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Nat Commun. 2019 May 7;10(1):2087. doi: 10.1038/s41467-019-10097-0.

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

Author information

1
TCR² Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA.
2
Department of Immunology, Faculty of Biology, BIOSS Center for Biological Signalling Studies, CIBSS-Centre for Integrative Biological Signalling Studies and Centre for Chronic Immunodeficiency CCI, University of Freiburg, Schänzlestraβe 18, Freiburg, 79104, Germany.
3
Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center and Harvard Medical School, Bldg. 149 13th Street, Charlestown, MA, USA.
4
TCR² Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. robert@tcr2.com.

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.

PMID:
31064990
PMCID:
PMC6504948
DOI:
10.1038/s41467-019-10097-0
[Indexed for MEDLINE]
Free PMC Article

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