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

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. Christian Baldeviano, Justin Quinn, Patrick Tavares, Qi Wei, Solly Weiler, Marcela V. Maus, Daniel Getts, Wolfgang W. Schamel and Robert Hofmeister ()
Additional contact information
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.

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10097-0

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