Nivolumab plus ipilimumab for potentially resectable hepatocellular carcinoma: long-term efficacy and biomarker exploration

Yih-Jyh Lin¹, Da-Liang Ou², Yung-Yeh Su³, Chia-Lang Hsu⁴, Chin-Fu Hsiao⁵, Bor-Sheng Ko⁶, San-Chi Chen⁷, Hung-Wei Wang⁸, Jing-Houng Wang⁹, Yao-Ming Wu¹⁰, Yung-Ming Jeng¹¹, Wei-Chen Lee¹², Shu-Cheng Chou¹³, Teng-Wei Chen¹⁴, Chang-Fang Chiu⁸, Shiuan Lin Jr¹⁵, Ching-Hung Hsieh², Chi-Chun Lee¹⁶, Yen-Shen Shen¹⁷, Ann-Lii Cheng¹⁸, Li-Tzong Chen¹⁹, Chiun Hsu²⁰

Affiliations

¹ Department of Surgery, National Cheng-Kung University Hospital, Tainan, Taiwan.
² Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
³ National Institute of Cancer Research, National Health Research Institute, Tainan, Taiwan; Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Internal Medicine, Kaohsiung Medical University Hospital, and Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁴ Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
⁵ Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
⁶ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
⁷ Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
⁸ Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
⁹ Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
¹⁰ Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
¹¹ Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
¹² Department of Surgery, Linkou Chang-Gung Memorial Hospital, Linkou, Taiwan.
¹³ Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
¹⁴ Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan.
¹⁵ Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
¹⁶ Department of Electrical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
¹⁷ Department of Surgery, National Cheng-Kung University Hospital, Tainan, Taiwan; Institute of Clinical Medicine, College of Medicine, National Chen Kung University, Tainan, Taiwan.
¹⁸ Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan. Electronic address: alcheng@ntu.edu.tw.
¹⁹ National Institute of Cancer Research, National Health Research Institute, Tainan, Taiwan; Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Internal Medicine, Kaohsiung Medical University Hospital, and Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: leochenk153@gmail.com.
²⁰ Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: hsuchiun@ntu.edu.tw.

PMID: 40972843
DOI: 10.1016/j.jhep.2025.08.035

Free article

Nivolumab plus ipilimumab for potentially resectable hepatocellular carcinoma: long-term efficacy and biomarker exploration

Yih-Jyh Lin et al. J Hepatol. 2025.

Free article

. 2025 Sep 17:S0168-8278(25)02471-7.

doi: 10.1016/j.jhep.2025.08.035. Online ahead of print.

Authors

Affiliations

¹ Department of Surgery, National Cheng-Kung University Hospital, Tainan, Taiwan.
² Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
³ National Institute of Cancer Research, National Health Research Institute, Tainan, Taiwan; Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Internal Medicine, Kaohsiung Medical University Hospital, and Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁴ Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
⁵ Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
⁶ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
⁷ Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
⁸ Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
⁹ Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
¹⁰ Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
¹¹ Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
¹² Department of Surgery, Linkou Chang-Gung Memorial Hospital, Linkou, Taiwan.
¹³ Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
¹⁴ Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan.
¹⁵ Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
¹⁶ Department of Electrical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
¹⁷ Department of Surgery, National Cheng-Kung University Hospital, Tainan, Taiwan; Institute of Clinical Medicine, College of Medicine, National Chen Kung University, Tainan, Taiwan.
¹⁸ Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan. Electronic address: alcheng@ntu.edu.tw.
¹⁹ National Institute of Cancer Research, National Health Research Institute, Tainan, Taiwan; Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Internal Medicine, Kaohsiung Medical University Hospital, and Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: leochenk153@gmail.com.
²⁰ Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: hsuchiun@ntu.edu.tw.

PMID: 40972843
DOI: 10.1016/j.jhep.2025.08.035

Abstract

Background and aims: Immune checkpoint inhibitor-based combination therapy has demonstrated high objective response rates in patients with hepatocellular carcinoma (HCC) and might improve clinical outcome as neoadjuvant or perioperative therapy. This study evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with potentially resectable HCC and explored predictive biomarkers of treatment response.

Methods: Eligible patients received nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks. Tumor response was assessed after two and four treatment cycles. Patients then proceeded to curative surgery or alternative treatments according to clinical guidelines. Serial tumor and peripheral blood samples were collected for genomic and transcriptomic analyses and immune cell profiling.

Results: Among the 43 enrolled patients (men/women: 37/6; viral/non-viral 41/2; Barcelona Clinic Liver Cancer stage A/B/C: 4/13/26; median tumor size: 8.7 cm), 24 underwent surgery, and eight achieved a major pathological response (>90% tumor necrosis). The estimated 4-year progression-free survival and overall survival rates were 44% (95% confidence interval [CI], 28-59%) and 60% (95% CI, 42-74%), respectively. Increased interferon-γ and tertiary lymphoid structure (TLS) signatures in resected tumors were associated with objective response. In a mouse liver cancer model, B cell depletion abolished the efficacy of anti-programmed death-1 plus anti-cytotoxic T lymphocyte-associated protein 4 therapy, supporting the mechanistic role of TLS. Peripheral blood T cell activation and exhaustion at baseline and post-immunotherapy, assessed using spectral flow cytometry and deep learning algorithms, correlated with response and survival.

Conclusions: Neoadjuvant nivolumab plus ipilimumab followed by surgery is feasible and might improve long-term survival in patients with potentially resectable HCC. Immunotherapy-induced TLS formation is associated with enhanced antitumor immunity.

Clinical trial number: NCT03510871.

Keywords: T cell exhaustion; dendritic cells; neoadjuvant; peripheral blood mononuclear cells; tertiary lymphoid structure.

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Conflict of interest statement

Declaration of Competing Interest CH received research fundings (to the institution) from Bristol-Myers Squibb/ ONO, GoldenBiotech, IPSEN, Roche and honorarium from AstraZeneca, Bristol-Myers Squibb/ONO, Eisai, MSD, and Roche. ALC received research fundings (to the institution) from Pilatus Biosciences Inc, and consulting fees from AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Genentech/Roche, Ipsen Innovation, Eisai, Ono Pharmaceutical, Sanofi, Omega Therapeutics and MSD, and honoraria for lectures, presentations, speakers bureaus, from Amgen Taiwan, Roche, and Ipsen Innovation, support for attending meetings and/or travel from Roche and AstraZeneca, participation on a Data Safety Monitoring Board or Advisory Board from Abbisko, and independent director for TTY Biopharma. LTC received research fundings (to the institution) from Ono Pharmaceutical, and consulting fees from Academab Biomedical Inc., and honoraria for lectures, presentations, speakers bureaus, from AstraZeneca, Astellas, Ono Pharmaceutical, and TTY Biopharma, participation on a Data Safety Monitoring Board or Advisory Board from AstraZeneca, Astellas, MSD, Ono Pharmaceutical, and TTY Biopharma. Other authors have no relevant conflict of interests to declare.

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Nivolumab plus ipilimumab for potentially resectable hepatocellular carcinoma: long-term efficacy and biomarker exploration

Affiliations

Nivolumab plus ipilimumab for potentially resectable hepatocellular carcinoma: long-term efficacy and biomarker exploration

Authors

Affiliations

Abstract

Conflict of interest statement

Associated data

LinkOut - more resources

Full Text Sources

Medical