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Using patient-derived tumor organoids from common epithelial cancers to analyze personalized T-cell responses to neoantigens
Adoptive cell transfer of tumor-infiltrating lymphocytes (TIL) can mediate durable complete responses in some patients with common epithelial cancers but does so infrequently. A better understanding of T-cell responses to neoantigens and tumor-related immune evasion mechanisms requires having the au...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10491521/ https://www.ncbi.nlm.nih.gov/pubmed/37368077 http://dx.doi.org/10.1007/s00262-023-03476-6 |
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author | Parikh, Anup Y. Masi, Robert Gasmi, Billel Hanada, Ken-ichi Parkhurst, Maria Gartner, Jared Sindiri, Sivasish Prickett, Todd Robbins, Paul Zacharakis, Nikolaos Beshiri, Mike Kelly, Kathleen Rosenberg, Steven A. Yang, James C. |
author_facet | Parikh, Anup Y. Masi, Robert Gasmi, Billel Hanada, Ken-ichi Parkhurst, Maria Gartner, Jared Sindiri, Sivasish Prickett, Todd Robbins, Paul Zacharakis, Nikolaos Beshiri, Mike Kelly, Kathleen Rosenberg, Steven A. Yang, James C. |
author_sort | Parikh, Anup Y. |
collection | PubMed |
description | Adoptive cell transfer of tumor-infiltrating lymphocytes (TIL) can mediate durable complete responses in some patients with common epithelial cancers but does so infrequently. A better understanding of T-cell responses to neoantigens and tumor-related immune evasion mechanisms requires having the autologous tumor as a reagent. We investigated the ability of patient-derived tumor organoids (PDTO) to fulfill this need and evaluated their utility as a tool for selecting T-cells for adoptive cell therapy. PDTO established from metastases from patients with colorectal, breast, pancreatic, bile duct, esophageal, lung, and kidney cancers underwent whole exomic sequencing (WES), to define mutations. Organoids were then evaluated for recognition by autologous TIL or T-cells transduced with cloned T-cell receptors recognizing defined neoantigens. PDTO were also used to identify and clone TCRs from TIL targeting private neoantigens and define those tumor-specific targets. PDTO were successfully established in 38/47 attempts. 75% were available within 2 months, a timeframe compatible with screening TIL for clinical administration. These lines exhibited good genetic fidelity with their parental tumors, especially for mutations with higher clonality. Immunologic recognition assays demonstrated instances of HLA allelic loss not found by pan-HLA immunohistochemistry and in some cases WES of fresh tumor. PDTO could also be used to show differences between TCRs recognizing the same antigen and to find and clone TCRs recognizing private neoantigens. PDTO can detect tumor-specific defects blocking T-cell recognition and may have a role as a selection tool for TCRs and TIL used in adoptive cell therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00262-023-03476-6. |
format | Online Article Text |
id | pubmed-10491521 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-104915212023-09-10 Using patient-derived tumor organoids from common epithelial cancers to analyze personalized T-cell responses to neoantigens Parikh, Anup Y. Masi, Robert Gasmi, Billel Hanada, Ken-ichi Parkhurst, Maria Gartner, Jared Sindiri, Sivasish Prickett, Todd Robbins, Paul Zacharakis, Nikolaos Beshiri, Mike Kelly, Kathleen Rosenberg, Steven A. Yang, James C. Cancer Immunol Immunother Research Adoptive cell transfer of tumor-infiltrating lymphocytes (TIL) can mediate durable complete responses in some patients with common epithelial cancers but does so infrequently. A better understanding of T-cell responses to neoantigens and tumor-related immune evasion mechanisms requires having the autologous tumor as a reagent. We investigated the ability of patient-derived tumor organoids (PDTO) to fulfill this need and evaluated their utility as a tool for selecting T-cells for adoptive cell therapy. PDTO established from metastases from patients with colorectal, breast, pancreatic, bile duct, esophageal, lung, and kidney cancers underwent whole exomic sequencing (WES), to define mutations. Organoids were then evaluated for recognition by autologous TIL or T-cells transduced with cloned T-cell receptors recognizing defined neoantigens. PDTO were also used to identify and clone TCRs from TIL targeting private neoantigens and define those tumor-specific targets. PDTO were successfully established in 38/47 attempts. 75% were available within 2 months, a timeframe compatible with screening TIL for clinical administration. These lines exhibited good genetic fidelity with their parental tumors, especially for mutations with higher clonality. Immunologic recognition assays demonstrated instances of HLA allelic loss not found by pan-HLA immunohistochemistry and in some cases WES of fresh tumor. PDTO could also be used to show differences between TCRs recognizing the same antigen and to find and clone TCRs recognizing private neoantigens. PDTO can detect tumor-specific defects blocking T-cell recognition and may have a role as a selection tool for TCRs and TIL used in adoptive cell therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00262-023-03476-6. Springer Berlin Heidelberg 2023-06-27 2023 /pmc/articles/PMC10491521/ /pubmed/37368077 http://dx.doi.org/10.1007/s00262-023-03476-6 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 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 | Research Parikh, Anup Y. Masi, Robert Gasmi, Billel Hanada, Ken-ichi Parkhurst, Maria Gartner, Jared Sindiri, Sivasish Prickett, Todd Robbins, Paul Zacharakis, Nikolaos Beshiri, Mike Kelly, Kathleen Rosenberg, Steven A. Yang, James C. Using patient-derived tumor organoids from common epithelial cancers to analyze personalized T-cell responses to neoantigens |
title | Using patient-derived tumor organoids from common epithelial cancers to analyze personalized T-cell responses to neoantigens |
title_full | Using patient-derived tumor organoids from common epithelial cancers to analyze personalized T-cell responses to neoantigens |
title_fullStr | Using patient-derived tumor organoids from common epithelial cancers to analyze personalized T-cell responses to neoantigens |
title_full_unstemmed | Using patient-derived tumor organoids from common epithelial cancers to analyze personalized T-cell responses to neoantigens |
title_short | Using patient-derived tumor organoids from common epithelial cancers to analyze personalized T-cell responses to neoantigens |
title_sort | using patient-derived tumor organoids from common epithelial cancers to analyze personalized t-cell responses to neoantigens |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10491521/ https://www.ncbi.nlm.nih.gov/pubmed/37368077 http://dx.doi.org/10.1007/s00262-023-03476-6 |
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