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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
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.
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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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