Kapetanovic et al. used targeted genomic mutagenesis of the FGxGT motif in the TRAJ region to develop Allogeneic-Engineered Decoupled (AED) T cells, for which TCR–antigen binding was functionally decoupled from CD3 signaling. AED T cells remained unresponsive to cognate antigen stimulation. When coadministered with the bispecific CD3/CD19 antibody, blinatumomab, primary AED T cells recognized and cleared human CD19+ tumor cells in a xenograft mouse model, without signs of alloreactivity, despite the presence of cognate antigen. AED T cells were compatible with other bispecific T cell engagers.
Contributed by Ute Burkhardt
ABSTRACT: Bispecific antibodies (biAbs) used in cancer immunotherapies rely on functional autologous T cells, which are often damaged and depleted in patients with haematological malignancies and in other immunocompromised patients. The adoptive transfer of allogeneic T cells from healthy donors can enhance the efficacy of biAbs, but donor T cells binding to host-cell antigens cause an unwanted alloreactive response. Here we show that allogeneic T cells engineered with a T-cell receptor that does not convert antigen binding into cluster of differentiation 3 (CD3) signalling decouples antigen-mediated T-cell activation from T-cell cytotoxicity while preserving the surface expression of the T-cell-receptor-CD3 signalling complex as well as biAb-mediated CD3 signalling and T-cell activation. In mice with CD19(+) tumour xenografts, treatment with the engineered human cells in combination with blinatumomab (a clinically approved biAb) led to the recognition and clearance of tumour cells in the absence of detectable alloreactivity. Our findings support the development of immunotherapies combining biAbs and 'off-the-shelf' allogeneic T cells.
Author Info: (1) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (2) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (3) Swis
Author Info: (1) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (2) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (3) Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland. School of Life Sciences, EPFL, Lausanne, Switzerland. Swiss Cancer Center Leman, Lausanne, Switzerland. (4) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (5) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (6) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (7) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (8) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (9) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (10) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (11) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (12) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. Life Science Zurich Graduate School, Systems Biology, ETH Zurich, University of Zurich, Zurich, Switzerland. (13) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (14) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (15) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (16) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (17) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (18) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (19) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (20) Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland. School of Life Sciences, EPFL, Lausanne, Switzerland. Swiss Cancer Center Leman, Lausanne, Switzerland. (21) Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. sai.reddy@ethz.ch.
