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Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response

Author

Listed:
  • Patrick A. Baeuerle

    (TCR² Therapeutics, Inc.)

  • Jian Ding

    (TCR² Therapeutics, Inc.)

  • Ekta Patel

    (TCR² Therapeutics, Inc.)

  • Niko Thorausch

    (University of Freiburg)

  • Holly Horton

    (TCR² Therapeutics, Inc.)

  • Jessica Gierut

    (TCR² Therapeutics, Inc.)

  • Irene Scarfo

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Rashmi Choudhary

    (TCR² Therapeutics, Inc.)

  • Olga Kiner

    (TCR² Therapeutics, Inc.)

  • Janani Krishnamurthy

    (TCR² Therapeutics, Inc.)

  • Bonnie Le

    (TCR² Therapeutics, Inc.)

  • Anna Morath

    (University of Freiburg)

  • G. Christian Baldeviano

    (TCR² Therapeutics, Inc.)

  • Justin Quinn

    (TCR² Therapeutics, Inc.)

  • Patrick Tavares

    (TCR² Therapeutics, Inc.)

  • Qi Wei

    (TCR² Therapeutics, Inc.)

  • Solly Weiler

    (TCR² Therapeutics, Inc.)

  • Marcela V. Maus

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Daniel Getts

    (TCR² Therapeutics, Inc.)

  • Wolfgang W. Schamel

    (University of Freiburg)

  • Robert Hofmeister

    (TCR² Therapeutics, Inc.)

Abstract

T cells expressing CD19-targeting chimeric antigen receptors (CARs) reveal high efficacy in the treatment of B cell malignancies. Here, we report that T cell receptor fusion constructs (TRuCs) comprising an antibody-based binding domain fused to T cell receptor (TCR) subunits can effectively reprogram an intact TCR complex to recognize tumor surface antigens. Unlike CARs, TRuCs become a functional component of the TCR complex. TRuC-T cells kill tumor cells as potently as second-generation CAR-T cells, but at significant lower cytokine release and despite the absence of an extra co-stimulatory domain. TRuC-T cells demonstrate potent anti-tumor activity in both liquid and solid tumor xenograft models. In several models, TRuC-T cells are more efficacious than respective CAR-T cells. TRuC-T cells are shown to engage the signaling capacity of the entire TCR complex in an HLA-independent manner.

Suggested Citation

  • Patrick A. Baeuerle & Jian Ding & Ekta Patel & Niko Thorausch & Holly Horton & Jessica Gierut & Irene Scarfo & Rashmi Choudhary & Olga Kiner & Janani Krishnamurthy & Bonnie Le & Anna Morath & G. Chris, 2019. "Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10097-0
    DOI: 10.1038/s41467-019-10097-0
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