitro growth inhibition assay for U3-1402 or patritumab with CM-3 cells. Data represent mean ± SEM of 6 replicate and 2 independent experiments. (D) Schematic of in vivo experiments. (E) Left: tumor volume curve of subcutaneous CM-3 tumors. Right: tumor volume 11 days after treatment initiation. n = 4–6 for each arm, pooled from 2 independent experiments. (F and G) Flow cytometry analysis of CD8+ TILs. n = 9–10, pooled from 2 independent experiments (F) or 4–5 (G) for each arm. (H) Left: flow cytometry analysis of IFN-γ– and TNF-α–producing CD8+ TILs. n = 6–7 for each arm. Right: representative flow cytometric plots of IFN-γ– and TNF-α–producing CD8+ TILs. Values in the figures indicate the frequency of IFN-γ– and TNF-α–producing CD8+ TILs. (I) Left: tumor volume curve of subcutaneous CM-3 tumors treated as indicated. Right: tumor volume 14 days after treatment initiation. n = 12 for each arm, pooled from 4 independent experiments. P values in E–I are shown on the horizontal lines. Each dot in E–I represents 1 tumor. Data were assessed by unpaired t tests.