2024
TIGIT expression in renal cell carcinoma infiltrating T cells is variable and inversely correlated with PD-1 and LAG3
Perales O, Jilaveanu L, Adeniran A, Su D, Hurwitz M, Braun D, Kluger H, Schoenfeld D. TIGIT expression in renal cell carcinoma infiltrating T cells is variable and inversely correlated with PD-1 and LAG3. Cancer Immunology, Immunotherapy 2024, 73: 192. PMID: 39105820, PMCID: PMC11303630, DOI: 10.1007/s00262-024-03773-8.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaRenal cell carcinoma tumorsT cellsTIGIT expressionCheckpoint inhibitorsPD-1Likelihood of response to therapyTumor-infiltrating T cellsCD3+ T cellsRenal cell carcinoma metastasisTreatment of renal cell carcinomaImmune checkpoint inhibitorsInfiltrating T cellsPurposeImmune checkpoint inhibitorsResponse to therapyT cell immunoglobulinCD3+ levelsMetastatic RCC specimensAdjacent normal renal tissuesNormal renal tissuesQuantitative immunofluorescence analysisCell carcinomaResistant diseasePotential therapeutic targetTissue microarray14 Natural killer cells have impaired cytotoxicity in advanced renal cell carcinoma
Moritz V, Xu W, Birch G, Meliki A, Bharadwaj M, Schindler N, Labaki C, Saliby R, Dinh K, Horst J, Sun M, Kashima S, Machaalani M, Lee G, Hurwitz M, McGregor B, Hirsch M, Shukla S, McDermott D, Signoretti S, Romee R, Choueiri T, Braun D. 14 Natural killer cells have impaired cytotoxicity in advanced renal cell carcinoma. The Oncologist 2024, 29: s7-s8. PMCID: PMC11301877, DOI: 10.1093/oncolo/oyae181.012.Peer-Reviewed Original ResearchNK cell phenotypeGene expression signaturesNK cell populationK562 target cellsNK cellsRenal cell carcinomaAdvanced ccRCCNK cell clustersLocalized ccRCCAnti-tumor activityNormal kidneyNatural killerCell carcinomaMarkers of tissue residencyAdvanced renal cell carcinomaProportion of NK cellsFunction of NK cellsExpression of cytotoxic genesTarget cellsNK cell dysfunctionTotal immune cellsNK cell subsetsCell phenotypeCell populationsCell renal cell carcinoma24 Applying genomic analysis to refine unclassified renal cell carcinoma
Yekeduz E, Braun D, Chehade R, Eid M, Labaki C, Machaalani M, Nassar A, Nawfal R, Saad E, Saliby R, Semaan K, Sun M, Hirsch M, Ürün Y, Zarif T, Choueiri T. 24 Applying genomic analysis to refine unclassified renal cell carcinoma. The Oncologist 2024, 29: s20-s20. PMCID: PMC11301928, DOI: 10.1093/oncolo/oyae181.032.Peer-Reviewed Original ResearchRenal cell carcinomaClear cell RCCRenal cell carcinoma subtypesAmerican Association for Cancer ResearchPapillary RCCGenomic alterationsOverall survivalNF2 alterationsCell carcinomaGenomic profilingPapillary renal cell carcinomaSubtype of renal cell carcinomaChromophobe renal cell carcinomaProportion of female patientsClear cell renal cell carcinomaMedian overall survivalCell renal cell carcinomaFrequent genomic alterationsCo-mutated genesCompare categorical variablesBenjamini-Hochberg correctionOncogenic signaling pathwaysMetastatic sitesFrequent subtype of renal cell carcinomaPrimary tumor44 Liquid biopsy epigenomic profiling for the detection of sarcomatoid renal cell carcinoma
Semaan K, Zarif T, Eid M, Canniff J, Phillips N, Fortunato B, Savignano H, Davidson M, Chehade R, Garinet S, Saad E, Saliby R, Sun M, Seo J, Berchuck J, Braun D, Freedman M, Choueiri T, Baca S. 44 Liquid biopsy epigenomic profiling for the detection of sarcomatoid renal cell carcinoma. The Oncologist 2024, 29: s4-s5. PMCID: PMC11301903, DOI: 10.1093/oncolo/oyae181.006.Peer-Reviewed Original ResearchRenal cell carcinomaCell-free DNASarcomatoid differentiationRegulatory elementsArea under the receiver operating characteristicCell carcinomaChIP-seqResponse to immune checkpoint blockadeSarcomatoid renal cell carcinomaHistological subtypes of cancerAssociated with poor survivalImmune checkpoint blockadeDana-Farber Cancer InstituteChIP-seq signalsHistone modification signalsActive regulatory elementsArea under the receiver operating characteristic curveWilcoxon rank sum testTissue samplesCell-free chromatinRank sum testReceiver operating characteristicCheckpoint blockadeFrozen tissue samplesEpithelioid subtypeEpigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma
El Zarif T, Semaan K, Eid M, Seo J, Garinet S, Davidsohn M, Sahgal P, Fortunato B, Canniff J, Nassar A, Abou Alaiwi S, Bakouny Z, Lakshminarayanan G, Savignano H, Lyons K, Matar S, Ali A, Saad E, Saliby R, Cordeiro P, Zhang Z, El Ahmar N, Laimon Y, Labaki C, Shah V, Freeman D, O'Toole J, Lee G, Hwang J, Pomerantz M, Signoretti S, Van Allen E, Xie W, Berchuck J, Viswanathan S, Braun D, Choueiri T, Freedman M, Baca S. Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma. Cell Reports 2024, 43: 114350. PMID: 38870013, DOI: 10.1016/j.celrep.2024.114350.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsRenal cell carcinomaSarcomatoid differentiationCell carcinomaResponse to immune checkpoint inhibitorsGene regulatory programsAssociated with poor survivalTreatment of renal cell carcinomaLow diagnostic yieldRandomized clinical trialsCheckpoint inhibitorsTumor histologyEpigenomic signaturesTranscription factor FOSL1Healthy volunteersPatient plasmaPoor survivalLiquid biopsyFOSL1 expressionClinical trialsProfiling histone modificationsDiagnostic approachImprove outcomesRegulatory programsPlasma samplesEmerging Novel Functional Imaging and Immunotherapy in Renal Cell Carcinoma and Current Treatment Sequencing Strategies After Immunotherapy.
Ali M, Eid M, Saliby R, Choi S, McKay R, Siva S, Braun D, Chen Y. Emerging Novel Functional Imaging and Immunotherapy in Renal Cell Carcinoma and Current Treatment Sequencing Strategies After Immunotherapy. American Society Of Clinical Oncology Educational Book 2024, 44: e438658. PMID: 38875505, DOI: 10.1200/edbk_438658.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaTreatment sequencing strategiesCell carcinomaImmune checkpoint inhibitors targeting PD-1Chimeric antigen receptor T-cell therapyCheckpoint inhibitors targeting PD-1Management of renal cell carcinomaAdvanced renal cell carcinomaProstate-specific membrane antigenLandscape of renal cell carcinomaRCC-associated antigensImmune checkpoint inhibitionT-cell therapyPrimary kidney tumorsAssess treatment responseChanging treatment landscapeCarbonic anhydrase IXFunctional imagingFunctional imaging modalitiesCheckpoint inhibitionPD-1Immunotherapy strategiesLAG-3Membrane antigenT cellsApplying genomic analysis to refine unclassified renal cell carcinoma.
Yekeduz E, Braun D, El Hajj Chehade R, Eid M, Labaki C, Machaalani M, Nassar A, Nawfal R, Saad E, Saliby R, Semaan K, Sun M, Hirsch M, Ürün Y, El Zarif T, CHOUEIRI T. Applying genomic analysis to refine unclassified renal cell carcinoma. Journal Of Clinical Oncology 2024, 42: 4551-4551. DOI: 10.1200/jco.2024.42.16_suppl.4551.Peer-Reviewed Original ResearchRenal cell carcinomaClear cell RCCRenal cell carcinoma subtypesAmerican Association for Cancer ResearchPapillary RCCGenomic alterationsOverall survivalCell carcinomaGenomic profilingPapillary renal cell carcinomaSubtype of renal cell carcinomaChromophobe renal cell carcinomaProportion of female patientsClear cell renal cell carcinomaMedian overall survivalCell renal cell carcinomaCo-mutated genesCompare categorical variablesBenjamini-Hochberg correctionOncogenic signaling pathwaysMetastatic sitesFrequent subtype of renal cell carcinomaPrimary tumorChi-square testNF2 alterationsExpression of the receptor tyrosine kinase AXL and clinical outcomes to cabozantinib and everolimus in patients with metastatic renal cell carcinoma enrolled in the METEOR trial.
Nabil Laimon Y, Paul M, Ghandour F, El Ahmar N, Matar S, Denize T, Bagheri Sheshdeh A, Savla V, Mohanna R, Sun M, Saliby R, Saad E, Machaalani M, Braun D, Aftab D, Xie W, CHOUEIRI T, Signoretti S. Expression of the receptor tyrosine kinase AXL and clinical outcomes to cabozantinib and everolimus in patients with metastatic renal cell carcinoma enrolled in the METEOR trial. Journal Of Clinical Oncology 2024, 42: 4543-4543. DOI: 10.1200/jco.2024.42.16_suppl.4543.Peer-Reviewed Original ResearchProgression-free survivalAssociated with progression-free survivalReceptor tyrosine kinase AXLTyrosine kinase inhibitorsRenal cell carcinomaImmune cellsMETEOR trialTyrosine kinase AXLAxl expressionTumor cellsCell carcinomaAssociated with shorter progression-free survivalMetastatic clear cell renal cell carcinomaAnti-PD-1 therapyLevels of AXL expressionMetastatic renal cell carcinomaMultitargeted tyrosine kinase inhibitorPresence of bone metastasesShorter progression-free survivalClear cell renal cell carcinomaIMDC risk groupsPretreatment tumor tissueVEGFR-TKI treatmentCell renal cell carcinomaDouble immunohistochemistry stainingIntratumoral T-cell infiltration and response to nivolumab plus ipilimumab in patients with metastatic clear cell renal cell carcinoma from the CheckMate-214 trial.
Matar S, Jegede O, Denize T, Ghandour F, Nabil Laimon Y, El Ahmar N, Bagheri Sheshdeh A, Savla V, Mohanna R, Catalano P, Braun D, Sun M, Gupta S, Vemula S, Freeman G, Motzer R, Atkins M, McDermott D, CHOUEIRI T, Signoretti S. Intratumoral T-cell infiltration and response to nivolumab plus ipilimumab in patients with metastatic clear cell renal cell carcinoma from the CheckMate-214 trial. Journal Of Clinical Oncology 2024, 42: 4536-4536. DOI: 10.1200/jco.2024.42.16_suppl.4536.Peer-Reviewed Original ResearchProgression-free survivalAssociated with progression-free survivalMultiplex immunofluorescenceClinical trialsClinical outcomesMetastatic clear cell renal cell carcinomaIntratumoral T cell infiltrationTreated with nivolumab monotherapyMetastatic clear cell RCCClear cell renal cell carcinomaResponse to nivolumabT cell infiltrationCell renal cell carcinomaPoor-risk patientsRenal cell carcinomaClear cell RCCFormalin fixed paraffinContinuous variablesNivolumab monotherapyCox proportional hazardsAntigen-experiencedCell RCCCell carcinomaLogistic regression modelsPositive associationImpact of renal cell carcinoma molecular subtypes on immunotherapy and targeted therapy outcomes
Saliby R, Labaki C, Jammihal T, Xie W, Sun M, Shah V, Saad E, Kane M, Kashima S, Sadak K, El Zarif T, Poduval D, Motzer R, Powles T, Rini B, Albiges L, Pal S, McGregor B, McKay R, Signoretti S, Van Allen E, Shukla S, Choueiri T, Braun D. Impact of renal cell carcinoma molecular subtypes on immunotherapy and targeted therapy outcomes. Cancer Cell 2024, 42: 732-735. PMID: 38579722, PMCID: PMC11130783, DOI: 10.1016/j.ccell.2024.03.002.Peer-Reviewed Original ResearchIntegrative Analysis of Germline Rare Variants in Clear and Non–clear Cell Renal Cell Carcinoma
Han S, Camp S, Chu H, Collins R, Gillani R, Park J, Bakouny Z, Ricker C, Reardon B, Moore N, Kofman E, Labaki C, Braun D, Choueiri T, AlDubayan S, Van Allen E. Integrative Analysis of Germline Rare Variants in Clear and Non–clear Cell Renal Cell Carcinoma. European Urology Open Science 2024, 62: 107-122. PMID: 38496821, PMCID: PMC10940785, DOI: 10.1016/j.euros.2024.02.006.Peer-Reviewed Original ResearchCopy number variantsGermline pathogenic variantsCryptic splice variantsNon-clear cell renal cell carcinomaCell renal cell carcinomaRare inherited mutationsRenal cell carcinomaPathogenic variantsSomatic eventsPopulation stratificationRisk of kidney cancerAge of cancer onsetGermline copy number variantsSplice variantsBurden of pathogenic variantsCell carcinomaEstimation of genetic riskRenal cell carcinoma riskRCC patientsCancer-free controlsCase-control analysisCase-control studyRenal cell carcinoma patientsClear cell renal cell carcinomaGermline rare variantsEvaluating intermediate endpoints (IE) for overall survival (OS) in metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI): An IMDC study.
Saliby R, Xie W, Wells J, Saad E, Eid M, Labaki C, Semaan K, Ferrier E, Lemelin A, Suárez C, Ruiz-Morales J, Powles T, Wood L, Ebrahimi H, de Velasco G, Takemura K, Agarwal N, Braun D, Heng D, Choueiri T. Evaluating intermediate endpoints (IE) for overall survival (OS) in metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI): An IMDC study. Journal Of Clinical Oncology 2024, 42: 400-400. DOI: 10.1200/jco.2024.42.4_suppl.400.Peer-Reviewed Original ResearchTime to next therapyTime to treatment failureInternational mRCC Database ConsortiumImmune checkpoint inhibitorsMetastatic renal cell carcinomaOverall survivalIntermediate endpointsHazard ratioInternational mRCC Database Consortium risk groupTreated with immune checkpoint inhibitorsDual immune checkpoint inhibitorsICI startICI-based regimensAssociated with OSAssociation of OSEndpoint of OSRenal cell carcinomaCheckpoint inhibitorsNext therapyMetastatic sitesDrug cessationTreatment failurePrimary endpointCell carcinomaMedian ageTumor-infiltrating CD163-positive macrophages and clinical outcomes to first-line nivolumab therapy in patients with advanced clear cell renal cell carcinoma (ccRCC) enrolled in the HCRN GU16-260 trial.
El Ahmar N, Matar S, Jegede O, Nabil Laimon Y, Savla V, Bagheri Sheshdeh A, Denize T, Mohanna R, Choueiri T, Catalano P, Braun D, Haas N, Hammers H, Bilen M, Stein M, Sosman J, Wu C, McDermott D, Atkins M, Signoretti S. Tumor-infiltrating CD163-positive macrophages and clinical outcomes to first-line nivolumab therapy in patients with advanced clear cell renal cell carcinoma (ccRCC) enrolled in the HCRN GU16-260 trial. Journal Of Clinical Oncology 2024, 42: 448-448. DOI: 10.1200/jco.2024.42.4_suppl.448.Peer-Reviewed Original ResearchClear cell renal cell carcinomaProgression-free survivalCD163-positive macrophagesTumor areaNivolumab therapyDensity of CD163-positive cellsCD8+ T cell infiltrationAssociated with progression-free survivalResponse to immune checkpoint inhibitorsAdvanced clear cell renal cell carcinomaAnti-PD-1 therapyTumor-infiltrating myeloid cellsProgression-free survival endpointAssociated with poor outcomesFirst-line nivolumabImmune checkpoint inhibitorsMyeloid cell infiltrationT cell infiltrationCell renal cell carcinomaRenal cell carcinomaPrimary tumor tissuesCD163-positive cellsCheckpoint inhibitorsCox proportional hazardsCell carcinomaDetection of sarcomatoid renal cell carcinoma using plasma cell-free DNA methylation.
Semaan K, El Zarif T, Seo J, Eid M, Canniff J, Fortunato B, Savignano H, Davidsohn M, Lakshminarayanan G, Saad E, Saliby R, Bakouny Z, Matar S, Nuzzo P, Berchuck J, Signoretti S, Braun D, Freedman M, Baca S, Choueiri T. Detection of sarcomatoid renal cell carcinoma using plasma cell-free DNA methylation. Journal Of Clinical Oncology 2024, 42: 449-449. DOI: 10.1200/jco.2024.42.4_suppl.449.Peer-Reviewed Original ResearchDifferentially methylated regionsRenal cell carcinomaCell-free DNAMeDIP-seqSarcomatoid differentiationDNA methylation signalsArea under the receiver operating characteristicHigh-throughput sequencingCell carcinomaCell-free DNA methylationFalse discovery rateResponse to immune checkpoint blockadeEpigenomic approachesCfMeDIP-seqSarcomatoid renal cell carcinomaMethylation immunoprecipitationDNA methylationHistological subtypes of cancerAssociated with poor survivalImmune checkpoint blockadeSubtypes of cancerDana-Farber Cancer InstituteSpatial heterogeneityArea under the receiver operating characteristic curveWilcoxon rank sum testMulti-omic characterization of acquired resistance to immune checkpoint inhibitors in patients with metastatic renal cell carcinoma.
Saad E, Labaki C, Miron B, Park J, Bakouny Z, Nassar A, Saliby R, Semaan K, Eid M, Meli K, Nabil Laimon Y, Geynisman D, Kokate R, Braun D, Signoretti S, McGregor B, Plimack E, Choueiri T, Van Allen E, Zibelman M. Multi-omic characterization of acquired resistance to immune checkpoint inhibitors in patients with metastatic renal cell carcinoma. Journal Of Clinical Oncology 2024, 42: 459-459. DOI: 10.1200/jco.2024.42.4_suppl.459.Peer-Reviewed Original ResearchMetastatic renal cell carcinomaImmune checkpoint inhibitorsTertiary lymphoid structuresWhole-exome sequencingDifferential gene expression analysisRenal cell carcinomaGene set enrichment analysisCheckpoint inhibitorsCell carcinomaB cellsAbsence of tertiary lymphoid structuresGene mutationsResistance to immune checkpoint inhibitorsPresence of tertiary lymphoid structuresImmune checkpoint inhibitor treatmentRNA-seqInitial response to therapyCD8+ T cell fractionCohort of ptsICI-based regimensDana-Farber Cancer InstituteT cell functionResponse to therapyNaive B cellsT-cell fractionImmune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model
Wang Y, Cho J, Kastrunes G, Buck A, Razimbaud C, Culhane A, Sun J, Braun D, Choueiri T, Wu C, Jones K, Nguyen Q, Zhu Z, Wei K, Zhu Q, Signoretti S, Freeman G, Hemberg M, Marasco W. Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model. IScience 2024, 27: 108879. PMID: 38327771, PMCID: PMC10847687, DOI: 10.1016/j.isci.2024.108879.Peer-Reviewed Original ResearchCAR-T cellsChimeric antigen receptorClear cell renal cell carcinomaHematopoietic stem cellsHuman leukocyte antigenTumor microenvironmentCarbonic anhydrase IXExhausted CD8<sup>+</sup> T cellsAnti-PD-L1 monoclonal antibodyCD34<sup>+</sup> hematopoietic stem cellsMouse modelCD8<sup>+</sup> T cellsEngineered CAR-T cellsTreatment of solid tumorsReversing ITMUnfavorable tumor microenvironmentImmunosuppressive tumor microenvironmentCell renal cell carcinomaOrthotopic mouse modelRenal cell carcinomaHuman clear cell renal cell carcinomaAntitumor immunityCAR-TCell carcinomaLeukocyte antigenUpdate on Biomarkers in Renal Cell Carcinoma.
Saliby R, Saad E, Kashima S, Schoenfeld D, Braun D. Update on Biomarkers in Renal Cell Carcinoma. American Society Of Clinical Oncology Educational Book 2024, 44: e430734. PMID: 38207251, DOI: 10.1200/edbk_430734.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsRenal cell carcinomaCell carcinomaMetastatic renal cell carcinomaTumor intrinsic featuresImmune checkpoint inhibitorsRobust predictive biomarkersCheckpoint inhibitorsDurable responsesOverall survivalCare regimensPathological characteristicsPredictive biomarkersTherapeutic responseTreatment paradigmImmune systemHost factorsTranscriptional signatureGenomic alterationsTumor heterogeneityBiomarkersCarcinomaBiomarker discoveryInnovative technological approachesRegimens
2023
Integrative Analyses of Tumor and Peripheral Biomarkers in the Treatment of Advanced Renal Cell Carcinoma
Choueiri T, Donahue A, Braun D, Rini B, Powles T, Haanen J, Larkin J, Mu X, Pu J, Teresi R, di Pietro A, Robbins P, Motzer R. Integrative Analyses of Tumor and Peripheral Biomarkers in the Treatment of Advanced Renal Cell Carcinoma. Cancer Discovery 2023, 14: of1-of18. PMID: 38385846, PMCID: PMC10905671, DOI: 10.1158/2159-8290.cd-23-0680.Peer-Reviewed Original ResearchProlonged progression-free survivalT cellsTreatment of advanced renal cell carcinomaImmunomodulatory mechanismsAdvanced renal cell carcinomaBaseline tumor tissuePD-L1 inhibitorsProgression-free survivalContribution of tumor biologyT cell numbersTumors harboring mutationsTumor molecular subtypeLongitudinal blood samplesRenal cell carcinomaCell-mediated mechanismsAnalysis of tumorsInnate immune subsetsJAVELIN RenalSunitinib armPD-L1Immune subsetsCell carcinomaMolecular subtypesTumor biologyTreatment regimensA Pooled Analysis of 3 Phase II Trials of Salvage Nivolumab/Ipilimumab After Nivolumab in Renal Cell Carcinoma
McKay R, Leucht K, Xie W, Jegede O, Braun D, Atkins M, Grimm M, Choueiri T. A Pooled Analysis of 3 Phase II Trials of Salvage Nivolumab/Ipilimumab After Nivolumab in Renal Cell Carcinoma. The Oncologist 2023, 29: 324-331. PMID: 37950901, PMCID: PMC10994246, DOI: 10.1093/oncolo/oyad298.Peer-Reviewed Original ResearchObjective response rateClear cell renal cell carcinomaRenal cell carcinomaProgression-free survivalCell renal cell carcinomaAdvanced clear cell renal cell carcinomaOverall survivalCell carcinomaPooled analysisSix-month progression-free survivalBest objective response rateActivity of nivolumabInitiation of nivolumabNivolumab/ipilimumabPoor-risk diseasePhase II trialEligible patientsII trialObjective responsePrior immunotherapyImproved survivalRisk diseaseClinical trialsIpilimumabNivolumabSpatially aware deep learning reveals tumor heterogeneity patterns that encode distinct kidney cancer states
Nyman J, Denize T, Bakouny Z, Labaki C, Titchen B, Bi K, Hari S, Rosenthal J, Mehta N, Jiang B, Sharma B, Felt K, Umeton R, Braun D, Rodig S, Choueiri T, Signoretti S, Van Allen E. Spatially aware deep learning reveals tumor heterogeneity patterns that encode distinct kidney cancer states. Cell Reports Medicine 2023, 4: 101189. PMID: 37729872, PMCID: PMC10518628, DOI: 10.1016/j.xcrm.2023.101189.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitionClear cell renal cell carcinomaCell renal cell carcinomaRenal cell carcinomaTumor immune stateCcRCC biologyICI responseTumor-immune interactionsCheckpoint inhibitionCell carcinomaImmune infiltrationPatient outcomesPathologist's analysisImmune featuresCcRCC tumorsTumor phenotypeTumorsModels of tumorWhole slide images