CAR T Cells Releasing IL-18 Convert to T-Bethigh FoxO1low Effectors that Exhibit Augmented Activity against Advanced Solid Tumors

Markus Chmielewski; Hinrich Abken

doi:10.1016/j.celrep.2017.11.063

CAR T Cells Releasing IL-18 Convert to T-Bet^high FoxO1^low Effectors that Exhibit Augmented Activity against Advanced Solid Tumors

Cell Rep. 2017 Dec 12;21(11):3205-3219. doi: 10.1016/j.celrep.2017.11.063.

Authors

Markus Chmielewski¹, Hinrich Abken²

Affiliations

¹ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Dept. I of Internal Medicine, University Hospital Cologne, Cologne, Germany. Electronic address: markus.chmielewski@uk-koeln.de.
² Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Dept. I of Internal Medicine, University Hospital Cologne, Cologne, Germany.

PMID: 29241547
DOI: 10.1016/j.celrep.2017.11.063

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-bet^high FoxO1^low 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.

MeSH terms

Animals
Carcinoembryonic Antigen / genetics
Carcinoembryonic Antigen / immunology
Cell Engineering
Dendritic Cells / immunology
Dendritic Cells / pathology
Disease Models, Animal
Forkhead Box Protein O1 / genetics
Forkhead Box Protein O1 / immunology*
Gene Expression
Humans
Immunotherapy, Adoptive / methods*
Interleukin-18 / genetics
Interleukin-18 / immunology*
Interleukin-18 / metabolism
Killer Cells, Natural / immunology
Killer Cells, Natural / pathology
Lung Neoplasms / immunology
Lung Neoplasms / mortality
Lung Neoplasms / pathology
Lung Neoplasms / therapy*
Macrophages / immunology
Macrophages / pathology
Mice
Mutant Chimeric Proteins / genetics
Mutant Chimeric Proteins / immunology
Pancreatic Neoplasms / immunology
Pancreatic Neoplasms / mortality
Pancreatic Neoplasms / pathology
Pancreatic Neoplasms / therapy*
Primary Cell Culture
Receptors, Antigen, T-Cell / genetics
Receptors, Antigen, T-Cell / immunology
Survival Analysis
T-Box Domain Proteins / genetics
T-Box Domain Proteins / immunology*
T-Lymphocytes / immunology*
T-Lymphocytes / pathology
T-Lymphocytes / transplantation
Transgenes
Tumor Cells, Cultured

Substances

Carcinoembryonic Antigen
Forkhead Box Protein O1
Foxo1 protein, mouse
Interleukin-18
Mutant Chimeric Proteins
Receptors, Antigen, T-Cell
T-Box Domain Proteins
T-box transcription factor TBX21