2024
First-in-human phase 1 dose-escalation results with livmoniplimab, an antibody targeting the GARP:TGF-ß1 complex, as monotherapy and in combination with the anti–PD-1 antibody budigalimab in patients with advanced solid tumors
Shimizu T, Powderly J, Razak A, LoRusso P, Miller K, Kao S, Kongpachith S, Tribouley C, Graham M, Stoll B, Patel M, Sahtout M, Blaney M, Leibman R, Golan T, Tolcher A. First-in-human phase 1 dose-escalation results with livmoniplimab, an antibody targeting the GARP:TGF-ß1 complex, as monotherapy and in combination with the anti–PD-1 antibody budigalimab in patients with advanced solid tumors. Frontiers In Oncology 2024, 14: 1376551. PMID: 39534099, PMCID: PMC11555770, DOI: 10.3389/fonc.2024.1376551.Peer-Reviewed Original ResearchAdvanced solid tumorsDose-escalation phaseDose escalationSolid tumorsSurface of regulatory T cellsRecommended phase 2 doseSuppress antitumor immune responsesCombination therapy cohortsDose-proportional PKMonotherapy-treated patientsPhase 2 doseMedian response durationAntitumor immune responseDose-limiting toxicityTherapy-treated patientsRegulatory T cellsMaximum administered doseFirst-in-humanDose escalation resultsGlycoprotein A repetitionsPromote tumor growthBlood biomarker dataDose expansionPretreated patientsEscalating dosesEnhanced Intratumoral Delivery of Immunomodulator Monophosphoryl Lipid A through Hyperbranched Polyglycerol–Coated Biodegradable Nanoparticles
Chang J, Shin K, Lewis J, Suh H, Lee J, Damsky W, Xu S, Bosenberg M, Saltzman W, Girardi M. Enhanced Intratumoral Delivery of Immunomodulator Monophosphoryl Lipid A through Hyperbranched Polyglycerol–Coated Biodegradable Nanoparticles. Journal Of Investigative Dermatology 2024, 145: 593-604. PMID: 39122142, DOI: 10.1016/j.jid.2024.07.019.Peer-Reviewed Original ResearchMonophosphoryl lipid ATumor microenvironmentImmunomodulatory agentsStimulation of anti-tumor immune responseEfficacy of monophosphoryl lipid AT-helper (Th)1 responsesAnti-tumor immune responseTumor-draining lymph nodesToxicity associated with systemic administrationImmune responseModel of malignant melanomaAgonist monophosphoryl lipid ABiodegradable nanoparticlesImmunogenic tumor microenvironmentAntitumor immune responseDraining lymph nodesSystemic side effectsNatural killer cellsGradual drug releaseKiller cellsAntitumor efficacyMalignant melanomaImproved survivalLymph nodesChemotherapeutic agentsLKB1 prevents ILC2 exhaustion to enhance antitumor immunity
Niu H, Zhang H, Wang D, Zhao L, Zhang Y, Zhou W, Zhang J, Su X, Sun J, Su B, Qiu J, Shen L. LKB1 prevents ILC2 exhaustion to enhance antitumor immunity. Cell Reports 2024, 43: 113579. PMID: 38670109, DOI: 10.1016/j.celrep.2023.113579.Peer-Reviewed Original ResearchAntitumor immunityPD-1Tumor immunityExpression of programmed cell death protein 1Group 2 innate lymphoid cellsBlockade of PD-1Cell death protein 1Lung melanoma metastasesAntitumor immune responseRegulating tumor immunityNuclear factor of activating T cells pathwayT-cell pathwayLiver kinase B1ILC2 functionMelanoma metastasesILC2sLymphoid cellsAllergic inflammationImmune homeostasisEffector functionsInactivating mutationsImmune responseHuman cancersCell pathwaysProtein 1Th2 Cells Are Associated with Tumor Recurrence Following Radiation
Abdelhakiem M, Bao R, Pifer P, Molkentine D, Molkentine J, Hefner A, Beadle B, Heymach J, Luke J, Ferris R, Pickering C, Wang J, Patel R, Skinner H. Th2 Cells Are Associated with Tumor Recurrence Following Radiation. Cancers 2024, 16: 1586. PMID: 38672668, PMCID: PMC11049347, DOI: 10.3390/cancers16081586.Peer-Reviewed Original ResearchHead and neck squamous cell carcinomaLocoregional recurrenceValidation cohortTh2 infiltrationDiscovery cohortTh2 cellsTreatment of multiple solid tumorsAssociated with locoregional recurrenceNeck squamous cell carcinomaAssociated with tumor recurrencePrognostic immune biomarkersAntitumor immune responseTumor immune infiltrationSquamous cell carcinomaMultiple solid tumorsIndependent validation cohortResponse to radiationImmune cell typesMechanism of radiation resistanceAssociated with outcomeAdjuvant radiationTumor recurrenceHNSCC tumorsCell carcinomaImmune infiltrationProgrammable Bacteria‐Based Biohybrids as Living Biotherapeutics for Enhanced Cancer Sonodynamic‐Immunotherapy
Wang C, Chen L, Zhu J, Wang C, Li M, Miao Y, Liu N, Ji Z, Pan F, Liu Y, Zhu J, Yang Y, Chen Q. Programmable Bacteria‐Based Biohybrids as Living Biotherapeutics for Enhanced Cancer Sonodynamic‐Immunotherapy. Advanced Functional Materials 2024, 34 DOI: 10.1002/adfm.202316092.Peer-Reviewed Original ResearchSonodynamic therapyAntitumor immune responseTumor-associated antigensImmune memory responsePrevent tumor recurrenceInhibit tumor metastasisOrthotopic colorectal tumorsAbscopal effectTumor recurrenceEffective sonodynamic therapyTumor siteNano-sonosensitizersTumor hypoxiaPathogen-associated molecular patternsColorectal tumorsMemory responsesTherapeutic delivery systemsTumor metastasisImmune responseTumorLive biotherapeuticsMetastasisBacterial pathogen-associated molecular patternsMolecular patternsOverexpressing catalaseTargeting STAT3 in tumor-associated antigen-presenting cells as a strategy for kidney and bladder cancer immunotherapy
Alcantara M, Tang W, Wang D, Kaniowski D, Kang E, Dizman N, Chehrazi-Raffle A, Meza L, Zengin Z, Hall J, Hsu J, Egelston C, Moreira D, Horsager A, Pal S, Kortylewski M. Targeting STAT3 in tumor-associated antigen-presenting cells as a strategy for kidney and bladder cancer immunotherapy. Frontiers In Immunology 2024, 14: 1274781. PMID: 38259453, PMCID: PMC10800835, DOI: 10.3389/fimmu.2023.1274781.Peer-Reviewed Original ResearchImmune checkpoint blockadeDendritic cellsCancer patientsBladder cancerT cellsTumor-associated antigen-presenting cellsTherapeutic efficacyLesser extent IL-10T cell-based immunotherapyImmune checkpoint inhibitorsTumor immune evasionAntitumor immune responseCD8 T cellsRegulatory T cellsBladder cancer immunotherapyCell-based immunotherapyAntigen-presenting cellsSTAT3 activationRenal cancer patientsBladder cancer patientsImmune cell activityMyeloid immune cellsICB resistanceIpilimumab immunotherapyCheckpoint inhibitors
2023
Radiation Synergizes with IL2/IL15 Stimulation to Enhance Innate Immune Activation and Antitumor Immunity.
Li X, Huntoon K, Wang Y, Lee D, Dong S, Antony A, Walkey C, Kim B, Jiang W. Radiation Synergizes with IL2/IL15 Stimulation to Enhance Innate Immune Activation and Antitumor Immunity. Molecular Cancer Therapeutics 2023, 23: 330-342. PMID: 37956421, DOI: 10.1158/1535-7163.mct-23-0236.Peer-Reviewed Original ResearchTumor growth inhibitionDendritic cellsAnti-PD-1 checkpoint inhibitorsAntigen-specific T cellsIL-2/ILGreater tumor infiltrationImmune stimulatory mechanismsMurine breast cancer modelAntitumor immune responseCombination of radiotherapyInnate immune activationType I interferon productionImmune-modulatory propertiesIL-15 receptorBreast cancer modelI interferon productionSuperior tumor growth inhibitionGrowth inhibitionInterferon genes (STING) pathwaySystemic immunotherapyWestern blot analysisCheckpoint inhibitorsMetastatic settingAntitumor immunitySurvival benefitAnti-TIGIT Antibody Tiragolumab Alone or With Atezolizumab in Patients With Advanced Solid Tumors
Kim T, Bedard P, LoRusso P, Gordon M, Bendell J, Oh D, Ahn M, Garralda E, D’Angelo S, Desai J, Hodi F, Wainberg Z, Delord J, Cassier P, Cervantes A, Gil-Martin M, Wu B, Patil N, Jin Y, Hoang T, Mendus D, Wen X, Meng R, Cho B. Anti-TIGIT Antibody Tiragolumab Alone or With Atezolizumab in Patients With Advanced Solid Tumors. JAMA Oncology 2023, 9: 1574-1582. PMID: 37768658, PMCID: PMC10540058, DOI: 10.1001/jamaoncol.2023.3867.Peer-Reviewed Original ResearchConceptsObjective response rateAdvanced solid tumorsAdverse eventsPhase 1bAntitumor activityCancer cohortNon-small cell lung cancer (NSCLC) cohortFrequent treatment-related adverse eventsInvestigator-assessed objective response rateSolid tumorsCell lung cancer cohortTreatment-related adverse eventsMajority of AEsEnd pointClinical cutoff dateDose-escalation cohortsDose-expansion cohortsEsophageal cancer cohortPhase 2 dosePrior cancer therapyPrimary end pointSecondary end pointsHalf of patientsNew safety signalsAntitumor immune responseTargeting PGLYRP1 promotes antitumor immunity while inhibiting autoimmune neuroinflammation
Schnell A, Huang L, Regan B, Singh V, Vonficht D, Bollhagen A, Wang M, Hou Y, Bod L, Sobel R, Chihara N, Madi A, Anderson A, Regev A, Kuchroo V. Targeting PGLYRP1 promotes antitumor immunity while inhibiting autoimmune neuroinflammation. Nature Immunology 2023, 24: 1908-1920. PMID: 37828379, PMCID: PMC10864036, DOI: 10.1038/s41590-023-01645-4.Peer-Reviewed Original ResearchConceptsPeptidoglycan recognition protein 1T cellsMyeloid cellsGenetic deletionPotent antitumor immune responsesCo-inhibitory moleculesExperimental autoimmune encephalomyelitisAntitumor immune responseImmune checkpoint blockadePromising targetSuccessful treatment optionT cell functionCentral nervous systemT cell activationMultiple human cancersAutoimmune neuroinflammationAntitumor immunityAutoimmune encephalomyelitisCheckpoint blockadeCheckpoint moleculesEffector phenotypeAutoimmune diseasesProinflammatory moleculesTissue inflammationTreatment optionsBSBM-18 SINGLE-CELL PROFILING TUMOR-INFILTRATING IMMUNE CELLS REVEALS CXCL13+ FOLLICULAR HELPER-LIKE CD4+ T CELLS IN HUMAN BRAIN TUMORS
Lu B, Lucca L, DiStasio M, Liu Y, Pham G, Buitrago-Pocasangre N, Arnal-Estape A, Moliterno J, Chiang V, Omuro A, Hafler D. BSBM-18 SINGLE-CELL PROFILING TUMOR-INFILTRATING IMMUNE CELLS REVEALS CXCL13+ FOLLICULAR HELPER-LIKE CD4+ T CELLS IN HUMAN BRAIN TUMORS. Neuro-Oncology Advances 2023, 5: iii4-iii4. PMCID: PMC10402449, DOI: 10.1093/noajnl/vdad070.014.Peer-Reviewed Original ResearchT cell populationsT cell functionT cellsHigh-grade gliomasBrain metastasesHuman brain tumorsImmune cellsBrain tumorsNon-small cell lung cancer brain metastasesB cellsAnti-PD-1 therapy responseCell lung cancer brain metastasesLung cancer brain metastasesProductive antitumor immune responsesFollicular helper T cellsT-cell receptor sequencingTumor-infiltrating T cellsAntitumor T-cell functionCancer brain metastasesCo-inhibitory receptorsAntitumor immune responseCell receptor sequencingLonger overall survivalCell functionTertiary lymphoid structuresNew insights into programmed cell death protein 1 blockade-associated cutaneous immune-related adverse events
Micevic G, Daniels A, Flavell R. New insights into programmed cell death protein 1 blockade-associated cutaneous immune-related adverse events. British Journal Of Dermatology 2023, 189: 355-357. PMID: 37471669, PMCID: PMC10503525, DOI: 10.1093/bjd/ljad236.Peer-Reviewed Original ResearchConceptsCutaneous immune-related adverse eventsImmune-related adverse eventsSelf-reactive T cellsCheckpoint receptor PD-1PD-1 inhibitorsHalf of patientsImmune checkpoint blockadeAntitumor immune responseReceptor PD-1Adverse eventsCheckpoint blockadePD-1Immune toleranceCTLA-4T cellsImmune responseLandmark studiesMolecular mechanismsFunctional roleCritical functional rolePatientsBlockadeDermatologistsImportant cluesIL-7R licenses a population of epigenetically poised memory CD8+ T cells with superior antitumor efficacy that are critical for melanoma memory
Micevic G, Daniels A, Flem-Karlsen K, Park K, Talty R, McGeary M, Mirza H, Blackburn H, Sefik E, Cheung J, Hornick N, Aizenbud L, Joshi N, Kluger H, Iwasaki A, Bosenberg M, Flavell R. IL-7R licenses a population of epigenetically poised memory CD8+ T cells with superior antitumor efficacy that are critical for melanoma memory. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2304319120. PMID: 37459511, PMCID: PMC10372654, DOI: 10.1073/pnas.2304319120.Peer-Reviewed Original ResearchConceptsIL-7R expressionT cellsIL-7RAntitumor memorySuperior antitumor efficacyCell-based therapiesTumor-specific T cellsAntigen-specific T cellsAntitumor efficacyPowerful antitumor immune responseMarkers of exhaustionTumor-specific CD8Antitumor immune responseIndependent prognostic factorAntitumor immune memoryMemory T cellsMajor risk factorSuperior antitumor activityFunctional CD8Memory CD8Prognostic factorsSurgical resectionAdvanced melanomaLymph nodesNaive mice
2022
Baseline gene expression profiling determines long-term benefit to programmed cell death protein 1 axis blockade
Vathiotis I, Salichos L, Martinez-Morilla S, Gavrielatou N, Aung T, Shafi S, Wong P, Jessel S, Kluger H, Syrigos K, Warren S, Gerstein M, Rimm D. Baseline gene expression profiling determines long-term benefit to programmed cell death protein 1 axis blockade. Npj Precision Oncology 2022, 6: 92. PMID: 36522538, PMCID: PMC9755314, DOI: 10.1038/s41698-022-00330-3.Peer-Reviewed Original ResearchProgression-free survivalLong-term benefitsPredictive valueAnti-PD-1 therapyCell death protein 1Baseline tumor samplesImmune checkpoint inhibitorsAntitumor immune responseCohort of patientsDeath protein 1Gene expression profilesAdvanced diseaseCheckpoint inhibitorsAdvanced melanomaAxis blockadeImmunotherapy outcomesTreatment initiationEarly outcomesDisease progressionMalignant melanomaBaseline gene expressionImmune responseBaseline gene expression profilesExpression profilesTumor samplesThe Crossroads of Cancer Epigenetics and Immune Checkpoint Therapy.
Micevic G, Bosenberg M, Yan Q. The Crossroads of Cancer Epigenetics and Immune Checkpoint Therapy. Clinical Cancer Research 2022, 29: 1173-1182. PMID: 36449280, PMCID: PMC10073242, DOI: 10.1158/1078-0432.ccr-22-0784.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsImmune checkpoint inhibitorsImmune checkpoint therapyT cell exhaustionCheckpoint therapyAntitumor immune responseT cell populationsCell-intrinsic immunityTypes of cancerViral mimicry responseLow response rateCheckpoint inhibitorsCurrent immunotherapiesPancreatic cancerSustained responsePreclinical modelsTreatment outcomesImmune responseEndogenous antigensResponse rateTumor typesMultiple epigenetic regulatorsCritical mediatorLow immunogenicityTherapyCancerCellular senescence is immunogenic and promotes anti-tumor immunity
Marin I, Boix O, Garcia-Garijo A, Sirois I, Caballe A, Zarzuela E, Ruano I, Attolini C, Prats N, López-Domínguez J, Kovatcheva M, Garralda E, Muñoz J, Caron E, Abad M, Gros A, Pietrocola F, Serrano M. Cellular senescence is immunogenic and promotes anti-tumor immunity. Cancer Discovery 2022, 13: 410-431. PMID: 36302218, PMCID: PMC7614152, DOI: 10.1158/2159-8290.cd-22-0523.Peer-Reviewed Original ResearchConceptsCD8 T cellsAntitumor immune responseImmunogenic cell deathDendritic cellsSenescent cancer cellsT cellsCancer cellsImmune responseAntigen-specific CD8 T cellsSenescent cellsRelease of alarminsAnti-tumor immunityInnate immune cellsHuman primary cancer cellsActivation of IFNCellular senescencePrimary cancer cellsAdaptive immune systemCell deathCD8 lymphocytesAntitumor protectionImmune cellsImmune systemContext of cancerInduction of senescence732MO The combination of ICT01, a γ9δ2 T cell-activating mAb, plus pembrolizumab induces a broad antitumor immune response and disease control in patients with CPI-failure melanoma, NSCLC and bladder cancer: EVICTION trial
Champiat S, Wermke M, Vicier C, de Bono J, Jungels C, Vey N, Kotecki N, Wetzko K, Ruhnke L, Garralda E, de Aguiar V, Lorusso P, de Gassart A, Valentin E, Brune P, Iche M, Leparquier C, Olive D, Marabelle A, Frohna P. 732MO The combination of ICT01, a γ9δ2 T cell-activating mAb, plus pembrolizumab induces a broad antitumor immune response and disease control in patients with CPI-failure melanoma, NSCLC and bladder cancer: EVICTION trial. Annals Of Oncology 2022, 33: s877-s878. DOI: 10.1016/j.annonc.2022.07.858.Peer-Reviewed Original ResearchClinical outcome following checkpoint therapy in renal cell carcinoma is associated with a burst of activated CD8 T cells in blood
Carlisle J, Jansen C, Cardenas M, Sobierajska E, Reyes A, Greenwald R, Del Balzo L, Prokhnevska N, Kucuk O, Carthon B, Mullane P, Osunkoya A, Baumgarten D, Hosseinzadeh F, Wilkinson S, Lake R, Sowalsky A, Liu Y, Master V, Bilen M, Kissick H. Clinical outcome following checkpoint therapy in renal cell carcinoma is associated with a burst of activated CD8 T cells in blood. Journal For ImmunoTherapy Of Cancer 2022, 10: e004803. PMID: 35863822, PMCID: PMC9310235, DOI: 10.1136/jitc-2022-004803.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaCD8 T cellsCheckpoint therapyT cellsHLA-DRCell carcinomaClinical benefitActivation markers HLA-DRAdvanced renal cell carcinomaPre-existing immune responsesImmune responsePredictor of clinical benefitPeripheral T cell activationPeripheral blood of patientsFlow cytometryT-cell receptor (TCR) sequencingIntratumoral T cellsAntitumor immune responseMarkers HLA-DRAbundant T cellsProportion of CD4Cornerstone of treatmentT cell activationBlood of patientsPredicting therapeutic responseAddressing CPI resistance in NSCLC: targeting TAM receptors to modulate the tumor microenvironment and future prospects
Peters S, Paz-Ares L, Herbst RS, Reck M. Addressing CPI resistance in NSCLC: targeting TAM receptors to modulate the tumor microenvironment and future prospects. Journal For ImmunoTherapy Of Cancer 2022, 10: e004863. PMID: 35858709, PMCID: PMC9305809, DOI: 10.1136/jitc-2022-004863.Peer-Reviewed Original ResearchConceptsImmunosuppressive tumor microenvironmentCheckpoint inhibitorsTAM receptorsImmune responseTumor microenvironmentOverall survivalLung cancerStandard first-line therapyLong-term clinical responseCell death protein 1Immunostimulatory tumor microenvironmentImmune checkpoint inhibitorsInhibitor-based regimensFirst-line therapyAntitumor immune responseDeath protein 1Cell lung cancerPatients' overall survivalStrong biological rationaleNew treatment approachesLong-term survivalActivation of Tyro3Majority of casesCPI therapyAdvanced NSCLCPembrolizumab (pembro) plus mFOLFOX7 or FOLFIRI for metastatic colorectal cancer (CRC) in KEYNOTE-651: Long-term follow-up of cohorts B and D.
Kim R, Tehfe M, Kavan P, Chaves J, Kortmansky J, Chen E, Lieu C, Wong L, Fakih M, Spencer K, Zhao Q, Predoiu R, Li C, Carpenter D, Leconte P, Chiorean E. Pembrolizumab (pembro) plus mFOLFOX7 or FOLFIRI for metastatic colorectal cancer (CRC) in KEYNOTE-651: Long-term follow-up of cohorts B and D. Journal Of Clinical Oncology 2022, 40: 3521-3521. DOI: 10.1200/jco.2022.40.16_suppl.3521.Peer-Reviewed Original ResearchCohort BColorectal cancerCohort DPMMR colorectal cancerRECIST v1.1End pointExploratory end pointsPD-L1 dataSingle-arm cohortAntitumor activityManageable safety profileMetastatic colorectal cancerPrimary end pointSecondary end pointsNew safety signalsAntitumor immune responseCombination of chemotherapyKRAS mutation statusGreater antitumor activityData cutoffStarting doseNeutrophil countPrior linesInvestigator reviewSafety profileRole of tumor infiltrating lymphocytes and spatial immune heterogeneity in sensitivity to PD-1 axis blockers in non-small cell lung cancer
de Rodas M, Nagineni V, Ravi A, Datar IJ, Mino-Kenudson M, Corredor G, Barrera C, Behlman L, Rimm DL, Herbst RS, Madabhushi A, Riess JW, Velcheti V, Hellmann MD, Gainor J, Schalper KA. Role of tumor infiltrating lymphocytes and spatial immune heterogeneity in sensitivity to PD-1 axis blockers in non-small cell lung cancer. Journal For ImmunoTherapy Of Cancer 2022, 10: e004440. PMID: 35649657, PMCID: PMC9161072, DOI: 10.1136/jitc-2021-004440.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerImmune checkpoint inhibitorsT-cell immunoglobulin mucin-3Cell lung cancerCytotoxic T cellsT cellsImmune heterogeneityLung cancerT cell exhaustion marker expressionPD-L1 positive patientsT cell exhaustion markersAdaptive antitumor immune responsesCell death protein 1Baseline tumor samplesExhaustion marker expressionIndependent NSCLC cohortsTumor immune heterogeneityT-cell densityAntitumor immune responseT cell infiltrationDeath protein 1Multi-institutional cohortActivation gene-3Helper T cellsRole of tumor
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