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 ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalHumansMelanomaMiceNivolumabReceptor Protein-Tyrosine KinasesConceptsStable 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 analysisSociety for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of melanoma, version 3.0
Pavlick A, Ariyan C, Buchbinder E, Davar D, Gibney G, Hamid O, Hieken T, Izar B, Johnson D, Kulkarni R, Luke J, Mitchell T, Mooradian M, Rubin K, Salama A, Shirai K, Taube J, Tawbi H, Tolley J, Valdueza C, Weiss S, Wong M, Sullivan R. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of melanoma, version 3.0. Journal For ImmunoTherapy Of Cancer 2023, 11: e006947. PMID: 37852736, PMCID: PMC10603365, DOI: 10.1136/jitc-2023-006947.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsClinical practice guidelinesCutaneous melanomaTreatment of melanomaPractice guidelinesProlongs recurrence-free survivalCancer clinical practice guidelinesCell death protein 1Metastatic cutaneous melanomaBispecific T cell engager (BiTE) therapyChemotherapy-resistant diseaseRecurrence-free survivalDeath protein 1Long-term followManagement of patientsSpecial patient populationsImmunotherapy of cancerConsensus-based recommendationsPossibility of cureUnique toxicity profileQuality of lifeIntratumoral immunotherapyNeoadjuvant strategiesAdvanced diseaseBrain metastasesA Phase II Trial of the CD40 Agonist Sotigalimab (APX005M) in Combination with Nivolumab in Subjects with Metastatic Melanoma with Disease Progression on Anti-PD-1
Weiss S, Sznol M, Shaheen M, Berciano-Guerrero M, Couselo E, Rodríguez-Abreu D, Boni V, Schuchter L, Gonzalez-Cao M, Arance A, Wei W, Ganti A, Hauke R, Berrocal A, Iannotti N, Hsu F, Kluger H. A Phase II Trial of the CD40 Agonist Sotigalimab (APX005M) in Combination with Nivolumab in Subjects with Metastatic Melanoma with Disease Progression on Anti-PD-1. Clinical Cancer Research 2023, 30: 74-81. PMID: 37535056, PMCID: PMC10767304, DOI: 10.1158/1078-0432.ccr-23-0475.Peer-Reviewed Original ResearchConceptsObjective response ratePhase II trialAdverse eventsPartial responseDisease progressionII trialGrade 3 adverse eventsAnti PD-1CD40 agonist antibodyElevated liver functionTreatment-related SAEsCommon adverse eventsActivation of CD40Subset of patientsFavorable safety profileAntigen presenting cellsStable diseaseMedian durationAdvanced melanomaAdditional patientsLiver functionSafety profileMetastatic melanomaPreclinical dataPresenting cellsLenvatinib or anti-VEGF in combination with anti-PD-1 differentially augments anti-tumor activity in melanoma
Tran T, Caulfield J, Zhang L, Schoenfeld D, Djureinovic D, Chiang V, Oria V, Weiss S, Olino K, Jilaveanu L, Kluger H. Lenvatinib or anti-VEGF in combination with anti-PD-1 differentially augments anti-tumor activity in melanoma. JCI Insight 2023, 8: e157347. PMID: 36821392, PMCID: PMC10132152, DOI: 10.1172/jci.insight.157347.Peer-Reviewed Original ResearchConceptsTumor microenvironmentAnti-VEGFCytokine/chemokine signalingCytokine/chemokine profilingBlood-brain barrier modelBlood vesselsLeukocyte transmigrationTumor-associated blood vesselsTumor-associated macrophagesIntratumoral blood vesselsAnti-angiogenesis effectAnti-tumor activityExtracranial diseasePlasmacytoid DCsImmune checkpointsPD-1Melanoma murine modelImmune infiltrationBBB modelChemokine profilingEndothelial stabilizationMurine modelLenvatinibCombined targetingMelanoma model
2021
Incidence and characteristics of metastatic intracranial lesions in stage III and IV melanoma: a single institute retrospective analysis
Sandhu MRS, Chiang VL, Tran T, Yu JB, Weiss S, Goldberg S, Aboian M, Kluger HM, Mahajan A. Incidence and characteristics of metastatic intracranial lesions in stage III and IV melanoma: a single institute retrospective analysis. Journal Of Neuro-Oncology 2021, 154: 197-203. PMID: 34351544, DOI: 10.1007/s11060-021-03813-8.Peer-Reviewed Original ResearchMeSH KeywordsBrain NeoplasmsHumansIncidenceMaleMelanomaPrognosisRetrospective StudiesTesticular NeoplasmsConceptsStage IV melanomaMetastatic brain lesionsStage IIIInitial diagnosisTumor RegistryOverall incidenceBrain lesionsBM incidenceSingle-institute retrospective analysisBM developmentBrain metastases incidenceIncidence of BMInstitution's tumor registryStage III patientsTime of diagnosisMetastatic intracranial lesionsCommon genetic mutationsTumor genetic profileGenetic profileBM occurrenceMedian durationAdvanced melanomaSurveillance regimenIII patientsMedian time
2020
Melanoma brain metastases have lower T-cell content and microvessel density compared to matched extracranial metastases
Weiss SA, Zito C, Tran T, Heishima K, Neumeister V, McGuire J, Adeniran A, Kluger H, Jilaveanu LB. Melanoma brain metastases have lower T-cell content and microvessel density compared to matched extracranial metastases. Journal Of Neuro-Oncology 2020, 152: 15-25. PMID: 32974852, PMCID: PMC7910371, DOI: 10.1007/s11060-020-03619-0.Peer-Reviewed Original ResearchConceptsT-cell contentMelanoma brain metastasesPD-L1 expressionLower microvessel densityMicrovessel densityBrain metastasesExtracranial metastasesMacrophage contentB cellsProspective therapeutic clinical trialsTumor-infiltrating T cellsImmune-modulating drugsImmune cell subsetsTherapeutic clinical trialsExtracerebral metastasesHigh CD68Low CD3Low CD8Systemic therapyIntracerebral metastasesMetastatic sitesCell subsetsMetastatic melanomaImmune cellsClinical trialsSurvival 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 survival
2019
PLEKHA5 regulates tumor growth in metastatic melanoma
Zhang H, Zhu H, Deng G, Zito CR, Oria VO, Rane CK, Zhang S, Weiss SA, Tran T, Adeniran A, Zhang F, Zhou J, Kluger Y, Bosenberg MW, Kluger HM, Jilaveanu LB. PLEKHA5 regulates tumor growth in metastatic melanoma. Cancer 2019, 126: 1016-1030. PMID: 31769872, PMCID: PMC7147081, DOI: 10.1002/cncr.32611.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAnimalsApoptosis Regulatory ProteinsBiomarkers, TumorBrain NeoplasmsCell ProliferationFemaleFollow-Up StudiesGene Expression Regulation, NeoplasticHumansIntracellular Signaling Peptides and ProteinsMaleMelanomaMiceMice, NudeMiddle AgedPhosphatidylinositol 3-KinasesPrognosisProto-Oncogene Proteins c-aktTOR Serine-Threonine KinasesTumor Cells, CulturedXenograft Model Antitumor AssaysYoung AdultConceptsTumor growthDisseminated melanomaExtracranial melanoma metastasesPI3K/AKT/mTOR pathwayMelanoma brain metastasesBetter overall survivalPI3K/Akt/mTORAKT/mTOR pathwayCell proliferationAkt/mTORMelanoma xenograft modelGrowth of tumorsS cell cycle transitionBrain metastasesOverall survivalPoor prognosisMetastatic melanomaMAPK/ERKSubcutaneous inoculationMelanoma metastasesXenograft modelClinical relevanceMelanoma growthNude miceCerebral specimensSeronegative autoimmune autonomic ganglionopathy from dual immune checkpoint inhibition in a patient with metastatic melanoma
Gao CA, Weber UM, Peixoto AJ, Weiss SA. Seronegative autoimmune autonomic ganglionopathy from dual immune checkpoint inhibition in a patient with metastatic melanoma. Journal For ImmunoTherapy Of Cancer 2019, 7: 262. PMID: 31623673, PMCID: PMC6796437, DOI: 10.1186/s40425-019-0748-0.Peer-Reviewed Original ResearchConceptsAutoimmune autonomic ganglionopathyImmune checkpoint inhibitor therapyMetastatic melanomaCheckpoint inhibitorsDual immune checkpoint inhibitionSympathetic nervous system responsesBackgroundImmune checkpoint inhibitorsCardiovascular autonomic testingCheckpoint inhibitor therapyImmune checkpoint inhibitionNervous system responsesEndocrine workupHypotension refractoryAutonomic testingImmunomodulatory therapyAdverse eventsCase presentationAFluid resuscitationInhibitor therapyCheckpoint inhibitionClinical outcomesDisease progressionNew symptomsEndocrine toxicityNivolumabImmunotherapy 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
Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial
Kluger HM, Chiang V, Mahajan A, Zito CR, Sznol M, Tran T, Weiss SA, Cohen JV, Yu J, Hegde U, Perrotti E, Anderson G, Ralabate A, Kluger Y, Wei W, Goldberg SB, Jilaveanu LB. Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial. Journal Of Clinical Oncology 2018, 37: 52-60. PMID: 30407895, PMCID: PMC6354772, DOI: 10.1200/jco.18.00204.Peer-Reviewed Original ResearchConceptsBrain metastasis responseBrain metastasesMetastasis responseAdverse eventsAnti-programmed cell death-1 (PD-1) agentsDeath ligand 1 (PD-L1) expressionModified Response Evaluation CriteriaPhase II clinical trialActive brain metastasesAsymptomatic brain metastasesCD8 cell densityNeurologic adverse eventsPembrolizumab-treated patientsUse of pembrolizumabMelanoma brain metastasesPrimary end pointLigand 1 expressionPhase II trialResponse Evaluation CriteriaT-cell infiltratesUntreated brain metastasesDeath ligand 1Two-year survivalOverall survival timeResult of progression
2017
Treatment Outcomes for Metastatic Melanoma of Unknown Primary in the New Era: A Single-Institution Study and Review of the Literature
Utter K, Goldman C, Weiss SA, Shapiro RL, Berman RS, Wilson MA, Pavlick AC, Osman I. Treatment Outcomes for Metastatic Melanoma of Unknown Primary in the New Era: A Single-Institution Study and Review of the Literature. Oncology 2017, 93: 249-258. PMID: 28746931, PMCID: PMC5617794, DOI: 10.1159/000478050.Peer-Reviewed Original ResearchConceptsMUP patientsProspective melanoma databaseSystemic therapyUnknown primaryMetastatic melanomaClinical trialsSingle-institution studyMKP patientsTreatment guidelinesPoor outcomeMelanoma databaseWorse outcomesTreatment outcomesPatientsBetter outcomesTherapyPatient dataMelanomaGoogle ScholarUnique populationSurvival dataOutcomesLimited dataImmunotherapyTrialsFrom the Guest Editors
Weiss SA, Kluger HM. From the Guest Editors. The Cancer Journal 2017, 23: 1-2. PMID: 28114248, PMCID: PMC5526070, DOI: 10.1097/ppo.0000000000000244.Peer-Reviewed Original Research
2016
Melanoma brain metastases: correlation of imaging features with genomic markers and patient survival
Bordia R, Zhong H, Lee J, Weiss S, Han SW, Osman I, Jain R. Melanoma brain metastases: correlation of imaging features with genomic markers and patient survival. Journal Of Neuro-Oncology 2016, 131: 341-348. PMID: 27822597, DOI: 10.1007/s11060-016-2305-8.Peer-Reviewed Original ResearchConceptsMelanoma brain metastasesSignificant prognostic factorsBRAF inhibitor treatmentPercent of lesionsBrain metastasesMedian survivalPrognostic factorsPatient survivalMultiple lesionsInhibitor treatmentT1-weighted hyperintensityBRAF mutation statusT1-weighted hyperintense signalsNumber of lesionsMethods PatientsRetrospective reviewInstitutional databaseLonger survivalHyperintense signalBrain MRIMelanoma metastasesSingle lesionEnhancement patternLarge lesionsLesion sizeImpact of aging on host immune response and survival in melanoma: an analysis of 3 patient cohorts
Weiss SA, Han J, Darvishian F, Tchack J, Han SW, Malecek K, Krogsgaard M, Osman I, Zhong J. Impact of aging on host immune response and survival in melanoma: an analysis of 3 patient cohorts. Journal Of Translational Medicine 2016, 14: 299. PMID: 27760559, PMCID: PMC5070187, DOI: 10.1186/s12967-016-1026-2.Peer-Reviewed Original ResearchConceptsMelanoma-specific survivalShorter melanoma-specific survivalHost immune responseImmune responseTCGA cohortAge groupsClinicopathologic featuresSurvival outcomesPatient cohortPrimary melanomaHost anti-tumor immune responseMelanoma diagnosisAnti-tumor immune responseMelanoma Cooperative GroupIndependent prognostic factorPopulation-based surveillanceEnd Results ProgramGreater prognostic impactMelanoma patient cohortTop upstream regulatorsYounger age groupsAge-related factorsBrisk TILsConclusionsOlder ageLymphocyte measurementsImmunologic heterogeneity of tumor-infiltrating lymphocyte composition in primary melanoma
Weiss SA, Han SW, Lui K, Tchack J, Shapiro R, Berman R, Zhong J, Krogsgaard M, Osman I, Darvishian F. Immunologic heterogeneity of tumor-infiltrating lymphocyte composition in primary melanoma. Human Pathology 2016, 57: 116-125. PMID: 27473267, PMCID: PMC5706446, DOI: 10.1016/j.humpath.2016.07.008.Peer-Reviewed Original ResearchMeSH KeywordsAgedBiomarkers, TumorCD3 ComplexDisease-Free SurvivalFemaleForkhead Transcription FactorsGene Expression ProfilingGene Expression Regulation, NeoplasticHumansImmunohistochemistryKaplan-Meier EstimateLeukocyte Common AntigensLymphocytes, Tumor-InfiltratingMaleMelanomaNeoplasm GradingPhenotypeProportional Hazards ModelsSkin NeoplasmsTime FactorsTreatment OutcomeConceptsAbsent tumor-infiltrating lymphocytesTumor-infiltrating lymphocytesBrisk tumor-infiltrating lymphocytesRecurrence-free survivalPrimary melanomaTIL gradeOverall survivalImmunologic heterogeneityPresence of TILsHost antitumor immune responseAntitumor immune responseImmune checkpoint regulatorsLymphocyte markers CD3T cell activation pathwaysEosin-stained sectionsGene expression profilesIndependent prognosticationLymphocyte compositionTIL countSurvival outcomesImproved prognosisPrognostic valueHistologic evaluationNonbriskImmune response
2015
Somatic and germline analyses of a long term melanoma survivor with a recurrent brain metastasis
Weiss S, Darvishian F, Tadepalli J, Shapiro R, Golfinos J, Pavlick A, Polsky D, Kirchhoff T, Osman I. Somatic and germline analyses of a long term melanoma survivor with a recurrent brain metastasis. BMC Cancer 2015, 15: 926. PMID: 26597176, PMCID: PMC4657192, DOI: 10.1186/s12885-015-1927-0.Peer-Reviewed Original ResearchConceptsMelanoma brain metastasesRecurrent brain metastasesBrain metastasesOverall survivalLong-term melanoma survivorsSingle nucleotide polymorphismsYear old manIndividual patient's tumorGenetic variantsMelanoma patientsMelanoma survivorsPrognostic informationFavorable outcomeNRAS wild typePatient outcomesConclusionsOur dataPatient tumorsImmune functionBrain tumorsExtended survivalOlder menPatientsClinical scenariosGermline analysisTherapeutic interventionsSensitivity of plasma BRAFmutant and NRASmutant cell‐free DNA assays to detect metastatic melanoma in patients with low RECIST scores and non‐RECIST disease progression
Chang GA, Tadepalli JS, Shao Y, Zhang Y, Weiss S, Robinson E, Spittle C, Furtado M, Shelton DN, Karlin-Neumann G, Pavlick A, Osman I, Polsky D. Sensitivity of plasma BRAFmutant and NRASmutant cell‐free DNA assays to detect metastatic melanoma in patients with low RECIST scores and non‐RECIST disease progression. Molecular Oncology 2015, 10: 157-165. PMID: 26440707, PMCID: PMC4695284, DOI: 10.1016/j.molonc.2015.09.005.Peer-Reviewed Original ResearchConceptsNew brain metastasesDisease progressionTreatment initiationBrain metastasesDisease activityCtDNA levelsMetastatic melanomaProgression eventsRECIST scoresUseful blood-based biomarkerImmune checkpoint blockadeDisease progression eventsBRAF inhibitor therapyBlood-based biomarkersCell-free DNA assaysCheckpoint blockadeMetastatic diseaseInhibitor therapyTreatment courseLDH levelsPatient managementUseful biomarkerPatientsDroplet digital PCR assaysProgressionRevisiting determinants of prognosis in cutaneous melanoma
Weiss SA, Hanniford D, Hernando E, Osman I. Revisiting determinants of prognosis in cutaneous melanoma. Cancer 2015, 121: 4108-4123. PMID: 26308244, PMCID: PMC4666819, DOI: 10.1002/cncr.29634.Peer-Reviewed Original ResearchMeSH KeywordsBiomarkers, TumorHumansMelanomaNeoplasm StagingPrognosisSkin NeoplasmsSurvival AnalysisConceptsDeterminants of prognosisCutaneous melanomaStaging systemCurrent staging modelsCurrent staging systemLymph node spreadPrimary tumor thicknessAmerican Joint CommitteeCancer (AJCC) staging systemPresence of ulcerationPrimary cutaneous melanomaUseful prognostic biomarkerMelanoma staging systemNew prognostic toolClinical surveillance strategiesAdjuvant therapyAdvanced diseaseDistant metastasisPatient selectionNode spreadSurvival outcomesTumor thicknessImmunologic markersPatient prognosisPatient outcomes