Baeuerle et al. engineered TCR fusion constructs (TRuCs) comprised of an antibody-based binding domain fused to the extracellular N-terminus of either CD3α,β,γ,δ or ε.TRuCs were integrated into intact TCR constructs, reprogramming them to recognize tumor surface antigens; target recognition engaged the full signaling capacity of the TCR complex. Compared to second generation CAR T cells, TRuC T cells were as capable of recognizing and killing target antigen-expressing cells in vitro, but produced lower levels of cytokines. In vivo, TRuCs more effectively controlled the growth of both solid and liquid tumors and extended survival.
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.
Author Info: (1) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (2) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (3) TCR(2) Therapeutics, I
Author Info: (1) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (2) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (3) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (4) 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, Schanzlestrabetae 18, Freiburg, 79104, Germany. (5) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (6) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (7) Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center and Harvard Medical School, Bldg. 149 13th Street, Charlestown, MA, USA. (8) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (9) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (10) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (11) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (12) 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, Schanzlestrabetae 18, Freiburg, 79104, Germany. (13) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (14) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (15) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (16) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (17) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (18) Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center and Harvard Medical School, Bldg. 149 13th Street, Charlestown, MA, USA. (19) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. (20) 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, Schanzlestrabetae 18, Freiburg, 79104, Germany. (21) TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA, 02142, USA. robert@tcr2.com.
