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Non-viral precision T cell receptor replacement for personalized cell therapy
T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells(1–3). Here we developed a clinical-grade approach based on CRISPR–Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encod...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9768791/ https://www.ncbi.nlm.nih.gov/pubmed/36356599 http://dx.doi.org/10.1038/s41586-022-05531-1 |
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author | Foy, Susan P. Jacoby, Kyle Bota, Daniela A. Hunter, Theresa Pan, Zheng Stawiski, Eric Ma, Yan Lu, William Peng, Songming Wang, Clifford L. Yuen, Benjamin Dalmas, Olivier Heeringa, Katharine Sennino, Barbara Conroy, Andy Bethune, Michael T. Mende, Ines White, William Kukreja, Monica Gunturu, Swetha Humphrey, Emily Hussaini, Adeel An, Duo Litterman, Adam J. Quach, Boi Bryant Ng, Alphonsus H. C. Lu, Yue Smith, Chad Campbell, Katie M. Anaya, Daniel Skrdlant, Lindsey Huang, Eva Yi-Hsuan Mendoza, Ventura Mathur, Jyoti Dengler, Luke Purandare, Bhamini Moot, Robert Yi, Michael C. Funke, Roel Sibley, Alison Stallings-Schmitt, Todd Oh, David Y. Chmielowski, Bartosz Abedi, Mehrdad Yuan, Yuan Sosman, Jeffrey A. Lee, Sylvia M. Schoenfeld, Adam J. Baltimore, David Heath, James R. Franzusoff, Alex Ribas, Antoni Rao, Arati V. Mandl, Stefanie J. |
author_facet | Foy, Susan P. Jacoby, Kyle Bota, Daniela A. Hunter, Theresa Pan, Zheng Stawiski, Eric Ma, Yan Lu, William Peng, Songming Wang, Clifford L. Yuen, Benjamin Dalmas, Olivier Heeringa, Katharine Sennino, Barbara Conroy, Andy Bethune, Michael T. Mende, Ines White, William Kukreja, Monica Gunturu, Swetha Humphrey, Emily Hussaini, Adeel An, Duo Litterman, Adam J. Quach, Boi Bryant Ng, Alphonsus H. C. Lu, Yue Smith, Chad Campbell, Katie M. Anaya, Daniel Skrdlant, Lindsey Huang, Eva Yi-Hsuan Mendoza, Ventura Mathur, Jyoti Dengler, Luke Purandare, Bhamini Moot, Robert Yi, Michael C. Funke, Roel Sibley, Alison Stallings-Schmitt, Todd Oh, David Y. Chmielowski, Bartosz Abedi, Mehrdad Yuan, Yuan Sosman, Jeffrey A. Lee, Sylvia M. Schoenfeld, Adam J. Baltimore, David Heath, James R. Franzusoff, Alex Ribas, Antoni Rao, Arati V. Mandl, Stefanie J. |
author_sort | Foy, Susan P. |
collection | PubMed |
description | T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells(1–3). Here we developed a clinical-grade approach based on CRISPR–Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encodes TCRβ). We also inserted into the TRAC locus two chains of a neoantigen-specific TCR (neoTCR) isolated from circulating T cells of patients. The neoTCRs were isolated using a personalized library of soluble predicted neoantigen–HLA capture reagents. Sixteen patients with different refractory solid cancers received up to three distinct neoTCR transgenic cell products. Each product expressed a patient-specific neoTCR and was administered in a cell-dose-escalation, first-in-human phase I clinical trial (NCT03970382). One patient had grade 1 cytokine release syndrome and one patient had grade 3 encephalitis. All participants had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease and the other eleven had disease progression as the best response on the therapy. neoTCR transgenic T cells were detected in tumour biopsy samples after infusion at frequencies higher than the native TCRs before infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs that recognize mutational neoantigens. Moreover, simultaneous knockout of the endogenous TCR and knock-in of neoTCRs using single-step, non-viral precision genome-editing are achieved. The manufacture of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene-edited neoTCR T cell products and the ability of the transgenic T cells to traffic to the tumours of patients are also demonstrated. |
format | Online Article Text |
id | pubmed-9768791 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-97687912022-12-21 Non-viral precision T cell receptor replacement for personalized cell therapy Foy, Susan P. Jacoby, Kyle Bota, Daniela A. Hunter, Theresa Pan, Zheng Stawiski, Eric Ma, Yan Lu, William Peng, Songming Wang, Clifford L. Yuen, Benjamin Dalmas, Olivier Heeringa, Katharine Sennino, Barbara Conroy, Andy Bethune, Michael T. Mende, Ines White, William Kukreja, Monica Gunturu, Swetha Humphrey, Emily Hussaini, Adeel An, Duo Litterman, Adam J. Quach, Boi Bryant Ng, Alphonsus H. C. Lu, Yue Smith, Chad Campbell, Katie M. Anaya, Daniel Skrdlant, Lindsey Huang, Eva Yi-Hsuan Mendoza, Ventura Mathur, Jyoti Dengler, Luke Purandare, Bhamini Moot, Robert Yi, Michael C. Funke, Roel Sibley, Alison Stallings-Schmitt, Todd Oh, David Y. Chmielowski, Bartosz Abedi, Mehrdad Yuan, Yuan Sosman, Jeffrey A. Lee, Sylvia M. Schoenfeld, Adam J. Baltimore, David Heath, James R. Franzusoff, Alex Ribas, Antoni Rao, Arati V. Mandl, Stefanie J. Nature Article T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells(1–3). Here we developed a clinical-grade approach based on CRISPR–Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encodes TCRβ). We also inserted into the TRAC locus two chains of a neoantigen-specific TCR (neoTCR) isolated from circulating T cells of patients. The neoTCRs were isolated using a personalized library of soluble predicted neoantigen–HLA capture reagents. Sixteen patients with different refractory solid cancers received up to three distinct neoTCR transgenic cell products. Each product expressed a patient-specific neoTCR and was administered in a cell-dose-escalation, first-in-human phase I clinical trial (NCT03970382). One patient had grade 1 cytokine release syndrome and one patient had grade 3 encephalitis. All participants had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease and the other eleven had disease progression as the best response on the therapy. neoTCR transgenic T cells were detected in tumour biopsy samples after infusion at frequencies higher than the native TCRs before infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs that recognize mutational neoantigens. Moreover, simultaneous knockout of the endogenous TCR and knock-in of neoTCRs using single-step, non-viral precision genome-editing are achieved. The manufacture of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene-edited neoTCR T cell products and the ability of the transgenic T cells to traffic to the tumours of patients are also demonstrated. Nature Publishing Group UK 2022-11-10 2023 /pmc/articles/PMC9768791/ /pubmed/36356599 http://dx.doi.org/10.1038/s41586-022-05531-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Foy, Susan P. Jacoby, Kyle Bota, Daniela A. Hunter, Theresa Pan, Zheng Stawiski, Eric Ma, Yan Lu, William Peng, Songming Wang, Clifford L. Yuen, Benjamin Dalmas, Olivier Heeringa, Katharine Sennino, Barbara Conroy, Andy Bethune, Michael T. Mende, Ines White, William Kukreja, Monica Gunturu, Swetha Humphrey, Emily Hussaini, Adeel An, Duo Litterman, Adam J. Quach, Boi Bryant Ng, Alphonsus H. C. Lu, Yue Smith, Chad Campbell, Katie M. Anaya, Daniel Skrdlant, Lindsey Huang, Eva Yi-Hsuan Mendoza, Ventura Mathur, Jyoti Dengler, Luke Purandare, Bhamini Moot, Robert Yi, Michael C. Funke, Roel Sibley, Alison Stallings-Schmitt, Todd Oh, David Y. Chmielowski, Bartosz Abedi, Mehrdad Yuan, Yuan Sosman, Jeffrey A. Lee, Sylvia M. Schoenfeld, Adam J. Baltimore, David Heath, James R. Franzusoff, Alex Ribas, Antoni Rao, Arati V. Mandl, Stefanie J. Non-viral precision T cell receptor replacement for personalized cell therapy |
title | Non-viral precision T cell receptor replacement for personalized cell therapy |
title_full | Non-viral precision T cell receptor replacement for personalized cell therapy |
title_fullStr | Non-viral precision T cell receptor replacement for personalized cell therapy |
title_full_unstemmed | Non-viral precision T cell receptor replacement for personalized cell therapy |
title_short | Non-viral precision T cell receptor replacement for personalized cell therapy |
title_sort | non-viral precision t cell receptor replacement for personalized cell therapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9768791/ https://www.ncbi.nlm.nih.gov/pubmed/36356599 http://dx.doi.org/10.1038/s41586-022-05531-1 |
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