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, 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 inhibitors
2023
Clinical 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 characteristics
2022
Immune 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 hormonesT cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma
Lozano AX, Chaudhuri AA, Nene A, Bacchiocchi A, Earland N, Vesely MD, Usmani A, Turner BE, Steen CB, Luca BA, Badri T, Gulati GS, Vahid MR, Khameneh F, Harris PK, Chen DY, Dhodapkar K, Sznol M, Halaban R, Newman AM. T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma. Nature Medicine 2022, 28: 353-362. PMID: 35027754, PMCID: PMC8866214, DOI: 10.1038/s41591-021-01623-z.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsImmune-related adverse eventsT-cell characteristicsIrAE developmentBlood samplesSevere immune-related adverse eventsAnti-PD-1 monotherapyCombination immune checkpoint inhibitorsT-cell receptor sequencingT cell abundanceCell receptor sequencingOrgan system involvementPeripheral blood samplesIrAE onsetCheckpoint inhibitorsAdverse eventsCheckpoint blockadeRNA sequencingTCR clonalityCombination therapyPatient cohortSystem involvementClinical managementTCR diversityImmunological state
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 patientsEfficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial
Powles T, Atkins MB, Escudier B, Motzer RJ, Rini BI, Fong L, Joseph RW, Pal SK, Sznol M, Hainsworth J, Stadler WM, Hutson TE, Ravaud A, Bracarda S, Suarez C, Choueiri TK, Reeves J, Cohn A, Ding B, Leng N, Hashimoto K, Huseni M, Schiff C, McDermott DF. Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial. European Urology 2021, 79: 665-673. PMID: 33678522, PMCID: PMC9357270, DOI: 10.1016/j.eururo.2021.01.003.Peer-Reviewed Original ResearchConceptsMetastatic clear cell renal cancerProgression-free survivalObjective response rateSafety of atezolizumabSecond-line atezolizumabSecond-line treatmentSunitinib monotherapyDisease progressionSunitinib armRandomized phase 2 clinical trialMedian progression-free survivalTreatment-related adverse eventsMetastatic renal cell carcinomaPhase 2 clinical trialGrade 3/4 eventsInvestigator-assessed progressionImmune checkpoint inhibitorsPhase 2 studyKaplan-Meier methodAdvanced kidney cancerVascular endothelial growth factorClear cell renal cancerRenal cell carcinomaEndothelial growth factorAtezolizumab 1200Resistance mechanisms to checkpoint inhibitors
Weiss SA, Sznol M. Resistance mechanisms to checkpoint inhibitors. Current Opinion In Immunology 2021, 69: 47-55. PMID: 33676271, DOI: 10.1016/j.coi.2021.02.001.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsPD-1/PD-L1 axisMultiple immune checkpoint inhibitorsPD1/PD-L1PD-L1 axisHuman translational studiesPre-clinical studiesPre-clinical animalResistance mechanismsCheckpoint inhibitorsPD-L1Clinical outcomesTreatment failureClinical trialsTranslational studiesCancer treatmentPotential mechanismsInhibitorsPatientsClinicTrialsAntibodiesMolecular correlates of response to nivolumab at baseline and on treatment in patients with RCC
Ross-Macdonald P, Walsh AM, Chasalow SD, Ammar R, Papillon-Cavanagh S, Szabo PM, Choueiri TK, Sznol M, Wind-Rotolo M. Molecular correlates of response to nivolumab at baseline and on treatment in patients with RCC. Journal For ImmunoTherapy Of Cancer 2021, 9: e001506. PMID: 33658305, PMCID: PMC7931766, DOI: 10.1136/jitc-2020-001506.Peer-Reviewed Original ResearchMeSH KeywordsB7-H1 AntigenBiomarkers, TumorCarcinoma, Renal CellCD4 AntigensCD8 AntigensCytokinesDrug Resistance, NeoplasmHumansImmune Checkpoint InhibitorsKidney NeoplasmsLymphocytes, Tumor-InfiltratingMutationNivolumabProgrammed Cell Death 1 ReceptorReceptors, Antigen, T-CellTime FactorsT-LymphocytesTreatment OutcomeConceptsClear cell renal cell carcinomaMetastatic clear cell renal cell carcinomaT cell infiltrationNivolumab responseExact testDeath ligand 1 (PD-L1) statusFirst-line treatment decisionsT-cell receptor clonalitySerum cytokine assaysImmune checkpoint inhibitorsNon-responding patientsDeath-1 receptorCell renal cell carcinomaSubset of patientsRenal cell carcinomaFisher's exact testWnt/β-cateninLogistic regression modelsRank sum testCD8 statusCheckpoint inhibitorsIndex lesionPatient selectionTCR clonalityCell carcinoma
2017
Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study
Callahan MK, Kluger H, Postow MA, Segal NH, Lesokhin A, Atkins MB, Kirkwood JM, Krishnan S, Bhore R, Horak C, Wolchok JD, Sznol M. Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study. Journal Of Clinical Oncology 2017, 36: jco.2017.72.285. PMID: 29040030, PMCID: PMC5946731, DOI: 10.1200/jco.2017.72.2850.Peer-Reviewed Original ResearchConceptsPhase I dose-escalation studyTreatment-related adverse eventsI dose-escalation studyDose-escalation studyAdvanced melanomaOverall survivalAdverse eventsOS ratesClinical activityGrade 3Common grade 3Doses of nivolumabDurable clinical activityModified WHO criteriaNivolumab Plus IpilimumabTreatment-related deathsUntreated advanced melanomaImmune checkpoint inhibitorsMedian overall survivalObjective response rateLong-term followSubsequent clinical developmentConcurrent nivolumabCheckpoint inhibitorsExpansion cohortEndocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management
Sznol M, Postow MA, Davies MJ, Pavlick AC, Plimack ER, Shaheen M, Veloski C, Robert C. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treatment Reviews 2017, 58: 70-76. PMID: 28689073, DOI: 10.1016/j.ctrv.2017.06.002.Peer-Reviewed Original ResearchConceptsImmune-related adverse eventsImmune checkpoint inhibitorsCytotoxic T-lymphocyte antigen-4Checkpoint inhibitorsEndocrine eventsAdverse eventsTypes of irAEsEndocrine-related adverse eventsT-lymphocyte antigen-4Replacement of hormonesDeath receptor-1Target organ damageClose patient monitoringImmune checkpoint blockadeNon-specific symptomsAppropriate laboratory testingImmune checkpoint proteinsCheckpoint blockadeGrade 1/2Organ damageClinical benefitAdrenal glandAntigen-4Endocrine functionGastrointestinal tract
2016
Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma
Choueiri TK, Fishman MN, Escudier B, McDermott DF, Drake CG, Kluger H, Stadler WM, Perez-Gracia JL, McNeel DG, Curti B, Harrison MR, Plimack ER, Appleman L, Fong L, Albiges L, Cohen L, Young TC, Chasalow SD, Ross-Macdonald P, Srivastava S, Jure-Kunkel M, Kurland JF, Simon JS, Sznol M. Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma. Clinical Cancer Research 2016, 22: 5461-5471. PMID: 27169994, PMCID: PMC5106340, DOI: 10.1158/1078-0432.ccr-15-2839.Peer-Reviewed Original ResearchConceptsMetastatic renal cell carcinomaTreatment-naïve patientsPD-L1 expressionTumor-associated lymphocytesTreatment biopsiesOverall survivalAnti-PD-1 immune checkpoint inhibitorImmune checkpoint inhibitorsMedian overall survivalNew safety signalsPD-1 inhibitionPhase 3 trialMedian percent changeRenal cell carcinomaUpregulation of IFNγTumor gene expressionNivolumab dosesSerum chemokinesCheckpoint inhibitorsChemokine levelsBaseline biopsiesCell carcinomaImmunomodulatory effectsPeripheral bloodClinical activity
2014
Induction of Antigen-Specific Immunity with a Vaccine Targeting NY-ESO-1 to the Dendritic Cell Receptor DEC-205
Dhodapkar MV, Sznol M, Zhao B, Wang D, Carvajal RD, Keohan ML, Chuang E, Sanborn RE, Lutzky J, Powderly J, Kluger H, Tejwani S, Green J, Ramakrishna V, Crocker A, Vitale L, Yellin M, Davis T, Keler T. Induction of Antigen-Specific Immunity with a Vaccine Targeting NY-ESO-1 to the Dendritic Cell Receptor DEC-205. Science Translational Medicine 2014, 6: 232ra51. PMID: 24739759, PMCID: PMC6151129, DOI: 10.1126/scitranslmed.3008068.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntigens, CDAntigens, NeoplasmCancer VaccinesCytokinesDendritic CellsDose-Response Relationship, ImmunologicEpitopesFemaleHumansImmunity, CellularImmunity, HumoralImmunoglobulin GInterferon-gammaLectins, C-TypeLymphocyte SubsetsMaleMembrane ProteinsMiddle AgedMinor Histocompatibility AntigensReceptors, Cell SurfaceT-LymphocytesVaccinationConceptsNY-ESO-1Immune checkpoint inhibitorsDendritic cellsToll-like receptorsTumor regressionNY-ESO-1-expressing tumorsTumor antigen NY-ESO-1Presence of DCsRobust antigen-specific immune responsesAntigen-specific immune responsesAntigen NY-ESO-1Combination immunotherapy strategiesStabilization of diseaseGrade 3 toxicityObjective tumor regressionImmune checkpoint blockadeT cell immunityAntigen-specific immunityPhase 1 trialTumor-associated antigensReceptor-specific monoclonal antibodyCheckpoint inhibitorsAdvanced malignanciesCheckpoint blockadeMedian duration