2023
Combinatorial Immunotherapy with Agonistic CD40 Activates Dendritic Cells to Express IL12 and Overcomes PD-1 Resistance.
Krykbaeva I, Bridges K, Damsky W, Pizzurro G, Alexander A, McGeary M, Park K, Muthusamy V, Eyles J, Luheshi N, Turner N, Weiss S, Olino K, Kaech S, Kluger H, Miller-Jensen K, Bosenberg M. Combinatorial Immunotherapy with Agonistic CD40 Activates Dendritic Cells to Express IL12 and Overcomes PD-1 Resistance. Cancer Immunology Research 2023, 11: 1332-1350. PMID: 37478171, DOI: 10.1158/2326-6066.cir-22-0699.Peer-Reviewed Original ResearchConceptsPD-1 resistanceDendritic cellsTumor regressionAnti-PD-1 resistanceActivates Dendritic CellsCytokine secretion profilingSystemic cytokine profileTriple therapy combinationInnate immune activationAdaptive immune responsesComplete tumor regressionMajority of miceSignificant clinical challengeMouse melanoma modelT cell activationAgonistic CD40Checkpoint inhibitorsDC subsetsTriple therapyCytokine profileImmune activationCombinatorial immunotherapyTherapy combinationsT cellsClinical challengeSurvival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab
Topalian S, Sznol M, McDermott D, Kluger H, Carvajal R, Sharfman W, Brahmer J, Lawrence D, Atkins M, Powderly J, Leming P, Lipson E, Puzanov I, Smith D, Taube J, Wigginton J, Kollia G, Gupta A, Pardoll D, Sosman J, Hodi F. Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab. Journal Of Clinical Oncology 2023, 41: 943-954. PMID: 36750016, DOI: 10.1200/jco.22.02272.Peer-Reviewed Original ResearchLong-term safetyOverall survivalToxicity ratesTumor regressionResponse durationOngoing randomized clinical trialsDurable tumor remissionNivolumab-treated patientsMedian overall survivalMedian response durationPD-1 blockadeObjective tumor regressionMaintenance of responseCell death 1Randomized clinical trialsSimilar patient populationsActivated T cellsDrug discontinuationIntravenous nivolumabNivolumab therapyNivolumab treatmentTreatment discontinuationObjective responseAdvanced melanomaDeath-1
2018
Durable tumor regression and overall survival (OS) in patients with advanced Merkel cell carcinoma (aMCC) receiving pembrolizumab as first-line therapy.
Nghiem P, Bhatia S, Lipson E, Sharfman W, Kudchadkar R, Friedlander P, Brohl A, Daud A, Kluger H, Reddy S, Burgess M, Hanks B, Olencki T, Boulmay B, Lundgren L, Ramchurren N, Homet Moreno B, Sharon E, Cheever M, Topalian S. Durable tumor regression and overall survival (OS) in patients with advanced Merkel cell carcinoma (aMCC) receiving pembrolizumab as first-line therapy. Journal Of Clinical Oncology 2018, 36: 9506-9506. DOI: 10.1200/jco.2018.36.15_suppl.9506.Peer-Reviewed Original Research
2014
Induction of Antigen-Specific Immunity with a Vaccine Targeting NY-ESO-1 to the Dendritic Cell Receptor DEC-205
Dhodapkar MV, Sznol M, Zhao B, Wang D, Carvajal RD, Keohan ML, Chuang E, Sanborn RE, Lutzky J, Powderly J, Kluger H, Tejwani S, Green J, Ramakrishna V, Crocker A, Vitale L, Yellin M, Davis T, Keler T. Induction of Antigen-Specific Immunity with a Vaccine Targeting NY-ESO-1 to the Dendritic Cell Receptor DEC-205. Science Translational Medicine 2014, 6: 232ra51. PMID: 24739759, PMCID: PMC6151129, DOI: 10.1126/scitranslmed.3008068.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntigens, CDAntigens, NeoplasmCancer VaccinesCytokinesDendritic CellsDose-Response Relationship, ImmunologicEpitopesFemaleHumansImmunity, CellularImmunity, HumoralImmunoglobulin GInterferon-gammaLectins, C-TypeLymphocyte SubsetsMaleMembrane ProteinsMiddle AgedMinor Histocompatibility AntigensReceptors, Cell SurfaceT-LymphocytesVaccinationConceptsNY-ESO-1Immune checkpoint inhibitorsDendritic cellsToll-like receptorsTumor regressionNY-ESO-1-expressing tumorsTumor antigen NY-ESO-1Presence of DCsRobust antigen-specific immune responsesAntigen-specific immune responsesAntigen NY-ESO-1Combination immunotherapy strategiesStabilization of diseaseGrade 3 toxicityObjective tumor regressionImmune checkpoint blockadeT cell immunityAntigen-specific immunityPhase 1 trialTumor-associated antigensReceptor-specific monoclonal antibodyCheckpoint inhibitorsAdvanced malignanciesCheckpoint blockadeMedian durationSurvival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab
Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia GD, Gupta A, Pardoll DM, Sosman JA, Hodi FS. Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab. Journal Of Clinical Oncology 2014, 32: 1020-1030. PMID: 24590637, PMCID: PMC4811023, DOI: 10.1200/jco.2013.53.0105.Peer-Reviewed Original ResearchConceptsLong-term safetyOverall survivalToxicity ratesTumor regressionResponse durationOngoing randomized clinical trialsDurable tumor remissionNivolumab-treated patientsMedian overall survivalMedian response durationPD-1 blockadeObjective tumor regressionMaintenance of responseCell death 1Randomized clinical trialsSimilar patient populationsActivated T cellsDrug discontinuationIntravenous nivolumabNivolumab therapyNivolumab treatmentTreatment discontinuationObjective responseAdvanced melanomaDeath-1
2013
Nivolumab plus Ipilimumab in Advanced Melanoma
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus Ipilimumab in Advanced Melanoma. New England Journal Of Medicine 2013, 369: 122-133. PMID: 23724867, PMCID: PMC5698004, DOI: 10.1056/nejmoa1302369.Peer-Reviewed Original ResearchConceptsObjective response ratePhase 1 trialAdverse eventsConcurrent therapyAdvanced melanomaTumor regressionClinical activityGrade 3Distinct immunologic mechanismsManageable safety profileProlongs overall survivalDurable tumor regressionSupportive preclinical dataRegimen groupImmunologic mechanismsObjective responseOverall survivalIntravenous dosesSafety profileTumor reductionPreclinical dataIpilimumabNivolumabPatientsMaximum doses
2012
Activity of cabozantinib (XL184) in metastatic melanoma: Results from a phase II randomized discontinuation trial (RDT).
Gordon M, Kluger H, Shapiro G, Kurzrock R, Edelman G, Samuel T, Moussa A, Ramies D, Laird A, Schimmoller F, Shen X, Daud A. Activity of cabozantinib (XL184) in metastatic melanoma: Results from a phase II randomized discontinuation trial (RDT). Journal Of Clinical Oncology 2012, 30: 8531-8531. DOI: 10.1200/jco.2012.30.15_suppl.8531.Peer-Reviewed Original ResearchProgression-free survivalMedian progression-free survivalObjective tumor regressionTumor regressionPost-baseline tumour assessmentMedian age 66 yearsActivity of cabozantinibGrade 3/4 AEsGrade 5 AEsMedian prior linesOpen-label leadAge 66 yearsStudy days 1BRAF mutation statusMeasurable diseaseDiverticular perforationEligible patientsPrimary endpointFree survivalPain reliefPrior linesMonth 6VEGFR-TKIDiscontinuation trialSafety profileActivity of cabozantinib (XL184) in metastatic NSCLC: Results from a phase II randomized discontinuation trial (RDT).
Hellerstedt B, Edelman G, Vogelzang N, Kluger H, Yasenchak C, Shen X, Ramies D, Gordon M, Lara P. Activity of cabozantinib (XL184) in metastatic NSCLC: Results from a phase II randomized discontinuation trial (RDT). Journal Of Clinical Oncology 2012, 30: 7514-7514. DOI: 10.1200/jco.2012.30.15_suppl.7514.Peer-Reviewed Original ResearchObjective tumor regressionMedian PFSTumor regressionWk 12Median age 67 yearsOverall disease control ratePost-baseline tumour assessmentPrior exposureActivity of cabozantinibDisease control rateGrade 3/4 AEsGrade 5 AEsMedian prior linesAge 67 yearsStudy days 1Dysregulation of METMET upregulationNSCLC ptsPrior EGFRPrior erlotinibRECIST responseTherapy 50Eligible patientsMeasurable diseaseMetastatic NSCLC