2023
A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better
Djureinovic D, Weiss S, Krykbaeva I, Qu R, Vathiotis I, Moutafi M, Zhang L, Perdigoto A, Wei W, Anderson G, Damsky W, Hurwitz M, Johnson B, Schoenfeld D, Mahajan A, Hsu F, Miller-Jensen K, Kluger Y, Sznol M, Kaech S, Bosenberg M, Jilaveanu L, Kluger H. A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better. Molecular Cancer 2023, 22: 182. PMID: 37964379, PMCID: PMC10644655, DOI: 10.1186/s12943-023-01884-x.Peer-Reviewed Original ResearchConceptsStable diseasePartial responseMacrophage populationsThree-drug regimenUnconfirmed partial responsePhase I trialLimited treatment optionsMonocyte/macrophage populationNon-classical monocytesMurine melanoma modelTreatment-related changesResultsThirteen patientsWorse survivalI trialInflammatory tumorPatient populationTreatment optionsImmune cellsDisease progressionMurine studiesPreclinical modelsResistant melanomaAntigen presentationMurine modelCyTOF analysisClinical Predictors of Survival in Patients With BRAFV600-Mutated Metastatic Melanoma Treated With Combined BRAF and MEK Inhibitors After Immune Checkpoint Inhibitors
Kahn A, Perry C, Etts K, Kluger H, Sznol M. Clinical Predictors of Survival in Patients With BRAFV600-Mutated Metastatic Melanoma Treated With Combined BRAF and MEK Inhibitors After Immune Checkpoint Inhibitors. The Oncologist 2023, 29: e507-e513. PMID: 37971411, PMCID: PMC10994263, DOI: 10.1093/oncolo/oyad300.Peer-Reviewed Original ResearchBRAF/MEK inhibitorsBRAF/MEK inhibitionImmune checkpoint inhibitorsBRAFV600E/K mutationsMEK inhibitorsCheckpoint inhibitorsClinical variablesMEK inhibitionRetrospective single-institution analysisIpilimumab/nivolumabFirst-line settingFirst-line therapyFirst-line treatmentMetastatic melanoma patientsLong-term outcomesPretreatment clinical variablesSingle-institution analysisStratification of patientsK mutationCombined BRAFECOG PSMedian OSRECIST 1.1Immunotherapy regimenClinical characteristics542 TIGIT as a potential therapeutic target in renal cell carcinoma
Kashima S, Soulati H, Madsen K, Sadak K, Wirth L, Hurwitz M, Kluger H, Sznol M, Humphrey P, Adeniran A, Kenney P, Braun D. 542 TIGIT as a potential therapeutic target in renal cell carcinoma. 2023, a616-a616. DOI: 10.1136/jitc-2023-sitc2023.0542.Peer-Reviewed Original Research736 A phase 1/2 open-label, dose-escalation study of ST-067, a decoy-resistant IL-18 cytokine, given as a monotherapy and with pembrolizumab in advanced solid tumor malignancies
Moser J, Sullivan R, Taylor M, Puzanov I, Falchook G, Sznol M, Paton V, Chonzi D, Garofalo B, Sonnemann M, Uppal H, Barton J, McQueen B, Ring A, Kluger H. 736 A phase 1/2 open-label, dose-escalation study of ST-067, a decoy-resistant IL-18 cytokine, given as a monotherapy and with pembrolizumab in advanced solid tumor malignancies. 2023, a829-a829. DOI: 10.1136/jitc-2023-sitc2023.0736.Peer-Reviewed Original Research
2025
Survival of patients with metastatic renal cell carcinoma with or without brain metastases.
Hurwitz M, Considine B, Hasson N, Savion Gaiger N, Nelson M, Chiang V, Kluger H, Braun D, Schoenfeld D, Sznol M, Leapman M. Survival of patients with metastatic renal cell carcinoma with or without brain metastases. Journal Of Clinical Oncology 2025, 43: 476-476. DOI: 10.1200/jco.2025.43.5_suppl.476.Peer-Reviewed Original ResearchMetastatic renal cell carcinomaImmune checkpoint inhibitorsClear cell RCCRenal cell carcinomaImmune checkpoint inhibitor therapyMetastatic clear cell RCCBrain metastasesOverall survivalCell carcinomaImmune checkpoint inhibitor eraPrevalence of brain metastasesMultivariate Cox proportional hazards modelAssociated with poor survivalMedian overall survivalAssociated with poor prognosisCompare overall survivalImproved overall survivalAdverse prognostic indicatorDevelopment of BMSurvival of patientsKaplan-Meier analysisYale Cancer CenterRetrospective cohort studyCox proportional hazards modelsProportional hazards model
2024
Causes of death and patterns of metastatic disease at the end of life for patients with advanced melanoma in the immunotherapy era
Lee D, McNamara M, Yang A, Yaskolko M, Kluger H, Tran T, Olino K, Clune J, Sznol M, Ishizuka J. Causes of death and patterns of metastatic disease at the end of life for patients with advanced melanoma in the immunotherapy era. Pigment Cell & Melanoma Research 2024, 37: 847-853. PMID: 39073002, PMCID: PMC11809125, DOI: 10.1111/pcmr.13188.Peer-Reviewed Original ResearchSite of metastasisPattern of metastatic diseaseMelanoma mortalityRetrospective observational cohort studyCause of cancer mortalityDistant lymph nodesObservational cohort studyDiagnosis to deathImmunotherapy eraAdvanced melanomaMetastatic diagnosisMetastatic diseaseMetastatic melanomaImmunotherapy treatmentRespiratory failureCause of deathMedian timeLymph nodesTherapeutic advancesCohort studyMelanomaImmunotherapyMechanism of deathPatientsEnd of lifeCauses of death and patterns of metastatic disease at the end of life for patients with advanced melanoma in the immunotherapy era.
Lee D, Yang A, McNamara M, Kluger H, Tran T, Olino K, Clune J, Sznol M, Ishizuka J. Causes of death and patterns of metastatic disease at the end of life for patients with advanced melanoma in the immunotherapy era. Journal Of Clinical Oncology 2024, 42: e21522-e21522. DOI: 10.1200/jco.2024.42.16_suppl.e21522.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsYale Cancer CenterAdvanced melanomaMetastatic diseaseMetastatic melanomaRespiratory failureSite of metastatic diseasePattern of metastatic diseaseDied of respiratory failureAnti-CTLA4 treatmentRetrospective observational cohort studyAnti-PD1 therapyDistant lymph nodesPatients aged >Site of diseaseSurvival of patientsObservational cohort studyMulti-system involvementDiagnosis to deathImmunotherapy eraAnti-PD1Checkpoint inhibitorsInstitutional review boardMetastatic sitesMetastatic diagnosisImmunotherapy Initiation at the End of Life in Patients With Metastatic Cancer in the US
Kerekes D, Frey A, Prsic E, Tran T, Clune J, Sznol M, Kluger H, Forman H, Becher R, Olino K, Khan S. Immunotherapy Initiation at the End of Life in Patients With Metastatic Cancer in the US. JAMA Oncology 2024, 10: 342-351. PMID: 38175659, PMCID: PMC10767643, DOI: 10.1001/jamaoncol.2023.6025.Peer-Reviewed Original ResearchNon-small cell lung cancerEnd of lifeMonth of deathImmunotherapy initiationCohort studyMAIN OUTCOMEStage IV non-small cell lung cancerCharlson-Deyo comorbidity indexHigh metastatic burdenInitiation of immunotherapyNational prescribing patternsRisk-adjusted patientsImmune checkpoint inhibitorsRetrospective cohort studyStage IV melanomaPercentage of patientsHigh-volume centersLocation of metastasesLow-volume centersOdds of deathCell lung cancerNational Clinical DatabaseLow-volume facilitiesDrug Administration approvalCheckpoint inhibitorsImmunotherapy utilization in stage IIIA melanoma: less may be more
Frey A, Kerekes D, Khan S, Tran T, Kluger H, Clune J, Ariyan S, Sznol M, Ishizuka J, Olino K. Immunotherapy utilization in stage IIIA melanoma: less may be more. Frontiers In Oncology 2024, 14: 1336441. PMID: 38380358, PMCID: PMC10876869, DOI: 10.3389/fonc.2024.1336441.Peer-Reviewed Original ResearchStage IIIA melanomaHigh-volume centersRisk-adjusted survivalLow-volume centersImmunotherapy utilizationAdjuvant immunotherapyStage IIIATreatment of stage III melanomaAcademic centersMultivariable Cox proportional hazards regressionStage III melanomaNational Cancer DatabaseStage III diseaseFactors associated with receiptCox proportional hazards regressionCompare patient outcomesProportional hazards regressionIII melanomaImmunotherapy receiptReceiving immunotherapyIII diseaseImmunotherapy agentsOverall survivalSurvival benefitAdjuvant treatment
2022
Coupled fibromodulin and SOX2 signaling as a critical regulator of metastatic outgrowth in melanoma
Oria VO, Zhang H, Zito CR, Rane CK, Ma XY, Provance OK, Tran TT, Adeniran A, Kluger Y, Sznol M, Bosenberg MW, Kluger HM, Jilaveanu LB. Coupled fibromodulin and SOX2 signaling as a critical regulator of metastatic outgrowth in melanoma. Cellular And Molecular Life Sciences 2022, 79: 377. PMID: 35737114, PMCID: PMC9226089, DOI: 10.1007/s00018-022-04364-5.Peer-Reviewed Original ResearchConceptsTumor suppressor Hippo pathwayNovel regulatory mechanismTumor vasculogenic mimicryMetastatic outgrowthExtracellular matrix componentsHippo pathwayRegulatory mechanismsMolecular eventsTumor-stroma interactionsCritical regulatorMetastatic competenceProgenitor markersProliferative stateFunctional roleFunctional studiesSOX2Vasculogenic mimicryDistinct phenotypesMatrix componentsEarly developmentFmodHigh expressionCritical processOutgrowthImportant roleImmune 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 hormonesAutoimmune retinopathy with associated anti-retinal antibodies as a potential immune-related adverse event associated with immunotherapy in patients with advanced cutaneous melanoma: case series and systematic review
Heng JS, Kim JM, Jones DK, Stoessel KM, Weiss SA, Sznol M, Kluger HM, Walter SD, Silverstein NA, Pointdujour-Lim R. Autoimmune retinopathy with associated anti-retinal antibodies as a potential immune-related adverse event associated with immunotherapy in patients with advanced cutaneous melanoma: case series and systematic review. BMJ Open Ophthalmology 2022, 7: e000889. PMID: 35047671, PMCID: PMC8724805, DOI: 10.1136/bmjophth-2021-000889.Peer-Reviewed Original ResearchConceptsAdvanced cutaneous melanomaAnti-retinal antibodiesImmune-related adverse eventsAutoimmune retinopathyCutaneous melanomaNivolumab immunotherapySystematic reviewAdverse eventsMucosal melanomaAcute exudative polymorphous vitelliform maculopathyPotential immune-related adverse eventsBilateral visual field lossNew visual symptomsImmune checkpoint inhibitionRetrospective chart reviewCutaneous melanoma patientsVaried clinical manifestationsVisual field lossComplete ophthalmic examinationScreening of patientsMeta-Analyses (PRISMA) guidelinesPreferred Reporting ItemsVitelliform maculopathyChart reviewFunduscopic changes
2021
Outcomes of Stereotactic Radiosurgery and Immunotherapy in Renal Cell Carcinoma Patients With Brain Metastases
Uezono H, Nam D, Kluger HM, Sznol M, Hurwitz M, Yu JB, Chiang VL. Outcomes of Stereotactic Radiosurgery and Immunotherapy in Renal Cell Carcinoma Patients With Brain Metastases. American Journal Of Clinical Oncology 2021, 44: 495-501. PMID: 34432667, DOI: 10.1097/coc.0000000000000849.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsRCC brain metastasesBrain metastasesRenal cell carcinomaStereotactic radiosurgeryOverall survivalUse of ICIsCentral nervous system toxicityRenal cell carcinoma patientsImpact of immunotherapyLocal control outcomesMedian overall survivalCell carcinoma patientsKaplan-Meier curvesNervous system toxicityBetter median OSLog-rank testMann-Whitney U testMargin doseMedian OSNonimmunotherapy groupSRS doseCheckpoint inhibitorsImmunotherapy groupCarcinoma patientsA Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non–Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1
Weiss SA, Djureinovic D, Jessel S, Krykbaeva I, Zhang L, Jilaveanu L, Ralabate A, Johnson B, Levit NS, Anderson G, Zelterman D, Wei W, Mahajan A, Trifan O, Bosenberg M, Kaech SM, Perry CJ, Damsky W, Gettinger S, Sznol M, Hurwitz M, Kluger HM. A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non–Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1. Clinical Cancer Research 2021, 27: 4757-4767. PMID: 34140403, PMCID: PMC9236708, DOI: 10.1158/1078-0432.ccr-21-0903.Peer-Reviewed Original ResearchConceptsAnti-PD-1/PD-L1Non-small cell lung cancerCell lung cancerRenal cell carcinomaPD-L1Lung cancerDisease progressionCommon treatment-related adverse eventsPD-1/PD-L1 inhibitorsTreatment-related adverse eventsPhase 2 doseSubstantial clinical challengeUnconfirmed partial responseDose-limiting toxicityPD-L1 inhibitorsPhase I trialDose-escalation designPro-inflammatory cytokinesMultiple tumor typesAsymptomatic elevationStable diseaseIntolerable toxicityAdverse eventsMedian durationPartial response
2020
Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02)
Diab A, Tannir NM, Bentebibel SE, Hwu P, Papadimitrakopoulou V, Haymaker C, Kluger HM, Gettinger SN, Sznol M, Tykodi SS, Curti BD, Tagliaferri MA, Zalevsky J, Hannah AL, Hoch U, Aung S, Fanton C, Rizwan A, Iacucci E, Liao Y, Bernatchez C, Hurwitz ME, Cho DC. Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02). Cancer Discovery 2020, 10: 1158-1173. PMID: 32439653, DOI: 10.1158/2159-8290.cd-19-1510.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic Agents, ImmunologicalAntineoplastic Combined Chemotherapy ProtocolsCarcinoma, Non-Small-Cell LungCarcinoma, Renal CellFemaleGene Expression Regulation, NeoplasticHumansImmune Checkpoint InhibitorsImmunotherapyInterleukin-2Kidney NeoplasmsLung NeoplasmsLymphocyte CountLymphocytes, Tumor-InfiltratingMaleMelanomaMiddle AgedNivolumabPolyethylene GlycolsProgrammed Cell Death 1 ReceptorTreatment OutcomeYoung AdultConceptsTreatment-related adverse eventsAdvanced solid tumorsPD-L1 statusSolid tumorsGrade 3/4 treatment-related adverse eventsPD-1/PD-L1 blockadeCommon treatment-related adverse eventsPhase I dose-escalation trialPoor prognostic risk factorsTotal objective response rateI dose-escalation studyI dose-escalation trialLongitudinal tumor biopsiesPD-L1 blockadeT-cell enhancementTreatment-related deathsObjective response ratePhase II doseDose-escalation studyDose-escalation trialDose-limiting toxicityFlu-like symptomsPrognostic risk factorsTumor-infiltrating lymphocytesCytotoxicity of CD8Survival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma
Klemen ND, Wang M, Rubinstein JC, Olino K, Clune J, Ariyan S, Cha C, Weiss SA, Kluger HM, Sznol M. Survival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma. Journal For ImmunoTherapy Of Cancer 2020, 8: e000341. PMID: 32209601, PMCID: PMC7103823, DOI: 10.1136/jitc-2019-000341.Peer-Reviewed Original ResearchConceptsCheckpoint inhibitorsOverall survivalMetastatic melanomaPrimary tumorLocal therapyCutaneous melanomaAnti-PD-1 antibodyAggressive multidisciplinary approachCutaneous primary tumorPrimary tumor histologyMedian overall survivalSingle institutional experienceRare melanoma subtypeMedian OSMetastatic diseaseProgressive diseaseAcral skinComplete responsePD-1PD-L1Uveal tractTumor histologyCombination therapyCTLA-4Longer survivalDefining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce
Kluger HM, Tawbi HA, Ascierto ML, Bowden M, Callahan MK, Cha E, Chen HX, Drake CG, Feltquate DM, Ferris RL, Gulley JL, Gupta S, Humphrey RW, LaVallee TM, Le DT, Hubbard-Lucey VM, Papadimitrakopoulou VA, Postow MA, Rubin EH, Sharon E, Taube JM, Topalian SL, Zappasodi R, Sznol M, Sullivan RJ. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. Journal For ImmunoTherapy Of Cancer 2020, 8: e000398. PMID: 32238470, PMCID: PMC7174063, DOI: 10.1136/jitc-2019-000398.Peer-Reviewed Original ResearchConceptsCancer immunotherapyClinical definitionNew agentsPD-1/PD-L1 blockadePD-1 pathway blockadeConsensus clinical definitionPD-L1 blockadeDeath receptor-1Immunotherapy of cancerStandard of careClinical trial designTreatment discontinuationMechanisms of resistancePathway blockadeClinical trialsConfirmatory scanPrimary resistancePatient benefitSecondary resistanceTrial designTreatment approachesUnmet needReceptor 1Tumor resistancePattern of response
2019
Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition—A Pooled Analysis of Patients With Advanced Melanoma
Regan MM, Werner L, Rao S, Gupte-Singh K, Hodi FS, Kirkwood JM, Kluger HM, Larkin J, Postow MA, Ritchings C, Sznol M, Tarhini AA, Wolchok JD, Atkins MB, McDermott DF. Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition—A Pooled Analysis of Patients With Advanced Melanoma. Journal Of Clinical Oncology 2019, 37: 3350-3358. PMID: 31498030, PMCID: PMC6901280, DOI: 10.1200/jco.19.00345.Peer-Reviewed Original ResearchConceptsTreatment-related adverse eventsTreatment-free survivalHigher treatment-related adverse eventsKaplan-Meier curvesTherapy initiationAdvanced melanomaICI therapyEnd pointGrade 3Outcome measuresLonger treatment-free survivalImmuno-oncology agentsSystemic therapy initiationThird end pointTreatment-free timeImmune checkpoint inhibitionSurvival end pointsEvent end pointsNovel outcome measuresCheckMate 067ICI cessationAdverse eventsTherapy cessationCheckpoint inhibitionPooled analysisPatterns of failure after immunotherapy with checkpoint inhibitors predict durable progression-free survival after local therapy for metastatic melanoma
Klemen ND, Wang M, Feingold PL, Cooper K, Pavri SN, Han D, Detterbeck FC, Boffa DJ, Khan SA, Olino K, Clune J, Ariyan S, Salem RR, Weiss SA, Kluger HM, Sznol M, Cha C. Patterns of failure after immunotherapy with checkpoint inhibitors predict durable progression-free survival after local therapy for metastatic melanoma. Journal For ImmunoTherapy Of Cancer 2019, 7: 196. PMID: 31340861, PMCID: PMC6657062, DOI: 10.1186/s40425-019-0672-3.Peer-Reviewed Original ResearchConceptsThree-year progression-free survivalProgression-free survivalDisease-specific survivalFive-year disease-specific survivalPatterns of failureDurable progression-free survivalLocal therapyStereotactic body radiotherapyMetastatic melanomaNew metastasesPatient selectionIndependent radiological reviewOngoing complete responseResultsFour hundred twentyEvidence of diseaseCNS metastasisCPI treatmentImmunotherapy failureCheckpoint inhibitorsMost patientsProgressive diseaseRadiological reviewComplete responsePD-1PD-L1A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors
Bentebibel SE, Hurwitz ME, Bernatchez C, Haymaker C, Hudgens CW, Kluger HM, Tetzlaff MT, Tagliaferri MA, Zalevsky J, Hoch U, Fanton C, Aung S, Hwu P, Curti BD, Tannir NM, Sznol M, Diab A. A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors. Cancer Discovery 2019, 9: 711-721. PMID: 30988166, DOI: 10.1158/2159-8290.cd-18-1495.Peer-Reviewed Original ResearchConceptsNKTR-214Tumor biopsiesDurable disease stabilizationImmuno-oncology agentsMulticenter phase IPathway-targeted agentsTreatment tumor biopsiesPhase II doseActivation of CD8Metastatic solid tumorsNatural killer cellsOutpatient regimenCheckpoint inhibitorsDisease stabilizationRegulatory cellsEffector phenotypeKiller cellsTreatment algorithmImmune activationTumor shrinkagePharmacodynamic markersImmune cellsClinical activityIL2 receptorHuman studies
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