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  Key Features Relevant to Select Antigens and TCR From the MHC-Mismatched Repertoire to Treat Cancer

Audehm, S., Glaser, M., Pecoraro, M., Braeunlein, E., Mall, S., Klar, R., et al. (2019). Key Features Relevant to Select Antigens and TCR From the MHC-Mismatched Repertoire to Treat Cancer. Frontiers in immunology, 10: 1485. doi:10.3389/fimmu.2019.01485.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-85EF-9 Version Permalink: http://hdl.handle.net/21.11116/0000-0004-85F0-6
Genre: Journal Article

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© 2019 Audehm, Glaser, Pecoraro, Bräunlein, Mall, Klar, Effenberger, Albers, Bianchi, Peper, Yusufi, Busch, Stevanović, Mann, Antes and Krackhardt.

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 Creators:
Audehm, Stefan1, Author
Glaser, Manuel1, Author
Pecoraro, Matteo2, Author              
Braeunlein, Eva1, Author
Mall, Sabine1, Author
Klar, Richard1, Author
Effenberger, Manuel1, Author
Albers, Julian1, Author
Bianchi, Henrique de Oliveira1, Author
Peper, Janet1, Author
Yusufi, Nahid1, Author
Busch, Dirk H.1, Author
Stevanovic, Stefan1, Author
Mann, Matthias2, Author              
Antes, Iris1, Author
Krackhardt, Angela M.1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: CYTOTOXIC T-LYMPHOCYTES; MOLECULAR-DYNAMICS; SIDE-CHAIN; IN-VITRO; MULTIPLE-MYELOMA; CELL POPULATIONS; NEURAL-NETWORKS; LEUKEMIA-CELLS; PEPTIDES; LIGANDSImmunology; T-cell receptor (TCR); peptide-MHC modeling (p-MHC modeling); adoptive T-cell transfer therapy; TCR cell therapy; TCR identification; TCR characterization; trimolecular complex (TCR-p-MHC); target antigen characterization;
 Abstract: Adoptive transfer of T cells transgenic for tumor-reactive T-cell receptors (TCR) is an attractive immunotherapeutic approach. However, clinical translation is so far limited due to challenges in the identification of suitable target antigens as well as TCRs that are concurrent safe and efficient. Definition of key characteristics relevant for effective and specific tumor rejection is essential to improve current TCR-based adoptive T-cell immunotherapies. We here characterized in-depth two TCRs derived from the human leukocyte antigen (HLA)-mismatched allogeneic repertoire targeting two different myeloperoxidase (MPO)-derived peptides presented by the same HLA-restriction element side by side comprising state of the art biochemical and cellular in vitro, in vivo, and in silico experiments. In vitro experiments reveal comparable functional avidities, off-rates, and cytotoxic activities for both TCRs. However, we observed differences especially with respect to cytokine secretion and cross-reactivity as well as in vivo activity. Biochemical and in silico analyses demonstrate different binding qualities of MPO-peptides to the HLA-complex determining TCR qualities. We conclude from our biochemical and in silico analyses of peptide-HLA-binding that rigid and high-affinity binding of peptides is one of the most important factors for isolation of TCRs with high specificity and tumor rejection capacity from the MHC-mismatched repertoire. Based on our results, we developed a workflow for selection of such TCRs with high potency and safety profile suitable for clinical translation.

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Language(s): eng - English
 Dates: 2019
 Publication Status: Published online
 Pages: 16
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: ISI: 000473265300002
DOI: 10.3389/fimmu.2019.01485
 Degree: -

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Title: Frontiers in immunology
  Abbreviation : Front immunol
Source Genre: Journal
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Publ. Info: Lausanne : Frontiers Media
Pages: - Volume / Issue: 10 Sequence Number: 1485 Start / End Page: - Identifier: ISSN: 1664-3224
CoNE: https://pure.mpg.de/cone/journals/resource/1664-3224