Cargando…
2064: Deconstructing the peptide specificity of TCR recognition
OBJECTIVES/SPECIFIC AIMS: The off-target and organ-specific toxicities observed in cancer immunotherapy present an obstacle to T-cell-based therapeutics. A recent clinical trial underscored the need for improved methods to define TCR specificity after melanoma patients treated with TCR engineered T-...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cambridge University Press
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6799170/ http://dx.doi.org/10.1017/cts.2017.195 |
_version_ | 1783460225053884416 |
---|---|
author | Riley, Timothy P. Mendoza, Juan Garcia, K. C. Baker, Brian M. |
author_facet | Riley, Timothy P. Mendoza, Juan Garcia, K. C. Baker, Brian M. |
author_sort | Riley, Timothy P. |
collection | PubMed |
description | OBJECTIVES/SPECIFIC AIMS: The off-target and organ-specific toxicities observed in cancer immunotherapy present an obstacle to T-cell-based therapeutics. A recent clinical trial underscored the need for improved methods to define TCR specificity after melanoma patients treated with TCR engineered T-cells suffered from fatal cardiovascular toxicity arising from the unpredicted recognition of a muscle-specific peptide. METHODS/STUDY POPULATION: To address this drawback to T-cell-based immunotherapies, we developed a novel protein engineering approach to define the peptide specificity of a given TCR. Here, directed evolution in a yeast display system produced a large scale peptide library, where recognition by the melanoma reactive DMF5 TCR acted as the guiding selective pressure. After this technique identified a panel of putative cross reactive peptides, sequence analysis and computational modeling followed by kinetic binding experiments and structural analysis determined the DMF5 TCR recognizes 2 distinct classes of peptides through chemically distinct mechanisms. RESULTS/ANTICIPATED RESULTS: This information led to the rational, structure-based design of additional cross reactive peptides and introduced a unique approach to screen the human proteome and identify the TCR targets which triggered undesired autoimmunity when this molecule was used in clinical trials. DISCUSSION/SIGNIFICANCE OF IMPACT: The distinct chemical nature of the 2 peptide classes suggest TCRs are more cross reactive than previously thought, presenting an obstacle to cell-based immunotherapy. Defining the peptide specificity of TCRs is of high interest to the immunology community, and will lead to improved approaches to designing engineered TCRs for cell therapy. |
format | Online Article Text |
id | pubmed-6799170 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cambridge University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-67991702019-10-28 2064: Deconstructing the peptide specificity of TCR recognition Riley, Timothy P. Mendoza, Juan Garcia, K. C. Baker, Brian M. J Clin Transl Sci Mechanistic Basic to Clinical OBJECTIVES/SPECIFIC AIMS: The off-target and organ-specific toxicities observed in cancer immunotherapy present an obstacle to T-cell-based therapeutics. A recent clinical trial underscored the need for improved methods to define TCR specificity after melanoma patients treated with TCR engineered T-cells suffered from fatal cardiovascular toxicity arising from the unpredicted recognition of a muscle-specific peptide. METHODS/STUDY POPULATION: To address this drawback to T-cell-based immunotherapies, we developed a novel protein engineering approach to define the peptide specificity of a given TCR. Here, directed evolution in a yeast display system produced a large scale peptide library, where recognition by the melanoma reactive DMF5 TCR acted as the guiding selective pressure. After this technique identified a panel of putative cross reactive peptides, sequence analysis and computational modeling followed by kinetic binding experiments and structural analysis determined the DMF5 TCR recognizes 2 distinct classes of peptides through chemically distinct mechanisms. RESULTS/ANTICIPATED RESULTS: This information led to the rational, structure-based design of additional cross reactive peptides and introduced a unique approach to screen the human proteome and identify the TCR targets which triggered undesired autoimmunity when this molecule was used in clinical trials. DISCUSSION/SIGNIFICANCE OF IMPACT: The distinct chemical nature of the 2 peptide classes suggest TCRs are more cross reactive than previously thought, presenting an obstacle to cell-based immunotherapy. Defining the peptide specificity of TCRs is of high interest to the immunology community, and will lead to improved approaches to designing engineered TCRs for cell therapy. Cambridge University Press 2018-05-10 /pmc/articles/PMC6799170/ http://dx.doi.org/10.1017/cts.2017.195 Text en © The Association for Clinical and Translational Science 2018 http://creativecommons.org/licenses/by/4.0/ This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Mechanistic Basic to Clinical Riley, Timothy P. Mendoza, Juan Garcia, K. C. Baker, Brian M. 2064: Deconstructing the peptide specificity of TCR recognition |
title | 2064: Deconstructing the peptide specificity of TCR recognition |
title_full | 2064: Deconstructing the peptide specificity of TCR recognition |
title_fullStr | 2064: Deconstructing the peptide specificity of TCR recognition |
title_full_unstemmed | 2064: Deconstructing the peptide specificity of TCR recognition |
title_short | 2064: Deconstructing the peptide specificity of TCR recognition |
title_sort | 2064: deconstructing the peptide specificity of tcr recognition |
topic | Mechanistic Basic to Clinical |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6799170/ http://dx.doi.org/10.1017/cts.2017.195 |
work_keys_str_mv | AT rileytimothyp 2064deconstructingthepeptidespecificityoftcrrecognition AT mendozajuan 2064deconstructingthepeptidespecificityoftcrrecognition AT garciakc 2064deconstructingthepeptidespecificityoftcrrecognition AT bakerbrianm 2064deconstructingthepeptidespecificityoftcrrecognition |