PMID- 31316521 OWN - NLM STAT- MEDLINE DCOM- 20201021 LR - 20201021 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 10 DP - 2019 TI - Key Features Relevant to Select Antigens and TCR From the MHC-Mismatched Repertoire to Treat Cancer. PG - 1485 LID - 10.3389/fimmu.2019.01485 [doi] LID - 1485 AB - 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. FAU - Audehm, Stefan AU - Audehm S AD - Klinik und Poliklinik fur Innere Medizin III, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany. FAU - Glaser, Manuel AU - Glaser M AD - Center for Integrated Protein Science at the Department for Biosciences, Technische Universitat Munchen, Freising, Germany. FAU - Pecoraro, Matteo AU - Pecoraro M AD - Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany. FAU - Braunlein, Eva AU - Braunlein E AD - Klinik und Poliklinik fur Innere Medizin III, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany. FAU - Mall, Sabine AU - Mall S AD - Klinik und Poliklinik fur Innere Medizin III, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany. FAU - Klar, Richard AU - Klar R AD - Klinik und Poliklinik fur Innere Medizin III, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany. FAU - Effenberger, Manuel AU - Effenberger M AD - Institut fur Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universitat Munchen, Munich, Germany. FAU - Albers, Julian AU - Albers J AD - Klinik und Poliklinik fur Innere Medizin III, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany. FAU - Bianchi, Henrique de Oliveira AU - Bianchi HO AD - Klinik und Poliklinik fur Innere Medizin III, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany. FAU - Peper, Janet AU - Peper J AD - Eberhard Karls University Tubingen, Interfaculty Institute for Cell Biology, Tubingen, Germany. FAU - Yusufi, Nahid AU - Yusufi N AD - Nuklearmedizin, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany. FAU - Busch, Dirk H AU - Busch DH AD - Institut fur Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universitat Munchen, Munich, Germany. FAU - Stevanovic, Stefan AU - Stevanovic S AD - Eberhard Karls University Tubingen, Interfaculty Institute for Cell Biology, Tubingen, Germany. AD - Partner Site Tubingen, German Cancer Consortium (DKTK), Tubingen, Germany. FAU - Mann, Matthias AU - Mann M AD - Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany. FAU - Antes, Iris AU - Antes I AD - Center for Integrated Protein Science at the Department for Biosciences, Technische Universitat Munchen, Freising, Germany. FAU - Krackhardt, Angela M AU - Krackhardt AM AD - Klinik und Poliklinik fur Innere Medizin III, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany. AD - Partner Site Munich, German Cancer Consortium (DKTK), Munich, Germany. AD - German Cancer Research Center (DKFZ), Heidelberg, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190628 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Cytokines) RN - 0 (HLA Antigens) RN - 0 (Peptides) RN - 0 (Receptors, Antigen, T-Cell) RN - EC 1.11.1.7 (Peroxidase) SB - IM MH - Animals MH - Cell Line MH - Cytokines/immunology MH - HLA Antigens/*immunology MH - Humans MH - Major Histocompatibility Complex/immunology MH - Mice, Transgenic MH - Models, Molecular MH - Neoplasms/immunology/therapy MH - Peptides/*immunology MH - Peroxidase/*immunology MH - Receptors, Antigen, T-Cell/*immunology PMC - PMC6611213 OTO - NOTNLM OT - T-cell receptor (TCR) OT - TCR cell therapy OT - TCR characterization OT - TCR identification OT - adoptive T-cell transfer therapy OT - peptide-MHC modeling (p-MHC modeling) OT - target antigen characterization OT - trimolecular complex (TCR-p-MHC) EDAT- 2019/07/19 06:00 MHDA- 2020/10/22 06:00 PMCR- 2019/01/01 CRDT- 2019/07/19 06:00 PHST- 2018/11/27 00:00 [received] PHST- 2019/06/13 00:00 [accepted] PHST- 2019/07/19 06:00 [entrez] PHST- 2019/07/19 06:00 [pubmed] PHST- 2020/10/22 06:00 [medline] PHST- 2019/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2019.01485 [doi] PST - epublish SO - Front Immunol. 2019 Jun 28;10:1485. doi: 10.3389/fimmu.2019.01485. eCollection 2019.