Cargando…

A Single Dose of Neoadjuvant PD-1 Blockade Predicts Clinical Outcomes in Resectable Melanoma

Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuva...

Descripción completa

Detalles Bibliográficos
Autores principales: Huang, Alexander C., Orlowski, Robert J., Xu, Xiaowei, Mick, Rosemarie, George, Sangeeth M., Yan, Patrick K., Manne, Sasikanth, Kraya, Adam A., Wubbenhorst, Bradley, Dorfman, Liza, D’Andrea, Kurt, Wenz, Brandon M., Liu, Shujing, Chilukuri, Lakshmi, Kozlov, Andrew, Carberry, Mary, Giles, Lydia, Kier, Melanie W., Quagliarello, Felix, McGettigan, Suzanne, Kreider, Kristin, Annamalai, Lakshmanan, Zhao, Qing, Mogg, Robin, Xu, Wei, Blumenschein, Wendy M., Yearley, Jennifer H., Linette, Gerald P., Amaravadi, Ravi K., Schuchter, Lynn M., Herati, Ramin S., Bengsch, Bertram, Nathanson, Katherine L., Farwell, Michael D., Karakousis, Giorgos C., John Wherry, E., Mitchell, Tara C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699626/
https://www.ncbi.nlm.nih.gov/pubmed/30804515
http://dx.doi.org/10.1038/s41591-019-0357-y
_version_ 1783444753101094912
author Huang, Alexander C.
Orlowski, Robert J.
Xu, Xiaowei
Mick, Rosemarie
George, Sangeeth M.
Yan, Patrick K.
Manne, Sasikanth
Kraya, Adam A.
Wubbenhorst, Bradley
Dorfman, Liza
D’Andrea, Kurt
Wenz, Brandon M.
Liu, Shujing
Chilukuri, Lakshmi
Kozlov, Andrew
Carberry, Mary
Giles, Lydia
Kier, Melanie W.
Quagliarello, Felix
McGettigan, Suzanne
Kreider, Kristin
Annamalai, Lakshmanan
Zhao, Qing
Mogg, Robin
Xu, Wei
Blumenschein, Wendy M.
Yearley, Jennifer H.
Linette, Gerald P.
Amaravadi, Ravi K.
Schuchter, Lynn M.
Herati, Ramin S.
Bengsch, Bertram
Nathanson, Katherine L.
Farwell, Michael D.
Karakousis, Giorgos C.
John Wherry, E.
Mitchell, Tara C.
author_facet Huang, Alexander C.
Orlowski, Robert J.
Xu, Xiaowei
Mick, Rosemarie
George, Sangeeth M.
Yan, Patrick K.
Manne, Sasikanth
Kraya, Adam A.
Wubbenhorst, Bradley
Dorfman, Liza
D’Andrea, Kurt
Wenz, Brandon M.
Liu, Shujing
Chilukuri, Lakshmi
Kozlov, Andrew
Carberry, Mary
Giles, Lydia
Kier, Melanie W.
Quagliarello, Felix
McGettigan, Suzanne
Kreider, Kristin
Annamalai, Lakshmanan
Zhao, Qing
Mogg, Robin
Xu, Wei
Blumenschein, Wendy M.
Yearley, Jennifer H.
Linette, Gerald P.
Amaravadi, Ravi K.
Schuchter, Lynn M.
Herati, Ramin S.
Bengsch, Bertram
Nathanson, Katherine L.
Farwell, Michael D.
Karakousis, Giorgos C.
John Wherry, E.
Mitchell, Tara C.
author_sort Huang, Alexander C.
collection PubMed
description Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8/27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease-free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pre-treatment immune signature (Neoadjuvant Response Signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.
format Online
Article
Text
id pubmed-6699626
institution National Center for Biotechnology Information
language English
publishDate 2019
record_format MEDLINE/PubMed
spelling pubmed-66996262019-08-25 A Single Dose of Neoadjuvant PD-1 Blockade Predicts Clinical Outcomes in Resectable Melanoma Huang, Alexander C. Orlowski, Robert J. Xu, Xiaowei Mick, Rosemarie George, Sangeeth M. Yan, Patrick K. Manne, Sasikanth Kraya, Adam A. Wubbenhorst, Bradley Dorfman, Liza D’Andrea, Kurt Wenz, Brandon M. Liu, Shujing Chilukuri, Lakshmi Kozlov, Andrew Carberry, Mary Giles, Lydia Kier, Melanie W. Quagliarello, Felix McGettigan, Suzanne Kreider, Kristin Annamalai, Lakshmanan Zhao, Qing Mogg, Robin Xu, Wei Blumenschein, Wendy M. Yearley, Jennifer H. Linette, Gerald P. Amaravadi, Ravi K. Schuchter, Lynn M. Herati, Ramin S. Bengsch, Bertram Nathanson, Katherine L. Farwell, Michael D. Karakousis, Giorgos C. John Wherry, E. Mitchell, Tara C. Nat Med Article Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8/27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease-free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pre-treatment immune signature (Neoadjuvant Response Signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade. 2019-02-25 2019-03 /pmc/articles/PMC6699626/ /pubmed/30804515 http://dx.doi.org/10.1038/s41591-019-0357-y Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Huang, Alexander C.
Orlowski, Robert J.
Xu, Xiaowei
Mick, Rosemarie
George, Sangeeth M.
Yan, Patrick K.
Manne, Sasikanth
Kraya, Adam A.
Wubbenhorst, Bradley
Dorfman, Liza
D’Andrea, Kurt
Wenz, Brandon M.
Liu, Shujing
Chilukuri, Lakshmi
Kozlov, Andrew
Carberry, Mary
Giles, Lydia
Kier, Melanie W.
Quagliarello, Felix
McGettigan, Suzanne
Kreider, Kristin
Annamalai, Lakshmanan
Zhao, Qing
Mogg, Robin
Xu, Wei
Blumenschein, Wendy M.
Yearley, Jennifer H.
Linette, Gerald P.
Amaravadi, Ravi K.
Schuchter, Lynn M.
Herati, Ramin S.
Bengsch, Bertram
Nathanson, Katherine L.
Farwell, Michael D.
Karakousis, Giorgos C.
John Wherry, E.
Mitchell, Tara C.
A Single Dose of Neoadjuvant PD-1 Blockade Predicts Clinical Outcomes in Resectable Melanoma
title A Single Dose of Neoadjuvant PD-1 Blockade Predicts Clinical Outcomes in Resectable Melanoma
title_full A Single Dose of Neoadjuvant PD-1 Blockade Predicts Clinical Outcomes in Resectable Melanoma
title_fullStr A Single Dose of Neoadjuvant PD-1 Blockade Predicts Clinical Outcomes in Resectable Melanoma
title_full_unstemmed A Single Dose of Neoadjuvant PD-1 Blockade Predicts Clinical Outcomes in Resectable Melanoma
title_short A Single Dose of Neoadjuvant PD-1 Blockade Predicts Clinical Outcomes in Resectable Melanoma
title_sort single dose of neoadjuvant pd-1 blockade predicts clinical outcomes in resectable melanoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699626/
https://www.ncbi.nlm.nih.gov/pubmed/30804515
http://dx.doi.org/10.1038/s41591-019-0357-y
work_keys_str_mv AT huangalexanderc asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT orlowskirobertj asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT xuxiaowei asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT mickrosemarie asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT georgesangeethm asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT yanpatrickk asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT mannesasikanth asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT krayaadama asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT wubbenhorstbradley asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT dorfmanliza asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT dandreakurt asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT wenzbrandonm asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT liushujing asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT chilukurilakshmi asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT kozlovandrew asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT carberrymary asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT gileslydia asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT kiermelaniew asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT quagliarellofelix asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT mcgettigansuzanne asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT kreiderkristin asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT annamalailakshmanan asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT zhaoqing asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT moggrobin asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT xuwei asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT blumenscheinwendym asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT yearleyjenniferh asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT linettegeraldp asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT amaravadiravik asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT schuchterlynnm asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT heratiramins asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT bengschbertram asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT nathansonkatherinel asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT farwellmichaeld asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT karakousisgiorgosc asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT johnwherrye asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT mitchelltarac asingledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT huangalexanderc singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT orlowskirobertj singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT xuxiaowei singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT mickrosemarie singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT georgesangeethm singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT yanpatrickk singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT mannesasikanth singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT krayaadama singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT wubbenhorstbradley singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT dorfmanliza singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT dandreakurt singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT wenzbrandonm singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT liushujing singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT chilukurilakshmi singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT kozlovandrew singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT carberrymary singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT gileslydia singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT kiermelaniew singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT quagliarellofelix singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT mcgettigansuzanne singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT kreiderkristin singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT annamalailakshmanan singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT zhaoqing singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT moggrobin singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT xuwei singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT blumenscheinwendym singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT yearleyjenniferh singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT linettegeraldp singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT amaravadiravik singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT schuchterlynnm singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT heratiramins singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT bengschbertram singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT nathansonkatherinel singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT farwellmichaeld singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT karakousisgiorgosc singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT johnwherrye singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma
AT mitchelltarac singledoseofneoadjuvantpd1blockadepredictsclinicaloutcomesinresectablemelanoma