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 microarray
2023
CD70 is Consistently Expressed in Primary and Metastatic Clear Cell Renal Cell Carcinoma
Huang R, Chen Z, Kroeger N, Pantuck A, Said J, Kluger H, Shuch B, Ye H. CD70 is Consistently Expressed in Primary and Metastatic Clear Cell Renal Cell Carcinoma. Clinical Genitourinary Cancer 2023, 22: 347-353. PMID: 38195301, DOI: 10.1016/j.clgc.2023.12.003.Peer-Reviewed Original ResearchRenal cell carcinomaClear cell renal cell carcinomaCell renal cell carcinomaMetastatic clear cell renal cell carcinomaMetastatic renal cell carcinomaCell carcinomaClear cell carcinomaCD70 expressionMetastatic tumorsRenal tumorsTherapeutic targetAdvanced renal cell carcinomaMetastatic clear cell carcinomaCancer-specific survivalPapillary renal cell carcinomaExpression of CD70Normal renal parenchymaPrimary renal tumorsPrimary tumor tissuesPromising therapeutic targetPotential therapeutic targetHypoxia pathway proteinsHypoxia-inducible factorSarcomatoid differentiationNormal human tissues1070 ‘Decoy-resistant’ IL-18 in combination with CTLA-4 blockade enhances anti-tumor efficacy in preclinical models of renal cell carcinoma
Schoenfeld D, Djureinovic D, Zhang L, Mann J, Huck J, Jilaveanu L, Ring A, Kluger H. 1070 ‘Decoy-resistant’ IL-18 in combination with CTLA-4 blockade enhances anti-tumor efficacy in preclinical models of renal cell carcinoma. 2023, a1177-a1179. DOI: 10.1136/jitc-2023-sitc2023.1070.Peer-Reviewed Original ResearchA modified IL-18 drug in combination with CTLA-4 blockade enhances anti-tumor efficacy in preclinical models of renal cell carcinoma
Schoenfeld D, Djureinovic D, Zhang L, Mann J, Huck J, Jilaveanu L, Ring A, Kluger H. A modified IL-18 drug in combination with CTLA-4 blockade enhances anti-tumor efficacy in preclinical models of renal cell carcinoma. The Oncologist 2023, 28: s7-s7. PMCID: PMC10445567, DOI: 10.1093/oncolo/oyad216.010.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsRenal cell carcinomaImmune cell depletion studiesCell depletion studiesT cellsAnti-tumor activityPreclinical modelsRENCA modelTumor growthNK cellsIL-18IL-18BPCell carcinomaAnti-PD-1/CTLAAnti-PD-1 therapyIntra-tumoral T cellsModest anti-tumor activityAnti-tumor immune responseCytokine/chemokine levelsCytokine/chemokine profilingDepletion studiesEarly phase clinical trialsDecoy receptor proteinEnrichment of CD8PD-1 blockadeImmune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases
Schoenfeld D, Moutafi M, Martinez S, Djureinovic D, Merkin R, Adeniran A, Braun D, Signoretti S, Choueiri T, Parisi F, Hurwitz M, Rimm D, Wei W, Jilaveanu L, Kluger H. Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases. Journal For ImmunoTherapy Of Cancer 2023, 11: e007240. PMID: 37586773, PMCID: PMC10432651, DOI: 10.1136/jitc-2023-007240.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaBrain metastasesPrimary tumorTumor microenvironmentDigital spatial profilingCell carcinomaActivation protein expressionInflammatory macrophage markersRCC brain metastasesInnate immune activatorsNormal kidney samplesProgressive stagesExtracranial metastasesTim-3Immune checkpointsImmune dysfunctionImmune activationRCC metastasisLonger survivalImmune activatorsMacrophage markersTreatment responseSeparate cohortTissue microarrayMetastatic samplesScRNA-seq defines dynamic T-cell subsets in longitudinal colon and peripheral blood samples in immune checkpoint inhibitor-induced colitis
Mann J, Lucca L, Austin M, Merkin R, Robert M, Al Bawardy B, Raddassi K, Aizenbud L, Joshi N, Hafler D, Abraham C, Herold K, Kluger H. ScRNA-seq defines dynamic T-cell subsets in longitudinal colon and peripheral blood samples in immune checkpoint inhibitor-induced colitis. Journal For ImmunoTherapy Of Cancer 2023, 11: e007358. PMID: 37586769, PMCID: PMC10432652, DOI: 10.1136/jitc-2023-007358.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsT cell subsetsCheckpoint inhibitorsImmune environmentImmune checkpoint inhibitor-induced colitisCheckpoint inhibitor-induced colitisPeripheral immune environmentsStages of colitisTreatment of colitisMerkel cell carcinomaT cell populationsPeripheral blood samplesCourse of progressionT cell receptorMultiple tumor typesAlternative cancer therapyCommon toxicitiesICI colitisTreatment discontinuationAdverse eventsBiologic therapyImmune suppressionCell carcinomaColitisBlood samplesCase report: Metastatic Merkel cell carcinoma presenting seven years after loco-regional disease resection of primary tumor with interval in-transit and nodal metastases
Rusheen J, Clune J, Ariyan S, Baumann R, Kluger H, Olino K, Weiss S. Case report: Metastatic Merkel cell carcinoma presenting seven years after loco-regional disease resection of primary tumor with interval in-transit and nodal metastases. Frontiers In Oncology 2023, 13: 1217816. PMID: 37476373, PMCID: PMC10354444, DOI: 10.3389/fonc.2023.1217816.Peer-Reviewed Case Reports and Technical NotesMerkel cell carcinomaDuration of surveillanceLate recurrenceCell carcinomaMetastatic Merkel cell carcinomaPrimary Merkel cell carcinomaMetastases 15 monthsSuch late recurrencesPredictors of recurrenceNodal recurrenceDefinitive therapyFirst recurrenceDisease resectionNodal metastasisPhysical examinationRare tumorPrimary diagnosisPrimary tumorRisk factorsHigh riskNational guidelinesRecurrenceOptimal durationPatientsCarcinomaOutcomes With Combination Pembrolizumab and Axitinib in Second and Further Line Treatment of Metastatic Renal Cell Carcinoma
Dizman N, Austin M, Considine B, Jessel S, Schoenfeld D, Merl M, Hurwitz M, Sznol M, Kluger H. Outcomes With Combination Pembrolizumab and Axitinib in Second and Further Line Treatment of Metastatic Renal Cell Carcinoma. Clinical Genitourinary Cancer 2023, 21: 221-229. PMID: 36681606, DOI: 10.1016/j.clgc.2023.01.002.Peer-Reviewed Original ResearchConceptsMetastatic renal cell carcinomaPembrolizumab/axitinibObjective response rateProgression-free survivalImmune checkpoint inhibitorsMedian progression-free survivalAdverse eventsRenal cell carcinomaCell carcinomaClear cell metastatic renal cell carcinomaVascular endothelial growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsCombination immune checkpoint inhibitorsGrade 5 adverse eventsPrior immune checkpoint inhibitorsSuperior progression-free survivalReceptor tyrosine kinase inhibitorsYale-New Haven HospitalFurther-line treatmentNivolumab/ipilimumabRECIST 1.1 criteriaResponse-evaluable patientsDisease control rateSecond-line therapyFirst-line treatment
2022
FRACTION-RCC: nivolumab plus ipilimumab for advanced renal cell carcinoma after progression on immuno-oncology therapy
Choueiri T, Kluger H, George S, Tykodi S, Kuzel T, Perets R, Nair S, Procopio G, Carducci M, Castonguay V, Folefac E, Lee C, Hotte S, Miller W, Saggi S, Lee C, Desilva H, Bhagavatheeswaran P, Motzer R, Escudier B. FRACTION-RCC: nivolumab plus ipilimumab for advanced renal cell carcinoma after progression on immuno-oncology therapy. Journal For ImmunoTherapy Of Cancer 2022, 10: e005780. PMID: 36328377, PMCID: PMC9639138, DOI: 10.1136/jitc-2022-005780.Peer-Reviewed Original ResearchConceptsAdvanced renal cell carcinomaObjective response rateDuration of responseIO therapyImmuno-oncology therapiesRenal cell carcinomaOverall survivalCell carcinomaAnti-PD-1/PD-L1 therapyImmune-mediated adverse eventsMedian DORProgression-free survival ratesTreatment-related deathsManageable safety profileMedian overall survivalPD-L1 therapyDurable clinical benefitKarnofsky performance statusPrimary outcome measureHigh unmet needExploratory endpointsIpilimumab armPFS ratesStable diseaseAdverse eventsSociety for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of nonmelanoma skin cancer
Silk AW, Barker CA, Bhatia S, Bollin KB, Chandra S, Eroglu Z, Gastman BR, Kendra KL, Kluger H, Lipson EJ, Madden K, Miller DM, Nghiem P, Pavlick AC, Puzanov I, Rabinowits G, Ruiz ES, Sondak VK, Tavss EA, Tetzlaff MT, Brownell I. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of nonmelanoma skin cancer. Journal For ImmunoTherapy Of Cancer 2022, 10: e004434. PMID: 35902131, PMCID: PMC9341183, DOI: 10.1136/jitc-2021-004434.Peer-Reviewed Original ResearchConceptsNonmelanoma skin cancerClinical practice guidelinesImmune checkpoint inhibitorsCutaneous squamous cell carcinomaMerkel cell carcinomaBasal cell carcinomaCell carcinomaPractice guidelinesSkin cancerCancer clinical practice guidelinesCancer care professionalsManagement of toxicitiesSpecial patient populationsSquamous cell carcinomaImmunotherapy of cancerConsensus-based recommendationsOwn clinical experienceRoutine clinical useCheckpoint inhibitorsMetastatic diseasePatient selectionPatients' qualityImmunotherapeutic treatmentPatient populationAggressive subtypeImmune Checkpoint Inhibitor-Induced Hypophysitis and Patterns of Loss of Pituitary Function
Jessel S, Weiss SA, Austin M, Mahajan A, Etts K, Zhang L, Aizenbud L, Perdigoto AL, Hurwitz M, Sznol M, Herold KC, Kluger HM. Immune Checkpoint Inhibitor-Induced Hypophysitis and Patterns of Loss of Pituitary Function. Frontiers In Oncology 2022, 12: 836859. PMID: 35350573, PMCID: PMC8958012, DOI: 10.3389/fonc.2022.836859.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsRenal cell carcinomaCombination immune checkpoint inhibitorsCell carcinomaClinical experienceSelect casesIncidence of hypophysitisInstitution's clinical experienceYale Cancer CenterObjective response rateAdrenal axis hormonesFree testosterone levelsMerkel cell carcinomaHigh rateMultiple tumor typesCheckpoint inhibitorsPituitary axesReal-world practiceFree testosteroneMedian timeMelanoma patientsOverall incidencePituitary functionTreatment delayAxis hormones
2021
Adverse Histopathologic Characteristics in Small Papillary Renal Cell Carcinomas Have Minimal Impact on Prognosis
Yang C, Shuch B, Kluger HM, Serrano M, Kibel AS, Humphrey PA, Adeniran AJ. Adverse Histopathologic Characteristics in Small Papillary Renal Cell Carcinomas Have Minimal Impact on Prognosis. American Journal Of Clinical Pathology 2021, 156: 550-558. PMID: 34424955, DOI: 10.1093/ajcp/aqab015.Peer-Reviewed Original ResearchConceptsPapillary renal cell carcinomaAdditional prognostic informationRenal cell carcinomaHistopathologic characteristicsTumor sizeCell carcinomaActive surveillancePrognostic informationRenal massesHigh World Health Organization/International SocietyWorld Health Organization/International SocietyLower disease-free survivalAdverse histologic featuresAdverse histopathologic featuresTumor histopathologic characteristicsUrological Pathology (ISUP) gradeDisease-free survivalDisease-specific survivalSmall renal massesWorse prognosisHistologic featuresHistopathologic featuresBiopsy examinationConsecutive casesHistologic diagnosisThree-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma
Nghiem P, Bhatia S, Lipson EJ, Sharfman WH, Kudchadkar RR, Brohl AS, Friedlander PA, Daud A, Kluger HM, Reddy SA, Boulmay BC, Riker A, Burgess MA, Hanks BA, Olencki T, Kendra K, Church C, Akaike T, Ramchurren N, Shinohara MM, Salim B, Taube JM, Jensen E, Kalabis M, Fling SP, Moreno B, Sharon E, Cheever MA, Topalian SL. Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma. Journal For ImmunoTherapy Of Cancer 2021, 9: e002478. PMID: 33879601, PMCID: PMC8061836, DOI: 10.1136/jitc-2021-002478.Peer-Reviewed Original ResearchConceptsProgression-free survivalMerkel cell carcinomaSalvage therapyStable diseaseCell carcinomaBaseline Eastern Cooperative Oncology Group performance statusEastern Cooperative Oncology Group performance statusAnti-programmed death-1 therapyCell death-1 pathway inhibitorsDeath-1 pathway inhibitorsDurable progression-free survivalFirst-line pembrolizumab therapyMedian progression-free survivalMulticenter phase II trialRefractory Merkel cell carcinomaTumor progressionAdvanced Merkel cell carcinomaMedian response durationFirst-line pembrolizumabPhase II trialProportion of patientsInitial disease progressionThree-year survivalDurable tumor regressionOverall response rateAgonistic CD40 Antibodies in Cancer Treatment
Djureinovic D, Wang M, Kluger HM. Agonistic CD40 Antibodies in Cancer Treatment. Cancers 2021, 13: 1302. PMID: 33804039, PMCID: PMC8000216, DOI: 10.3390/cancers13061302.Peer-Reviewed Original ResearchAgonistic CD40 antibodyCD40 antibodyDendritic cellsAntigen presentationClinical developmentEarly phase clinical trialsAgonist CD40 antibodyActivation of CD8Pro-inflammatory effectsAntigen-presenting cellsT cell functionRenal cell carcinomaAnti-tumor effectsPhase clinical trialsAnti-tumor activityT cell activationCancer Genome AtlasSystemic therapyCell carcinomaCostimulatory moleculesCD40 expressionClinical trialsPancreatic adenocarcinomaPreclinical modelsT cellsAssessment of Age, Period, and Birth Cohort Effects and Trends in Merkel Cell Carcinoma Incidence in the United States
Jacobs D, Huang H, Olino K, Weiss S, Kluger H, Judson BL, Zhang Y. Assessment of Age, Period, and Birth Cohort Effects and Trends in Merkel Cell Carcinoma Incidence in the United States. JAMA Dermatology 2021, 157: 59-65. PMID: 33146688, PMCID: PMC7643047, DOI: 10.1001/jamadermatol.2020.4102.Peer-Reviewed Original ResearchConceptsMerkel cell carcinomaBirth cohort effectsCell carcinomaIncidence rateCalendar periodBirth cohortPatient ageNew casesCohort effectsEnd Results Program databaseCross-sectional retrospective studyLongitudinal cohort studyHigh incidence rateAge-adjusted ratesRisk factor exposureRecent birth cohortsCohort studyCarcinoma incidenceRetrospective studyNeuroendocrine cancerAge effectsProgram databaseCohort analysisMAIN OUTCOMECarcinoma
2020
Primary Treatment Selection for Clinically Node-Negative Merkel Cell Carcinoma of the Head and Neck
Jacobs D, Olino K, Park HS, Clune J, Cheraghlou S, Girardi M, Burtness B, Kluger H, Judson BL. Primary Treatment Selection for Clinically Node-Negative Merkel Cell Carcinoma of the Head and Neck. Otolaryngology 2020, 164: 1214-1221. PMID: 33079010, DOI: 10.1177/0194599820967001.Peer-Reviewed Original ResearchConceptsNode-negative Merkel cell carcinomaLymph node evaluationImproved overall survivalPrimary tumor excisionMerkel cell carcinomaCase volumeOverall survivalSurgical managementCell carcinomaTumor excisionTreatment selectionNode evaluationCox proportional hazards regressionGuideline-recommended carePrimary treatment selectionNational Cancer DatabaseNode-negative diseasePercentage of patientsRetrospective cohort analysisInitial surgical managementKaplan-Meier analysisWide local excisionProportional hazards regressionRates of receiptInitial managementCardiac Biventricular Metastasis From Renal Cell Carcinoma
Latifi AN, Ibe U, Arbune A, Kluger H, Baldassarre LA. Cardiac Biventricular Metastasis From Renal Cell Carcinoma. Cureus 2020, 12: e10870. PMID: 33178523, PMCID: PMC7652367, DOI: 10.7759/cureus.10870.Peer-Reviewed Original ResearchRenal cell carcinomaMetastatic renal cell carcinomaCardiac metastasisCell carcinomaRecurrent metastatic renal cell carcinomaCircumferential pericardial effusionSecondary cardiac tumorsAdvanced metastatic diseaseExtent of diseaseShortness of breathSite of involvementCardiac magnetic resonanceCardiac tumorsRespiratory failureMetastatic diseasePericardial effusionSystemic therapyBiventricular hypertrophyMultiple lesionsPrimary tumorPatient's diseaseTissue biopsiesMetastasisVentricular wallDiseaseNeoadjuvant anti–programmed cell death 1 therapy for locally advanced basal cell carcinoma in treatment-naive patients: A case series
Ligtenberg KG, Hu JK, Damsky W, Olino K, Kluger H, Clune J, Cowper SE, Panse G, Leventhal J, Weiss SA. Neoadjuvant anti–programmed cell death 1 therapy for locally advanced basal cell carcinoma in treatment-naive patients: A case series. JAAD Case Reports 2020, 6: 628-633. PMID: 32613057, PMCID: PMC7317689, DOI: 10.1016/j.jdcr.2020.05.010.Peer-Reviewed Case Reports and Technical NotesHigh WHO/ISUP Grade and Unfavorable Architecture, Rather Than Typing of Papillary Renal Cell Carcinoma, May Be Associated With Worse Prognosis
Yang C, Shuch B, Kluger H, Humphrey PA, Adeniran AJ. High WHO/ISUP Grade and Unfavorable Architecture, Rather Than Typing of Papillary Renal Cell Carcinoma, May Be Associated With Worse Prognosis. The American Journal Of Surgical Pathology 2020, 44: 582-593. PMID: 32101890, DOI: 10.1097/pas.0000000000001455.Peer-Reviewed Original ResearchConceptsPapillary renal cell carcinomaType 2 papillary renal cell carcinomaDisease-free survivalWHO/ISUP gradeHigh WHO/ISUP gradeOverall survivalRenal cell carcinomaISUP gradeWorld Health OrganizationPRCC typeType 1Hazard ratioPathologic stageCell carcinomaMicropapillary architectureHistologic parametersType 2Stepwise multivariate Cox regression analysisWorse disease-free survivalMultivariate Cox regression analysisTumor areaType 1 histologyUrological Pathology (ISUP) gradeCox regression analysisMixed type 1