2024
How Far We’ve Come
Sznol M, Weber J. How Far We’ve Come. The Cancer Journal 2024, 30: 47-47. PMID: 38527256, DOI: 10.1097/ppo.0000000000000710.Peer-Reviewed Original ResearchImmunotherapy 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 treatmentInterferon-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
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 characteristicsA 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 analysis736 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 Research542 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 Research
2022
Maximizing the value of phase III trials in immuno-oncology: A checklist from the Society for Immunotherapy of Cancer (SITC)
Atkins MB, Abu-Sbeih H, Ascierto PA, Bishop MR, Chen DS, Dhodapkar M, Emens LA, Ernstoff MS, Ferris RL, Greten TF, Gulley JL, Herbst RS, Humphrey RW, Larkin J, Margolin KA, Mazzarella L, Ramalingam SS, Regan MM, Rini BI, Sznol M. Maximizing the value of phase III trials in immuno-oncology: A checklist from the Society for Immunotherapy of Cancer (SITC). Journal For ImmunoTherapy Of Cancer 2022, 10: e005413. PMID: 36175037, PMCID: PMC9528604, DOI: 10.1136/jitc-2022-005413.Peer-Reviewed Original ResearchConceptsPhase III trialsImmunotherapy of cancerIII trialsCurative responseImmune checkpoint inhibitor monotherapyCell death protein 1Checkpoint inhibitor monotherapyDefinitive predictive biomarkersDurable clinical benefitProgression-free survivalMinority of patientsDeath protein 1Variety of indicationsClinical trial designAnimal tumor modelsLimited Phase IDrug development programsImmunotherapy combinationsInvestigational chemotherapyImmunotherapy fieldInhibitor monotherapyOverall survivalDismal prognosisClinical benefitSurvival outcomesSafety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors
Sanborn RE, Pishvaian MJ, Callahan MK, Weise A, Sikic BI, Rahma O, Cho DC, Rizvi NA, Sznol M, Lutzky J, Bauman JE, Bitting RL, Starodub A, Jimeno A, Reardon DA, Kaley T, Iwamoto F, Baehring JM, Subramaniam DS, Aragon-Ching JB, Hawthorne TR, Rawls T, Yellin M, Keler T. Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors. Journal For ImmunoTherapy Of Cancer 2022, 10: e005147. PMID: 35940825, PMCID: PMC9364417, DOI: 10.1136/jitc-2022-005147.Peer-Reviewed Original ResearchConceptsObjective response rateAnti-PD-1/L1Solid tumorsAnti-PD-1 therapyIntratumoral T cell infiltrationBetter progression-free survivalAnti-CD27 antibodyKey clinical endpointsTumor PD-L1Tumor-specific cohortsAdvanced solid tumorsProgression-free survivalRefractory solid tumorsOverall survival rateT cell infiltrationBetter clinical outcomesSquamous cell carcinomaOvarian cancer patientsPhase 2Phase 1Nivolumab monotherapyAdverse eventsImmune signaturesPD-L1Proinflammatory changesCoupled 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 roleFirst-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
Kim TW, Burris HA, de Miguel Luken MJ, Pishvaian MJ, Bang YJ, Gordon M, Awada A, Camidge DR, Hodi FS, McArthur GA, Miller WH, Cervantes A, Chow LQ, Lesokhin AM, Rutten A, Sznol M, Rishipathak D, Chen SC, Stefanich E, Pourmohamad T, Anderson M, Kim J, Huseni M, Rhee I, Siu LL. First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors. Clinical Cancer Research 2022, 28: of1-of12. PMID: 35699599, PMCID: PMC9662912, DOI: 10.1158/1078-0432.ccr-21-4020.Peer-Reviewed Original ResearchConceptsAdverse eventsImmune activationT cellsMost common treatment-related adverse eventsCommon treatment-related adverse eventsSolid tumorsTreatment-related adverse eventsRenal cell carcinoma patientsNon-small cell lung carcinomaRegulatory T cell functionTriple-negative breast cancerPD-1/PD-L1 antagonistsDose-escalation stageInfusion-related reactionsAdvanced solid tumorsRefractory solid tumorsCell carcinoma patientsDose-limiting toxicityEffector T cellsSubset of patientsFavorable safety profileHuman phase IPD-L1 antagonistsT cell functionCell lung carcinomaBempegaldesleukin plus Nivolumab in First-line Metastatic Urothelial Carcinoma: Results from PIVOT-02
Siefker-Radtke AO, Cho DC, Diab A, Sznol M, Bilen MA, Balar AV, Grignani G, Puente E, Tang L, Chien D, Hoch U, Choudhury A, Yu D, Currie SL, Tagliaferri MA, Zalevsky J, Hurwitz ME, Tannir NM. Bempegaldesleukin plus Nivolumab in First-line Metastatic Urothelial Carcinoma: Results from PIVOT-02. European Urology 2022, 82: 365-373. PMID: 35643589, DOI: 10.1016/j.eururo.2022.05.002.Peer-Reviewed Original ResearchConceptsTreatment-related adverse eventsMetastatic urothelial carcinomaObjective response rateProgression-free survivalExploratory biomarker analysisOverall survivalUrothelial carcinomaGrade 3/4 treatment-related adverse eventsResponse rateMedian progression-free survivalTreatment-related side effectsCisplatin-ineligible patientsMedian overall survivalPhase 1/2 studyComplete response rateFirst-line treatmentSubset of patientsChemotherapy-free treatmentTumor response assessmentSingle-arm designUnivariate logistic regressionBiomarker analysisMeasurable diseaseMedian durationTreatment landscapeBempegaldesleukin plus nivolumab in first-line renal cell carcinoma: results from the PIVOT-02 study
Tannir NM, Cho DC, Diab A, Sznol M, Bilen MA, Balar AV, Grignani G, Puente E, Tang L, Chien D, Hoch U, Choudhury A, Yu D, Currie SL, Tagliaferri MA, Zalevsky J, Siefker-Radtke AO, Hurwitz ME. Bempegaldesleukin plus nivolumab in first-line renal cell carcinoma: results from the PIVOT-02 study. Journal For ImmunoTherapy Of Cancer 2022, 10: e004419. PMID: 35444058, PMCID: PMC9021810, DOI: 10.1136/jitc-2021-004419.Peer-Reviewed Original ResearchConceptsTreatment-related adverse eventsRenal cell carcinomaProgression-free survivalAdvanced clear cell renal cell carcinomaClear cell renal cell carcinomaFirst-line therapyOverall survivalCell carcinomaGrade 3/4 treatment-related adverse eventsSingle-arm phase 1/2 studyMedian progression-free survivalMedian overall survivalObjective response ratePhase 1/2 studyCent of patientsPreliminary antitumor activitySingle-arm designAdverse eventsComplete responseBaseline biomarkersTreatment optionsExploratory biomarkersRCC cohortBempegaldesleukinNivolumabImmune 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 stateAutoimmune 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
Phase Ib Study of Atezolizumab Plus Interferon-α with or without Bevacizumab in Patients with Metastatic Renal Cell Carcinoma and Other Solid Tumors
Blank CU, Wong DJ, Ho TH, Bauer TM, Lee CB, Bene-Tchaleu F, Zhu J, Zhang X, Cha E, Sznol M. Phase Ib Study of Atezolizumab Plus Interferon-α with or without Bevacizumab in Patients with Metastatic Renal Cell Carcinoma and Other Solid Tumors. Current Oncology 2021, 28: 5466-5479. PMID: 34940094, PMCID: PMC8700717, DOI: 10.3390/curroncol28060455.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaObjective response ratePEG-interferon α-2aPhase Ib studyInterferon α-2bArm BSolid tumorsCell carcinomaClinical activityΑ-2aΑ-2bIb studyVascular endothelial growth factor inhibitorsFrequent treatment-related toxicitiesHigher objective response rateMetastatic renal cell carcinomaArm DTreatment-related toxicityPreliminary clinical activityGrowth factor inhibitorsMetastatic solid tumorsAcceptable tolerabilityFactor inhibitorsSafety profileCombination therapyTIL 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