2022
First-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 carcinoma
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 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
2017
Phase 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
Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma
Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, Hernandez G, Mier J, He X, Hodi FS, Denker M, Leveque V, Cañamero M, Babitski G, Koeppen H, Ziai J, Sharma N, Gaire F, Chen DS, Waterkamp D, Hegde PS, McDermott DF. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nature Communications 2016, 7: 12624. PMID: 27571927, PMCID: PMC5013615, DOI: 10.1038/ncomms12624.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntigens, NeoplasmAntineoplastic Combined Chemotherapy ProtocolsB7-H1 AntigenBevacizumabCarcinoma, Renal CellCD8-Positive T-LymphocytesCell MovementDrug SynergismFemaleHumansKidneyKidney NeoplasmsMaleMaximum Tolerated DoseMiddle AgedTreatment OutcomeVascular Endothelial Growth Factor AConceptsAntigen-specific T-cell migrationT cell migrationT cellsCombination treatmentAnti-tumor immune activationPD-L1 checkpoint inhibitionMetastatic renal cell carcinomaAddition of atezolizumabIntra-tumoral CD8Subset of patientsT cell infiltrationImmune cell activityRenal cell carcinomaEndothelial cell activationVariety of cancersLymphocytes increasesPeripheral CD8Checkpoint inhibitorsDurable responsesCheckpoint inhibitionImmune activationCell carcinomaVascular normalizationReceptor increasesCell activation
2015
Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo
Das R, Verma R, Sznol M, Boddupalli CS, Gettinger SN, Kluger H, Callahan M, Wolchok JD, Halaban R, Dhodapkar MV, Dhodapkar KM. Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo. The Journal Of Immunology 2015, 194: 950-959. PMID: 25539810, PMCID: PMC4380504, DOI: 10.4049/jimmunol.1401686.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntigens, SurfaceAntineoplastic Combined Chemotherapy ProtocolsCTLA-4 AntigenCytokinesGene Expression ProfilingGene Expression Regulation, NeoplasticHumansImmunophenotypingIpilimumabLymphocytes, Tumor-InfiltratingNeoplasmsNivolumabProgrammed Cell Death 1 ReceptorSignal TransductionT-Lymphocyte SubsetsConceptsPD-1T cellsCTLA-4Checkpoint blockadeCombination therapyReceptor occupancyCombination immune checkpoint blockadeCTLA-4 immune checkpointsPD-1 receptor occupancyTransitional memory T cellsAnti-PD-1 therapyAnti CTLA-4Immune-based combinationsPD-1 blockadeSoluble IL-2RImmune checkpoint blockadeNK cell functionMemory T cellsTherapy-induced changesT cell activationTumor T cellsHuman T cellsRemarkable antitumor effectImmunologic changesImmunologic effects
2012
Advances in the Treatment of Metastatic Melanoma: New Immunomodulatory Agents
Sznol M. Advances in the Treatment of Metastatic Melanoma: New Immunomodulatory Agents. Seminars In Oncology 2012, 39: 192-203. PMID: 22484191, DOI: 10.1053/j.seminoncol.2012.01.007.Peer-Reviewed Original ResearchConceptsNew immunomodulatory agentsImmunomodulatory agentsMetastatic melanomaT cell activationT cellsAdverse eventsDendritic cellsClinical activityOngoing phase III trialsRandomized phase III studyCo-inhibitory receptor PD-1Co-stimulatory antibodiesMajor adverse eventsPhase III studyPhase III trialsReceptor PD-1Durable clinical responsesImmune cell subsetsSubsequent clinical trialsParticular T cellsActivated T cellsMechanism of actionAdvanced diseaseClinical responseIII study