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Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1
BACKGROUND: Several predictive biomarkers are currently approved or are under investigation for the selection of patients for checkpoint blockade. Tumor PD-L1 expression is used for stratification of non-small cell lung (NSCLC) patients, with tumor mutational burden (TMB) also being explored with pr...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371497/ https://www.ncbi.nlm.nih.gov/pubmed/30744692 http://dx.doi.org/10.1186/s40425-018-0492-x |
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author | Smith, Kellie N. Llosa, Nicolas J. Cottrell, Tricia R. Siegel, Nicholas Fan, Hongni Suri, Prerna Chan, Hok Yee Guo, Haidan Oke, Teniola Awan, Anas H. Verde, Franco Danilova, Ludmila Anagnostou, Valsamo Tam, Ada J. Luber, Brandon S. Bartlett, Bjarne R. Aulakh, Laveet K. Sidhom, John-William Zhu, Qingfeng Sears, Cynthia L. Cope, Leslie Sharfman, William H. Thompson, Elizabeth D. Riemer, Joanne Marrone, Kristen A. Naidoo, Jarushka Velculescu, Victor E. Forde, Patrick M. Vogelstein, Bert Kinzler, Kenneth W. Papadopoulos, Nickolas Durham, Jennifer N. Wang, Hao Le, Dung T. Justesen, Sune Taube, Janis M. Diaz, Luis A. Brahmer, Julie R. Pardoll, Drew M. Anders, Robert A. Housseau, Franck |
author_facet | Smith, Kellie N. Llosa, Nicolas J. Cottrell, Tricia R. Siegel, Nicholas Fan, Hongni Suri, Prerna Chan, Hok Yee Guo, Haidan Oke, Teniola Awan, Anas H. Verde, Franco Danilova, Ludmila Anagnostou, Valsamo Tam, Ada J. Luber, Brandon S. Bartlett, Bjarne R. Aulakh, Laveet K. Sidhom, John-William Zhu, Qingfeng Sears, Cynthia L. Cope, Leslie Sharfman, William H. Thompson, Elizabeth D. Riemer, Joanne Marrone, Kristen A. Naidoo, Jarushka Velculescu, Victor E. Forde, Patrick M. Vogelstein, Bert Kinzler, Kenneth W. Papadopoulos, Nickolas Durham, Jennifer N. Wang, Hao Le, Dung T. Justesen, Sune Taube, Janis M. Diaz, Luis A. Brahmer, Julie R. Pardoll, Drew M. Anders, Robert A. Housseau, Franck |
author_sort | Smith, Kellie N. |
collection | PubMed |
description | BACKGROUND: Several predictive biomarkers are currently approved or are under investigation for the selection of patients for checkpoint blockade. Tumor PD-L1 expression is used for stratification of non-small cell lung (NSCLC) patients, with tumor mutational burden (TMB) also being explored with promising results, and mismatch-repair deficiency is approved for tumor site-agnostic disease. While tumors with high PD-L1 expression, high TMB, or mismatch repair deficiency respond well to checkpoint blockade, tumors with lower PD-L1 expression, lower mutational burdens, or mismatch repair proficiency respond much less frequently. CASE PRESENTATION: We studied two patients with unexpected responses to checkpoint blockade monotherapy: a patient with PD-L1-negative and low mutational burden NSCLC and one with mismatch repair proficient colorectal cancer (CRC), both of whom lack the biomarkers associated with response to checkpoint blockade, yet achieved durable clinical benefit. Both maintained T-cell responses in peripheral blood to oncogenic driver mutations – BRAF-N581I in the NSCLC and AKT1-E17K in the CRC – years after treatment initiation. Mutation-specific T cells were also found in the primary tumor and underwent dynamic perturbations in the periphery upon treatment. CONCLUSIONS: These findings suggest that T cell responses to oncogenic driver mutations may be more prevalent than previously appreciated and could be harnessed in immunotherapeutic treatment, particularly for patients who lack the traditional biomarkers associated with response. Comprehensive studies are warranted to further delineate additional predictive biomarkers and populations of patients who may benefit from checkpoint blockade. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40425-018-0492-x) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6371497 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-63714972019-02-21 Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1 Smith, Kellie N. Llosa, Nicolas J. Cottrell, Tricia R. Siegel, Nicholas Fan, Hongni Suri, Prerna Chan, Hok Yee Guo, Haidan Oke, Teniola Awan, Anas H. Verde, Franco Danilova, Ludmila Anagnostou, Valsamo Tam, Ada J. Luber, Brandon S. Bartlett, Bjarne R. Aulakh, Laveet K. Sidhom, John-William Zhu, Qingfeng Sears, Cynthia L. Cope, Leslie Sharfman, William H. Thompson, Elizabeth D. Riemer, Joanne Marrone, Kristen A. Naidoo, Jarushka Velculescu, Victor E. Forde, Patrick M. Vogelstein, Bert Kinzler, Kenneth W. Papadopoulos, Nickolas Durham, Jennifer N. Wang, Hao Le, Dung T. Justesen, Sune Taube, Janis M. Diaz, Luis A. Brahmer, Julie R. Pardoll, Drew M. Anders, Robert A. Housseau, Franck J Immunother Cancer Case Report BACKGROUND: Several predictive biomarkers are currently approved or are under investigation for the selection of patients for checkpoint blockade. Tumor PD-L1 expression is used for stratification of non-small cell lung (NSCLC) patients, with tumor mutational burden (TMB) also being explored with promising results, and mismatch-repair deficiency is approved for tumor site-agnostic disease. While tumors with high PD-L1 expression, high TMB, or mismatch repair deficiency respond well to checkpoint blockade, tumors with lower PD-L1 expression, lower mutational burdens, or mismatch repair proficiency respond much less frequently. CASE PRESENTATION: We studied two patients with unexpected responses to checkpoint blockade monotherapy: a patient with PD-L1-negative and low mutational burden NSCLC and one with mismatch repair proficient colorectal cancer (CRC), both of whom lack the biomarkers associated with response to checkpoint blockade, yet achieved durable clinical benefit. Both maintained T-cell responses in peripheral blood to oncogenic driver mutations – BRAF-N581I in the NSCLC and AKT1-E17K in the CRC – years after treatment initiation. Mutation-specific T cells were also found in the primary tumor and underwent dynamic perturbations in the periphery upon treatment. CONCLUSIONS: These findings suggest that T cell responses to oncogenic driver mutations may be more prevalent than previously appreciated and could be harnessed in immunotherapeutic treatment, particularly for patients who lack the traditional biomarkers associated with response. Comprehensive studies are warranted to further delineate additional predictive biomarkers and populations of patients who may benefit from checkpoint blockade. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40425-018-0492-x) contains supplementary material, which is available to authorized users. BioMed Central 2019-02-11 /pmc/articles/PMC6371497/ /pubmed/30744692 http://dx.doi.org/10.1186/s40425-018-0492-x Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Case Report Smith, Kellie N. Llosa, Nicolas J. Cottrell, Tricia R. Siegel, Nicholas Fan, Hongni Suri, Prerna Chan, Hok Yee Guo, Haidan Oke, Teniola Awan, Anas H. Verde, Franco Danilova, Ludmila Anagnostou, Valsamo Tam, Ada J. Luber, Brandon S. Bartlett, Bjarne R. Aulakh, Laveet K. Sidhom, John-William Zhu, Qingfeng Sears, Cynthia L. Cope, Leslie Sharfman, William H. Thompson, Elizabeth D. Riemer, Joanne Marrone, Kristen A. Naidoo, Jarushka Velculescu, Victor E. Forde, Patrick M. Vogelstein, Bert Kinzler, Kenneth W. Papadopoulos, Nickolas Durham, Jennifer N. Wang, Hao Le, Dung T. Justesen, Sune Taube, Janis M. Diaz, Luis A. Brahmer, Julie R. Pardoll, Drew M. Anders, Robert A. Housseau, Franck Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1 |
title | Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1 |
title_full | Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1 |
title_fullStr | Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1 |
title_full_unstemmed | Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1 |
title_short | Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1 |
title_sort | persistent mutant oncogene specific t cells in two patients benefitting from anti-pd-1 |
topic | Case Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371497/ https://www.ncbi.nlm.nih.gov/pubmed/30744692 http://dx.doi.org/10.1186/s40425-018-0492-x |
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