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The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients

Bispecific T cell engagers (TCEs) have shown promise in the treatment of various cancers, but the immunological mechanism and molecular determinants of primary and acquired resistance to TCEs remain poorly understood. Here, we identify conserved behaviors of bone marrow-residing T cells in multiple...

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Main Authors: Friedrich, Mirco (Author) , Neri, Paola (Author) , Kehl, Niklas (Author) , Michel, Julius (Author) , Steiger, Simon (Author) , Kilian, Michael (Author) , Leblay, Noémie (Author) , Maity, Ranjan (Author) , Sankowski, Roman (Author) , Lee, Holly (Author) , Barakat, Elie (Author) , Ahn, Sungwoo (Author) , Weinhold, Niels (Author) , Rippe, Karsten (Author) , Bunse, Lukas (Author) , Platten, Michael (Author) , Goldschmidt, Hartmut (Author) , Müller-Tidow, Carsten (Author) , Raab, Marc-Steffen (Author) , Bahlis, Nizar J. (Author)
Format: Article (Journal)
Language:English
Published: 10 April 2023
In: Cancer cell
Year: 2023, Volume: 41, Issue: 4, Pages: 711-725.e1-e6
ISSN:1878-3686
DOI:10.1016/j.ccell.2023.02.008
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ccell.2023.02.008
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1535610823000363
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Author Notes:Mirco J. Friedrich, Paola Neri, Niklas Kehl, Julius Michel, Simon Steiger, Michael Kilian, Noémie Leblay, Ranjan Maity, Roman Sankowski, Holly Lee, Elie Barakat, Sungwoo Ahn, Niels Weinhold, Karsten Rippe, Lukas Bunse, Michael Platten, Hartmut Goldschmidt, Carsten Müller-Tidow, Marc-Steffen Raab, and Nizar J. Bahlis
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Summary:Bispecific T cell engagers (TCEs) have shown promise in the treatment of various cancers, but the immunological mechanism and molecular determinants of primary and acquired resistance to TCEs remain poorly understood. Here, we identify conserved behaviors of bone marrow-residing T cells in multiple myeloma patients undergoing BCMAxCD3 TCE therapy. We show that the immune repertoire reacts to TCE therapy with cell state-dependent clonal expansion and find evidence supporting the coupling of tumor recognition via major histocompatibility complex class I (MHC class I), exhaustion, and clinical response. We find the abundance of exhausted-like CD8+ T cell clones to be associated with clinical response failure, and we describe loss of target epitope and MHC class I as tumor-intrinsic adaptations to TCEs. These findings advance our understanding of the in vivo mechanism of TCE treatment in humans and provide the rationale for predictive immune-monitoring and conditioning of the immune repertoire to guide future immunotherapy in hematological malignancies.
Item Description:Online verfügbar 9 March 2023, Version des Artikels 10 April 2023
in press
Gesehen am 28.03.2023
Physical Description:Online Resource
ISSN:1878-3686
DOI:10.1016/j.ccell.2023.02.008

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