ArticleHepatology (Baltimore, Md.)2021
Immunomodulatory Effects of Lenvatinib Plus Anti-Programmed Cell Death Protein 1 in Mice and Rationale for Patient Enrichment in Hepatocellular Carcinoma.
Article in Hepatology (Baltimore, Md.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 94 papers, 2 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
94 citing papers in PubMed, 2 syntheses or guidelines pooled it, 156 citations in OpenAlex.
- Pooled it
- Efficacy and safety of lenvatinib versus sorafenib in first-line treatment of advanced hepatocellular carcinoma: A meta-analysis.Frontiers in oncology · 2022Pooled it
- Envafolimab plus lenvatinib and transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: a prospective, single-arm, phase II study.Signal transduction and targeted therapy · 2024Trial
- CyberKnife SBRT plus lenvatinib and tislelizumab versus doublet systemic therapy for hepatocellular carcinoma with macrovascular invasion: A real-world IPTW-adjusted study.Clinical and translational radiation oncology · 2027Article
- Programmed cell death in inflammation: interactions and holistic perspective.Cellular & molecular immunology · 2026Review
- Comparison of effectiveness and safety of pembrolizumab plus lenvatinib versus nivolumab plus cabozantinib for metastatic renal cell carcinoma: a real-world study.International journal of clinical oncology · 2026Article
- Lenvatinib Added to Nivolumab and Ipilimumab Improves Tumor Control and Progression-Free Survival in Unresectable Hepatocellular Carcinoma.Liver cancer · 2026Article
- Regulatory T Cells in Hepatocellular Carcinoma: Spatial Niches, Biomarkers, and Clinical Implications.International journal of molecular sciences · 2026Review
- Article
- Multi-tyrosine kinase inhibitors: exploring immunomodulatory effects on various immune cell types in cancer.Cancer cell international · 2026Review
- Elemene Augments the Effects of Anti-PD-1 Immunotherapy on Hepatocellular Carcinoma by Regulating the miR-130a-5p/SPP/MHC-I Axis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Spatiotemporal dynamics of tumor-associated neutrophils: bridging the gap between cancer progression and immunotherapy.Molecular cancer · 2026Review
- HAIC combined with lenvatinib and tislelizumab for HCC with concurrent PVTT and pulmonary metastasis: a multicenter propensity score matching analysis.Therapeutic advances in medical oncology · 2026Article
- Preclinical exploration and current clinical applications of immunotherapeutic strategies for hepatocellular carcinoma.Frontiers in immunology · 2026Review
- Prognostic value of radiological and pathological complete response following immune-based conversion therapy in patients with unresectable hepatocellular carcinoma (GUIDANCE004).JHEP reports : innovation in hepatology · 2025Article
- Neoadjuvant systemic therapy for hepatocellular carcinoma: challenges and opportunities-a narrative review.Hepatobiliary surgery and nutrition · 2025Review
- Efficacy of hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma: survival outcomes and prognostic factors from a systematic review and meta-analysis.Hepatobiliary surgery and nutrition · 2025Article
- Formosanin C inhibits triple-negative breast cancer progression by suppressing the phosphorylation of STAT3 and the polarization of M2 macrophages.Breast cancer research and treatment · 2025Article
- Comprehensive analysis of immune subtype characterization on identification of potential cells and drugs to predict response to immune checkpoint inhibitors for hepatocellular carcinoma.Genes & diseases · 2025Article
- A precision image-guided model of stereotactic ablative radiotherapy for hepatocellular carcinoma.Disease models & mechanisms · 2025Article
34 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
20 authors at 5 institutions in 3 countries.
Funding
Abstract
BACKGROUND AND
aimsLenvatinib is an effective drug in advanced HCC. Its combination with the anti-PD1 (programmed cell death protein 1) immune checkpoint inhibitor, pembrolizumab, has generated encouraging results in phase Ib and is currently being tested in phase III trials. Here, we aimed to explore the molecular and immunomodulatory effects of lenvatinib alone or in combination with anti-PD1. APPROACH AND
resultsWe generated three syngeneic models of HCC in C57BL/6J mice (subcutaneous and orthotopic) and randomized animals to receive placebo, lenvatinib, anti-PD1, or combination treatment. Flow cytometry, transcriptomic, and immunohistochemistry analyses were performed in tumor and blood samples. A gene signature, capturing molecular features associated with the combination therapy, was used to identify a subset of candidates in a cohort of 228 HCC patients who might respond beyond what is expected for monotherapies. In mice, the combination treatment resulted in tumor regression and shorter time to response compared to monotherapies (P < 0.001). Single-agent anti-PD1 induced dendritic and T-cell infiltrates, and lenvatinib reduced the regulatory T cell (Treg) proportion. However, only the combination treatment significantly inhibited immune suppressive signaling, which was associated with the TGFß pathway and induced an immune-active microenvironment (P < 0.05 vs. other therapies). Based on immune-related genomic profiles in human HCC, 22% of patients were identified as potential responders beyond single-agent therapies, with tumors characterized by Treg cell infiltrates, low inflammatory signaling, and VEGFR pathway activation.
conclusionsLenvatinib plus anti-PD1 exerted unique immunomodulatory effects through activation of immune pathways, reduction of Treg cell infiltrate, and inhibition of TGFß signaling. A gene signature enabled the identification of ~20% of human HCCs that, although nonresponding to single agents, could benefit from the proposed combination.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.