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肝癌肝移植术后复发转移的免疫治疗

刘少儒 许磊波

刘少儒, 许磊波. 肝癌肝移植术后复发转移的免疫治疗[J]. 器官移植, 2021, 12(3): 272-279. doi: 10.3969/j.issn.1674-7445.2021.03.004
引用本文: 刘少儒, 许磊波. 肝癌肝移植术后复发转移的免疫治疗[J]. 器官移植, 2021, 12(3): 272-279. doi: 10.3969/j.issn.1674-7445.2021.03.004
Liu Shaoru, Xu Leibo. Immunotherapy of recurrence and metastasis after liver transplantation for liver cancer[J]. ORGAN TRANSPLANTATION, 2021, 12(3): 272-279. doi: 10.3969/j.issn.1674-7445.2021.03.004
Citation: Liu Shaoru, Xu Leibo. Immunotherapy of recurrence and metastasis after liver transplantation for liver cancer[J]. ORGAN TRANSPLANTATION, 2021, 12(3): 272-279. doi: 10.3969/j.issn.1674-7445.2021.03.004

肝癌肝移植术后复发转移的免疫治疗

doi: 10.3969/j.issn.1674-7445.2021.03.004
基金项目: 

国家自然科学基金 81772597

详细信息
    作者简介:

    刘少儒,男,1996年生,硕士研究生,研究方向为肝移植,Email: liushr23@mail2.sysu.edu.cn

    许磊波,留德医学博士,中山大学孙逸仙纪念医院肝脏移植中心副主任医师、博士研究生导师、博士后合作导师;从事肝胆胰外科/肝脏移植工作十余年,曾在德国杜伊斯堡-埃森大学医院和德国明斯特大学医院留学两年。擅长肝胆胰外科常见疾患的外科治疗以及肝胆系统肿瘤的全程、系统综合治疗,尤其擅长各种终末期肝病及肝脏肿瘤的肝移植治疗和肝移植围手术期管理。兼任中国医药教育协会腹部肿瘤专业委员会循证医学组委员、中国研究型医院学会加速康复外科专业委员会肝脏移植加速康复学组委员、广东省医学会外科学分会青年委员、广东省医师协会外科医师分会委员、广东省医师协会器官移植医师分会委员。兼任《器官移植》《中华肝脏外科手术学电子杂志》通讯编委等职务。以第一作者或通信作者在《Journal of Hepatology》 《Annals of Surgery》等国际著名学术期刊上发表SCI论文13篇(单篇最高影响因子>20);主持包括2项国家自然科学基金在内的各类基金项目9项,入选广东省“杰出青年医学人才”、广州市“珠江科技新星”人才培养专项、中山大学“青年教师培育项目”和中山大学孙逸仙纪念医院“逸仙优秀青年医学人才”培养计划

    通讯作者:

    许磊波,Email: xuleibo3@mail.sysu.edu.cn

  • 中图分类号: R617, R735.7

Immunotherapy of recurrence and metastasis after liver transplantation for liver cancer

More Information
  • 摘要: 原发性肝癌(肝癌)是我国肝移植的主要适应证之一,但肝癌肝移植受者术后5年生存率不足50%,术后复发转移是影响受者长期生存的主要原因。目前,以程序性细胞死亡蛋白1(PD-1)/程序性细胞死亡蛋白配体1(PD-L1)免疫检查点抑制剂为代表的免疫治疗在中晚期肝癌治疗中取得显著疗效,但其在肝癌肝移植术后肿瘤复发转移受者中能否应用尚有较多争议,主要原因在于其在发挥作用的同时可能会引起急性排斥反应。本文总结了免疫治疗在肝癌肝移植术后复发转移受者中的应用进展,以期通过免疫治疗改善肝癌肝移植受者的生存率。

     

  • 表  1  肝癌肝移植术后复发转移受者免疫治疗的临床特征

    Table  1.   Clinical characteristics of immunotherapy for recipients with recurrence and metastasis after liver transplantationfor liver cancer

    研究者 受者年龄(岁) 性别 术后时间(年) 免疫抑制剂 免疫治疗 结局 排斥反应 生存时间(月)
    汪国营, 等[22] 48 1.0 Tac+西罗莫司 帕博利珠单抗 疾病进展 8.0
    Varkaris A, et al[23] 70 8.0 Tac 帕博利珠单抗 疾病进展 3.0
    Gassmann D, et al[24] 53 2.0 依维莫司+MMF 纳武单抗 器官衰竭 0.8
    Friend BD, et al[25] 14 3.0 Tac 纳武单抗 器官衰竭 2.0
    20 4.0 Tac 纳武单抗 器官衰竭 1.0
    Amjad W, et al[26] 62 1.3 Tac+MMF 纳武单抗 完全缓解 24.0
    Rammohan A, et al[27] 57 3.3 Tac+MMF+糖皮质激素 帕博利珠单抗 完全缓解 10.0
    De Toni EN, et al[28] 41 1.0 Tac 纳武单抗 分离反应后疾病进展 10.0
    DeLeon TT, et al[29] 56 2.7 Tac 纳武单抗 疾病进展 1.2
    55 7.8 Tac+MMF 纳武单抗 疾病进展 1.1
    34 3.7 Tac 纳武单抗 疾病进展 1.3
    63 1.2 Tac 纳武单抗 未知 0.3
    68 1.1 Tac 纳武单抗 未知 0.9
    注:①为文章投稿时受者仍在随访。
    下载: 导出CSV

    表  2  肝癌肝移植术后新发其他肿瘤受者免疫治疗的临床特征

    Table  2.   Clinical characteristics of immunotherapy for recipients with other de novo tumors after liver transplantationfor liver cancer

    研究者 受者年龄(岁) 性别 术后时间(年) 免疫抑制剂 免疫治疗 结局 排斥反应 生存时间(月)
    DeLeon TT, et al[29] 54 5.5 依维莫司+MMF 帕博利珠单抗 完全缓解 21.1
    Kuo JC, et al[30] 62 5.0 Tac+MMF 伊匹单抗+帕博利珠单抗 部分缓解 18.0
    Morales RE, et al[31] 67 10.0 西罗莫司 伊匹单抗 部分缓解 10.0
    注:①为文章投稿时受者仍在随访。
    下载: 导出CSV
  • [1] SIEGEL RL, MILLER KD, JEMAL A. Cancer statistics, 2019[J]. CA Cancer J Clin, 2019, 69(1): 7-34. DOI: 10.3322/caac.21551.
    [2] 中华人民共和国国家卫生健康委员会医政医管局. 原发性肝癌诊疗规范(2019年版)[J]. 临床肝胆病杂志, 2020, 36(2): 277-292. DOI: 10.3969/j.issn.1001-5256.2020.02.007.

    Medical Administration and Hospital Administration of the National Health Commission of the People's Republic of China. Guidelines for diagnosis and treatment of primary liver cancer in China (2019 edition) [J]. J Clin Hepatol, 2020, 36(2): 277-292. DOI: 10.3969/j.issn.1001-5256.2020.02.007.
    [3] EGGERMONT AMM, BLANK CU, MANDALA M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma[J]. N Engl J Med, 2018, 378(19): 1789-1801. DOI: 10.1056/NEJMoa1802357.
    [4] HELLMANN MD, CIULEANU TE, PLUZANSKI A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden[J]. N Engl J Med, 2018, 378(22): 2093-2104. DOI: 10.1056/NEJMoa1801946.
    [5] QIN S, REN Z, MENG Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial[J]. Lancet Oncol, 2020, 21(4): 571-580. DOI: 10.1016/S1470-2045(20)30011-5.
    [6] 中国医师协会器官移植医师分会, 中华医学会器官移植学分会. 中国肝癌肝移植临床实践指南(2018版)[J]. 临床肝胆病杂志, 2019, 35(2): 275-280. DOI: 10.3969/j.issn.1001-5256.2019.02.008.

    Branch of Organ Transplant Physicians of Chinese Medical Doctor Association, Branch of Organ Transplantation of Chinese Medical Association. The clinical practice guideline on liver transplantation for hepatocellular carcinoma in China (2018 edition) [J]. J Clin Hepatol, 2019, 35(2): 275-280. DOI: 10.3969/j.issn.1001-5256.2019.02.008.
    [7] MA LJ, FENG FL, DONG LQ, et al. Clinical significance of PD-1/PD-Ls gene amplification and overexpression in patients with hepatocellular carcinoma[J]. Theranostics, 2018, 8(20): 5690-5702. DOI: 10.7150/thno.28742.
    [8] CALDERARO J, ROUSSEAU B, AMADDEO G, et al. Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features[J]. Hepatology, 2016, 64(6): 2038-2046. DOI: 10.1002/hep.28710.
    [9] DAI X, XUE J, HU J, et al. Positive expression of programmed death ligand 1 in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma[J]. Transl Oncol, 2017, 10(4): 511-517. DOI: 10.1016/j.tranon.2017.03.009.
    [10] MORITA M, FUJINO M, JIANG G, et al. PD-1/B7-H1 interaction contribute to the spontaneous acceptance of mouse liver allograft[J]. Am J Transplant, 2010, 10(1): 40-46. DOI: 10.1111/j.1600-6143.2009.02859.x.
    [11] DANG N, WAER M, SPRANGERS B, et al. Intratumoral immunotherapy with anti-PD-1 and TLR9 agonist induces systemic antitumor immunity without accelerating rejection of cardiac allografts[J]. Am J Transplant, 2021, 21(1): 60-72. DOI: 10.1111/ajt.16105.
    [12] LIPSON EJ, NAQVI FF, LOSS MJ, et al. Kidney retransplantation after anti-programmed cell death-1 (PD-1)-related allograft rejection[J]. Am J Transplant, 2020, 20(8): 2264-2268. DOI: 10.1111/ajt.15856.
    [13] 王英, 余希, 施明, 等. 肝移植术后急性排斥患者外周血中T淋巴细胞上PD-1分子表达的特征及意义[J]. 细胞与分子免疫学杂志, 2013, 29(12): 1312-1314. https://www.cnki.com.cn/Article/CJFDTOTAL-XBFM201312023.htm

    WANG Y, YU X, SHI M, et al. Characteristics and significance of PD-1 on T lymphocytes in peripheral blood of acute rejection patients after liver transplantation[J]. Chin J Cell Mol Immunol, 2013, 29(12): 1312-1314. https://www.cnki.com.cn/Article/CJFDTOTAL-XBFM201312023.htm
    [14] ZENG Q, YUAN XY, LI W, et al. Effects of tacrolimus (FK506) and mycophenolate mofetil (MMF) on regulatory T cells and co-inhibitory receptors in the peripheral blood of human liver allograft patients[J]. Immunopharmacol Immunotoxicol, 2019, 41(3): 380-385. DOI: 10.1080/08923973.2018.1533026.
    [15] ZENG Q, YUAN X, CAO J, et al. Mycophenolate mofetil enhances the effects of tacrolimus on the inhibitory function of regulatory T cells in patients after liver transplantation via PD-1 and TIGIT receptors[J]. Immunopharmacol Immunotoxicol, 2021, 43(2): 239-246. DOI: 10.1080/08923973.2021.1891247.
    [16] SU Z, DHUSIA K, WU Y. A computational study of co-inhibitory immune complex assembly at the interface between T cells and antigen presenting cells[J]. PLoS Comput Biol, 2021, 17(3): e1008825. DOI: 10.1371/journal.pcbi.1008825.
    [17] NING Z, LIU K, XIONG H. Roles of BTLA in immunity and immune disorders[J]. Front Immunol, 2021, 12: 654960. DOI: 10.3389/fimmu.2021.654960.
    [18] CHEN W, PANDEY M, SUN H, et al. Development of a mechanism of action-reflective, dual target cell-based reporter bioassay for a bispecific monoclonal antibody targeting human CTLA-4 and PD-1[J]. MAbs, 2021, 13(1): 1914359. DOI: 10.1080/19420862.2021.1914359.
    [19] CHEN X, GAO A, ZHANG F, et al. ILT4 inhibition prevents TAM- and dysfunctional T cell-mediated immunosuppression and enhances the efficacy of anti-PD-L1 therapy in NSCLC with EGFR activation[J]. Theranostics, 2021, 11(7): 3392-3416. DOI: 10.7150/thno.52435.
    [20] WANG M, MA X, ZHOU K, et al. Discovery of pyrrole-imidazole polyamides as PD-L1 expression inhibitors and their anticancer activity via immune and nonimmune pathways[J]. J Med Chem, 2021, DOI: 10.1021/acs.jmedchem.1c00120[Epub ahead of print].
    [21] SHAN T, CHEN S, CHEN X, et al. M2-TAM subsets altered by lactic acid promote T-cell apoptosis through the PD-L1/PD-1 pathway[J]. Oncol Rep, 2020, 44(5): 1885-1894. DOI: 10.3892/or.2020.7767.
    [22] 汪国营, 唐晖, 张英才, 等. 程序性死亡受体(PD)-1单克隆抗体治疗肝癌肝移植术后复发诱发急性免疫性肝炎: 附1例报告[J]. 器官移植, 2016, 7(1): 44-47. DOI: 10.3969/j.issn.1674-7445.2016.01.008.

    WANG GY, TANG H, ZHANG YC, et al. Programmed death receptor (PD)-1 monoclonal antibody-induced acute immune hepatitis in the treatment of recurrent hepatocellular carcinoma after liver transplantation: a case report[J]. Organ Transplant, 2016, 7(1): 44-47. DOI: 10.3969/j.issn.1674-7445.2016.01.008.
    [23] VARKARIS A, LEWIS DW, NUGENT FW. Preserved liver transplant after PD-1 pathway inhibitor for hepatocellular carcinoma[J]. Am J Gastroenterol, 2017, 112(12): 1895-1896. DOI: 10.1038/ajg.2017.387.
    [24] GASSMANN D, WEILER S, MERTENS JC, et al. Liver allograft failure after nivolumab treatment-a case report with systematic literature research[J]. Transplant Direct, 2018, 4(8): e376. DOI: 10.1097/TXD.0000000000000814.
    [25] FRIEND BD, VENICK RS, MCDIARMID SV, et al. Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma[J]. Pediatr Blood Cancer, 2017, 64(12). DOI: 10.1002/pbc.26682.
    [26] AMJAD W, KOTIAH S, GUPTA A, et al. Successful treatment of disseminated hepatocellular carcinoma after liver transplantation with nivolumab[J]. J Clin Exp Hepatol, 2020, 10(2): 185-187. DOI: 10.1016/j.jceh.2019.11.009.
    [27] RAMMOHAN A, REDDY MS, FAROUK M, et al. Pembrolizumab for metastatic hepatocellular carcinoma following live donor liver transplantation: the silver bullet? [J]. Hepatology, 2018, 67(3): 1166-1168. DOI: 10.1002/hep.29575.
    [28] DE TONI EN, GERBES AL. Tapering of immunosuppression and sustained treatment with nivolumab in a liver transplant recipient[J]. Gastroenterology, 2017, 152(6): 1631-1633. DOI: 10.1053/j.gastro.2017.01.063.
    [29] DELEON TT, SALOMAO MA, AQEL BA, et al. Pilot evaluation of PD-1 inhibition in metastatic cancer patients with a history of liver transplantation: the Mayo Clinic experience[J]. J Gastrointest Oncol, 2018, 9(6): 1054-1062. DOI: 10.21037/jgo.2018.07.05.
    [30] KUO JC, LILLY LB, HOGG D. Immune checkpoint inhibitor therapy in a liver transplant recipient with a rare subtype of melanoma: a case report and literature review[J]. Melanoma Res, 2018, 28(1): 61-64. DOI: 10.1097/CMR.0000000000000410.
    [31] MORALES RE, SHOUSHTARI AN, WALSH MM, et al. Safety and efficacy of ipilimumab to treat advanced melanoma in the setting of liver transplantation[J]. J Immunother Cancer, 2015, 3: 22. DOI: 10.1186/s40425-015-0066-0.
    [32] RANGANATH HA, PANELLA TJ. Administration of ipilimumab to a liver transplant recipient with unresectable metastatic melanoma[J]. J Immunother, 2015, 38(5): 211. DOI: 10.1097/CJI.0000000000000077.
    [33] SCHVARTSMAN G, PEREZ K, SOOD G, et al. Immune checkpoint inhibitor therapy in a liver transplant recipient with melanoma[J]. Ann Intern Med, 2017, 167(5): 361-362. DOI: 10.7326/L17-0187.
    [34] DE BRUYN P, VAN GESTEL D, OST P, et al. Immune checkpoint blockade for organ transplant patients with advanced cancer: how far can we go?[J]. Curr Opin Oncol, 2019, 31(2): 54-64. DOI: 10.1097/CCO.0000000000000505.
    [35] CHEN DS, MELLMAN I. Elements of cancer immunity and the cancer-immune set point[J]. Nature, 2017, 541(7637): 321-330. DOI: 10.1038/nature21349.
    [36] AGUIRRE LE, GUZMAN ME, LOPES G, et al. Immune checkpoint inhibitors and the risk of allograft rejection: a comprehensive analysis on an emerging issue[J]. Oncologist, 2019, 24(3): 394-401. DOI: 10.1634/theoncologist.2018-0195.
    [37] TIO M, RAI R, EZEOKE OM, et al. Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection[J]. Eur J Cancer, 2018, 104: 137-144. DOI: 10.1016/j.ejca.2018.09.017.
    [38] EL-KHOUEIRY AB, SANGRO B, YAU T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial[J]. Lancet, 2017, 389(10088): 2492-2502. DOI: 10.1016/S0140-6736(17)31046-2.
    [39] GARANT A, GUILBAULT C, EKMEKJIAN T, et al. Concomitant use of corticosteroids and immune checkpoint inhibitors in patients with hematologic or solid neoplasms: a systematic review[J]. Crit Rev Oncol Hematol, 2017, 120: 86-92. DOI: 10.1016/j.critrevonc.2017.10.009.
    [40] BARNETT R, BARTA VS, JHAVERI KD. Preserved renal-allograft function and the PD-1 pathway inhibitor nivolumab[J]. N Engl J Med, 2017, 376(2): 191-192. DOI: 10.1056/NEJMc1614298.
    [41] YE Q, LING S, JIANG G, et al. Sirolimus-based immunosuppression improves the prognosis of liver transplantation recipients with low TSC1/2 expression in hepatocellular carcinoma beyond the Milan criteria[J]. Eur J Surg Oncol, 2021, DOI: 10.1016/j.ejso.2021.04.001[Epub ahead of print].
    [42] BONNEFOY N, OLIVE D, VANHOVE B. Next generation of anti-immune checkpoints antibodies[J]. Med Sci (Paris), 2019, 35(12): 966-974. DOI: 10.1051/medsci/2019193.
    [43] PRICEMAN SJ, TILAKAWARDANE D, JEANG B, et al. Regional delivery of chimeric antigen receptor-engineered T cells effectively targets HER2(+) breast cancer metastasis to the brain[J]. Clin Cancer Res, 2018, 24(1): 95-105. DOI: 10.1158/1078-0432.CCR-17-2041.
    [44] KOCHENDERFER JN, SOMERVILLE RPT, LU T, et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels[J]. J Clin Oncol, 2017, 35(16): 1803-1813. DOI: 10.1200/JCO.2016.71.3024.
    [45] MAUDE SL, LAETSCH TW, BUECHNER J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia[J]. N Engl J Med, 2018, 378(5): 439-448. DOI: 10.1056/NEJMoa1709866.
    [46] WEBER EW, MAUS MV, MACKALL CL. The emerging landscape of immune cell therapies[J]. Cell, 2020, 181(1): 46-62. DOI: 10.1016/j.cell.2020.03.001.
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  • 收稿日期:  2021-01-22
  • 网络出版日期:  2021-05-19
  • 刊出日期:  2021-05-15

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