Differential role of Th1 and Th2 cytokines in autotoxicity driven by CD19-specific second-generation chimeric antigen receptor T cells in a mouse model

E J Cheadle, V Sheard, D G Rothwell, J S Bridgeman, G Ashton, V Hanson, A W Mansoor, R E Hawkins, D E Gilham

Research output: Contribution to journalArticlepeer-review


T cells engrafted with chimeric AgRs (CAR) are showing exciting potential for targeting B cell malignancies in early-phase clinical trials. To determine whether the second-generation CAR was essential for optimal antitumor activity, two CD28-based CAR constructs targeting CD19 were tested for their ability to redirect mouse T cell function against established B cell lymphoma in a BALB/c syngeneic model system. T cells armed with either CAR eliminated A20 B cell lymphoma in vivo; however, one construct induced a T cell dose-dependent acute toxicity associated with a raised serum Th1 type cytokine profile on transfer into preconditioned mice. Moreover, a chronic toxicity manifested as granuloma-like formation in spleen, liver, and lymph nodes was observed in animals receiving T cells bearing either CD28 CAR, albeit with different kinetics dependent upon the specific receptor used. This phenotype was associated with an expansion of CD4+ CAR+ T cells and CD11b+ Gr-1(+) myeloid cells and increased serum Th2-type cytokines, including IL-10 and IL-13. Mouse T cells engrafted with a first-generation CAR failed to develop such autotoxicity, whereas toxicity was not apparent when T cells bearing the same receptors were transferred into C57BL/6 or C3H animals. In summary, the adoptive transfer of second-generation CD19-specific CAR T cells can result in a cell dose-dependent acute toxicity, whereas the prolonged secretion of high levels of Th2 cytokines from these CAR T cells in vivo drives a granulomatous reaction resulting in chronic toxicity. Strategies that prevent a prolonged Th2-cytokine biased CAR T cell response are clearly warranted.
Original languageEnglish
Pages (from-to)3654-65
Number of pages12
JournalJ Immunol
Issue number8
Publication statusPublished - 2014


  • Adoptive Transfer/adverse effects
  • Animals
  • Antigens, CD19/genetics/*immunology
  • Cluster Analysis
  • Cytokines/*metabolism
  • *Cytotoxicity, Immunologic
  • Gene Expression Profiling
  • Humans
  • Immunophenotyping
  • Lymphoma, B-Cell/genetics/immunology/metabolism/therapy
  • Mice
  • Mice, Inbred BALB C
  • Phenotype
  • Receptors, Antigen, T-Cell/genetics/*metabolism
  • Recombinant Fusion Proteins/genetics/metabolism
  • T-Lymphocyte Subsets/*immunology/*metabolism/transplantation
  • Th1 Cells/immunology/metabolism
  • Th2 Cells/immunology/metabolism


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