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dc.contributor.authorGonzalez-Exposito, R
dc.contributor.authorSemiannikova, M
dc.contributor.authorGriffiths, B
dc.contributor.authorKhan, K
dc.contributor.authorBarber, LJ
dc.contributor.authorWoolston, A
dc.contributor.authorSpain, G
dc.contributor.authorvon Loga, K
dc.contributor.authorChalloner, B
dc.contributor.authorPatel, R
dc.contributor.authorRanes, M
dc.contributor.authorSwain, A
dc.contributor.authorThomas, J
dc.contributor.authorBryant, A
dc.contributor.authorSaffery, C
dc.contributor.authorFotiadis, N
dc.contributor.authorGuettler, S
dc.contributor.authorMansfield, D
dc.contributor.authorMelcher, A
dc.contributor.authorPowles, T
dc.contributor.authorRao, S
dc.contributor.authorWatkins, D
dc.contributor.authorChau, I
dc.contributor.authorMatthews, N
dc.contributor.authorWallberg, F
dc.contributor.authorStarling, N
dc.contributor.authorCunningham, D
dc.contributor.authorGerlinger, M
dc.date.accessioned2019-03-26T16:12:32Z
dc.date.issued2019-04-15
dc.identifier.citationJournal for immunotherapy of cancer, 2019, 7 (1), pp. 101 - ?
dc.identifier.issn2051-1426
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3166
dc.identifier.eissn2051-1426
dc.identifier.doi10.1186/s40425-019-0575-3
dc.description.abstractBackground The T cell bispecific antibody cibisatamab (CEA-TCB) binds Carcino-Embryonic Antigen (CEA) on cancer cells and CD3 on T cells, which triggers T cell killing of cancer cell lines expressing moderate to high levels of CEA at the cell surface. Patient derived colorectal cancer organoids (PDOs) may more accurately represent patient tumors than established cell lines which potentially enables more detailed insights into mechanisms of cibisatamab resistance and sensitivity.Methods We established PDOs from multidrug-resistant metastatic CRCs. CEA expression of PDOs was determined by FACS and sensitivity to cibisatamab immunotherapy was assessed by co-culture of PDOs and allogeneic CD8 T cells.Results PDOs could be categorized into 3 groups based on CEA cell-surface expression: CEA hi (n = 3), CEA lo (n = 1) and CEA mixed PDOs (n = 4), that stably maintained populations of CEA hi and CEA lo cells, which has not previously been described in CRC cell lines. CEA hi PDOs were sensitive whereas CEA lo PDOs showed resistance to cibisatamab. PDOs with mixed expression showed low sensitivity to cibisatamab, suggesting that CEA lo cells maintain cancer cell growth. Culture of FACS-sorted CEA hi and CEA lo cells from PDOs with mixed CEA expression demonstrated high plasticity of CEA expression, contributing to resistance acquisition through CEA antigen loss. RNA-sequencing revealed increased WNT/β-catenin pathway activity in CEA lo cells. Cell surface CEA expression was up-regulated by inhibitors of the WNT/β-catenin pathway.Conclusions Based on these preclinical findings, heterogeneity and plasticity of CEA expression appear to confer low cibisatamab sensitivity in PDOs, supporting further clinical evaluation of their predictive effect in CRC. Pharmacological inhibition of the WNT/β-catenin pathway may be a rational combination to sensitize CRCs to cibisatamab. Our novel PDO and T cell co-culture immunotherapy models enable pre-clinical discovery of candidate biomarkers and combination therapies that may inform and accelerate the development of immuno-oncology agents in the clinic.
dc.formatElectronic
dc.format.extent101 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCD8-Positive T-Lymphocytes
dc.subjectHumans
dc.subjectColorectal Neoplasms
dc.subjectCarcinoembryonic Antigen
dc.subjectAntibodies, Bispecific
dc.subjectCoculture Techniques
dc.subjectTissue Culture Techniques
dc.subjectDrug Screening Assays, Antitumor
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectDrug Resistance, Neoplasm
dc.subjectGenetic Heterogeneity
dc.subjectGPI-Linked Proteins
dc.subjectAntineoplastic Agents, Immunological
dc.titleCEA expression heterogeneity and plasticity confer resistance to the CEA-targeting bispecific immunotherapy antibody cibisatamab (CEA-TCB) in patient-derived colorectal cancer organoids.
dc.typeJournal Article
dcterms.dateAccepted2019-03-22
rioxxterms.versionofrecord10.1186/s40425-019-0575-3
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-04-15
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfJournal for immunotherapy of cancer
pubs.issue1
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Development & Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials/Gastrointestinal Cancers Clinical Trials (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Development & Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy/Translational Immunotherapy (TL)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structural Biology of Cell Signalling
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
pubs.organisational-group/ICR/Students/PhD and MPhil/19/20 Starting Cohort
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Development & Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials/Gastrointestinal Cancers Clinical Trials (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Development & Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy/Translational Immunotherapy (TL)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structural Biology of Cell Signalling
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
pubs.organisational-group/ICR/Students/PhD and MPhil/19/20 Starting Cohort
pubs.publication-statusPublished
pubs.volume7
pubs.embargo.termsNot known
icr.researchteamGastrointestinal Cancers Clinical Trialsen_US
icr.researchteamMedicine (RMH Smith Cunningham)en_US
icr.researchteamDevelopment & Canceren_US
icr.researchteamTranslational Oncogenomicsen_US
icr.researchteamTargeted Therapyen_US
icr.researchteamTranslational Immunotherapyen_US
icr.researchteamStructural Biology of Cell Signallingen_US
dc.contributor.icrauthorSemiannikova, Mariaen
dc.contributor.icrauthorGriffiths, Beatriceen
dc.contributor.icrauthorSpain, Georgiaen
dc.contributor.icrauthorChalloner, Benjaminen
dc.contributor.icrauthorBarber, Louiseen
dc.contributor.icrauthorSwain, Amandaen
dc.contributor.icrauthorMansfield, Daviden
dc.contributor.icrauthorCunningham, Daviden
dc.contributor.icrauthorGuettler, Sebastianen
dc.contributor.icrauthorChau, Ianen
dc.contributor.icrauthorStarling, Naureenen
dc.contributor.icrauthorGerlinger, Marcoen
dc.contributor.icrauthorWoolston, Andrewen
dc.contributor.icrauthorMelcher, Alanen


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