Sequencing of Checkpoint or BRAF/MEK Inhibitors on Brain Metastases in Melanoma.
Ascierto P, Mandalà M, Ferrucci P, Guidoboni M, Rutkowski P, Ferraresi V, Arance A, Guida M, Maiello E, Gogas H, Richtig E, Quaglino P, Lebbé C, Helgadottir H, Queirolo P, Spagnolo F, Tucci M, Del Vecchio M, Gonzalez-Cao M, Minisini A, De Placido S, Sanmamed M, Casula M, Bulgarelli J, Pisano M, Piccinini C, Piccin L, Cossu A, Mallardo D, Paone M, Vitale M, Melero I, Grimaldi A, Giannarelli D, Palmieri G, Dummer R, Sileni V. Sequencing of Checkpoint or BRAF/MEK Inhibitors on Brain Metastases in Melanoma. NEJM Evidence 2024, 3: evidoa2400087. PMID: 39315864, DOI: 10.1056/evidoa2400087.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitionBrain metastasesBRAF/MEK inhibitorsArm BArm AProgressive diseaseCheckpoint inhibitionBrain metastases-free survivalImmune checkpoint inhibitor ipilimumabMetastases-free survival ratesDevelopment of brain metastasesCheckpoint inhibitor ipilimumabMetastases-free survivalUnresectable metastatic melanomaV600-mutant melanomaCheckpoint inhibitorsInhibitor ipilimumabMetastatic melanomaBRAF/MEK inhibitionArm CReviewed patientsBRAF/MEKThree-arm trialEncorafenibFollow-upMHC class I and II-deficient humanized mice are suitable tools to test the long-term antitumor efficacy of immune checkpoint inhibitors and T-cell engagers
Eguren-Santamaria I, de Piérola E, Camps G, Martín-Muñoz P, Campos M, Cuculescu D, Aguilera-Buenosvinos I, López I, Salido-Vallejo R, Alexandru R, De Andrea C, Álvarez-Gigli L, Berraondo P, Melero I, Sanmamed M. MHC class I and II-deficient humanized mice are suitable tools to test the long-term antitumor efficacy of immune checkpoint inhibitors and T-cell engagers. Journal For ImmunoTherapy Of Cancer 2024, 12: e008516. PMID: 39244214, PMCID: PMC11381650, DOI: 10.1136/jitc-2023-008516.Peer-Reviewed Original ResearchConceptsPeripheral blood mononuclear cellsHuman peripheral blood mononuclear cellsT-cell engagersNSG miceMajor histocompatibility complexSevere XGVHDImmunodeficient miceAntitumor effectTumor rejectionImmunotherapy agentsAntitumor activityAntitumor efficacy of immune checkpoint inhibitorsEfficacy of immune checkpoint inhibitorsHT29 human colon carcinoma cellsLong-term antitumor efficacyDevelopment of cancer immunotherapyAdministration of nivolumabImmune checkpoint inhibitorsCancer immunotherapy agentsT cell clonesHuman colon carcinoma cellsAlanine aminotransferase levelsMajor histocompatibility complex class IBlood mononuclear cellsHuman immune cellsThyroid dysfunction caused by immune checkpoint inhibitors improves cancer outcomes.
García-Goñi M, Vázquez Gutiérrez B, Sanmamed M, Martín-Algarra S, Luis Pérez-Gracia J, Olmedo M, Chumbiauca E, Martín-Calvo N, Galofré J. Thyroid dysfunction caused by immune checkpoint inhibitors improves cancer outcomes. Endocrine Related Cancer 2024, 31 PMID: 39013402, DOI: 10.1530/erc-24-0064.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsImmune-related adverse eventsRisk of progressionOverall survivalPrimary tumorThyroid dysfunctionPatients treated with immune checkpoint inhibitorsCancer patients treated with immune checkpoint inhibitorsAssociated with higher ORRImmune checkpoint inhibitor regimenTreated with atezolizumabLonger overall survivalCox proportional hazards modelsResponse to treatmentProbability of recurrenceMultivariable-adjusted regressionRisk of mortalityProportional hazards modelIndependent of ageCheckpoint inhibitorsRECIST v1.1Higher ORRCombination therapyUrothelial cancerClinical presentationShort-term cultured tumor fragments to study immunotherapy combinations based on CD137 (4-1BB) agonism
Eguren-Santamaría I, Rodríguez I, Herrero-Martin C, de Piérola E, Azpilikueta A, Sánchez-Gregorio S, Bolaños E, Gomis G, Molero-Glez P, Chacón E, Mínguez J, Chiva S, Diez-Caballero F, de Andrea C, Teijeira Á, Sanmamed M, Melero I. Short-term cultured tumor fragments to study immunotherapy combinations based on CD137 (4-1BB) agonism. OncoImmunology 2024, 13: 2373519. PMID: 38988823, PMCID: PMC11236292, DOI: 10.1080/2162402x.2024.2373519.Peer-Reviewed Original ResearchConceptsTumor fragmentsImmunotherapy combinationsIFNg productionActivation markersClinical response to PD-1 blockadeResponse to PD-1 blockadeAgonistic anti-CD137 mAbAnti-PD-1 treatmentAnti-CD137 mAbAnti-PD-1PD-1 blockadeSyngeneic immunocompetent miceInfiltrating T cellsShort-term cultureUnmet medical needAnti-CD137Contralateral tumorsBilateral tumorsCancer immunotherapyTissue culture supernatantsImmunocompetent miceSolid malignanciesT cellsMAb combinationsMouse tumorsUp-regulated PLA2G10 in cancer impairs T cell infiltration to dampen immunity
Zhang T, Yu W, Cheng X, Yeung J, Ahumada V, Norris P, Pearson M, Yang X, van Deursen W, Halcovich C, Nassar A, Vesely M, Zhang Y, Zhang J, Ji L, Flies D, Liu L, Langermann S, LaRochelle W, Humphrey R, Zhao D, Zhang Q, Zhang J, Gu R, Schalper K, Sanmamed M, Chen L. Up-regulated PLA2G10 in cancer impairs T cell infiltration to dampen immunity. Science Immunology 2024, 9: eadh2334. PMID: 38669316, DOI: 10.1126/sciimmunol.adh2334.Peer-Reviewed Original ResearchConceptsT cell infiltrationT cell exclusionT cellsResistance to anti-PD-1 immunotherapyPoor T-cell infiltrationAnti-PD-1 immunotherapyImmunogenic mouse tumorsT cell mobilizationHuman cancer tissuesTherapeutic immunotherapyCancer immunotherapyMouse tumorsChemokine systemImmunotherapyTumor tissuesImpaired infiltrationTumorLipid metabolitesHuman cancersCancer tissuesInfiltrationA2 groupCancerPLA2G10Up-regulatedSequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial
Ascierto P, Casula M, Bulgarelli J, Pisano M, Piccinini C, Piccin L, Cossu A, Mandalà M, Ferrucci P, Guidoboni M, Rutkowski P, Ferraresi V, Arance A, Guida M, Maiello E, Gogas H, Richtig E, Fierro M, Lebbe C, Helgadottir H, Queirolo P, Spagnolo F, Tucci M, Del Vecchio M, Cao M, Minisini A, De Placido S, Sanmamed M, Mallardo D, Paone M, Vitale M, Melero I, Grimaldi A, Giannarelli D, Dummer R, Sileni V, Palmieri G. Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial. Nature Communications 2024, 15: 146. PMID: 38167503, PMCID: PMC10761671, DOI: 10.1038/s41467-023-44475-6.Peer-Reviewed Original ResearchConceptsOverall survivalSurvival outcomesNoncomparative phase II trialTotal progression-free survivalLong-term survival outcomesMEK inhibitionBRAF/MEK inhibitionFirst-line treatment approachFirst-line treatment optionBRAF/MEK inhibitorsT-lymphocyte antigen-4Cell death protein 1BRAFV600-mutant melanomaDual checkpoint blockadeFirst-line immunotherapyMetastatic BRAF V600Serum interferon gammaPhase II trialProgression-free survivalDeath protein 1BRAFV600-mutant metastatic melanomaLow baseline levelsBiomarker analysisCombination BRAFSequential immunotherapy