1. Immunomodulatory Effects of Lenvatinib Plus Anti-Programmed Cell Death Protein 1 in Mice and Rationale for Patient Enrichment in Hepatocellular Carcinoma.
- Author
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Torrens L, Montironi C, Puigvehí M, Mesropian A, Leslie J, Haber PK, Maeda M, Balaseviciute U, Willoughby CE, Abril-Fornaguera J, Piqué-Gili M, Torres-Martín M, Peix J, Geh D, Ramon-Gil E, Saberi B, Friedman SL, Mann DA, Sia D, and Llovet JM
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Hepatocellular immunology, Cell Line, Tumor transplantation, Disease Models, Animal, Drug Screening Assays, Antitumor, Drug Synergism, Female, Humans, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Liver Neoplasms immunology, Liver Neoplasms pathology, Male, Mice, Phenylurea Compounds therapeutic use, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Quinolines therapeutic use, Tumor Escape drug effects, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Carcinoma, Hepatocellular drug therapy, Liver Neoplasms drug therapy, Phenylurea Compounds pharmacology, Programmed Cell Death 1 Receptor antagonists & inhibitors, Quinolines pharmacology
- Abstract
Background and Aims: Lenvatinib 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 Results: We 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., Conclusions: Lenvatinib 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., (© 2021 by the American Association for the Study of Liver Diseases.)
- Published
- 2021
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