Decoy-resistant IL-18 reshapes the tumor microenvironment and enhances rejection by anti-CTLA-4 in renal cell carcinoma
Schoenfeld D, Djureinovic D, Su D, Zhang L, Lu B, Kamga L, Mann J, Huck J, Hurwitz M, Braun D, Jilaveanu L, Ring A, Kluger H. Decoy-resistant IL-18 reshapes the tumor microenvironment and enhances rejection by anti-CTLA-4 in renal cell carcinoma. JCI Insight 2024 PMID: 39561007, DOI: 10.1172/jci.insight.184545.Peer-Reviewed Original ResearchAnti-CTLA-4Renal cell carcinomaIL-18IL-18BPCell carcinomaTumor microenvironmentTumor typesPatients treated with immune checkpoint inhibitorsRegulatory T cell levelsAnti-PD-1 treatmentCD8+ T cellsAnti-PD-1Immune checkpoint inhibitorsCell renal cell carcinomaNon-responder patientsMyeloid cell populationsT cell levelsCytokine interleukin-18Anti-cancer efficacySecreted binding proteinCheckpoint inhibitorsResponding patientsPreclinical modelsT cellsMurine model662 A phase1 study of autologous engineered CD4+ and CD8+ T cells, HLA-A*11:01-restricted, KRAS G12V-specific, transgenic TCR; CD8α/β coreceptor and a FAS41BB switch receptor in patients with solid tumors
Mitchell S, Khan B, Payumo F, Gabriela Chiorean E, Gahvari Z, Randolph Hecht J, Hurwitz M, Leidner R, Lenz H, Pelster M, Schoenfeld A, Punekar S, Zhao D, Basu S, Nagorsen D. 662 A phase1 study of autologous engineered CD4+ and CD8+ T cells, HLA-A*11:01-restricted, KRAS G12V-specific, transgenic TCR; CD8α/β coreceptor and a FAS41BB switch receptor in patients with solid tumors. 2024, a759-a759. DOI: 10.1136/jitc-2024-sitc2024.0662.Peer-Reviewed Original ResearchAFNT-211: A phase 1 study of autologous CD4+ and CD8+ T cells engineered to express a high avidity HLA-A*11:01-restricted, KRAS G12V-specific, transgenic TCR, a CD8α/β coreceptor, and a FAS41BB switch receptor in patients with advanced/metastatic solid tumors.
Mitchell S, Khan B, Payumo F, Chiorean E, Gahvari Z, Hecht J, Hurwitz M, Leidner R, Lenz H, Pelster M, Punekar S, Schoenfeld A, Zhao D, Vallaster M, Nagorsen D. AFNT-211: A phase 1 study of autologous CD4+ and CD8+ T cells engineered to express a high avidity HLA-A*11:01-restricted, KRAS G12V-specific, transgenic TCR, a CD8α/β coreceptor, and a FAS41BB switch receptor in patients with advanced/metastatic solid tumors. Journal Of Clinical Oncology 2024, 42: tps8650-tps8650. DOI: 10.1200/jco.2024.42.16_suppl.tps8650.Peer-Reviewed Original ResearchOptimal biological doseCD8+ T cellsAutologous CD4+Advanced/metastatic solid tumorsT cellsSolid tumorsSwitch receptorsDose expansionDose escalationCD4+Transgenic TCRMechanism of actionDose-limiting toxicity observation periodRecommended phase 2 doseT cell cytotoxic activityIncreased T cell activationCD4+ T cellsHelper T cell responsesPreventing T cell exhaustionPost-treatment follow-up periodChimeric switch receptorsPhase 2 doseImmunosuppressive tumor microenvironmentT cell exhaustionDuration of responseSLAMF7+ CD8+ T cells exhibit decreased anti-tumor responses in renal cell carcinoma
Wirth L, Hugaboom M, Street K, Ruthen N, Jegede O, Schindler N, McDermott D, Plimack E, Sosman J, Haas N, Hurwitz M, Hammers H, Signoretti S, Atkins M, Wu C, Braun D. SLAMF7+ CD8+ T cells exhibit decreased anti-tumor responses in renal cell carcinoma. The Journal Of Immunology 2024, 212: 1491_5876-1491_5876. DOI: 10.4049/jimmunol.212.supp.1491.5876.Peer-Reviewed Original ResearchCD8+ T cellsImmune-checkpoint inhibitorsRenal cell carcinomaCD8+ T-cell effector functionT cell effector functionT cellsCell carcinomaResistance to immune-checkpoint inhibitorsEffector functionsPopulation of CD8+ T cellsCD3+ T cellsTreatment of renal cell carcinomaHealthy human PBMCTumor-infiltrating lymphocytesAnti-tumor responsesPatient T cellsReduction of pro-inflammatory cytokinesAnti-tumor functionPro-inflammatory cytokinesSingle-cell transcriptome analysisNivolumab monotherapySLAMF7 expressionClinical benefitGranzyme BIFN-g