癌癥免疫檢查點療法的現(xiàn)在和未來 研究人員初步證明了阻斷CTLA-4和PD-1的效果后,臨床治療效果非常顯著。這種療法目前被我們普遍熟知的說法是 “免疫檢查點療法”(immune checkpoint therapy),這種療法從根本上改變了尤其是癌癥晚期患者的治療結(jié)果。
不過,和其它癌癥療法類似,免疫檢查點療法也會產(chǎn)生嚴(yán)重的副作用,甚至?xí)<盎颊呱_@主要源于過度免疫反應(yīng)誘發(fā)了自身免疫反應(yīng),不過這點通常是可以控制的。目前,研究人員正在深入研究以闡明該療法的分子機制,他們希望未來能夠改善該療法,從而能夠減小副作用。 在上述兩種療法中,PD-1檢查點療法被認(rèn)為更優(yōu),在多種類型癌癥的治療過程中能夠有效發(fā)揮作用,包括肺癌、腎癌、淋巴瘤和黑色素瘤等。最新的臨床研究結(jié)果則顯示,同時靶向作用CTLA-4和PD-1的聯(lián)合療法或許能夠更加有效地治療黑色素瘤患者。 因此,艾利森和本庶佑希望能夠?qū)⒉煌寞煼ńY(jié)合來解除免疫系統(tǒng)的抑制,從而更加有效地消除腫瘤。目前研究人員正在對多種類型癌癥進行大量的檢查點療法,新的檢查點蛋白也正在作為靶點進行測試。 100多年以來,科學(xué)家們一直希望能夠通過改進患者自身的機體免疫系統(tǒng)來抵御癌癥。在這兩位諾貝爾獎獲獎?wù)呷〉弥卮蟀l(fā)現(xiàn)之前,癌癥臨床研究所取得的進展并不顯著,如今,檢查點療法帶來了徹底治愈癌癥的曙光,同時也從根本上改變了我們看待癌癥和管理癌癥的模式。 Ishida, Y., Agata, Y., Shibahara, K., & Honjo, T. (1992). Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J., 11(11), 3887–3895. Leach, D. R., Krummel, M. F., & Allison, J. P. (1996). Enhancement of antitumor immunity by CTLA-4 blockade. Science, 271(5256), 1734–1736. Kwon, E. D., Hurwitz, A. A., Foster, B. A., Madias, C., Feldhaus, A. L., Greenberg, N. M., Burg, M.B. & Allison, J.P. (1997). Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer. Proc Natl Acad Sci USA, 94(15), 8099–8103. Nishimura, H., Nose, M., Hiai, H., Minato, N., & Honjo, T. (1999). Development of Lupus-like Autoimmune Diseases by Disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity, 11, 141–151. Freeman, G.J., Long, A.J., Iwai, Y., Bourque, K., Chernova, T., Nishimura, H., Fitz, L.J., Malenkovich, N., Okazaki, T., Byrne, M.C., Horton, H.F., Fouser, L., Carter, L., Ling, V., Bowman, M.R., Carreno, B.M., Collins, M., Wood, C.R. & Honjo, T. (2000). Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med, 192(7), 1027– 1034. Hodi, F.S., Mihm, M.C., Soiffer, R.J., Haluska, F.G., Butler, M., Seiden, M.V., Davis, T., Henry-Spires, R., MacRae, S., Willman, A., Padera, R., Jaklitsch, M.T., Shankar, S., Chen, T.C., Korman, A., Allison, J.P. & Dranoff, G. (2003). Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA, 100(8), 4712-4717. Iwai, Y., Terawaki, S., & Honjo, T. (2005). PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol, 17(2), 133–144. |
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