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 modelTIGIT 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 microarrayDevelopment of anex vivo patient-derived tumor model (PDTM) to assess the tumor microenvironment in renal cell carcinoma (RCC)
Kashima S, Gupta R, Moritz V, Sadak K, Adeniran A, Humphrey P, Dinulescu D, Palmer D, Hammond S, Bosenberg M, Hurwitz M, Kenney P, Braun D. Development of anex vivo patient-derived tumor model (PDTM) to assess the tumor microenvironment in renal cell carcinoma (RCC). The Oncologist 2024, 29: s5-s6. PMCID: PMC11301923, DOI: 10.1093/oncolo/oyae181.008.Peer-Reviewed Original ResearchRCC tumor microenvironmentPatient-derived tumor modelsRenal cell carcinomaImmune checkpoint inhibitorsT cell functionPeripheral blood mononuclear cellsEnzyme-linked immunosorbent assayTumor microenvironmentT cellsFlow cytometryTumor fragmentsIFN-gTumor modelTumor samplesCytokine productionHealthy donor peripheral blood mononuclear cellsImpact of immune checkpoint inhibitorsAnti-PD-1 monoclonal antibodyDonor peripheral blood mononuclear cellsCD4+CD25+ regulatory T cellsCD8+ T cell populationsResection of renal cell carcinomaSurgical resection of renal cell carcinomaAnti-PD-1 antibodyMetastatic renal cell carcinoma20 Evaluating intermediate endpoints for overall survival in metastatic renal cell carcinoma treated with immune checkpoint inhibitors: an IMDC study
Saliby R, Xie W, Wells C, Saad E, Eid M, Semaan K, Labaki C, Ferrier E, Zarba M, Ebrahimi H, Ravi P, Suarez C, Morales J, McKay R, Powles T, Wood L, Lalani A, Pal S, de Velasco G, Takemura K, Agarwal N, Braun D, Heng D, Choueiri T. 20 Evaluating intermediate endpoints for overall survival in metastatic renal cell carcinoma treated with immune checkpoint inhibitors: an IMDC study. The Oncologist 2024, 29: s8-s9. PMCID: PMC11301915, DOI: 10.1093/oncolo/oyae181.013.Peer-Reviewed Original ResearchTime to next therapyInternational mRCC Database ConsortiumTime to treatment failureInternational mRCC Database Consortium risk groupOverall survivalObjective responseFollow-upIndividual patient dataLandmark analysisTreatment failureInternational Metastatic Renal-Cell Carcinoma Database ConsortiumMetastatic renal cell carcinoma treated with immune checkpoint inhibitorsRisk groupsEndpoint of overall survivalMonths of follow-upIntermediate endpointsICI-based regimensImmune checkpoint inhibitorsImmune-checkpoint inhibitorsMedian follow-upAnalysis of OSAssociated with OSAssociation of OSPost-therapy initiationFollow-up time22 Association of a germline single nucleotide polymorphism (SNP) in the interleukin-7 (IL7) gene with immune-related adverse events (irAEs)
Saad E, Mehrabad E, Labaki C, Saliby R, Semaan K, Eid M, Machaalani M, Chehade R, Nawfal R, Sun M, Sharon E, Shah P, Vemula S, Gupta S, Braun D, Van Allen E, Gusev A, Choueiri T. 22 Association of a germline single nucleotide polymorphism (SNP) in the interleukin-7 (IL7) gene with immune-related adverse events (irAEs). The Oncologist 2024, 29: s1-s2. PMCID: PMC11301885, DOI: 10.1093/oncolo/oyae181.003.Peer-Reviewed Original ResearchImmune-related adverse eventsMetastatic non-small cell lung cancerMetastatic renal cell carcinomaImmune checkpoint inhibitorsProgression-free survivalWhole-exome sequencingRecurrent grade 2Overall survivalGrade 2Interleukin-7Single nucleotide polymorphismsNivolumab armPembrolizumab armSomatic alterationsAdverse eventsTreatment armsPrediction of immune-related adverse eventsCumulative rates of adverse eventsTumor whole-exome sequencingRates of grade 2Non-small cell lung cancerGermline single nucleotide polymorphismsClinical trials of patientsAssociated with significantly higher ratesPD-1 inhibitorsEpigenomic 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 samplesInvestigation of T cell phenotypes associated with response or resistance to immune checkpoint inhibitors (ICI) through single-cell analysis of renal cell carcinoma (RCC).
Kashima S, Ye Z, Meliki A, Hugaboom M, Schindler N, Graham J, Moritz V, El Ahmar N, Nabil Laimon Y, Canniff J, Saliby R, Lee G, Machaalani M, Sun M, Xu W, Signoretti S, McGregor B, McKay R, CHOUEIRI T, Braun D. Investigation of T cell phenotypes associated with response or resistance to immune checkpoint inhibitors (ICI) through single-cell analysis of renal cell carcinoma (RCC). Journal Of Clinical Oncology 2024, 42: 4515-4515. DOI: 10.1200/jco.2024.42.16_suppl.4515.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsRenal cell carcinomaCD8+ T cell infiltrationT cell infiltrationNon-respondersTumor microenvironmentT cellsRCC tumor microenvironmentResistance to immune checkpoint inhibitorsICI responseImmune checkpoint inhibitor treatmentImmune checkpoint inhibitor efficacyCD8+ T cellsExpressed PD-1ICI-treated patientsGene programGene signature scoresTumor mutation loadCellular compositionGene expression signaturesSingle-cell transcriptome analysisCheckpoint inhibitorsPD-1Partial responseSystemic therapyEvaluating 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 carcinomaMulti-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 fractionCellular and molecular determinants of limited anti-tumor immunity in chromophobe renal carcinoma (ChRCC).
Labaki C, Alchoueiry M, Bi K, Zhang L, Hobeika C, Bakouny Z, El Ahmar N, Matar S, Priolo C, Khabibullin D, Schindler N, Camp S, Saliby R, Saad E, Signoretti S, Van Allen E, Shukla S, Henske E, Choueiri T, Braun D. Cellular and molecular determinants of limited anti-tumor immunity in chromophobe renal carcinoma (ChRCC). Journal Of Clinical Oncology 2024, 42: 476-476. DOI: 10.1200/jco.2024.42.4_suppl.476.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsAnti-tumor immunityCell of originScRNA-seq dataPutative cell of originHLA class I genesCD8+Class I genesPD-1T cellsI geneSingle-cell T-cell receptorPoor responseResponse to immune checkpoint inhibitorsExpression of HLA class I genesInfiltration of CD8+Infiltration of T cellsCD4+ T cellsDegree of clonal expansionDownregulation of antigen presentationProportion of CD8+T cell clonotypesChromophobe renal carcinomaMolecular determinantsProtein processing pathwayUpdate 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
Antigenic 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 effectsAntigenImmunotherapyLeveraging immune resistance archetypes in solid cancer to inform next-generation anticancer therapies
Anderson K, Braun D, Buqué A, Gitto S, Guerriero J, Horton B, Keenan B, Kim T, Overacre-Delgoffe A, Ruella M, Triplett T, Veeranki O, Verma V, Zhang F. Leveraging immune resistance archetypes in solid cancer to inform next-generation anticancer therapies. Journal For ImmunoTherapy Of Cancer 2023, 11: e006533. PMID: 37399356, PMCID: PMC10314654, DOI: 10.1136/jitc-2022-006533.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsImmune resistance mechanismsImmune resistanceChimeric antigen receptor T cellsAntigen receptor T cellsImmune checkpoint inhibitorsReceptor T cellsVariety of malignanciesNew therapeutic strategiesResistance mechanismsCheckpoint inhibitorsDurable responsesMost patientsAnticancer immunotherapyTherapy combinationsCurrent therapiesT cellsIndividual patientsSolid cancersTherapeutic strategiesTumor profilingPatientsOverall efficacySuppressive mechanismsBispecific antibodiesTumor microenvironmentImmunobiology and Metabolic Pathways of Renal Cell Carcinoma
Braun D, Chakraborty A. Immunobiology and Metabolic Pathways of Renal Cell Carcinoma. Hematology/Oncology Clinics Of North America 2023, 37: 827-840. PMID: 37246090, DOI: 10.1016/j.hoc.2023.04.012.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsRenal cell carcinomaCell carcinomaAdvanced renal cell carcinomaClear cell renal cell carcinomaImmune checkpoint inhibitorsCell renal cell carcinomaNew treatment targetsFuture clinical developmentCheckpoint inhibitorsNovel therapeutic developmentDurable responsesMost patientsMetabolic dysregulationDistinct tumorsClinical developmentImmune pathwaysTreatment targetsTherapeutic developmentCarcinomaCurrent understandingMetabolic pathwaysPatientsImmunobiologyTumorsPathwayThe Changing Landscape of Immunotherapy for Advanced Renal Cancer
Kashima S, Braun D. The Changing Landscape of Immunotherapy for Advanced Renal Cancer. Urologic Clinics Of North America 2023, 50: 335-349. PMID: 36948676, DOI: 10.1016/j.ucl.2023.01.012.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsRenal cell carcinomaAdvanced renal cell carcinomaCell carcinomaCentral therapeutic strategyAdvanced renal cancerDurable clinical benefitImmune checkpoint inhibitorsImmunecheckpoint inhibitorsCheckpoint inhibitorsCytokine therapyImmunogenic tumorsMost patientsSystemic therapyClinical benefitCombination therapyCurrent therapiesInterleukin-2Renal cancerTherapeutic strategiesTherapyCarcinomaInhibitorsImmunotherapyPatientsInterferon
2022
Germline variants associated with toxicity to immune checkpoint blockade
Groha S, Alaiwi S, Xu W, Naranbhai V, Nassar A, Bakouny Z, El Zarif T, Saliby R, Wan G, Rajeh A, Adib E, Nuzzo P, Schmidt A, Labaki C, Ricciuti B, Alessi J, Braun D, Shukla S, Keenan T, Van Allen E, Awad M, Manos M, Rahma O, Zubiri L, Villani A, Fairfax B, Hammer C, Khan Z, Reynolds K, Semenov Y, Schrag D, Kehl K, Freedman M, Choueiri T, Gusev A. Germline variants associated with toxicity to immune checkpoint blockade. Nature Medicine 2022, 28: 2584-2591. PMID: 36526723, PMCID: PMC10958775, DOI: 10.1038/s41591-022-02094-6.Peer-Reviewed Original ResearchConceptsImmune-related adverse eventsImmune checkpoint inhibitorsGrade immune-related adverse eventsGermline variantsICI initiationCheckpoint inhibitorsAdverse eventsCheckpoint blockadeImproved survivalDiscovery cohortLymphocyte homeostasisSignificant associationCancer typesIL7Remarkable responsePatientsCritical regulatorGenome-wide significant associationAssociationWide association studyIndependent studiesAssociation studiesBlockadeCohortVariantsDual CDKN2A/MTAP loss compared to CDKN2A loss alone and response to immune-checkpoint inhibitors (ICI) in advanced solid tumors.
Adib E, Nassar A, El Zarif T, Kale N, Rakaee M, Mouhieddine T, Abou Alaiwi S, Freeman D, Labban M, Akl E, Haddad R, Hodi F, Sonpavde G, Giannakis M, Braun D, Gusev A, Choueiri T, Overstreet E, Stone E, Kwiatkowski D. Dual CDKN2A/MTAP loss compared to CDKN2A loss alone and response to immune-checkpoint inhibitors (ICI) in advanced solid tumors. Journal Of Clinical Oncology 2022, 40: 2622-2622. DOI: 10.1200/jco.2022.40.16_suppl.2622.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsTumor-infiltrating lymphocytesLow TIL densityTreatment failureOverall survivalHazard ratioTIL densityGenomic alterationsCell carcinomaNon-small cell lung cancerDana-Farber Cancer InstituteCancer typesNeck squamous cell carcinomaAdvanced solid tumorsConcurrent systemic therapyCell lung cancerSquamous cell carcinomaTumor mutational burdenRenal cell carcinomaMelanoma tissue samplesMTAP lossHomozygous deletionECOG PSEsophagogastric carcinomaMetastatic setting
2021
Beyond conventional immune-checkpoint inhibition — novel immunotherapies for renal cell carcinoma
Braun DA, Bakouny Z, Hirsch L, Flippot R, Van Allen EM, Wu CJ, Choueiri TK. Beyond conventional immune-checkpoint inhibition — novel immunotherapies for renal cell carcinoma. Nature Reviews Clinical Oncology 2021, 18: 199-214. PMID: 33437048, PMCID: PMC8317018, DOI: 10.1038/s41571-020-00455-z.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaImmune checkpoint inhibitorsCell carcinomaAdvanced stage renal cell carcinomaContext of RCCNovel immune-based therapiesAntigen-directed therapiesImmunotherapy-based combinationsSuccess of antibodiesAntitumour immune responseDurable clinical benefitImmune-based therapiesT cell infiltrationCancer-immunity cycleImmune-based treatmentsTreatment of patientsMost renal cell carcinomasTumor CD8Most patientsImmune checkpointsPD-1Innovative immunotherapiesTherapeutic vaccinesWorse prognosisClinical benefit
2019
State of the Future: Translational Approaches in Renal Cell Carcinoma in the Immunotherapy Era
Bakouny Z, Flippot R, Braun D, Lalani A, Choueiri T. State of the Future: Translational Approaches in Renal Cell Carcinoma in the Immunotherapy Era. European Urology Focus 2019, 6: 37-40. PMID: 30827939, DOI: 10.1016/j.euf.2019.02.014.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaCell carcinomaImmune systemTherapeutic resistanceMetastatic renal cell carcinomaImmune checkpoint inhibitorsMetastatic kidney cancerSubset of patientsPatient's immune systemImmunotherapy eraCheckpoint inhibitorsTreatment optionsKidney cancerPatientsTranslational approachTranslational researchImaging modalitiesCarcinomaTherapyTumorsNovel technological advancesSubstantial numberBiomarker discoveryBrief reportTumor spheroids