FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2983600820> ?p ?o ?g. }

• W2983600820 endingPage "4367" @default.
• W2983600820 startingPage "4367" @default.
• W2983600820 abstract "Introduction: Maintenance therapy with the immunomodulatory drug (IMiD) lenalidomide improves progression-free survival (PFS) and overall survival among patients with multiple myeloma (MM). It has been suggested that IMiDs enhance immune-mediated anti-tumor responses through increased activation and proliferation of T cells and natural killer (NK) cells as well as inhibition of regulatory T cells. Despite the effectiveness of this therapy, nearly all patients relapse for reasons that remain uncharacterized. We sought to elucidate mechanisms of resistance to lenalidomide maintenance through investigation of mutations in cell-free DNA (cfDNA) and identification of changes in the innate and adaptive immune system by single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs). While MM is a cancer of plasma cells that primarily reside in the bone marrow, we focused on the peripheral blood which offers a comprehensive view of multiple sites of disease including extramedullary locations commonly found at the time of relapse. Methods: Twenty-four patients with MM and no minimal residual disease by 10-color flow cytometry and IGHVnext-generation sequencing (Invivoscribe) after induction therapy with or without an autologous stem cell transplant were selected for analysis. All patients were enrolled in NCT02538198 at Memorial Sloan Kettering Cancer Center. Peripheral blood was collected serially including timepoints prior to lenalidomide maintenance and after disease progression. Plasma and PBMCs were isolated by Ficoll-Paque density gradient centrifugation. cfDNA was extracted from plasma and targeted next-generation sequencing using a 70-gene panel of recurrently mutated genes in myeloma was performed using the QIAseq Targeted DNA kit (QIAGEN). DNA sequencing was also performed using the same gene panel on granulocytes to exclude germline variants. On PBMC samples, 5' gene expression and T and B cell receptor single-cell sequencing were performed using the Chromium Single Cell V(D)J kit (10X Genomics). Analysis of single-cell sequencing was performed on the top 100 principal components and visualized by Uniform Manifold Approximation and Projection (UMAP). A regression-based classifier was trained to automatically assign clustered cells into 26 immune cell phenotypes using lists of genes reported to be uniquely expressed by each cell type. Results: cfDNA sequencing was performed on 12 patients characterized as durable responders (PFS > 57 months) and 12 early progressors (median PFS 25 months). Prior to maintenance therapy, no significant difference was observed in the number of cfDNA mutations between these groups. The number of non-synonymous somatic mutations in cfDNA tended to increase over time and was significantly higher among patients taking lenalidomide for more than 2 years compared to patients at the time of relapsed disease (mean number of mutations was 7 in responders versus 3 in progressors).ZNF292was among the genes most significantly mutated in responders compared to progressors. ZNF292encodes a zinc finger protein involved in RNA binding and has previously been identified as a potential source of tumor-associated antigens in patients with monoclonal gammopathy of undetermined significance. To identify changes in immune cell phenotype and function that associate with disease progression, we performed single-cell RNA sequencing on PBMCs from the 12 progressors before maintenance and at the time of relapse. The median number of cells sequenced per PBMC sample was 3,132. Over 90% of cells could automatically be classified into a specific immune cell type by their gene expression. We observed the frequency of NK cells and plasmablasts were significantly increased at the time progression on lenalidomide while monocytes, dendritic cells, and basophils were decreased. Conclusion: Mechanisms of resistance among patients receiving treatment with IMiDs is not well known. Using targeted sequencing of cfDNA, we identify patients responding to maintenance tended to have a higher mutational load in cfDNA including genes previously reported to encode tumor-associated antigens. Additionally, we show that a decline in antigen-presenting dendritic cells is more common at the time of disease progression. Taken together, these results suggest reduced neoantigen production and a decline in antigen presentation may contribute to IMiD resistance. Disclosures Landgren: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Green:Celgene: Consultancy; Cellectar Biosciences: Research Funding; Seattle Genetics: Research Funding; Juno Therapeutics: Consultancy, Patents & Royalties, Research Funding; GSK: Consultancy." @default.
• W2983600820 created "2019-11-22" @default.
• W2983600820 creator A5004667245 @default.
• W2983600820 creator A5007024434 @default.
• W2983600820 creator A5007184899 @default.
• W2983600820 creator A5023284324 @default.
• W2983600820 creator A5048966043 @default.
• W2983600820 creator A5058926927 @default.
• W2983600820 creator A5078046623 @default.
• W2983600820 creator A5082004555 @default.
• W2983600820 date "2019-11-13" @default.
• W2983600820 modified "2023-10-02" @default.
• W2983600820 title "Reduced Antigen Presentation May Contribute to Immunomodulatory Drug Resistance in Multiple Myeloma" @default.
• W2983600820 doi "https://doi.org/10.1182/blood-2019-126222" @default.
• W2983600820 hasPublicationYear "2019" @default.
• W2983600820 type Work @default.
• W2983600820 sameAs 2983600820 @default.
• W2983600820 citedByCount "0" @default.
• W2983600820 crossrefType "journal-article" @default.
• W2983600820 hasAuthorship W2983600820A5004667245 @default.
• W2983600820 hasAuthorship W2983600820A5007024434 @default.
• W2983600820 hasAuthorship W2983600820A5007184899 @default.
• W2983600820 hasAuthorship W2983600820A5023284324 @default.
• W2983600820 hasAuthorship W2983600820A5048966043 @default.
• W2983600820 hasAuthorship W2983600820A5058926927 @default.
• W2983600820 hasAuthorship W2983600820A5078046623 @default.
• W2983600820 hasAuthorship W2983600820A5082004555 @default.
• W2983600820 hasBestOaLocation W29836008201 @default.
• W2983600820 hasConcept C121608353 @default.
• W2983600820 hasConcept C126322002 @default.
• W2983600820 hasConcept C137061746 @default.
• W2983600820 hasConcept C143998085 @default.
• W2983600820 hasConcept C202751555 @default.
• W2983600820 hasConcept C203014093 @default.
• W2983600820 hasConcept C2776063141 @default.
• W2983600820 hasConcept C2776364478 @default.
• W2983600820 hasConcept C2779823535 @default.
• W2983600820 hasConcept C2780007613 @default.
• W2983600820 hasConcept C502942594 @default.
• W2983600820 hasConcept C55493867 @default.
• W2983600820 hasConcept C71924100 @default.
• W2983600820 hasConcept C86803240 @default.
• W2983600820 hasConcept C8891405 @default.
• W2983600820 hasConceptScore W2983600820C121608353 @default.
• W2983600820 hasConceptScore W2983600820C126322002 @default.
• W2983600820 hasConceptScore W2983600820C137061746 @default.
• W2983600820 hasConceptScore W2983600820C143998085 @default.
• W2983600820 hasConceptScore W2983600820C202751555 @default.
• W2983600820 hasConceptScore W2983600820C203014093 @default.
• W2983600820 hasConceptScore W2983600820C2776063141 @default.
• W2983600820 hasConceptScore W2983600820C2776364478 @default.
• W2983600820 hasConceptScore W2983600820C2779823535 @default.
• W2983600820 hasConceptScore W2983600820C2780007613 @default.
• W2983600820 hasConceptScore W2983600820C502942594 @default.
• W2983600820 hasConceptScore W2983600820C55493867 @default.
• W2983600820 hasConceptScore W2983600820C71924100 @default.
• W2983600820 hasConceptScore W2983600820C86803240 @default.
• W2983600820 hasConceptScore W2983600820C8891405 @default.
• W2983600820 hasIssue "Supplement_1" @default.
• W2983600820 hasLocation W29836008201 @default.
• W2983600820 hasOpenAccess W2983600820 @default.
• W2983600820 hasPrimaryLocation W29836008201 @default.
• W2983600820 hasRelatedWork W2043076184 @default.
• W2983600820 hasRelatedWork W2381196212 @default.
• W2983600820 hasRelatedWork W2917241286 @default.
• W2983600820 hasRelatedWork W2938456301 @default.
• W2983600820 hasRelatedWork W3028592890 @default.
• W2983600820 hasRelatedWork W3121407702 @default.
• W2983600820 hasRelatedWork W3198246197 @default.
• W2983600820 hasRelatedWork W4233315676 @default.
• W2983600820 hasRelatedWork W4283376564 @default.
• W2983600820 hasRelatedWork W4297629692 @default.
• W2983600820 hasVolume "134" @default.
• W2983600820 isParatext "false" @default.
• W2983600820 isRetracted "false" @default.
• W2983600820 magId "2983600820" @default.
• W2983600820 workType "article" @default.