Abstract
Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells has achieved remarkable efficacy in the treatment of hematopoietic malignancies. However, eradicating large solid tumors in advanced stages of the disease remains challenging. We explored augmentation of the anti-tumor immune reaction by establishing an acute inflammatory reaction. Systematic screening indicates that IL-18 polarizes CAR T cells toward T-bethigh FoxO1low effectors with an acute inflammatory response. CAR T cells engineered with inducible IL-18 release exhibited superior activity against large pancreatic and lung tumors that were refractory to CAR T cells without cytokines. IL-18 CAR T cell treatment was accompanied by an overall change in the immune cell landscape associated with the tumor. More specifically, CD206- M1 macrophages and NKG2D+ NK cells increased in number, whereas Tregs, suppressive CD103+ DCs, and M2 macrophages decreased, suggesting that "iIL18 TRUCKs" can be used to sensitize large solid tumor lesions for successful immune destruction.
Keywords:
CAR; CEA; IL-12; IL-18; TRUCK; adoptive cell therapy; carcinoembryonic antigen; chimeric antigen receptor; pancreatic carcinoma.
Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
MeSH terms
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Animals
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Carcinoembryonic Antigen / genetics
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Carcinoembryonic Antigen / immunology
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Cell Engineering
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Dendritic Cells / immunology
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Dendritic Cells / pathology
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Disease Models, Animal
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Forkhead Box Protein O1 / genetics
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Forkhead Box Protein O1 / immunology*
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Gene Expression
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Humans
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Immunotherapy, Adoptive / methods*
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Interleukin-18 / genetics
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Interleukin-18 / immunology*
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Interleukin-18 / metabolism
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Killer Cells, Natural / immunology
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Killer Cells, Natural / pathology
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Lung Neoplasms / immunology
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Lung Neoplasms / mortality
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Lung Neoplasms / pathology
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Lung Neoplasms / therapy*
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Macrophages / immunology
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Macrophages / pathology
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Mice
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Mutant Chimeric Proteins / genetics
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Mutant Chimeric Proteins / immunology
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Pancreatic Neoplasms / immunology
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Pancreatic Neoplasms / mortality
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Pancreatic Neoplasms / pathology
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Pancreatic Neoplasms / therapy*
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Primary Cell Culture
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology
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Survival Analysis
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / immunology*
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T-Lymphocytes / immunology*
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T-Lymphocytes / pathology
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T-Lymphocytes / transplantation
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Transgenes
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Tumor Cells, Cultured
Substances
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Carcinoembryonic Antigen
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Forkhead Box Protein O1
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Foxo1 protein, mouse
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Interleukin-18
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Mutant Chimeric Proteins
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Receptors, Antigen, T-Cell
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T-Box Domain Proteins
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T-box transcription factor TBX21