肾癌信号通路及免疫治疗进展.pptx

肾癌信号通路及免疫治疗进展调控肿瘤血管生成的信号通路VHL-HIF-VEGFPI3K-Akt-mTORVHL-HIF-VEGFCampbell-Walsh Urology 10th edSantoni M et al. Int J Cancer. (2014)Buczek M et al. Biochim Biophys Acta. (2014) PI3K-Akt-mTORAlbiges L et al. Oncologist. (2012)Dienstmann R et al. Mol Cancer Ther. (2014)How can we manage resistanceAdjusting dosecombination therapySwitch to another targeted therapyDevelopment of novel agents targetingHouk BE et al. Cancer Chemother Pharmacol. (2010) 肾癌的免疫治疗IFNIL-2VaccineSantoni M et al. Int J Cancer. (2014)Checkpoint inhibitorKyi C, et al. FEBS Lett. (2014)CTLA-4与PD-1区别CTLA4PD-1T细胞表达时间抗原接触后48h抗原长期接触后产生配体表达由抗原提呈细胞表达CD80 (B7.1)/CD80 (B7.2) 肿瘤或炎性组织表达PD-L1 (B7-H1) 抗原提成细胞表达PD-L2 (B7-DC) 小鼠相关基因敲除由于自身免疫反应导致迅速死亡由于自身免疫反应导致慢性死亡阻断后反应抗肿瘤T细胞特异性弱抗肿瘤T细胞特异性强PD-1/PD-L1 blockade in RCCPD-1Thompson RH, et al. Clin Cancer Res. (2007) Thompson RH, et al. Clin Cancer Res. (2007) PD-L1Thompson RH, et al. Cancer Res. (2006)Jilaveanu LB et al. J Cancer. (2014)primary end point : comparison of PFS to assess whether a dose-response relationship exists. Secondary end points : PFS, objective response rate (ORR), time to response, duration of response, overall survival (OS), and AE rate.Tripathi A, et al. BioDrugs. (2014)Philips GK, et al. Int Immunol. (2014)Cancer ImmunotherapyAscierto PA, et al. J Transl Med. (2014)谢 谢！Tumor antigen recognition by T-cells is dependent on T-cell receptor (TCR) recognition of a peptide ligand major histocompatibility complex (MHC). Following TCR engagement, T-cell activation and acquisition of effector functions requires costimulatory signals mediated by CD28 binding to a B7 family molecule (B7.1 or B7.2) on the antigen-presenting cell (APC). Activation-induced upregulation of inhibitory receptors, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), and others then acts to downmodulate T-cell effector functions when engaged with cognate ligands. CTLA-4 competes with CD28 for binding to B7 molecules expressed on APCs, an interactio