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
2019
A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors
Bentebibel SE, Hurwitz ME, Bernatchez C, Haymaker C, Hudgens CW, Kluger HM, Tetzlaff MT, Tagliaferri MA, Zalevsky J, Hoch U, Fanton C, Aung S, Hwu P, Curti BD, Tannir NM, Sznol M, Diab A. A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors. Cancer Discovery 2019, 9: 711-721. PMID: 30988166, DOI: 10.1158/2159-8290.cd-18-1495.Peer-Reviewed Original ResearchConceptsNKTR-214Tumor biopsiesDurable disease stabilizationImmuno-oncology agentsMulticenter phase IPathway-targeted agentsTreatment tumor biopsiesPhase II doseActivation of CD8Metastatic solid tumorsNatural killer cellsOutpatient regimenCheckpoint inhibitorsDisease stabilizationRegulatory cellsEffector phenotypeKiller cellsTreatment algorithmImmune activationTumor shrinkagePharmacodynamic markersImmune cellsClinical activityIL2 receptorHuman studies
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
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-L1
2011
Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab
Yuan J, Adamow M, Ginsberg BA, Rasalan TS, Ritter E, Gallardo HF, Xu Y, Pogoriler E, Terzulli SL, Kuk D, Panageas KS, Ritter G, Sznol M, Halaban R, Jungbluth AA, Allison JP, Old LJ, Wolchok JD, Gnjatic S. Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 16723-16728. PMID: 21933959, PMCID: PMC3189057, DOI: 10.1073/pnas.1110814108.Peer-Reviewed Original ResearchConceptsNY-ESO-1-seropositive patientsNY-ESO-1 antibodyT cell responsesClinical benefitImmune responseIpilimumab treatmentNY-ESO-1 immune responsesNY-ESO-1 serum antibodyTumor antigen-specific immune responsesCytotoxic T-lymphocyte antigen-4NY-ESO-1 immunityT-lymphocyte antigen-4Antigen-specific immune responsesIpilimumab-treated patientsAdvanced melanoma patientsAdvanced metastatic melanomaCancer/testis antigensSubset of patientsNY-ESO-1Significant survival advantageCD8 responsesAdoptive transferClinical outcomesMelanoma patientsProspective studyWhite Paper on Adoptive Cell Therapy for Cancer with Tumor-Infiltrating Lymphocytes: A Report of the CTEP Subcommittee on Adoptive Cell Therapy
Weber J, Atkins M, Hwu P, Radvanyi L, Sznol M, Yee C, Committee O. White Paper on Adoptive Cell Therapy for Cancer with Tumor-Infiltrating Lymphocytes: A Report of the CTEP Subcommittee on Adoptive Cell Therapy. Clinical Cancer Research 2011, 17: 1664-1673. PMID: 21325070, DOI: 10.1158/1078-0432.ccr-10-2272.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesClinical Trials as TopicHumansImmunotherapy, AdoptiveLeukemiaLymphocytes, Tumor-InfiltratingMelanomaPatient CareConceptsAdoptive T-cell therapyTumor-infiltrating lymphocytesAdoptive cell therapyInterleukin-2TIL therapyClinical trialsRandomized phase II/III clinical trialsExpansion of TILTumor antigen-specific T cellsHigh-dose IL-2Phase II/III clinical trialsHigh-dose interleukin-2Autologous tumor-infiltrating lymphocytesLonger progression-free survivalPhase II/IIIAntigen-specific T cellsCell therapyT cell-based therapiesTIL infusion productsClinical response rateNonrandomized clinical trialProgression-free survivalStage IV melanomaMetastatic melanoma patientsT-cell therapy