Immunomodulatory Effects of Lenvatinib Plus Anti-Programmed Cell Death Protein 1 in Mice and Rationale for Patient Enrichment in Hepatocellular Carcinoma.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Carcinoma, Hepatocellular
/ drug therapy
Cell Line, Tumor
/ transplantation
Disease Models, Animal
Drug Screening Assays, Antitumor
Drug Synergism
Female
Humans
Immune Checkpoint Inhibitors
/ pharmacology
Liver Neoplasms
/ drug therapy
Male
Mice
Phenylurea Compounds
/ pharmacology
Programmed Cell Death 1 Receptor
/ antagonists & inhibitors
Protein Kinase Inhibitors
/ pharmacology
Quinolines
/ pharmacology
Tumor Escape
/ drug effects
Tumor Microenvironment
/ drug effects
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
revised:
25
05
2021
received:
25
11
2020
accepted:
13
06
2021
pubmed:
23
6
2021
medline:
14
1
2022
entrez:
22
6
2021
Statut:
ppublish
Résumé
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. 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. 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.
Sections du résumé
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.
Substances chimiques
Immune Checkpoint Inhibitors
0
Pdcd1 protein, mouse
0
Phenylurea Compounds
0
Programmed Cell Death 1 Receptor
0
Protein Kinase Inhibitors
0
Quinolines
0
lenvatinib
EE083865G2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2652-2669Subventions
Organisme : Cancer Research UK
ID : 26813
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK128289
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK056621
Pays : United States
Organisme : Cancer Research UK
ID : C18342/A23390
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C9380/A26813
Pays : United Kingdom
Informations de copyright
© 2021 by the American Association for the Study of Liver Diseases.
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