肿瘤学概论恶性肿瘤的生物治疗与靶向治疗.ppt

* WHO announced in 1979 宣布人类消灭了天花，我们也期待着有朝一日宣布人类克服了癌症 ? 1995年 — AllisonKrummel:体外实验发现阻断CTLA-4可以增 强T细胞效应? 1996年 — 临床前研究抗CTLA-4抗体导致鼠模型的肿瘤消退 ? 1999年 — Medarex公司Ipilimumab单抗的研发成功 ? 2002年 — I期研究数据公布? 2008年 — 抗CTLA-4的I/ II期数据在ASCO公布? 2010年 — III期注册研究结果发表,MDX010-20? 2011年 — III期研究结果发表,CA184-024;同年Ipilimumab 被美国和欧洲批准为治疗不可切除或转移性黑色素瘤? 2011 — 正在进行的研究:其他肿瘤的联合治疗和辅助治疗 ? 1990s ― 日本生物学家发现PD-1? 2006年 ― 科学家Drew Pardoll开始抗PD-1的早期试验:入组39 例患者涵盖5个癌种? 2008年 ― 5例患者肿瘤缩小,生存时间超过预期,受到医学 界关注? 2012年 — NivolumabI/II期数据在新英格兰杂志发表? 2014年 — Nivolumab和MK3475被FDA批准治疗晚期黑色素瘤? 2015年 — Nivolumab被FDA批准治疗晚期鳞状NSCLC, CHECKMATE017 * Understanding the events in generating and regulating anti-tumor immunity suggests at least three sites for therapeutic intervention: promoting the antigen presentation functions of DCs, promoting the production of protective T cell responses, and overcoming immunosuppression in the tumor bed. Anti-tumor immune responses must begin with the capture of tumor-associated antigens by DCs, either delivered exogenously or captured from dead or dying tumor cells. The DCs process the captured antigen for presentation or cross- presentation on MHC class II and class I molecules (respectively) and migrate to draining lymph nodes. If capture and presentation occurred in the presence of an immunogenic maturation stimulus, DCs will elicit anti-cancer effector T cell responses in the lymph node; if no such stimulus was received, DCs will instead induce tolerance leading to T cell deletion, anergy, or the production of Tregs. In the lymph node, antigen presentation to T cells will elicit responses depending on the type of DC maturation stimulus received and on the interaction of T-cell costimulatory molecules with their surface receptors on DCs. Thus, interaction of CD28 or OX40 with CD80/86 or OX40L will promote potentially protective T cell responses, while interaction of CTLA4 with CD80/86 or PD-1 with PD-L1/PD-L2 will suppress T cell responses, and possibly promote Treg formatio