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Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function

Author

Listed:
  • Benjamin Salzer

    (St. Anna Children’s Cancer Research Institute (CCRI)
    Christian Doppler Laboratory for Next Generation CAR T Cells)

  • Christina M. Schueller

    (St. Anna Children’s Cancer Research Institute (CCRI))

  • Charlotte U. Zajc

    (St. Anna Children’s Cancer Research Institute (CCRI)
    Christian Doppler Laboratory for Next Generation CAR T Cells)

  • Timo Peters

    (Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University of Vienna)

  • Michael A. Schoeber

    (St. Anna Children’s Cancer Research Institute (CCRI))

  • Boris Kovacic

    (St. Anna Children’s Cancer Research Institute (CCRI))

  • Michelle C. Buri

    (St. Anna Children’s Cancer Research Institute (CCRI))

  • Elisabeth Lobner

    (University of Natural Resources and Life Sciences)

  • Omer Dushek

    (Sir William Dunn School of Pathology, University of Oxford)

  • Johannes B. Huppa

    (Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University of Vienna)

  • Christian Obinger

    (Institute of Biochemistry, University of Natural Resources and Life Sciences)

  • Eva M. Putz

    (St. Anna Children’s Cancer Research Institute (CCRI))

  • Wolfgang Holter

    (St. Anna Children’s Cancer Research Institute (CCRI)
    St. Anna Kinderspital, Medical University of Vienna)

  • Michael W. Traxlmayr

    (Christian Doppler Laboratory for Next Generation CAR T Cells
    Institute of Biochemistry, University of Natural Resources and Life Sciences)

  • Manfred Lehner

    (St. Anna Children’s Cancer Research Institute (CCRI)
    Christian Doppler Laboratory for Next Generation CAR T Cells
    St. Anna Kinderspital, Medical University of Vienna)

Abstract

T cells engineered to express chimeric antigen receptors (CAR-T cells) have shown impressive clinical efficacy in the treatment of B cell malignancies. However, the development of CAR-T cell therapies for solid tumors is hampered by the lack of truly tumor-specific antigens and poor control over T cell activity. Here we present an avidity-controlled CAR (AvidCAR) platform with inducible and logic control functions. The key is the combination of (i) an improved CAR design which enables controlled CAR dimerization and (ii) a significant reduction of antigen-binding affinities to introduce dependence on bivalent interaction, i.e. avidity. The potential and versatility of the AvidCAR platform is exemplified by designing ON-switch CARs, which can be regulated with a clinically applied drug, and AND-gate CARs specifically recognizing combinations of two antigens. Thus, we expect that AvidCARs will be a highly valuable platform for the development of controllable CAR therapies with improved tumor specificity.

Suggested Citation

  • Benjamin Salzer & Christina M. Schueller & Charlotte U. Zajc & Timo Peters & Michael A. Schoeber & Boris Kovacic & Michelle C. Buri & Elisabeth Lobner & Omer Dushek & Johannes B. Huppa & Christian Obi, 2020. "Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17970-3
    DOI: 10.1038/s41467-020-17970-3
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    Cited by:

    1. Ian D. Ferguson & Bonell Patiño-Escobar & Sami T. Tuomivaara & Yu-Hsiu T. Lin & Matthew A. Nix & Kevin K. Leung & Corynn Kasap & Emilio Ramos & Wilson Nieves Vasquez & Alexis Talbot & Martina Hale & A, 2022. "The surfaceome of multiple myeloma cells suggests potential immunotherapeutic strategies and protein markers of drug resistance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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