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 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 analysis
2022
Safety, 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 cohortBempegaldesleukinNivolumabT 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 biomarkersOutcomes of Stereotactic Radiosurgery and Immunotherapy in Renal Cell Carcinoma Patients With Brain Metastases
Uezono H, Nam D, Kluger HM, Sznol M, Hurwitz M, Yu JB, Chiang VL. Outcomes of Stereotactic Radiosurgery and Immunotherapy in Renal Cell Carcinoma Patients With Brain Metastases. American Journal Of Clinical Oncology 2021, 44: 495-501. PMID: 34432667, DOI: 10.1097/coc.0000000000000849.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsRCC brain metastasesBrain metastasesRenal cell carcinomaStereotactic radiosurgeryOverall survivalUse of ICIsCentral nervous system toxicityRenal cell carcinoma patientsImpact of immunotherapyLocal control outcomesMedian overall survivalCell carcinoma patientsKaplan-Meier curvesNervous system toxicityBetter median OSLog-rank testMann-Whitney U testMargin doseMedian OSNonimmunotherapy groupSRS doseCheckpoint inhibitorsImmunotherapy groupCarcinoma patientsA Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non–Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1
Weiss SA, Djureinovic D, Jessel S, Krykbaeva I, Zhang L, Jilaveanu L, Ralabate A, Johnson B, Levit NS, Anderson G, Zelterman D, Wei W, Mahajan A, Trifan O, Bosenberg M, Kaech SM, Perry CJ, Damsky W, Gettinger S, Sznol M, Hurwitz M, Kluger HM. A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non–Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1. Clinical Cancer Research 2021, 27: 4757-4767. PMID: 34140403, PMCID: PMC9236708, DOI: 10.1158/1078-0432.ccr-21-0903.Peer-Reviewed Original ResearchConceptsAnti-PD-1/PD-L1Non-small cell lung cancerCell lung cancerRenal cell carcinomaPD-L1Lung cancerDisease progressionCommon treatment-related adverse eventsPD-1/PD-L1 inhibitorsTreatment-related adverse eventsPhase 2 doseSubstantial clinical challengeUnconfirmed partial responseDose-limiting toxicityPD-L1 inhibitorsPhase I trialDose-escalation designPro-inflammatory cytokinesMultiple tumor typesAsymptomatic elevationStable diseaseIntolerable toxicityAdverse eventsMedian durationPartial responseEfficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial
Powles T, Atkins MB, Escudier B, Motzer RJ, Rini BI, Fong L, Joseph RW, Pal SK, Sznol M, Hainsworth J, Stadler WM, Hutson TE, Ravaud A, Bracarda S, Suarez C, Choueiri TK, Reeves J, Cohn A, Ding B, Leng N, Hashimoto K, Huseni M, Schiff C, McDermott DF. Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial. European Urology 2021, 79: 665-673. PMID: 33678522, PMCID: PMC9357270, DOI: 10.1016/j.eururo.2021.01.003.Peer-Reviewed Original ResearchConceptsMetastatic clear cell renal cancerProgression-free survivalObjective response rateSafety of atezolizumabSecond-line atezolizumabSecond-line treatmentSunitinib monotherapyDisease progressionSunitinib armRandomized phase 2 clinical trialMedian progression-free survivalTreatment-related adverse eventsMetastatic renal cell carcinomaPhase 2 clinical trialGrade 3/4 eventsInvestigator-assessed progressionImmune checkpoint inhibitorsPhase 2 studyKaplan-Meier methodAdvanced kidney cancerVascular endothelial growth factorClear cell renal cancerRenal cell carcinomaEndothelial growth factorAtezolizumab 1200Resistance mechanisms to checkpoint inhibitors
Weiss SA, Sznol M. Resistance mechanisms to checkpoint inhibitors. Current Opinion In Immunology 2021, 69: 47-55. PMID: 33676271, DOI: 10.1016/j.coi.2021.02.001.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsPD-1/PD-L1 axisMultiple immune checkpoint inhibitorsPD1/PD-L1PD-L1 axisHuman translational studiesPre-clinical studiesPre-clinical animalResistance mechanismsCheckpoint inhibitorsPD-L1Clinical outcomesTreatment failureClinical trialsTranslational studiesCancer treatmentPotential mechanismsInhibitorsPatientsClinicTrialsAntibodiesMolecular correlates of response to nivolumab at baseline and on treatment in patients with RCC
Ross-Macdonald P, Walsh AM, Chasalow SD, Ammar R, Papillon-Cavanagh S, Szabo PM, Choueiri TK, Sznol M, Wind-Rotolo M. Molecular correlates of response to nivolumab at baseline and on treatment in patients with RCC. Journal For ImmunoTherapy Of Cancer 2021, 9: e001506. PMID: 33658305, PMCID: PMC7931766, DOI: 10.1136/jitc-2020-001506.Peer-Reviewed Original ResearchMeSH KeywordsB7-H1 AntigenBiomarkers, TumorCarcinoma, Renal CellCD4 AntigensCD8 AntigensCytokinesDrug Resistance, NeoplasmHumansImmune Checkpoint InhibitorsKidney NeoplasmsLymphocytes, Tumor-InfiltratingMutationNivolumabProgrammed Cell Death 1 ReceptorReceptors, Antigen, T-CellT-LymphocytesTime FactorsTreatment OutcomeConceptsClear cell renal cell carcinomaMetastatic clear cell renal cell carcinomaT cell infiltrationNivolumab responseExact testDeath ligand 1 (PD-L1) statusFirst-line treatment decisionsT-cell receptor clonalitySerum cytokine assaysImmune checkpoint inhibitorsNon-responding patientsDeath-1 receptorCell renal cell carcinomaSubset of patientsRenal cell carcinomaFisher's exact testWnt/β-cateninLogistic regression modelsRank sum testCD8 statusCheckpoint inhibitorsIndex lesionPatient selectionTCR clonalityCell carcinoma
2020
Revisiting anti-CTLA-4 antibodies in combination with PD-1 blockade for cancer immunotherapy
Sznol M, Melero I. Revisiting anti-CTLA-4 antibodies in combination with PD-1 blockade for cancer immunotherapy. Annals Of Oncology 2020, 32: 295-297. PMID: 33307201, DOI: 10.1016/j.annonc.2020.11.018.Peer-Reviewed Original ResearchSafety and efficacy of combination nivolumab plus ipilimumab in patients with advanced melanoma: results from a North American expanded access program (CheckMate 218)
Hodi FS, Chapman PB, Sznol M, Lao CD, Gonzalez R, Smylie M, Daniels GA, Thompson JA, Kudchadkar R, Sharfman W, Atkins M, Spigel DR, Pavlick A, Monzon J, Kim KB, Ernst S, Khushalani NI, van Dijck W, Lobo M, Hogg D. Safety and efficacy of combination nivolumab plus ipilimumab in patients with advanced melanoma: results from a North American expanded access program (CheckMate 218). Melanoma Research 2020, 31: 67-75. PMID: 33234846, PMCID: PMC7757740, DOI: 10.1097/cmr.0000000000000708.Peer-Reviewed Original ResearchConceptsAdvanced melanomaEastern Cooperative Oncology Group performance statusUnresectable stage III/IV melanomaStage III/IV melanomaTreatment-related adverse eventsElevated lactate dehydrogenase levelBRAF wild-type tumorsOverall survival dataRandomized clinical trialsLactate dehydrogenase levelsAccess programBRAF-mutant tumorsRelevant patient subgroupsWild-type tumorsCombination nivolumabEligible patientsOS ratesCheckpoint inhibitorsTreatment discontinuationAdverse eventsPerformance statusUnacceptable toxicityMucosal melanomaPatient subgroupsClinical trialsTebentafusp, 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 melanomaMogamulizumab in Combination with Durvalumab or Tremelimumab in Patients with Advanced Solid Tumors: A Phase I Study
Zamarin D, Hamid O, Nayak-Kapoor A, Sahebjam S, Sznol M, Collaku A, Fox FE, Marshall MA, Hong DS. Mogamulizumab in Combination with Durvalumab or Tremelimumab in Patients with Advanced Solid Tumors: A Phase I Study. Clinical Cancer Research 2020, 26: 4531-4541. PMID: 32586937, PMCID: PMC8375360, DOI: 10.1158/1078-0432.ccr-20-0328.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic Agents, ImmunologicalAntineoplastic Combined Chemotherapy ProtocolsDose-Response Relationship, DrugFemaleHumansLymphocyte DepletionMaleMiddle AgedNeoplasm StagingPancreatic NeoplasmsReceptors, CCR4T-Lymphocytes, RegulatoryYoung AdultConceptsAdvanced solid tumorsDose escalationSolid tumorsCohort expansionEffector regulatory T cellsC chemokine receptor 4Phase IDose-expansion cohortsAdvanced pancreatic cancerObjective response rateMajority of patientsRegulatory T cellsChemokine receptor 4Potent antitumor efficacyMogamulizumab treatmentCheckpoint inhibitorsDose expansionExpansion cohortIntratumoral TregsPrimary endpointClinical responseEscalation studyBaseline degreePharmacodynamic profilePancreatic cancer