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.

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.

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