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275 Translational endpoints associated with STK11 mutations in patients with non-squamous NSCLC
BackgroundEmerging data suggest poor outcome to anti- PD(L)1 blocking agents in patients with STK11mut tumors1. In the current study, we undertook in-depth translational evaluations of three Ph1/Ph2 independent studies of Durvalumab ± Tremelimumab to elucidate the biology associated with STK11 mutat...
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Published in: | Journal for immunotherapy of cancer 2020-11, Vol.8 (Suppl 3), p.A300-A300 |
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description | BackgroundEmerging data suggest poor outcome to anti- PD(L)1 blocking agents in patients with STK11mut tumors1. In the current study, we undertook in-depth translational evaluations of three Ph1/Ph2 independent studies of Durvalumab ± Tremelimumab to elucidate the biology associated with STK11 mutations leading to reduced clinical response in patients with non-squamous NSCLC.MethodsMutational status was evaluated by ctDNA or Foundation One CDx as previously described1. RNA sequencing was conducted on baseline frozen biopsies (N=70). Selected proteins (N=66) were measured by Myriad RBM multiplexed immunoassays on baseline serum (n=91). Screening and longitudinal whole blood was assessed for circulating quantities of T, B or NK cells and activated or memory T cell subsets using bioanalytically-validated, flow cytometry-based immunophenotyping assays. Exploratory analyses of translational endpoints according to STK11 mutational status were conducted by Wilcoxon rank-sum test.ResultsIn the periphery, a reduced number (> 2-fold decreased in median quantities) of NK cells, CD4+ effector memory, CD4+ HLA-DR+, CD8+ effector memory and CD8+ HLA-DR+ T cells was observed at baseline and following treatments in patients with STK11mut vs. STK11wt tumors. At baseline, increased levels of IL6 (p=0.002) and the neutrophil-attracting cytokine IL8 (p=0.02) were found in serum of patients with STK11mut tumors. In the tumor microenvironment, significantly increased expression (p< 0.05; fold change > 2) of markers associated with neutrophils, (i.e. CXCL2, IL6, CSF3), Th17 contexture (i.e. IL17A) and immune checkpoints (i.e. KIRs, PD-L1) was found in STK11mut vs. STK11wt tumors.ConclusionsThe poor outcomes to immunotherapy observed in NSCLC patients with STK11mut tumors might be determined by a compromised peripheral and intra-tumoral immune phenotype. These results might help the development of novel therapeutic interventions able to unleash response to immune checkpoints in NSCLC patients harboring STK11 mutations.Trial RegistrationNCT01693562, NCT02087423, NCT02000947ReferenceJure Kunkel Met al, JCO. 2018.36.15_suppl.3028. |
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fullrecord | <record><control><sourceid>proquest_9YT</sourceid><recordid>TN_cdi_doaj_primary_oai_doaj_org_article_5c3d2d7a986d4daa8ddca0615a24657c</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><doaj_id>oai_doaj_org_article_5c3d2d7a986d4daa8ddca0615a24657c</doaj_id><sourcerecordid>2552987497</sourcerecordid><originalsourceid>FETCH-LOGICAL-b1377-88d5b6aeb9eaaa129b2b30d6bb5b2983a767eb22c77ac1503da41f3bad0af21d3</originalsourceid><addsrcrecordid>eNpFkU1LxDAQhosguKz-BgOeu-ajadqjFD8WFz1sPYdJk9WUtuk2KeLNi3_UX2K7q3iaYXh4Z5gnii4JXhHC0uvahiqmmOJ4uy6LuVlhKvhJtKCYk5gkND2LLryvMcYEM5Zl2SKCifj-_CoH6HwDwboOGmQ63TvbBY_Ae1dZCEajdxve0LZ8JAS1YzigHtkO9VNrZvYAdK6L_X6E1o0ePW2LTXEene6g8ebity6jl7vbsniIN8_36-JmEyvChIizTHOVglG5AQBCc0UVwzpViiuaZwxEKoyitBICKsIx05CQHVOgMewo0WwZrY-52kEt-8G2MHxIB1YeBm54lTAEWzVG8oppqgXkWaoTDZBpXQFOCQeapFxUU9bVMasf3H40PsjajcP0Gi8p59M5IsnFRNEjpdr_hQTL2YacbchZgvyzIWcb7AcghoHw</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2552987497</pqid></control><display><type>article</type><title>275 Translational endpoints associated with STK11 mutations in patients with non-squamous NSCLC</title><source>BMJ Open Access Journals</source><creator>Wu, Song ; Standifer, Nathan ; Reyes, Melissa de los ; Oberst, Micheal ; Raja, Rajv ; Barrett, Carl ; Ascierto, Maria</creator><creatorcontrib>Wu, Song ; Standifer, Nathan ; Reyes, Melissa de los ; Oberst, Micheal ; Raja, Rajv ; Barrett, Carl ; Ascierto, Maria</creatorcontrib><description>BackgroundEmerging data suggest poor outcome to anti- PD(L)1 blocking agents in patients with STK11mut tumors1. In the current study, we undertook in-depth translational evaluations of three Ph1/Ph2 independent studies of Durvalumab ± Tremelimumab to elucidate the biology associated with STK11 mutations leading to reduced clinical response in patients with non-squamous NSCLC.MethodsMutational status was evaluated by ctDNA or Foundation One CDx as previously described1. RNA sequencing was conducted on baseline frozen biopsies (N=70). Selected proteins (N=66) were measured by Myriad RBM multiplexed immunoassays on baseline serum (n=91). Screening and longitudinal whole blood was assessed for circulating quantities of T, B or NK cells and activated or memory T cell subsets using bioanalytically-validated, flow cytometry-based immunophenotyping assays. Exploratory analyses of translational endpoints according to STK11 mutational status were conducted by Wilcoxon rank-sum test.ResultsIn the periphery, a reduced number (> 2-fold decreased in median quantities) of NK cells, CD4+ effector memory, CD4+ HLA-DR+, CD8+ effector memory and CD8+ HLA-DR+ T cells was observed at baseline and following treatments in patients with STK11mut vs. STK11wt tumors. At baseline, increased levels of IL6 (p=0.002) and the neutrophil-attracting cytokine IL8 (p=0.02) were found in serum of patients with STK11mut tumors. In the tumor microenvironment, significantly increased expression (p< 0.05; fold change > 2) of markers associated with neutrophils, (i.e. CXCL2, IL6, CSF3), Th17 contexture (i.e. IL17A) and immune checkpoints (i.e. KIRs, PD-L1) was found in STK11mut vs. STK11wt tumors.ConclusionsThe poor outcomes to immunotherapy observed in NSCLC patients with STK11mut tumors might be determined by a compromised peripheral and intra-tumoral immune phenotype. These results might help the development of novel therapeutic interventions able to unleash response to immune checkpoints in NSCLC patients harboring STK11 mutations.Trial RegistrationNCT01693562, NCT02087423, NCT02000947ReferenceJure Kunkel Met al, JCO. 2018.36.15_suppl.3028.</description><identifier>EISSN: 2051-1426</identifier><identifier>DOI: 10.1136/jitc-2020-SITC2020.0275</identifier><language>eng</language><publisher>London: BMJ Publishing Group LTD</publisher><subject>Immunotherapy ; Lung cancer ; Mutation ; Tumors</subject><ispartof>Journal for immunotherapy of cancer, 2020-11, Vol.8 (Suppl 3), p.A300-A300</ispartof><rights>Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2020 Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2552987497/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2552987497?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>314,777,781,25735,27531,27532,27906,27907,36994,44572,74876,77351,77382</link.rule.ids><linktorsrc>$$Uhttp://dx.doi.org/10.1136/jitc-2020-SITC2020.0275$$EView_record_in_BMJ_Publishing_Group_Ltd$$FView_record_in_$$GBMJ_Publishing_Group_Ltd</linktorsrc></links><search><creatorcontrib>Wu, Song</creatorcontrib><creatorcontrib>Standifer, Nathan</creatorcontrib><creatorcontrib>Reyes, Melissa de los</creatorcontrib><creatorcontrib>Oberst, Micheal</creatorcontrib><creatorcontrib>Raja, Rajv</creatorcontrib><creatorcontrib>Barrett, Carl</creatorcontrib><creatorcontrib>Ascierto, Maria</creatorcontrib><title>275 Translational endpoints associated with STK11 mutations in patients with non-squamous NSCLC</title><title>Journal for immunotherapy of cancer</title><description>BackgroundEmerging data suggest poor outcome to anti- PD(L)1 blocking agents in patients with STK11mut tumors1. In the current study, we undertook in-depth translational evaluations of three Ph1/Ph2 independent studies of Durvalumab ± Tremelimumab to elucidate the biology associated with STK11 mutations leading to reduced clinical response in patients with non-squamous NSCLC.MethodsMutational status was evaluated by ctDNA or Foundation One CDx as previously described1. RNA sequencing was conducted on baseline frozen biopsies (N=70). Selected proteins (N=66) were measured by Myriad RBM multiplexed immunoassays on baseline serum (n=91). Screening and longitudinal whole blood was assessed for circulating quantities of T, B or NK cells and activated or memory T cell subsets using bioanalytically-validated, flow cytometry-based immunophenotyping assays. Exploratory analyses of translational endpoints according to STK11 mutational status were conducted by Wilcoxon rank-sum test.ResultsIn the periphery, a reduced number (> 2-fold decreased in median quantities) of NK cells, CD4+ effector memory, CD4+ HLA-DR+, CD8+ effector memory and CD8+ HLA-DR+ T cells was observed at baseline and following treatments in patients with STK11mut vs. STK11wt tumors. At baseline, increased levels of IL6 (p=0.002) and the neutrophil-attracting cytokine IL8 (p=0.02) were found in serum of patients with STK11mut tumors. In the tumor microenvironment, significantly increased expression (p< 0.05; fold change > 2) of markers associated with neutrophils, (i.e. CXCL2, IL6, CSF3), Th17 contexture (i.e. IL17A) and immune checkpoints (i.e. KIRs, PD-L1) was found in STK11mut vs. STK11wt tumors.ConclusionsThe poor outcomes to immunotherapy observed in NSCLC patients with STK11mut tumors might be determined by a compromised peripheral and intra-tumoral immune phenotype. These results might help the development of novel therapeutic interventions able to unleash response to immune checkpoints in NSCLC patients harboring STK11 mutations.Trial RegistrationNCT01693562, NCT02087423, NCT02000947ReferenceJure Kunkel Met al, JCO. 2018.36.15_suppl.3028.</description><subject>Immunotherapy</subject><subject>Lung cancer</subject><subject>Mutation</subject><subject>Tumors</subject><issn>2051-1426</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNpFkU1LxDAQhosguKz-BgOeu-ajadqjFD8WFz1sPYdJk9WUtuk2KeLNi3_UX2K7q3iaYXh4Z5gnii4JXhHC0uvahiqmmOJ4uy6LuVlhKvhJtKCYk5gkND2LLryvMcYEM5Zl2SKCifj-_CoH6HwDwboOGmQ63TvbBY_Ae1dZCEajdxve0LZ8JAS1YzigHtkO9VNrZvYAdK6L_X6E1o0ePW2LTXEene6g8ebity6jl7vbsniIN8_36-JmEyvChIizTHOVglG5AQBCc0UVwzpViiuaZwxEKoyitBICKsIx05CQHVOgMewo0WwZrY-52kEt-8G2MHxIB1YeBm54lTAEWzVG8oppqgXkWaoTDZBpXQFOCQeapFxUU9bVMasf3H40PsjajcP0Gi8p59M5IsnFRNEjpdr_hQTL2YacbchZgvyzIWcb7AcghoHw</recordid><startdate>202011</startdate><enddate>202011</enddate><creator>Wu, Song</creator><creator>Standifer, Nathan</creator><creator>Reyes, Melissa de los</creator><creator>Oberst, Micheal</creator><creator>Raja, Rajv</creator><creator>Barrett, Carl</creator><creator>Ascierto, Maria</creator><general>BMJ Publishing Group LTD</general><general>BMJ Publishing Group</general><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>DOA</scope></search><sort><creationdate>202011</creationdate><title>275 Translational endpoints associated with STK11 mutations in patients with non-squamous NSCLC</title><author>Wu, Song ; Standifer, Nathan ; Reyes, Melissa de los ; Oberst, Micheal ; Raja, Rajv ; Barrett, Carl ; Ascierto, Maria</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b1377-88d5b6aeb9eaaa129b2b30d6bb5b2983a767eb22c77ac1503da41f3bad0af21d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Immunotherapy</topic><topic>Lung cancer</topic><topic>Mutation</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Song</creatorcontrib><creatorcontrib>Standifer, Nathan</creatorcontrib><creatorcontrib>Reyes, Melissa de los</creatorcontrib><creatorcontrib>Oberst, Micheal</creatorcontrib><creatorcontrib>Raja, Rajv</creatorcontrib><creatorcontrib>Barrett, Carl</creatorcontrib><creatorcontrib>Ascierto, Maria</creatorcontrib><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection (Proquest)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest - Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Directory of Open Access Journals(OpenAccess)</collection><jtitle>Journal for immunotherapy of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Wu, Song</au><au>Standifer, Nathan</au><au>Reyes, Melissa de los</au><au>Oberst, Micheal</au><au>Raja, Rajv</au><au>Barrett, Carl</au><au>Ascierto, Maria</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>275 Translational endpoints associated with STK11 mutations in patients with non-squamous NSCLC</atitle><jtitle>Journal for immunotherapy of cancer</jtitle><date>2020-11</date><risdate>2020</risdate><volume>8</volume><issue>Suppl 3</issue><spage>A300</spage><epage>A300</epage><pages>A300-A300</pages><eissn>2051-1426</eissn><abstract>BackgroundEmerging data suggest poor outcome to anti- PD(L)1 blocking agents in patients with STK11mut tumors1. In the current study, we undertook in-depth translational evaluations of three Ph1/Ph2 independent studies of Durvalumab ± Tremelimumab to elucidate the biology associated with STK11 mutations leading to reduced clinical response in patients with non-squamous NSCLC.MethodsMutational status was evaluated by ctDNA or Foundation One CDx as previously described1. RNA sequencing was conducted on baseline frozen biopsies (N=70). Selected proteins (N=66) were measured by Myriad RBM multiplexed immunoassays on baseline serum (n=91). Screening and longitudinal whole blood was assessed for circulating quantities of T, B or NK cells and activated or memory T cell subsets using bioanalytically-validated, flow cytometry-based immunophenotyping assays. Exploratory analyses of translational endpoints according to STK11 mutational status were conducted by Wilcoxon rank-sum test.ResultsIn the periphery, a reduced number (> 2-fold decreased in median quantities) of NK cells, CD4+ effector memory, CD4+ HLA-DR+, CD8+ effector memory and CD8+ HLA-DR+ T cells was observed at baseline and following treatments in patients with STK11mut vs. STK11wt tumors. At baseline, increased levels of IL6 (p=0.002) and the neutrophil-attracting cytokine IL8 (p=0.02) were found in serum of patients with STK11mut tumors. In the tumor microenvironment, significantly increased expression (p< 0.05; fold change > 2) of markers associated with neutrophils, (i.e. CXCL2, IL6, CSF3), Th17 contexture (i.e. IL17A) and immune checkpoints (i.e. KIRs, PD-L1) was found in STK11mut vs. STK11wt tumors.ConclusionsThe poor outcomes to immunotherapy observed in NSCLC patients with STK11mut tumors might be determined by a compromised peripheral and intra-tumoral immune phenotype. These results might help the development of novel therapeutic interventions able to unleash response to immune checkpoints in NSCLC patients harboring STK11 mutations.Trial RegistrationNCT01693562, NCT02087423, NCT02000947ReferenceJure Kunkel Met al, JCO. 2018.36.15_suppl.3028.</abstract><cop>London</cop><pub>BMJ Publishing Group LTD</pub><doi>10.1136/jitc-2020-SITC2020.0275</doi><oa>free_for_read</oa></addata></record> |
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title | 275 Translational endpoints associated with STK11 mutations in patients with non-squamous NSCLC |
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