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IMMU-18. FAVORABLE OUTCOME IN REPLICATION REPAIR DEFICIENT HYPERMUTANT BRAIN TUMORS TO IMMUNE CHECKPOINT INHIBITION: AN INTERNATIONAL RRD CONSORTIUM REGISTRY STUDY
Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond to immune checkpoint inhibition (ICI). We performed a consortium registry study of ICI in recurrent RRD cancers. Clinical and companion biomarkers were collected longitudinally on all patients. Biomarkers...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715575/ http://dx.doi.org/10.1093/neuonc/noaa222.374 |
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author | Bouffet, Eric Sudhaman, Sumedha Chung, Jiil Kelly, Jacalyn Coblentz, Ailish Edwards, Melissa Lipman, Tatiana Zhang, Cindy Ercan, Ayse Bahar Sambira, Lauren Bendel, Anne Bielack, Stefan Koustenis, Elisabeth Blumenthal, Deborah Bowers, Daniel Broniscer, Alberto Bronsema, Annika Carroll, Sara Chiaravalli, Stefano Cole, Kristina Constantini, Shlomi De Mola, Rebecca Loret Dunn, Gavin Fröjd, Charlotta Gass, David Gauvain, Karen George, Ben Hijiya, Nobuko Hoffman, Lindsey Knipstein, Jeffrey Laetsch, Ted Larouche, Valérie Lassaletta, Alvaro Lindhorst, Scott Lossos, Alexander Luna-Fineman, Sandra Magimairajan, Vanan Mason, Gary Mason, Warren Massimino, Maura Mordechai, Oz Opocher, Enrico Oren, Michal Osborn, Michael Reddy, Alyssa Remke, Mark Roy, Sumita Sabel, Magnus Samuel, David Schneider, Kami Sen, Santanu Stearns, Duncan Sumerauer, David Thomas, Gregory Tomboc, Patrick Van Damme, An Wierman, Margaret Winer, Ira Yen, Lee Yi Zapotocky, Michal Ziegler, David Zimmermann, Stefanie Dvir, Rina Rechavi, Gidi Durno, Carol Aronson, Melyssa Taylor, Michael Dirks, Peter Pugh, Trevor Shlien, Adam Hawkins, Cynthia Morgenstern, Daniel Tabori, Uri |
author_facet | Bouffet, Eric Sudhaman, Sumedha Chung, Jiil Kelly, Jacalyn Coblentz, Ailish Edwards, Melissa Lipman, Tatiana Zhang, Cindy Ercan, Ayse Bahar Sambira, Lauren Bendel, Anne Bielack, Stefan Koustenis, Elisabeth Blumenthal, Deborah Bowers, Daniel Broniscer, Alberto Bronsema, Annika Carroll, Sara Chiaravalli, Stefano Cole, Kristina Constantini, Shlomi De Mola, Rebecca Loret Dunn, Gavin Fröjd, Charlotta Gass, David Gauvain, Karen George, Ben Hijiya, Nobuko Hoffman, Lindsey Knipstein, Jeffrey Laetsch, Ted Larouche, Valérie Lassaletta, Alvaro Lindhorst, Scott Lossos, Alexander Luna-Fineman, Sandra Magimairajan, Vanan Mason, Gary Mason, Warren Massimino, Maura Mordechai, Oz Opocher, Enrico Oren, Michal Osborn, Michael Reddy, Alyssa Remke, Mark Roy, Sumita Sabel, Magnus Samuel, David Schneider, Kami Sen, Santanu Stearns, Duncan Sumerauer, David Thomas, Gregory Tomboc, Patrick Van Damme, An Wierman, Margaret Winer, Ira Yen, Lee Yi Zapotocky, Michal Ziegler, David Zimmermann, Stefanie Dvir, Rina Rechavi, Gidi Durno, Carol Aronson, Melyssa Taylor, Michael Dirks, Peter Pugh, Trevor Shlien, Adam Hawkins, Cynthia Morgenstern, Daniel Tabori, Uri |
author_sort | Bouffet, Eric |
collection | PubMed |
description | Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond to immune checkpoint inhibition (ICI). We performed a consortium registry study of ICI in recurrent RRD cancers. Clinical and companion biomarkers were collected longitudinally on all patients. Biomarkers included tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference was obtained by RNAseq and T cell rearrangement was collected in the tumor and in blood throughout treatment. Of the 46 tumors on the study, 32 were brain tumors with glioblastoma in 96%. Rapid, objective responses (>50%) were observed in 50% of glioblastomas. Three year overall survival for the whole cohort was 48+/-8% which compares favorably with historical controls. Brain tumors fared worse with OS of 39+/-10% and late recurrences observed even after 2 years of therapy (p=0.02). Tumor size and acute “flare” constitute poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens correlated with response to ICI (p=0.02). Specific signatures extracted from SNVs and total mutations predicted response to ICI and favorable outcome (p=0.005). RNA inference and TCR reveal that the FLARE phenotype is mostly acute nonspecific immune response and not true progression. Finally, glioblastomas (n=8) which failed single agent ICI had favorable responses to combinational immunotherapies with prolonged survival of 65%+/-8% at one year after failure vs 0 for other patients (p=0.01). RRD glioblastomas exhibit favorable outcome and responses to ICI. Combinational therapies based on tumor and immune signatures of these cancers are necessary. |
format | Online Article Text |
id | pubmed-7715575 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-77155752020-12-09 IMMU-18. FAVORABLE OUTCOME IN REPLICATION REPAIR DEFICIENT HYPERMUTANT BRAIN TUMORS TO IMMUNE CHECKPOINT INHIBITION: AN INTERNATIONAL RRD CONSORTIUM REGISTRY STUDY Bouffet, Eric Sudhaman, Sumedha Chung, Jiil Kelly, Jacalyn Coblentz, Ailish Edwards, Melissa Lipman, Tatiana Zhang, Cindy Ercan, Ayse Bahar Sambira, Lauren Bendel, Anne Bielack, Stefan Koustenis, Elisabeth Blumenthal, Deborah Bowers, Daniel Broniscer, Alberto Bronsema, Annika Carroll, Sara Chiaravalli, Stefano Cole, Kristina Constantini, Shlomi De Mola, Rebecca Loret Dunn, Gavin Fröjd, Charlotta Gass, David Gauvain, Karen George, Ben Hijiya, Nobuko Hoffman, Lindsey Knipstein, Jeffrey Laetsch, Ted Larouche, Valérie Lassaletta, Alvaro Lindhorst, Scott Lossos, Alexander Luna-Fineman, Sandra Magimairajan, Vanan Mason, Gary Mason, Warren Massimino, Maura Mordechai, Oz Opocher, Enrico Oren, Michal Osborn, Michael Reddy, Alyssa Remke, Mark Roy, Sumita Sabel, Magnus Samuel, David Schneider, Kami Sen, Santanu Stearns, Duncan Sumerauer, David Thomas, Gregory Tomboc, Patrick Van Damme, An Wierman, Margaret Winer, Ira Yen, Lee Yi Zapotocky, Michal Ziegler, David Zimmermann, Stefanie Dvir, Rina Rechavi, Gidi Durno, Carol Aronson, Melyssa Taylor, Michael Dirks, Peter Pugh, Trevor Shlien, Adam Hawkins, Cynthia Morgenstern, Daniel Tabori, Uri Neuro Oncol Immunotherapy Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond to immune checkpoint inhibition (ICI). We performed a consortium registry study of ICI in recurrent RRD cancers. Clinical and companion biomarkers were collected longitudinally on all patients. Biomarkers included tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference was obtained by RNAseq and T cell rearrangement was collected in the tumor and in blood throughout treatment. Of the 46 tumors on the study, 32 were brain tumors with glioblastoma in 96%. Rapid, objective responses (>50%) were observed in 50% of glioblastomas. Three year overall survival for the whole cohort was 48+/-8% which compares favorably with historical controls. Brain tumors fared worse with OS of 39+/-10% and late recurrences observed even after 2 years of therapy (p=0.02). Tumor size and acute “flare” constitute poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens correlated with response to ICI (p=0.02). Specific signatures extracted from SNVs and total mutations predicted response to ICI and favorable outcome (p=0.005). RNA inference and TCR reveal that the FLARE phenotype is mostly acute nonspecific immune response and not true progression. Finally, glioblastomas (n=8) which failed single agent ICI had favorable responses to combinational immunotherapies with prolonged survival of 65%+/-8% at one year after failure vs 0 for other patients (p=0.01). RRD glioblastomas exhibit favorable outcome and responses to ICI. Combinational therapies based on tumor and immune signatures of these cancers are necessary. Oxford University Press 2020-12-04 /pmc/articles/PMC7715575/ http://dx.doi.org/10.1093/neuonc/noaa222.374 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Immunotherapy Bouffet, Eric Sudhaman, Sumedha Chung, Jiil Kelly, Jacalyn Coblentz, Ailish Edwards, Melissa Lipman, Tatiana Zhang, Cindy Ercan, Ayse Bahar Sambira, Lauren Bendel, Anne Bielack, Stefan Koustenis, Elisabeth Blumenthal, Deborah Bowers, Daniel Broniscer, Alberto Bronsema, Annika Carroll, Sara Chiaravalli, Stefano Cole, Kristina Constantini, Shlomi De Mola, Rebecca Loret Dunn, Gavin Fröjd, Charlotta Gass, David Gauvain, Karen George, Ben Hijiya, Nobuko Hoffman, Lindsey Knipstein, Jeffrey Laetsch, Ted Larouche, Valérie Lassaletta, Alvaro Lindhorst, Scott Lossos, Alexander Luna-Fineman, Sandra Magimairajan, Vanan Mason, Gary Mason, Warren Massimino, Maura Mordechai, Oz Opocher, Enrico Oren, Michal Osborn, Michael Reddy, Alyssa Remke, Mark Roy, Sumita Sabel, Magnus Samuel, David Schneider, Kami Sen, Santanu Stearns, Duncan Sumerauer, David Thomas, Gregory Tomboc, Patrick Van Damme, An Wierman, Margaret Winer, Ira Yen, Lee Yi Zapotocky, Michal Ziegler, David Zimmermann, Stefanie Dvir, Rina Rechavi, Gidi Durno, Carol Aronson, Melyssa Taylor, Michael Dirks, Peter Pugh, Trevor Shlien, Adam Hawkins, Cynthia Morgenstern, Daniel Tabori, Uri IMMU-18. FAVORABLE OUTCOME IN REPLICATION REPAIR DEFICIENT HYPERMUTANT BRAIN TUMORS TO IMMUNE CHECKPOINT INHIBITION: AN INTERNATIONAL RRD CONSORTIUM REGISTRY STUDY |
title | IMMU-18. FAVORABLE OUTCOME IN REPLICATION REPAIR DEFICIENT HYPERMUTANT BRAIN TUMORS TO IMMUNE CHECKPOINT INHIBITION: AN INTERNATIONAL RRD CONSORTIUM REGISTRY STUDY |
title_full | IMMU-18. FAVORABLE OUTCOME IN REPLICATION REPAIR DEFICIENT HYPERMUTANT BRAIN TUMORS TO IMMUNE CHECKPOINT INHIBITION: AN INTERNATIONAL RRD CONSORTIUM REGISTRY STUDY |
title_fullStr | IMMU-18. FAVORABLE OUTCOME IN REPLICATION REPAIR DEFICIENT HYPERMUTANT BRAIN TUMORS TO IMMUNE CHECKPOINT INHIBITION: AN INTERNATIONAL RRD CONSORTIUM REGISTRY STUDY |
title_full_unstemmed | IMMU-18. FAVORABLE OUTCOME IN REPLICATION REPAIR DEFICIENT HYPERMUTANT BRAIN TUMORS TO IMMUNE CHECKPOINT INHIBITION: AN INTERNATIONAL RRD CONSORTIUM REGISTRY STUDY |
title_short | IMMU-18. FAVORABLE OUTCOME IN REPLICATION REPAIR DEFICIENT HYPERMUTANT BRAIN TUMORS TO IMMUNE CHECKPOINT INHIBITION: AN INTERNATIONAL RRD CONSORTIUM REGISTRY STUDY |
title_sort | immu-18. favorable outcome in replication repair deficient hypermutant brain tumors to immune checkpoint inhibition: an international rrd consortium registry study |
topic | Immunotherapy |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715575/ http://dx.doi.org/10.1093/neuonc/noaa222.374 |
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