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Cancer Discov. 2020 Mar 19. pii: CD-19-0945. doi: 10.1158/2159-8290.CD-19-0945. [Epub ahead of print]

Tuning the Antigen Density Requirement for CAR T Cell Activity.

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Stanford University School of Medicine.
Department of Pediatrics, Stanford University School of Medicine.
Department of Cellular and Molecular Pharmacology, University of California, San Francisco.
Stanford University.
Department of Bioengineering, Stanford University School of Medicine.
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital.
Stanford Cancer Institute, Stanford University School of Medicine.
Pediatrics, Stanford University School of Medicine.
Pediatric Oncology Branch, National Institute of Health.
Pediatrics Department, Stanford University School of Medicine.
Department of Pediatrics, Stanford University.
Pediatrics and Medicine, Stanford University


Insufficient reactivity against cells with low antigen density has emerged as an important cause of CAR 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 the CAR construct in axicabtagene-ciloleucel (CD19-CD28z) outperforms that in tisagenlecleucel (CD19-4-1BBz) against antigen low tumors. Enhancing signal strength by including additional ITAMs in the CAR enables recognition of low antigen density cells, while ITAM deletions blunt signal and increase the antigen density threshold. Further, replacement of the CD8 hinge-transmembrane (H/T) region of a 4-1BBz CAR with a CD28-H/T lowers the threshold for CAR reactivity despite identical signaling molecules. CARs incorporating a CD28-H/T demonstrate a more stable and efficient immunological synapse. Precise design of CARs can tune the threshold for antigen recognition and endow 4-1BBz-CARs with enhanced capacity to recognize antigen low targets while retaining a superior capacity for persistence.

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