細胞因子誘導的殺傷細胞

細胞因子誘導的殺傷細胞Cytokine-induced killer cells, CIK),又稱細胞因子激活殺傷細胞,是一組T細胞-自然殺傷細胞NK)樣表型的適應免疫細胞混合體。醫生通過向外周血單核細胞臍帶血單核細胞中注入干擾素-γ抗CD3單株抗體、重組人體白血球介素1族2族等細胞因子誘導形成殺傷細胞。

通常情況下,免疫細胞通過識別呈遞在受感染細胞表面的主要組織相容性複合體MHC)而釋放細胞因子,引發細胞裂解英語细胞裂解細胞凋亡。然而,CIK細胞具備不受MHC分子限制的殺傷作用,能夠識別未能呈遞抗原或MHC的受感染細胞甚至惡性腫瘤細胞,並產生迅速及準確的免疫反應。而這些未能呈遞MHC的異常細胞不能被T細胞識別及清除[1][2][3]。這一特殊能力,使得終末分化的CD3+CD56+ CIK細胞能夠具備抗腫瘤細胞毒性,以對抗MHC限制性和非MHC限制性的癌症細胞的能力。該特徵也使得CIK細胞成為治療癌症病毒感染的潛在治療方法之一[4]

命名與歷史

「細胞因子誘導的殺傷細胞」的命名,來源於終末分化的CIK細胞成熟必須通過細胞因子刺激。一些資料稱其為「類似T細胞的自然殺傷細胞」,是因為其與自然殺傷細胞有密切關聯。也有人主張將CIK細胞視為自然殺傷細胞的子類[5]

1991年,英戈·G·H·施密特-沃爾夫醫生(G.H. Schmidt-Wolf)首次描述CIK細胞[1],並在1999年開始進行癌症臨床實驗[6]

機制

實驗證明淋巴細胞在暴露於干擾素-γ、抗CD3抗體、白血球介素-1和白血球介素-2後,能夠裂解新鮮的、非培養的癌症細胞(包括原發性和轉移性癌細胞)。CIK細胞對這些淋巴因子(特別是白血球介素-2)敏感,並能夠裂解那些對NK細胞或LAK細胞活動產生抗性的腫瘤細胞。

通過抽取外周血或臍帶血(比如簡單的抽血),醫師可以提取出外周血單核細胞臍帶血單核細胞。在一定時效期內,提取出來的細胞在體外暴露於干擾素-γ、抗CD3抗體、白血球介素-1和白血球介素-2中;這些細胞因子會強烈刺激CIK細胞的增殖和成熟[1][2][4][7]。之後,成熟的CIK細胞將被回輸給供體或其他異體。

功能

因為CIK細胞可以殺死自然殺傷細胞或LAK細胞無法裂解的細胞,所以具備獨特的功能。

CIK細胞同時具備T細胞NK細胞樣表型特徵,二者功能的獨特組合,產生強有力而又廣泛的不受MHC限制的抗腫瘤細胞毒性,具備廣譜抗腫瘤效果[2][4]。CIK細胞識別腫瘤的確切機制和其靶向殺傷作用尚不完全清楚。NK樣細胞除了通過TCR/CD3英語CD3 (immunology),還通過細胞間接觸依賴性的NKG2D英語NKG2DDNAM-1英語DNAM-1NKp30英語NKp30介導來識別腫瘤。這些受體和細胞表面標誌使CIK細胞能夠消滅不呈遞主要組織相容性複合體的細胞,這點可由CIK細胞能夠裂解非免疫原性、異基英語allogeneic同系英語syngeneic的腫瘤細胞證明。特別是實體腫瘤細胞和血液腫瘤細胞均呈遞NKG2D英語NKG2D配體,CIK細胞能夠裂解帶有該標記的癌細胞。此外CIK細胞能夠特異地識別腫瘤細胞和受病毒感染的細胞,而不對健康細胞做出反應[1][2][3][4]

免疫調節性T細胞會抑制CIK細胞的功能[8]

癌症治療的臨床試驗

CIK細胞與白血球介素-2聯合治療癌症療法,已經開始在小鼠和人體臨床實驗中進行,試驗顯示其毒性較低。

在大量的I期和II期臨床試驗中,自體和異體CIK細胞對不同腫瘤實體顯示出廣譜的高毒性潛力,且只有輕微副作用。在許多案例中,CIK細胞治療完全緩解腫瘤,延長患者生存時間並改善生活質量,甚至在癌症晚期也如此。CIK細胞治療的使用限制於臨床研究,但這種治療方法也可能在未來進入一線治療[9][10]

2011年,獨立機構國際CIK細胞臨床實驗目錄(International registry on CIK cells,縮寫IRCC)成立,該機構致力於收集使用CIK細胞的臨床試驗數據和後續分析,以描繪CIK細胞研究的最新狀況,其主要側重於評估CIK細胞治療在臨床試驗中的效果和副作用。[9][10]

發展及挑戰

CIK細胞治療仍處於臨床實驗階段[11][12]。在臨床實驗中,研究人員通過細胞因子基因技術(例如白血球介素-2),成功進行了體外細胞轉染。CIK細胞經過基因改造,增殖率和細胞毒性顯著增加[13]。1999年,基因轉染的CIK細胞首次用於已轉移的癌症治療,共有十例患者參加此次實驗[6]。開始有證據顯示,CIK細胞與樹突細胞相互作用,可以進一步提高抗腫瘤療效;而二者聯合培養更可減少調節性T細胞的數量,從而使CD3+CD56+細胞群體擴增[14][15]。在體外研究顯示,CIK細胞在對特定腫瘤抗原有特異性的嵌合抗原受體英語chimeric antigen receptor引導下,針對呈遞這種抗原的腫瘤細胞的選擇和激活能力有所增加[16][17]。體外實驗和體內實驗還表明,CIK細胞與雙特異性抗體英語bispecific antibodies(能同時與細胞毒性效應細胞和致病抗原結合的抗體)聯合,活性比單獨的CIK細胞要強[18][19]

然而,用於癌症治療的CIK細胞臨床實驗很有限[20][21]。最根本的問題在於,以這種方法培養的免疫細胞靶向性不強[22],CIK細胞無法躲過癌症的免疫抑制、預後效果有限[23];與此同時CAR-T(或聯合使用[24])在實驗中有更好的效果[25]。儘管對於CIK細胞及其治療方法在學術界存有爭議[26],但在中國一些民營醫院(莆田系)已經以高昂收費方式進行、部分省份已將未成熟的CIK治療納入醫保範圍,2016年4月爆發的魏則西事件更將CIK細胞及免疫治療推到風口浪尖[27]

相關條目

參考

  1. ^ 1.0 1.1 1.2 1.3 Schmidt-Wolf, IG; Negrin, RS; Kiem, HP; Blume, KG; Weissman, IL. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity.. The Journal of Experimental Medicine. 1 July 1991, 174 (1): 139–49. PMID 1711560. doi:10.1084/jem.174.1.139. 
  2. ^ 2.0 2.1 2.2 2.3 Schmidt-Wolf, IG; Lefterova, P; Mehta, BA; Fernandez, LP; Huhn, D; Blume, KG; Weissman, IL; Negrin, RS. Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells.. Experimental hematology. December 1993, 21 (13): 1673–9. PMID 7694868. 
  3. ^ 3.0 3.1 Lu, PH; Negrin, RS. A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency.. Journal of immunology (Baltimore, Md. : 1950). 15 August 1994, 153 (4): 1687–96. PMID 7519209. 
  4. ^ 4.0 4.1 4.2 4.3 Pievani, A; Borleri, G; Pende, D; Moretta, L; Rambaldi, A; Golay, J; Introna, M. Dual-functional capability of CD3+CD56+ CIK cells, a T-cell subset that acquires NK function and retains TCR-mediated specific cytotoxicity.. Blood. 22 September 2011, 118 (12): 3301–10. PMID 21821703. doi:10.1182/blood-2011-02-336321. 
  5. ^ Godfrey, DI; MacDonald, HR; Kronenberg, M; Smyth, MJ; Van Kaer, L. NKT cells: what's in a name?. Nature reviews. Immunology. March 2004, 4 (3): 231–7. PMID 15039760. doi:10.1038/nri1309. 
  6. ^ 6.0 6.1 Schmidt-Wolf, IG; Finke, S; Trojaneck, B; Denkena, A; Lefterova, P; Schwella, N; Heuft, HG; Prange, G; Korte, M; Takeya, M; Dorbic, T; Neubauer, A; Wittig, B; Huhn, D. Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-2 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma.. British Journal of Cancer. November 1999, 81 (6): 1009–16. PMID 10576658. doi:10.1038/sj.bjc.6690800. 
  7. ^ Introna, M; Pievani, A; Borleri, G; Capelli, C; Algarotti, A; Micò, C; Grassi, A; Oldani, E; Golay, J; Rambaldi, A. Feasibility and safety of adoptive immunotherapy with CIK cells after cord blood transplantation.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. November 2010, 16 (11): 1603–7. PMID 20685246. doi:10.1016/j.bbmt.2010.05.015. 
  8. ^ Li, H; Yu, JP; Cao, S; Wei, F; Zhang, P; An, XM; Huang, ZT; Ren, XB. CD4 +CD25 + regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients.. Journal of clinical immunology. May 2007, 27 (3): 317–26. PMID 17468835. doi:10.1007/s10875-007-9076-0. 
  9. ^ 9.0 9.1 Schmeel, LC; Schmeel, FC; Coch, C; Schmidt-Wolf, IG. Cytokine-induced killer (CIK) cells in cancer immunotherapy: report of the international registry on CIK cells (IRCC).. Journal of cancer research and clinical oncology. 8 November 2014, 141: 839–49. PMID 25381063. doi:10.1007/s00432-014-1864-3. 
  10. ^ 10.0 10.1 Hontscha, C; Borck, Y; Zhou, H; Messmer, D; Schmidt-Wolf, IG. Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC).. Journal of cancer research and clinical oncology. February 2011, 137 (2): 305–10. PMID 20407789. doi:10.1007/s00432-010-0887-7. 
  11. ^ No proof for alleged health benefits of DC-CIK. South China Morning Post Publishers Ltd. 2012-10-23 [2016-05-02]. (原始內容存檔於2016-04-26) (英語). 
  12. ^ Linn Yeh-Ching; Yong Hao-Xiang; Niam M; Lim TJ; Chu S; Choong A; Chuah C; Goh YT; Hwang W; Loh Y; Ng HJ; Suck G; Chan M; Koh M. A phase I/II clinical trial of autologous cytokine-induced killer cells as adjuvant immunotherapy for acute and chronic myeloid leukemia in clinical remission. Cytotherapy. 2012-08, 14 (7): 851–859. doi:10.3109/14653249.2012.694419 (英語). 
  13. ^ Jäkel, Clara E; Schmidt-Wolf, Ingo GH. An update on new adoptive immunotherapy strategies for solid tumors with cytokine-induced killer cells. Expert Opinion on Biological Therapy. July 2014, 14 (7): 905–916. doi:10.1517/14712598.2014.900537. 
  14. ^ Märten, A; Ziske, C; Schöttker, B; Renoth, S; Weineck, S; Buttgereit, P; Schakowski, F; von Rücker, A; Sauerbruch, T; Schmidt-Wolf, IG. Interactions between dendritic cells and cytokine-induced killer cells lead to an activation of both populations.. Journal of immunotherapy (Hagerstown, Md. : 1997). 2000, 24 (6): 502–10. PMID 11759073. doi:10.1097/00002371-200111000-00007. 
  15. ^ Schmidt, J; Eisold, S; Büchler, MW; Märten, A. Dendritic cells reduce number and function of CD4+CD25+ cells in cytokine-induced killer cells derived from patients with pancreatic carcinoma.. Cancer immunology, immunotherapy : CII. November 2004, 53 (11): 1018–26. PMID 15185013. doi:10.1007/s00262-004-0554-4. 
  16. ^ Hombach, AA; Rappl, G; Abken, H. Arming cytokine-induced killer cells with chimeric antigen receptors: CD28 outperforms combined CD28-OX40 "super-stimulation".. Molecular therapy : the journal of the American Society of Gene Therapy. December 2013, 21 (12): 2268–77. PMID 23985696. doi:10.1038/mt.2013.192. 
  17. ^ Tettamanti, Sarah; Marin, Virna; Pizzitola, Irene; Magnani, Chiara F.; Giordano Attianese, Greta M. P.; Cribioli, Elisabetta; Maltese, Francesca; Galimberti, Stefania; Lopez, Angel F.; Biondi, Andrea; Bonnet, Dominique; Biagi, Ettore. Targeting of acute myeloid leukaemia by cytokine-induced killer cells redirected with a novel CD123-specific chimeric antigen receptor. British Journal of Haematology. May 2013, 161 (3): 389–401. doi:10.1111/bjh.12282. 
  18. ^ Chan, JK; Hamilton, CA; Cheung, MK; Karimi, M; Baker, J; Gall, JM; Schulz, S; Thorne, SH; Teng, NN; Contag, CH; Lum, LG; Negrin, RS. Enhanced killing of primary ovarian cancer by retargeting autologous cytokine-induced killer cells with bispecific antibodies: a preclinical study.. Clinical cancer research : an official journal of the American Association for Cancer Research. 15 March 2006, 12 (6): 1859–67. PMID 16551871. doi:10.1158/1078-0432.ccr-05-2019. 
  19. ^ Tita-Nwa, F; Moldenhauer, G; Herbst, M; Kleist, C; Ho, AD; Kornacker, M. Cytokine-induced killer cells targeted by the novel bispecific antibody CD19xCD5 (HD37xT5.16) efficiently lyse B-lymphoma cells.. Cancer immunology, immunotherapy : CII. December 2007, 56 (12): 1911–20. PMID 17487487. doi:10.1007/s00262-007-0333-0. 
  20. ^ 肿瘤免疫疗法“中外有别” 行业标准亟待完善. 搜狐網. 2015-07-09 [2016-05-02]. (原始內容存檔於2016-05-02). 
  21. ^ Stuart H. Orkin, David E. Fisher, A. Thomas Look, Samuel Lux IV, David Ginsburg, David G. Nathan Elsevier Health Sciences. Oncology of Infancy and Childhood , 編. Oncology of infancy and childhood. Philadelphia: Saunders Elsevier. 2009: 228. ISBN 9781437721386. 
  22. ^ Zhong R; Teng J, Han B, Zhong H. Dendritic cells combining with cytokine-induced killer cells synergize chemotherapy in patients with late-stage non-small cell lung cancer.. Cancer Immunol Immunother. 2011-10, 60 (10): 1497–1502 [2016-05-02]. doi:10.1007/s00262-011-1060-0. (原始內容存檔於2016-09-20) (英語). 
  23. ^ Shi SB1; Ma TH, Li CH, Tang XY. Effect of maintenance therapy with dendritic cells: cytokine-induced killer cells in patients with advanced non-small cell lung cancer.. Tumori. 2012-05-06, 98 (3): 314–319. doi:10.1700/1125.12398 (英語). 
  24. ^ Hombach, Andreas A.; Rappl, Gunter; Abken, Hinrich; Gunter Rappl, Hinrich Abken. Arming cytokine induced killer cells with chimeric antigen receptors (CARs): CD28 outperforms combined CD28-OX40 "super-stimulation". Molecular Therapy. 2013-08-28 [2016-05-04]. doi:10.1038/mt.2013.192. (原始內容存檔於2014-07-19). 
  25. ^ 魏则西治疗的疑团 监管缺位背后的疗法之争. 新京報. 2016年5月4日 [2016-05-04]. (原始內容存檔於2016-05-06). 
  26. ^ 王文浩; 李貴新, 劉錦. CIK 细胞在肿瘤过继细胞治疗中的疗效评价 (PDF). 國際腫瘤學雜誌. 2013, (40.002): 106–108 [2016-05-04]. (原始內容存檔 (PDF)於2016-08-04). 
  27. ^ 羅朝淑. 滥用之殇:肿瘤免疫治疗救不了魏则西. 科技日報. [2016-05-04]. (原始內容存檔於2016-06-02). 

外部連結