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

Stefan Audehm; Manuel Glaser; Matteo Pecoraro; Eva Bräunlein; Sabine Mall; Richard Klar; Manuel Effenberger; Julian Albers; Henrique de Oliveira Bianchi; Janet Peper; Nahid Yusufi; Dirk H Busch; Stefan Stevanović; Matthias Mann; Iris Antes; Angela M Krackhardt

doi:10.3389/fimmu.2019.01485

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

Stefan Audehm, Manuel Glaser, Matteo Pecoraro, Eva Bräunlein, Sabine Mall, Richard Klar, Manuel Effenberger, Julian Albers, Henrique de Oliveira Bianchi, Janet Peper, Nahid Yusufi, Dirk H Busch, Stefan Stevanović, Matthias Mann, Iris Antes, Angela M Krackhardt

2 Citations (Scopus)

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.

Original language	English
Article number	1485
Journal	Frontiers in Immunology
Volume	10
ISSN	1664-3224
DOIs	https://doi.org/10.3389/fimmu.2019.01485
Publication status	Published - 28 Jun 2019
Externally published	Yes

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Audehm, S., Glaser, M., Pecoraro, M., Bräunlein, E., Mall, S., Klar, R., Effenberger, M., Albers, J., Bianchi, H. D. O., Peper, J., Yusufi, N., Busch, D. H., Stevanović, S., Mann, M., Antes, I., & Krackhardt, A. M. (2019). Key Features Relevant to Select Antigens and TCR From the MHC-Mismatched Repertoire to Treat Cancer. Frontiers in Immunology, 10, Article 1485. https://doi.org/10.3389/fimmu.2019.01485

Audehm, S, Glaser, M, Pecoraro, M, Bräunlein, E, Mall, S, Klar, R, Effenberger, M, Albers, J, Bianchi, HDO, Peper, J, Yusufi, N, Busch, DH, Stevanović, S, Mann, M, Antes, I & Krackhardt, AM 2019, 'Key Features Relevant to Select Antigens and TCR From the MHC-Mismatched Repertoire to Treat Cancer', Frontiers in Immunology, vol. 10, 1485. https://doi.org/10.3389/fimmu.2019.01485

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

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.",

author = "Stefan Audehm and Manuel Glaser and Matteo Pecoraro and Eva Br{\"a}unlein and Sabine Mall and Richard Klar and Manuel Effenberger and Julian Albers and Bianchi, {Henrique de Oliveira} and Janet Peper and Nahid Yusufi and Busch, {Dirk H} and Stefan Stevanovi{\'c} and Matthias Mann and Iris Antes and Krackhardt, {Angela M}",

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AU - Audehm, Stefan

AU - Glaser, Manuel

AU - Pecoraro, Matteo

AU - Bräunlein, Eva

AU - Mall, Sabine

AU - Klar, Richard

AU - Effenberger, Manuel

AU - Albers, Julian

AU - Bianchi, Henrique de Oliveira

AU - Peper, Janet

AU - Yusufi, Nahid

AU - Busch, Dirk H

AU - Stevanović, Stefan

AU - Mann, Matthias

AU - Antes, Iris

AU - Krackhardt, Angela M

PY - 2019/6/28

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N2 - 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.

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.

U2 - 10.3389/fimmu.2019.01485

DO - 10.3389/fimmu.2019.01485

M3 - Journal article

C2 - 31316521

SN - 1664-3224

VL - 10

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 1485

ER -

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

Abstract

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