2024
Decoy-resistant IL-18 reshapes the tumor microenvironment and enhances rejection by anti-CTLA-4 in renal cell carcinoma
Schoenfeld D, Djureinovic D, Su D, Zhang L, Lu B, Kamga L, Mann J, Huck J, Hurwitz M, Braun D, Jilaveanu L, Ring A, Kluger H. Decoy-resistant IL-18 reshapes the tumor microenvironment and enhances rejection by anti-CTLA-4 in renal cell carcinoma. JCI Insight 2024 PMID: 39561007, DOI: 10.1172/jci.insight.184545.Peer-Reviewed Original ResearchAnti-CTLA-4Renal cell carcinomaIL-18IL-18BPCell carcinomaTumor microenvironmentTumor typesPatients treated with immune checkpoint inhibitorsRegulatory T cell levelsAnti-PD-1 treatmentCD8+ T cellsAnti-PD-1Immune checkpoint inhibitorsCell renal cell carcinomaNon-responder patientsMyeloid cell populationsT cell levelsCytokine interleukin-18Anti-cancer efficacySecreted binding proteinCheckpoint inhibitorsResponding patientsPreclinical modelsT cellsMurine model1705P Association between baseline radiological tumor burden (BRTB) and outcomes in metastatic clear cell renal cell carcinoma (mccRCC) treated with first line (1L) immunotherapy (IO)-based regimens
Nawfal R, Semaan K, Eid M, Paul M, Saliby R, Chehade R, Machaalani M, Saad E, Phillips N, Canniff J, Vasseur D, Zarif T, Yekeduz E, Sun M, Baca S, Braun D, Xie W, Krajewski K, Choueiri T. 1705P Association between baseline radiological tumor burden (BRTB) and outcomes in metastatic clear cell renal cell carcinoma (mccRCC) treated with first line (1L) immunotherapy (IO)-based regimens. Annals Of Oncology 2024, 35: s1022-s1023. DOI: 10.1016/j.annonc.2024.08.1798.Peer-Reviewed Original Research14 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 carcinoma46 Radiological tumor burden is an independent risk factor for survival in patients with metastatic clear cell renal cell carcinoma (mccRCC) treated with first line immunotherapy (IO)-based regimens
Nawfal R, Eid M, Semaan K, Paul M, Saliby R, Chehade R, Machaalani M, Phillips N, Canniff J, Saad E, Vasseur D, Zarif T, Yekeduz E, Sun M, Baca S, Braun D, Xie W, Krajewski K, Choueiri T. 46 Radiological tumor burden is an independent risk factor for survival in patients with metastatic clear cell renal cell carcinoma (mccRCC) treated with first line immunotherapy (IO)-based regimens. The Oncologist 2024, 29: s25-s26. PMCID: PMC11301862, DOI: 10.1093/oncolo/oyae181.041.Peer-Reviewed Original ResearchIO-based regimensTumor burdenOverall survivalTreatment failureMultivariate analysisPrognostic factorsCT scanMetastatic clear cell renal cell carcinomaAssociated with treatment failureMultivariate Cox regression modelClear cell renal cell carcinomaHistory of nephrectomyIMDC risk groupsImmunotherapy-based regimensAssociated with OSMedian follow-upCell renal cell carcinomaDana-Farber Cancer InstituteLog-rank testIndependent risk factorRenal cell carcinomaKaplan-Meier curvesCT scan reportsManagement of patientsCox regression models24 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 tumorApplying 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 alterationsMolecular analysis of the HCRN GU16-260-Cohort A phase II study of first-line (1L) nivolumab (nivo) and salvage nivo + ipilimumab (ipi) in patients (pts) with advanced clear cell renal cell carcinoma (accRCC).
Zaemes J, Hugaboom M, Shah V, Haas N, McDermott D, Jegede O, Bilen M, Stein M, Sosman J, Alter R, Plimack E, Hurwitz M, Wu C, Einstein D, Hammers H, Signoretti S, West D, Denize T, Atkins M, Braun D. Molecular analysis of the HCRN GU16-260-Cohort A phase II study of first-line (1L) nivolumab (nivo) and salvage nivo + ipilimumab (ipi) in patients (pts) with advanced clear cell renal cell carcinoma (accRCC). Journal Of Clinical Oncology 2024, 42: 4546-4546. DOI: 10.1200/jco.2024.42.16_suppl.4546.Peer-Reviewed Original ResearchObjective response rateImmune checkpoint blockadeProgression-free survivalProgressive diseaseAnti-VEGFOverall survivalAssociated with higher progression-free survivalTumor samplesAdvanced clear cell renal cell carcinomaCombined immune checkpoint blockadeHigher progression-free survivalIncreased PFSImmune checkpoint blockade therapyShorter progression-free survivalClear cell renal cell carcinomaAnti-VEGF therapyCell renal cell carcinomaWeeks of therapyRenal cell carcinomaBiomarkers of efficacyFFPE tumor samplesNIVO monotherapyCheckpoint blockadeDecreased OSProspective trialsExpression 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 stainingAdvanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587).
Serzan M, Jegede O, Alter R, Bilen M, Braun D, Einstein D, Haas N, Herchenhorn D, King J, Runcie K, Sosman J, Sternberg C, Yang Y, Signoretti S, CHOUEIRI T, Atkins M. Advanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587). Journal Of Clinical Oncology 2024, 42: tps4614-tps4614. DOI: 10.1200/jco.2024.42.16_suppl.tps4614.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsArm BArm APrimary endpointRate of immune-related adverse eventsMetastatic clear cell renal cell carcinomaImmune-related adverse eventsMolecular predictors of responseVEGF receptor tyrosine kinase inhibitorReceptor tyrosine kinase inhibitorsEnhance T cell primingOne-sided significance levelClear cell renal cell carcinomaAnti-PD1 inhibitorsIMDC risk groupsTreatment free intervalProgression-free survivalT cell primingTreatment-free survivalCell renal cell carcinomaSubpopulations of TregsFirst-line treatmentRenal cell carcinomaPredictors of responseAssociated with increased presenceIntratumoral 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 variantsTumor-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 carcinomaAdvanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587).
Serzan M, Jegede O, Bilen M, Braun D, Einstein D, Haas N, Hammers H, King J, Runcie K, Sosman J, Sternberg C, Yang Y, Choueiri T, Signoretti S, Atkins M. Advanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587). Journal Of Clinical Oncology 2024, 42: tps492-tps492. DOI: 10.1200/jco.2024.42.4_suppl.tps492.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsArm BArm APrimary endpointRate of immune-related adverse eventsMetastatic clear cell renal cell carcinomaImmune-related adverse eventsMolecular predictors of responseVEGF receptor tyrosine kinase inhibitorReceptor tyrosine kinase inhibitorsEnhance T cell primingOne-sided significance levelClear cell renal cell carcinomaAnti-PD1 inhibitorsIMDC risk groupsTreatment free intervalProgression-free survivalT cell primingTreatment-free survivalCell renal cell carcinomaSubpopulations of TregsFirst-line treatmentRenal cell carcinomaPredictors of responseAnti-tumor activityImmune-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 antigenPD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti-PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients.
Denize T, Jegede O, Matar S, El Ahmar N, West D, Walton E, Bagheri A, Savla V, Nabil Laimon Y, Gupta S, Vemula S, Braun D, Burke K, Catalano P, Freeman G, Motzer R, Atkins M, McDermott D, Sharpe A, Choueiri T, Signoretti S. PD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti-PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients. Clinical Cancer Research 2024, 30: 803-813. PMID: 38060202, PMCID: PMC10922154, DOI: 10.1158/1078-0432.ccr-23-2274.Peer-Reviewed Original ResearchPD-1 expressionObjective response rateProgression-free survivalLow objective response rateShorter progression-free survivalPD-1 blockadeRegulatory T cellsShorter overall survivalOverall survivalPD-1Nivolumab armT cellsMetastatic clear-cell renal cell carcinoma patientsMetastatic clear cell renal cell carcinomaAnti-PD-1 therapyIntratumoral regulatory T cellsClear cell renal cell carcinoma patientsRenal cell carcinoma patientsClear cell renal cell carcinomaPD-1 inhibitorsPD-1 inhibitionCell carcinoma patientsCell renal cell carcinomaExpression of CD8Tumor-infiltrating Tregs
2023
A 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 imagesAntigenic targets in clear cell renal cell carcinoma
Schindler N, Braun D. Antigenic targets in clear cell renal cell carcinoma. Kidney Cancer 2023, 7: 81-91. PMID: 38014393, PMCID: PMC10475986, DOI: 10.3233/kca-230006.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsRenal cell carcinomaImmune checkpoint inhibitorsCell carcinomaImmune-related adverse effectsEffective anti-tumor immunityAdvanced renal cell carcinomaClear cell renal cell carcinomaAntigen-directed immunotherapySafety of immunotherapyClear cell histologyAnti-tumor immunityCell renal cell carcinomaCheckpoint inhibitorsCell histologyICI responseMost patientsNeoantigen loadCurrent therapiesAntigenic targetsLong-term benefitsMutation burdenTarget antigenAdverse effectsAntigenImmunotherapyEmerging Biomarkers of Response to Systemic Therapies in Metastatic Clear Cell Renal Cell Carcinoma
Labaki C, Saliby R, Bakouny Z, Saad E, Semaan K, Eid M, Lalani A, Choueiri T, Braun D. Emerging Biomarkers of Response to Systemic Therapies in Metastatic Clear Cell Renal Cell Carcinoma. Hematology/Oncology Clinics Of North America 2023, 37: 937-942. PMID: 37407357, DOI: 10.1016/j.hoc.2023.05.021.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsMetastatic clear cell renal cell carcinomaClear cell renal cell carcinomaCell renal cell carcinomaRenal cell carcinomaSystemic therapyCell carcinomaImmunotherapy-based regimensBiomarkers of responseSystemic regimensClinical responseValid biomarkersPromising biomarkerHeterogeneous outcomesTherapyBiomarkersRegimensPatientsCarcinomaMccRCCResponse