医学免疫学课件：PD-1信号通路在肿瘤免疫逃逸及其治疗中的作用

1、PD-1信号通路在肿瘤免疫逃逸及其治疗中的作用Introduction /health/2015/08/24/jimmy-carter-gets-new-melanoma-treatment-here-how-it-works.htmlBackground Immune Surveillance against Cancer/ni/journal/v3/n11/fig_tab/ni1102-991_F2.htmlBackground Tumor Immunity EscapeEscape from recognition Block the activationlead to anergyRe

2、leasing inhibitory cytokineUpregulate checkpoint moleculeIMMUNE CHECKPOINTPD1 (programmed cell death 1)Highly present on activated T cells, B cells and DC.ITIM (immunoreceptor tyrosine-based inhibitory motif) and ITSM (immunoreceptor tyrosine-based switch motif) Akt unactivated/news/10/119959.htmIMM

3、UNE CHECKPOINTPDL-1 (programmed cell death ligand-1)Expressed on various kind of cellsCo-inhibitory factorPDL-2not well studiedChen, L. and X. Han(2015). AntiPD-1/PD-L1 therapy of human cancer: past, present, and future. Journal of Clinical Investigation 125(9): 3384-3391.IMMUNE CHECKPOINTImmunosupp

4、ression in Cancer MicroenvironmentPDL-1 highly expressed on the surface of tumor tissue cellsVarious of mechanismsChen, L. and X. Han(2015). AntiPD-1/PD-L1 therapy of human cancer: past, present, and future. Journal of Clinical Investigation 125(9): 3384-3391.IMMUNE CHECKPOINTHuman Adaptive Resistan

5、ce ModelChen, L. and X. Han(2015). AntiPD-1/PD-L1 therapy of human cancer: past, present, and future. Journal of Clinical Investigation 125(9): 3384-3391.CLINICAL THERAPYAnti-PD1/anti-PDL1 mAb/contents/zh-Hans/image?imageKey=ONC%2F90357&topicKey=ONC%2F90312&source=see_linkCLINICAL THERAPYAnti-PD1 mA

6、b通用名：Nivolumab商品名：Opdivo适应症：肺癌、黑色素瘤、肾癌/metastatic-nsclc#CLINICAL THERAPYAnti-PD1 mAb通用名：Nivolumab商品名：Opdivo适应症：肺癌、黑色素瘤、肾癌通用名：Pembrolizumab商品名：Keytruda适应症：肺癌、黑色素瘤、头颈部鳞状细胞癌CLINICAL THERAPYAnti-PDL1 mAbPatients are subgrouped into IC0, IC1, IC2, IC3 according to the PDL1 expression on the tumor cell su

7、rfaceRittmeyer, A. and F. Barlesi, et al. (2016). Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. The Lancet.CURRENT PROBLEMAdverse eventPneumonitis ColitisRash, fatigue, muscle pain,

8、etcEfficacyRelapse after initial regression Mutation on interferon-receptorassociated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2) and antigen-presenting protein beta-2-microglobulin (B2M)FUTUREHoos, A.(2016). Development of immuno-oncology drugs - from CTLA4 to PD1 to the next generations. Nat Re

9、v Drug Discov 15(4): 235-47.ACKNOWLEDGEMENTNaidoo, J. and D. B. Page, et al. (2015). Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Annals of Oncology: mdv383.Pardoll, D. M.(2012). The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer 12(4): 252-

10、264.Ribas, A. and O. Hamid, et al. (2016). Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. JAMA 315(15): 1600.Rittmeyer, A. and F. Barlesi, et al. (2016). Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer

11、 (OAK): a phase 3, open-label, multicentre randomised controlled trial. The Lancet.Swaika, A. and W. A. Hammond, et al. (2015). Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy. Molecular Immunology 67(2): 4-17.Tumeh, P. C. and C. L. Harview, et al. (2014). PD-1 blockade induces re

12、sponses by inhibiting adaptive immune resistance. Nature 515(7528): 568-571.Zaretsky, J. M. and A. Garcia-Diaz, et al. (2016). Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. N Engl J Med 375(9): 819-29.Balar, A. V. and M. D. Galsky, et al. (2016). Atezolizumab as first-l

13、ine treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. The Lancet.Blank, C. and A. Mackensen(2007). Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infectio

14、ns and tumor evasion. Cancer Immunology, Immunotherapy 56(5): 739-745.Brahmer, J. and K. L. Reckamp, et al. (2015). Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 373(2): 123-35.Chen, L. and X. Han(2015). AntiPD-1/PD-L1 therapy of human cancer: past, pr

15、esent, and future. Journal of Clinical Investigation 125(9): 3384-3391.Folkl, A. and D. Bienzle(2010). Structure and function of programmed death (PD) molecules. Veterinary Immunology and Immunopathology 134(1-2): 33-38.Gandini, S. and D. Massi, et al. (2016). PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: A systematic review and meta-analysis. Critical Reviews in Oncology/Hematology 100: 88-98.Hoos, A.(2016). Development of immuno-oncology drugs - from CTLA4 to PD1 to the next generations. Nat Rev Drug Discov 15(4): 235-47.李浩 与 徐迎新等(2016). PD-1/PD-L1信号