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, 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 lifeInterferon-stimulated neutrophils as a predictor of immunotherapy response
Benguigui M, Cooper T, Kalkar P, Schif-Zuck S, Halaban R, Bacchiocchi A, Kamer I, Deo A, Manobla B, Menachem R, Haj-Shomaly J, Vorontsova A, Raviv Z, Buxbaum C, Christopoulos P, Bar J, Lotem M, Sznol M, Ariel A, Shen-Orr S, Shaked Y. Interferon-stimulated neutrophils as a predictor of immunotherapy response. Cancer Cell 2024, 42: 253-265.e12. PMID: 38181798, PMCID: PMC10864002, DOI: 10.1016/j.ccell.2023.12.005.Peer-Reviewed Original ResearchImmunotherapy responseNon-small cell lung cancerAnti-PD1 responseAnti-PD1 therapyCohort of patientsNon-responsive tumorsCell lung cancerAnti-cancer immunotherapyPre-clinical findingsBlood-borne biomarkersCytotoxic TLung cancerPredictive biomarkersCurrent biomarkersTreatment responseNeutrophilsLY6EBiomarkersActive biomarkersPatientsMiceFurther mechanistic understandingActivationResponseImmunotherapy
2021
Resistance 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 mechanismsInhibitorsPatientsClinicTrialsAntibodies
2018
Evaluation of classical clinical endpoints as surrogates for overall survival in patients treated with immune checkpoint blockers: a systematic review and meta-analysis
Kaufman HL, Schwartz LH, William WN, Sznol M, Fahrbach K, Xu Y, Masson E, Vergara-Silva A. Evaluation of classical clinical endpoints as surrogates for overall survival in patients treated with immune checkpoint blockers: a systematic review and meta-analysis. Journal Of Cancer Research And Clinical Oncology 2018, 144: 2245-2261. PMID: 30132118, DOI: 10.1007/s00432-018-2738-x.Peer-Reviewed Original ResearchConceptsImmune checkpoint blockersOS hazard ratioPFS hazard ratioHazard ratioOverall survivalPFS ratesOS ratesCheckpoint blockersPooled analysisClinical endpointsSolid tumor patientsChemotherapy armTreatment armsOdds ratioTumor patientsPredictive valueChemotherapySystematic reviewImperfect surrogatePatientsEndpointBlockersCongress proceedingsSurvivalArmCollateral Damage: Insulin-Dependent Diabetes Induced With Checkpoint Inhibitors
Stamatouli AM, Quandt Z, Perdigoto AL, Clark PL, Kluger H, Weiss SA, Gettinger S, Sznol M, Young A, Rushakoff R, Lee J, Bluestone JA, Anderson M, Herold KC. Collateral Damage: Insulin-Dependent Diabetes Induced With Checkpoint Inhibitors. Diabetes 2018, 67: dbi180002. PMID: 29937434, PMCID: PMC6054443, DOI: 10.2337/dbi18-0002.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Agents, ImmunologicalAutoimmune DiseasesB7-H1 AntigenDiabetes Mellitus, Type 1Genetic Predisposition to DiseaseGenotypeHLA-DR4 AntigenHumansHypoglycemic AgentsInsulinInsulin SecretionIsoantibodiesKetosisModels, ImmunologicalNeoplasmsPancreasPancreatitisProgrammed Cell Death 1 ReceptorConceptsInsulin-dependent diabetesCheckpoint inhibitorsAdverse eventsHLA-DR4Classic type 1 diabetesPD-L1 checkpoint inhibitorsEvidence of pancreatitisImmune adverse eventsSolid organ cancersType 1 diabetesPeridiagnosis periodPositive autoantibodiesL1 antibodyInsulin-DependentHigh riskPatientsDiabetesCancerInhibitorsKetoacidosisAutoimmuneAutoantibodiesPancreatitisComplicationsSyndromeA Serum Protein Signature Associated with Outcome after Anti–PD-1 Therapy in Metastatic Melanoma
Weber JS, Sznol M, Sullivan RJ, Blackmon S, Boland G, Kluger HM, Halaban R, Bacchiocchi A, Ascierto PA, Capone M, Oliveira C, Meyer K, Grigorieva J, Asmellash SG, Roder J, Roder H. A Serum Protein Signature Associated with Outcome after Anti–PD-1 Therapy in Metastatic Melanoma. Cancer Immunology Research 2018, 6: 79-86. PMID: 29208646, DOI: 10.1158/2326-6066.cir-17-0412.Peer-Reviewed Original ResearchConceptsAcute phase reactantsCheckpoint inhibitorsOverall survivalPhase reactantsIpilimumab-treated patientsPD-1 blockadeTrials of nivolumabBetter overall survivalIndependent patient cohortsPretreatment serumPD-1Melanoma patientsValidation cohortMetastatic melanomaMultipeptide vaccinePatient cohortPooled analysisWorse outcomesClinical dataPatientsMultivariate analysisComplement cascadeMass spectrometry analysisNivolumabCohortCombination Strategies PD-1/PD-L1 Antagonists
Sznol M. Combination Strategies PD-1/PD-L1 Antagonists. The Cancer Journal 2018, 24: 54-57. PMID: 29360729, DOI: 10.1097/ppo.0000000000000304.Peer-Reviewed Original ResearchConceptsPD-1/PD-L1 antagonistsPD-L1 antagonistsClinical antitumor activityEarly clinical developmentClinical trial designOptimal combination partnersSuboptimal responsePromising regimensCombination partnersMechanisms of resistanceCombination trialsClinical progressIndividual patientsOptimal doseBiomarker strategiesTrial designClinical developmentOverall outcomeAntagonistPatientsPrior exposureAntitumor activityRegimensAgentsInnate
2017
Long-Term Outcomes in Patients With BRAF V600–Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib
Long GV, Eroglu Z, Infante J, Patel S, Daud A, Johnson DB, Gonzalez R, Kefford R, Hamid O, Schuchter L, Cebon J, Sharfman W, McWilliams R, Sznol M, Redhu S, Gasal E, Mookerjee B, Weber J, Flaherty KT. Long-Term Outcomes in Patients With BRAF V600–Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib. Journal Of Clinical Oncology 2017, 36: jco.2017.74.102. PMID: 28991513, PMCID: PMC10466457, DOI: 10.1200/jco.2017.74.1025.Peer-Reviewed Original ResearchConceptsBRAF V600-mutant metastatic melanomaProgression-free survivalNormal lactate dehydrogenaseMetastatic melanomaD monotherapyCombination therapyMEK inhibitor combination therapyInhibitor-naive patientsLong-term OSTrametinib combination therapyNew safety signalsBRAF inhibitor dabrafenibInhibitor combination therapyLactate dehydrogenaseIncreased OSC. PatientsOverall survivalComplete responseAdditional patientsTerm outcomesSafety signalsLandmark analysisSafety outcomesOrgan sitesPatientsPhase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors
Tolcher AW, Sznol M, Hu-Lieskovan S, Papadopoulos KP, Patnaik A, Rasco DW, Di Gravio D, Huang B, Gambhire D, Chen Y, Thall AD, Pathan N, Schmidt EV, Chow LQM. Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors. Clinical Cancer Research 2017, 23: 5349-5357. PMID: 28634283, DOI: 10.1158/1078-0432.ccr-17-1243.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsCombined Modality TherapyDiagnostic ImagingDrug MonitoringFemaleHumansImmunoglobulin GMaleMaximum Tolerated DoseMiddle AgedMolecular Targeted TherapyNeoplasm StagingNeoplasmsRetreatmentT-Lymphocyte SubsetsTreatment OutcomeTumor Necrosis Factor Receptor Superfamily, Member 9ConceptsAdvanced solid tumorsSolid tumorsTreatment-emergent adverse eventsPeripheral blood CD8Phase Ib studyTreatment-related discontinuationsDose-limiting toxicityCostimulatory receptor 4Event continual reassessment methodT cell costimulatory receptor 4Clin Cancer ResSupport further investigationBlood CD8Partial responseAdverse eventsDose escalationReceptor 4Clinical activityT cellsIb studyCombination treatmentContinual reassessment methodPatientsGrade 1Cancer Res
2016
Phase I trial of daily triapine in combination with cisplatin chemotherapy for advanced-stage malignancies
Kunos CA, Chu E, Beumer JH, Sznol M, Ivy SP. Phase I trial of daily triapine in combination with cisplatin chemotherapy for advanced-stage malignancies. Cancer Chemotherapy And Pharmacology 2016, 79: 201-207. PMID: 27878356, PMCID: PMC5226891, DOI: 10.1007/s00280-016-3200-x.Peer-Reviewed Original ResearchConceptsPhase I trialSolid tumor malignanciesI trialObjective responseTumor malignancyDaily days 1Frequent grade 3Advanced-stage malignanciesDose-finding phase I trialResultsThe MTDStable diseasePrimary endpointSecondary endpointsVulvar cancerElectrolyte abnormalitiesAdverse eventsCisplatin chemotherapyUterine cervixGrade 3Day 1Day 2Day 3PatientsMalignancyDifferent schedulesSafety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma
Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, Sznol M, Long GV, Li H, Waxman IM, Jiang J, Robert C. Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. Journal Of Clinical Oncology 2016, 35: jco.2015.66.138. PMID: 28068177, DOI: 10.1200/jco.2015.66.1389.Peer-Reviewed Original ResearchConceptsTreatment-related adverse eventsSelect adverse eventsObjective response rateImmune-modulating agentsTreatment-related select adverse eventsAdverse eventsNivolumab monotherapyAdvanced melanomaSafety profileGrade 3Grade treatment-related adverse eventsProgression-free survival benefitHigher objective response rateRenal adverse eventsPhase III trialsDrug-related deathsNumber of dosesIII trialsSurvival benefitMedian timePooled analysisSafety guidelinesRetrospective analysisSafety dataPatients
2015
Immune therapy of metastatic melanoma developing after allogeneic bone marrow transplant
Cecchini M, Sznol M, Seropian S. Immune therapy of metastatic melanoma developing after allogeneic bone marrow transplant. Journal For ImmunoTherapy Of Cancer 2015, 3: 10. PMID: 25806109, PMCID: PMC4372324, DOI: 10.1186/s40425-015-0054-4.Peer-Reviewed Original ResearchAllogeneic stem cell transplantationStem cell transplantationMetastatic melanomaCell transplantationAllogeneic bone marrow transplantSafety of immunotherapyPost-transplant patientsBone marrow transplantHost diseaseTransplant patientsImmune therapyMarrow transplantTheoretical riskMelanomaImmunotherapyPatientsTransplantationTherapyGVHDTransplantGraftDiseaseTherapeutic Combinations of Immune-Modulating Antibodies in Melanoma and Beyond
Cohen J, Sznol M. Therapeutic Combinations of Immune-Modulating Antibodies in Melanoma and Beyond. Seminars In Oncology 2015, 42: 488-494. PMID: 25965368, DOI: 10.1053/j.seminoncol.2015.02.014.Peer-Reviewed Original ResearchConceptsImmune modulating antibodiesCheckpoint inhibitorsMetastatic renal cell carcinomaPD-1/PD-L1 antagonistsSelection of patientsPD-L1 antagonistsRenal cell carcinomaNumber of malignanciesAutoimmune toxicityCell carcinomaCombination therapyMetastatic melanomaTherapeutic combinationsSingle agentCostimulatory agentsOptimal outcomesAntibodiesPatientsMalignancyPromising activityMelanomaFuture combinationInhibitorsCarcinomaAgonists
2013
Ipilimumab-induced Perforating Colitis
Mitchell KA, Kluger H, Sznol M, Hartman DJ. Ipilimumab-induced Perforating Colitis. Journal Of Clinical Gastroenterology 2013, 47: 781-785. PMID: 23632354, PMCID: PMC6091636, DOI: 10.1097/mcg.0b013e31828f1d51.Peer-Reviewed Original ResearchConceptsIpilimumab-induced colitisSteroid therapyHistologic findingsT-lymphocyte-associated antigen 4Common side effectsAssociated histologic findingsBowel perforationSubtotal colectomyMucosal biopsiesSegmental resectionStandard treatmentAntigen-4Metastatic melanomaColitisSide effectsMonoclonal antibodiesTherapyIpilimumabColectomyDiarrheaPatientsPerforationTreatmentResectionBiopsyNivolumab plus Ipilimumab in Advanced Melanoma
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus Ipilimumab in Advanced Melanoma. New England Journal Of Medicine 2013, 369: 122-133. PMID: 23724867, PMCID: PMC5698004, DOI: 10.1056/nejmoa1302369.Peer-Reviewed Original ResearchConceptsObjective response ratePhase 1 trialAdverse eventsConcurrent therapyAdvanced melanomaTumor regressionClinical activityGrade 3Distinct immunologic mechanismsManageable safety profileProlongs overall survivalDurable tumor regressionSupportive preclinical dataRegimen groupImmunologic mechanismsObjective responseOverall survivalIntravenous dosesSafety profileTumor reductionPreclinical dataIpilimumabNivolumabPatientsMaximum doses
2011
Molecular Markers of Response to Treatment for Melanoma
Sznol M. Molecular Markers of Response to Treatment for Melanoma. The Cancer Journal 2011, 17: 127-133. PMID: 21427556, DOI: 10.1097/ppo.0b013e318212dd5a.Peer-Reviewed Original ResearchConceptsImmune therapyAnti-tumor immune responseInitial high response rateStandard of careFraction of patientsUseful predictive biomarkerHigh response rateMost patientsMetastatic melanomaPredictive biomarkersClinical activityImmune responseIndividual patientsPotent small molecule inhibitorsDurable benefitMultiple active agentsSmall molecule inhibitorsResponse ratePatientsMutant BRAFOverall populationTherapyMolecule inhibitorsMelanomaTumors
2010
A phase 2 trial of dasatinib in advanced melanoma
Kluger HM, Dudek AZ, McCann C, Ritacco J, Southard N, Jilaveanu LB, Molinaro A, Sznol M. A phase 2 trial of dasatinib in advanced melanoma. Cancer 2010, 117: 2202-2208. PMID: 21523734, PMCID: PMC3116034, DOI: 10.1002/cncr.25766.Peer-Reviewed Original ResearchConceptsProgression-free survivalC-kit mutationsPhase 2 trialResponse ratePartial responseMedian progression-free survivalMelanoma cell proliferationDaily dasatinibMucosal primaryPFS ratesStarting dosageCommon toxicitiesUnresectable melanomaAdvanced melanomaPleural effusionMelanoma patientsPredictive biomarkersMinor responseCombination trialsTumor assessmentDose reductionPatientsPrespecified endpointsDasatinibMelanomaIncidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032
Rubinstein JC, Sznol M, Pavlick AC, Ariyan S, Cheng E, Bacchiocchi A, Kluger HM, Narayan D, Halaban R. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. Journal Of Translational Medicine 2010, 8: 67. PMID: 20630094, PMCID: PMC2917408, DOI: 10.1186/1479-5876-8-67.Peer-Reviewed Original ResearchConceptsV600K mutationsClinical trialsBRAF V600E/K mutationK mutationPotential therapeutic responseMutant BRAF inhibitorsBRAF inhibitor PLX4032BRAF V600K mutationMelanoma patientsTherapeutic responseBRAF mutationsPatientsV600E mutationInhibitor PLX4032BRAF kinasePLX4032TrialsCommon mutationsMutationsMelanomaIncidenceMelanoma: A model for testing new agents in combination therapies
Ascierto PA, Streicher HZ, Sznol M. Melanoma: A model for testing new agents in combination therapies. Journal Of Translational Medicine 2010, 8: 38. PMID: 20406483, PMCID: PMC2873374, DOI: 10.1186/1479-5876-8-38.Peer-Reviewed Original ResearchConceptsC-Kit inhibitorsAdvanced melanomaImmune modulatorsIntroduction of interferonNew single agentsMulti-modality treatmentReliable predictive biomarkersSelection of patientsAdoptive cellular therapyAnti-angiogenesis agentsValidation of PatientAdditional molecular targetsImmunologic modulatorsAdvanced diseaseCombination therapyPredictive biomarkersIL-2High success rateIndividual patientsNew agentsSmall molecule inhibitorsPatientsSingle agentResponse rateAnticancer modalities
2009
Betting on immunotherapy for melanoma
Sznol M. Betting on immunotherapy for melanoma. Current Oncology Reports 2009, 11: 397-404. PMID: 19679015, DOI: 10.1007/s11912-009-0053-z.Peer-Reviewed Original ResearchConceptsAdvanced melanomaAntigen-specific T cell expansionEffective antitumor immune responseAntitumor immune responseEffective treatment optionT cell expansionAntigen-specific lymphocytesTumor defense mechanismsDurable remissionsPreparative regimensConditioning regimensAdoptive immunotherapyImmune therapyCancer vaccinesImmune activationTreatment optionsPredictive biomarkersPrimary tumorTumor immunobiologyClinical trialsAntigen presentationImmune responseHigh riskNew cytokinePatients