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 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 diagnosis
2021
TIL in Melanoma—Similar Approaches, Different Results, Unanswered Questions
Sznol M. TIL in Melanoma—Similar Approaches, Different Results, Unanswered Questions. Clinical Cancer Research 2021, 27: 5156-5157. PMID: 34413160, DOI: 10.1158/1078-0432.ccr-21-2450.Peer-Reviewed Original ResearchBempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma
Diab A, Tykodi SS, Daniels GA, Maio M, Curti BD, Lewis KD, Jang S, Kalinka E, Puzanov I, Spira AI, Cho DC, Guan S, Puente E, Nguyen T, Hoch U, Currie SL, Lin W, Tagliaferri MA, Zalevsky J, Sznol M, Hurwitz ME. Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma. Journal Of Clinical Oncology 2021, 39: 2914-2925. PMID: 34255535, PMCID: PMC8425826, DOI: 10.1200/jco.21.00675.Peer-Reviewed Original ResearchConceptsProgression-free survivalImmune-mediated adverse eventsMedian progression-free survivalObjective response rateMetastatic melanomaOverall survivalResponse rateAdverse eventsTarget lesionsGrade 3Stage III/IV melanomaEnd pointPhase II cohortComplete response rateMedian overall survivalPrimary end pointRadiologic evidenceUntreated patientsDurable responsesPolyfunctional responsesOS ratesBlood biomarkersComplete clearanceMedian changeExploratory biomarkers
2020
Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma
Middleton MR, McAlpine C, Woodcock VK, Corrie P, Infante JR, Steven NM, Evans TRJ, Anthoney A, Shoushtari AN, Hamid O, Gupta A, Vardeu A, Leach E, Naidoo R, Stanhope S, Lewis S, Hurst J, O’Kelly I, Sznol M. Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma. Clinical Cancer Research 2020, 26: 5869-5878. PMID: 32816891, PMCID: PMC9210997, DOI: 10.1158/1078-0432.ccr-20-1247.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAtaxia Telangiectasia Mutated ProteinsCD3 ComplexCD8-Positive T-LymphocytesCell ProliferationChemokine CXCL10Cytotoxicity, ImmunologicDisease-Free SurvivalFemaleGene Expression Regulation, NeoplasticGp100 Melanoma AntigenHumansImmunityInterferon-gammaMaleMelanomaMiddle AgedNeoplasm ProteinsReceptors, Antigen, T-CellReceptors, CXCR3Recombinant Fusion ProteinsTumor MicroenvironmentConceptsT cellsBispecific fusion proteinMetastatic melanomaT cell receptorSerum CXCL10Multicenter phase I/II trialPhase I/II trialTreatment-related adverse eventsHigh-affinity T-cell receptorsAppearance of rashMetastatic cutaneous melanomaAntitumor immune responseOverall survival rateMetastatic uveal melanomaCytotoxic T cellsPathway-related markersTumor biopsy samplesMechanism of actionII trialAdverse eventsAdvanced melanomaBroad therapeutic potentialPatient survivalPatient cohortCutaneous melanomaBempegaldesleukin plus nivolumab in untreated, unresectable or metastatic melanoma: Phase III PIVOT IO 001 study design
Khushalani NI, Diab A, Ascierto PA, Larkin J, Sandhu S, Sznol M, Koon HB, Jarkowski A, Zhou M, Statkevich P, Geese WJ, Long GV. Bempegaldesleukin plus nivolumab in untreated, unresectable or metastatic melanoma: Phase III PIVOT IO 001 study design. Future Oncology 2020, 16: 2165-2175. PMID: 32723187, DOI: 10.2217/fon-2020-0351.Peer-Reviewed Original ResearchConceptsMetastatic melanomaKey secondary end pointEnd pointSafety/tolerabilityObjective response ratePD-1 inhibitorsPrimary end pointSecondary end pointsFirst-line therapyProgression-free survivalNatural killer cellsOverall survivalSurvival benefitAdvanced melanomaKiller cellsClinical trialsEffector TClinical activityNivolumabBempegaldesleukinResponse rateMelanomaPathway agonistStudy designPhase IIISurvival 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 survivalBempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy
Sharma M, Khong H, Fa’ak F, Bentebibel SE, Janssen LME, Chesson BC, Creasy CA, Forget MA, Kahn LMS, Pazdrak B, Karki B, Hailemichael Y, Singh M, Vianden C, Vennam S, Bharadwaj U, Tweardy DJ, Haymaker C, Bernatchez C, Huang S, Rajapakshe K, Coarfa C, Hurwitz ME, Sznol M, Hwu P, Hoch U, Addepalli M, Charych DH, Zalevsky J, Diab A, Overwijk WW. Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy. Nature Communications 2020, 11: 661. PMID: 32005826, PMCID: PMC6994577, DOI: 10.1038/s41467-020-14471-1.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, Monoclonal, HumanizedCarcinoma, Renal CellCD8-Positive T-LymphocytesCohort StudiesDrug Therapy, CombinationFemaleHumansInterferon-gammaInterleukin-2IpilimumabLymphocyte ActivationMelanomaMiceMice, Inbred C57BLPolyethylene GlycolsProdrugsReceptors, Interleukin-2T-Lymphocytes, RegulatoryTumor Necrosis Factor-alphaConceptsNKTR-214Interleukin-2Treg depletionT cellsHigh-dose interleukin-2Suppressive regulatory T cellsSuperior anti-tumor activityAnti-tumor CD8Dose interleukin-2Peptide-based vaccinationRegulatory T cellsCheckpoint blockade therapyTreatment-associated toxicityIL-2 pathwayRenal cell carcinomaAnti-tumor activityAnti-cancer therapyMechanism of actionTreg dynamicsIntratumoral TregsBlockade therapyCytokines IFNCell carcinomaMetastatic melanomaTherapeutic impact
2019
Immunotherapy of Melanoma: Facts and Hopes
Weiss SA, Wolchok JD, Sznol M. Immunotherapy of Melanoma: Facts and Hopes. Clinical Cancer Research 2019, 25: 5191-5201. PMID: 30923036, PMCID: PMC6726509, DOI: 10.1158/1078-0432.ccr-18-1550.Peer-Reviewed Original ResearchConceptsOverall survivalMetastatic diseaseImmune therapyPredictive biomarkersNivolumab/ipilimumab combinationRandomized phase III trialLong-term clinical benefitImmunobiology of tumorsDuration of therapyPhase III trialsLong-term survivorsEffective immune therapyAdjuvant settingIpilimumab combinationMetastatic settingIII trialsPatient subsetsClinical benefitImmune modulationMetastatic melanomaClinical trialsSingle agentTherapyTrue increaseCell therapyPatterns 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-L1
2018
A 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 analysisNivolumabCohort
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 sitesPatientsChanges in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients
Sanmamed MF, Perez-Gracia JL, Schalper KA, Fusco JP, Gonzalez A, Rodriguez-Ruiz ME, Oñate C, Perez G, Alfaro C, Martín-Algarra S, Andueza MP, Gurpide A, Morgado M, Wang J, Bacchiocchi A, Halaban R, Kluger H, Chen L, Sznol M, Melero I. Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients. Annals Of Oncology 2017, 28: 1988-1995. PMID: 28595336, PMCID: PMC5834104, DOI: 10.1093/annonc/mdx190.Peer-Reviewed Original ResearchConceptsSerum IL-8 levelsIL-8 levelsCell lung cancer patientsLung cancer patientsNSCLC patientsCancer patientsMelanoma patientsPD1/PD-L1 therapyAnti-PD-1 treatmentAnti-PD-1 blockadeSerum interleukin-8 levelsPD-L1 therapyImmune checkpoint blockadeInterleukin-8 levelsLonger overall survivalBiomarkers of responseMann-Whitney testCheckpoint blockadeFirst doseOverall survivalStrength of associationClinical benefitReceiver operation characteristic curveMetastatic melanomaSurrogate biomarkerNuclear IRF-1 expression as a mechanism to assess “Capability” to express PD-L1 and response to PD-1 therapy in metastatic melanoma
Smithy JW, Moore LM, Pelekanou V, Rehman J, Gaule P, Wong PF, Neumeister VM, Sznol M, Kluger HM, Rimm DL. Nuclear IRF-1 expression as a mechanism to assess “Capability” to express PD-L1 and response to PD-1 therapy in metastatic melanoma. Journal For ImmunoTherapy Of Cancer 2017, 5: 25. PMID: 28331615, PMCID: PMC5359951, DOI: 10.1186/s40425-017-0229-2.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedB7-H1 AntigenBiomarkers, PharmacologicalDisease-Free SurvivalFemaleGene Expression Regulation, NeoplasticHumansImmunotherapyInterferon Regulatory Factor-1IpilimumabMaleMelanomaMiddle AgedNeoplasm MetastasisNeoplasms, Second PrimaryNivolumabProgrammed Cell Death 1 ReceptorConceptsProgression-free survivalObjective radiographic responsePD-L1 expressionPD-L1IRF-1 expressionMetastatic melanomaAnti-PD-1 therapyCombination ipilimumab/nivolumabHigh PD-L1 expressionAnti-PD-1 immunotherapyYale-New Haven HospitalIpilimumab/nivolumabPD-1 therapyPR/CRPre-treatment formalinRECIST v1.1 criteriaDeath ligand 1Valuable predictive biomarkerMajor unmet needNew Haven HospitalInterferon regulatory factor 1Combination ipilimumabProgressive diseaseRadiographic responseComplete response
2016
Cyclosporine for Dry Eye Associated With Nivolumab
Nguyen AT, Elia M, Materin MA, Sznol M, Chow J. Cyclosporine for Dry Eye Associated With Nivolumab. Cornea 2016, 35: 399-401. PMID: 26771550, DOI: 10.1097/ico.0000000000000724.Peer-Reviewed Original ResearchConceptsDry eye diseaseMetastatic melanomaTopical cyclosporineCorneal perforationDry eyeEye diseaseSevere dry eye symptomsBilateral dry eyesDry Eye AssociatedOcular surface inflammationSevere dry eyeDry eye symptomsImprovement of symptomsNivolumab therapyIntensive regimenSurface inflammationEye symptomsMetastatic diseaseClinical outcomesAggressive lubricationRight eyeCase reportNivolumabOcular surfaceAntitumor effects
2015
Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites
Kluger HM, Zito CR, Barr ML, Baine MK, Chiang VL, Sznol M, Rimm DL, Chen L, Jilaveanu LB. Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites. Clinical Cancer Research 2015, 21: 3052-3060. PMID: 25788491, PMCID: PMC4490112, DOI: 10.1158/1078-0432.ccr-14-3073.Peer-Reviewed Original ResearchConceptsPD-L1 expressionT-cell contentPD-1/PD-L1 inhibitorsHigher T-cell contentT-cell infiltratesPD-L1 inhibitorsAnatomic sitesBrain metastasesMetastatic melanomaTissue microarrayHigh PD-L1 expressionLess PD-L1 expressionLow PD-L1 expressionTumor PD-L1 expressionHigher TIL contentImproved overall survivalT cell infiltrationLess T cellsMetastatic melanoma samplesExtracerebral metastasesCerebral metastasesOverall survivalDermal metastasesImproved survivalPD-L1Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. New England Journal Of Medicine 2015, 373: 23-34. PMID: 26027431, PMCID: PMC5698905, DOI: 10.1056/nejmoa1504030.Peer-Reviewed Original ResearchConceptsProgression-free survivalMedian progression-free survivalIpilimumab groupMetastatic melanomaNivolumab groupUntreated patientsPD-L1Negative tumorsTreatment-related adverse eventsLonger progression-free survivalUnresectable stage IIICoprimary end pointsCTLA-4 blockadePhase 3 studyPD-1 ligandsCombined NivolumabAdverse eventsOverall survivalPD-1Combination therapyUntreated melanomaIpilimumabNivolumabGrade 3Stage IIIImmune 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
2014
Blockade of the B7-H1/PD-1 Pathway as a Basis for Combination Anticancer Therapy
Sznol M. Blockade of the B7-H1/PD-1 Pathway as a Basis for Combination Anticancer Therapy. The Cancer Journal 2014, 20: 290-295. PMID: 25098290, DOI: 10.1097/ppo.0000000000000056.Peer-Reviewed Original ResearchConceptsPD-1/PD-L1 blockadePD-L1 blockadeT cell responsesTumor-specific T-cell responsesB7-H1/PDCell responsesOverall risk-benefit ratioAntitumor T-cell responsesTumor microenvironmentAnimal tumor model systemsAbundant preclinical dataAutoimmune-like toxicitiesSubset of patientsRecent clinical trialsRisk-benefit ratioT lymphocyte suppressionEarly clinical developmentActivated T lymphocytesTumor model systemsCombination anticancer therapyClinical responseDurable responsesDeath-1Metastatic melanomaPreclinical data