Engineered allogeneic T cells decoupling T-cell-receptor and CD3 signalling enhance the antitumour activity of bispecific antibodies.

Autor: Kapetanovic E; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Weber CR; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Bruand M; Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.; School of Life Sciences, EPFL, Lausanne, Switzerland.; Swiss Cancer Center Leman, Lausanne, Switzerland., Pöschl D; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Kucharczyk J; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Hirth E; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Dietsche C; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Khan R; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Wagner B; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Belli O; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Vazquez-Lombardi R; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Castellanos-Rueda R; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.; Life Science Zurich Graduate School, Systems Biology, ETH Zurich, University of Zurich, Zurich, Switzerland., Di Roberto RB; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Kalinka K; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Raess L; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Ly K; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Rai S; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Dittrich PS; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Platt RJ; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland., Oricchio E; Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.; School of Life Sciences, EPFL, Lausanne, Switzerland.; Swiss Cancer Center Leman, Lausanne, Switzerland., Reddy ST; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. sai.reddy@ethz.ch.
Jazyk: angličtina
Zdroj: Nature biomedical engineering [Nat Biomed Eng] 2024 Sep 25. Date of Electronic Publication: 2024 Sep 25.
DOI: 10.1038/s41551-024-01255-x
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE