2022
Germline variants associated with toxicity to immune checkpoint blockade
Groha S, Alaiwi S, Xu W, Naranbhai V, Nassar A, Bakouny Z, El Zarif T, Saliby R, Wan G, Rajeh A, Adib E, Nuzzo P, Schmidt A, Labaki C, Ricciuti B, Alessi J, Braun D, Shukla S, Keenan T, Van Allen E, Awad M, Manos M, Rahma O, Zubiri L, Villani A, Fairfax B, Hammer C, Khan Z, Reynolds K, Semenov Y, Schrag D, Kehl K, Freedman M, Choueiri T, Gusev A. Germline variants associated with toxicity to immune checkpoint blockade. Nature Medicine 2022, 28: 2584-2591. PMID: 36526723, PMCID: PMC10958775, DOI: 10.1038/s41591-022-02094-6.Peer-Reviewed Original ResearchConceptsImmune-related adverse eventsImmune checkpoint inhibitorsGrade immune-related adverse eventsGermline variantsICI initiationCheckpoint inhibitorsAdverse eventsCheckpoint blockadeImproved survivalDiscovery cohortLymphocyte homeostasisSignificant associationCancer typesIL7Remarkable responsePatientsCritical regulatorGenome-wide significant associationAssociationWide association studyIndependent studiesAssociation studiesBlockadeCohortVariants
2020
Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma
Braun DA, Hou Y, Bakouny Z, Ficial M, Sant’ Angelo M, Forman J, Ross-Macdonald P, Berger AC, Jegede OA, Elagina L, Steinharter J, Sun M, Wind-Rotolo M, Pignon JC, Cherniack AD, Lichtenstein L, Neuberg D, Catalano P, Freeman GJ, Sharpe AH, McDermott DF, Van Allen EM, Signoretti S, Wu CJ, Shukla SA, Choueiri TK. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nature Medicine 2020, 26: 909-918. PMID: 32472114, PMCID: PMC7499153, DOI: 10.1038/s41591-020-0839-y.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntigen PresentationAntineoplastic Agents, ImmunologicalCarcinoma, Renal CellCD8-Positive T-LymphocytesChromosome DeletionChromosomes, Human, Pair 6Chromosomes, Human, Pair 9Class I Phosphatidylinositol 3-KinasesDNA-Binding ProteinsExome SequencingFemaleFluorescent Antibody TechniqueGene DeletionGenomicsHistocompatibility Antigens Class IIHistone DemethylasesHistone-Lysine N-MethyltransferaseHumansKidney NeoplasmsLymphocytes, Tumor-InfiltratingMaleMiddle AgedMutationNivolumabPrognosisProteasome Endopeptidase ComplexPTEN PhosphohydrolaseSequence Analysis, RNATOR Serine-Threonine KinasesTranscription FactorsTuberous Sclerosis Complex 1 ProteinTumor Suppressor ProteinsUbiquitin ThiolesteraseVon Hippel-Lindau Tumor Suppressor ProteinConceptsAdvanced clear cell renal cell carcinomaClear cell renal cell carcinomaPD-1 blockadeCell renal cell carcinomaRenal cell carcinomaCell carcinomaDegree of CD8Numerous chromosomal alterationsProspective clinical trialsSomatic alterationsInfiltrated tumorsClinical responseCell infiltrationTherapeutic responseClinical trialsTherapeutic efficacyBlockadeCcRCC tumorsTumorsPBRM1 mutationsModulates responseCD8Chromosomal alterationsImmunofluorescence analysisCarcinoma
2016
Genomic Approaches to Understanding Response and Resistance to Immunotherapy
Braun D, Burke K, Van Allen E. Genomic Approaches to Understanding Response and Resistance to Immunotherapy. Clinical Cancer Research 2016, 22: 5642-5650. PMID: 27698000, PMCID: PMC5135569, DOI: 10.1158/1078-0432.ccr-16-0066.Peer-Reviewed Original ResearchConceptsSubset of patientsCheckpoint blockadeSuch therapyImmune checkpoint blockadeImmune-based therapiesNumber of patientsLow intratumoral heterogeneityDurable responsesImmune checkpointsAdvanced cancerLoss of PTENNeoantigen loadPoint of careCertain patientsMechanisms of resistanceResistant tumorsPatientsTherapyTumor progressionImmunotherapyAppropriate functional studiesIntratumoral heterogeneityLimited responseBlockadePositive correlates