Synergistic effects of combined immunotherapy strategies in a model of multifocal hepatocellular carcinoma.
CD137
CTLA-4
IL-2
PD-1
hepatocellular carcinoma
hydrodynamic gene transfer
immunotherapy
Journal
Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894
Informations de publication
Date de publication:
18 04 2023
18 04 2023
Historique:
received:
16
09
2022
revised:
20
10
2022
accepted:
20
03
2023
medline:
21
4
2023
pubmed:
12
4
2023
entrez:
11
4
2023
Statut:
ppublish
Résumé
Immune checkpoint-inhibitor combinations are the best therapeutic option for advanced hepatocellular carcinoma (HCC) patients, but improvements in efficacy are needed to improve response rates. We develop a multifocal HCC model to test immunotherapies by introducing c-myc using hydrodynamic gene transfer along with CRISPR-Cas9-mediated disruption of p53 in mouse hepatocytes. Additionally, induced co-expression of luciferase, EGFP, and the melanosomal antigen gp100 facilitates studies on the underlying immunological mechanisms. We show that treatment of the mice with a combination of anti-CTLA-4 + anti-PD1 mAbs results in partial clearance of the tumor with an improvement in survival. However, the addition of either recombinant IL-2 or an anti-CD137 mAb markedly improves both outcomes in these mice. Combining tumor-specific adoptive T cell therapy to the aCTLA-4/aPD1/rIL2 or aCTLA-4/aPD1/aCD137 regimens enhances efficacy in a synergistic manner. As shown by multiplex tissue immunofluorescence and intravital microscopy, combined immunotherapy treatments enhance T cell infiltration and the intratumoral performance of T lymphocytes.
Identifiants
pubmed: 37040772
pii: S2666-3791(23)00119-2
doi: 10.1016/j.xcrm.2023.101009
pmc: PMC10140615
pii:
doi:
Substances chimiques
Antibodies, Monoclonal
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101009Informations de copyright
Copyright © 2023. Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of interests I.M. acknowledges grants from Roche, Alligator, Genmab, BMS, AstraZeneca, Pharmamar, and Bioncotech, as well as consultancy fees from BMS, Roche, Genmab, Numab, F-Star, Biolinerx, Pierre Fabre, Sanofi, Gossamer, Alligator, AstraZeneca, and Pharmamar. B.S. received consulting fees from Adaptimmune, AstraZeneca, Bayer, BMS, BTG, Eisai, Exelixis, Eli-Lilly, IPSEN, Merck, Onxeo, Roche, and Sirtex; lecture fees from AstraZeneca, Bayer, BMS, Eisai, Eli-Lilly, Incyte, IPSEN, Roche, and Sirtex; and institutional research grants from BMS and Sirtex.
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