Tuning the Antigen Density Requirement for CAR T-cell Activity

Abstract Insufficient reactivity against cells with low antigen density has emerged as an important cause of chimeric antigen receptor (CAR) T-cell resistance. Little is known about factors that modulate the threshold for antigen recognition. We demonstrate that CD19 CAR activity is dependent upon antigen density and that the CAR construct in axicabtagene ciloleucel (CD19-CD28ζ) outperforms that in tisagenlecleucel (CD19-4-1BBζ) against antigen-low tumors. Enhancing signal strength by including additional immunoreceptor tyrosine-based activation motifs (ITAM) in the CAR enables recognition of low-antigen-density cells, whereas ITAM deletions blunt signal and increase the antigen density threshold. Furthermore,…

• HH
  Howard Hughes Medical Institute
• JC
  Jane Coffin Childs Memorial Fund for Medical Research
• AS
  American Society of Hematology
• SB
  St. Baldrick's Foundation

  Award: SU2C-AACR-DT-27-17
• VA
  Virginia and D.K. Ludwig Fund for Cancer Research
• PI
  Parker Institute for Cancer Immunotherapy
• DK
  Deutsche Krebshilfe

  Award: P-91650709
• NI
  National Institutes of Health

  Awards: P01CA217959-01, R35 (1R35GM130332), T32GM007365, 5P30CA124435, U54-CA232568-01
• SO
  School of Medicine, Stanford University
• HH
  Hyundai Hope On Wheels