肿瘤浸润淋巴细胞在实体瘤治疗中的研究进展

摘要/Abstract

摘要： 肿瘤浸润淋巴细胞（TILs）是迁移到肿瘤组织中天然存在的异质淋巴细胞（白细胞）群体，其对肿瘤细胞表面抗原的识别具有特异性。TIL疗法是指通过从肿瘤中分离出TILs，在体外培养并扩增后回注以治疗患者的一种过继细胞疗法。尽管TIL疗法在临床试验中展现出一定的有效性，但其所进行的临床试验相对较少，已完成的临床试验样本量也相对较小，其成功应用目前仍然局限于几种肿瘤。本研究梳理了TIL疗法的发展历史和TIL制备方法，概述了近年来TIL疗法在黑色素瘤、非小细胞肺癌、宫颈癌、卵巢癌等多种癌症中的应用进展及不良反应，对比分析其他各类过继细胞疗法，讨论了当前TIL疗法的局限性，并展望了TIL疗法更广泛的临床应用及发展方向，旨在为TIL疗法进行临床肿瘤免疫治疗及产品开发提供参考。

关键词: font-size:medium, ">肿瘤浸润淋巴细胞；癌症治疗；免疫疗法；基因编辑；临床试验

Abstract: Tumor-infiltrating lymphocytes (TILs) are a heterogeneous population of lymphocytes (white blood cells) that migrate into tumor tissues and have specific recognition of antigens on tumor cells.TIL therapy is an adoptive cell therapy in which infiltrating lymphocytes are isolated from tumors， grown in vitro， expanded， and injected back to treat patients.Although TIL therapy has shown some efficacy in clinical trials， but relatively few clinical trials have been conducted， the sample size of completed clinical trials is relatively small， and its successful use is still limited to a few kinds of tumors.Based on this， this study reviewed the developing history of TIL therapies and the TIL preparation methods， summarized the progress in recent years of TIL therapies applied in melanoma， non-small cell lung cancer， cervical cancer， ovarian cancer and in the application of various types of cancer and adverse reactions， compared TIL therapy with other kinds of adoptive cell therapy， and discussed the current limitations of the treatment.The broader clinical application and development direction of TIL therapy were prospected， aiming to provide reference for TIL therapy in clinical tumor immunotherapy and product development.

Key words: font-size:medium, ">Tumor-infiltrating lymphocyte, Cancer treatment, Immunotherapy, Gene editing, Clinical trials

中图分类号:

任嘉慧a, 周云乔b, 高鹏翼a, 张琪c, 张秀军, 王铁山d. 肿瘤浸润淋巴细胞在实体瘤治疗中的研究进展[J]. 中国医药导刊, 2022, 24(11): 1062-1067.

REN Jiahuia, ZHOU Yunqiaob, GAO Pengyia, ZHANG Qic, ZHANG Xiujun, WANG Tieshand. Research Progress of Tumor-Infiltrating Lymphocytes in the Treatment of Solid Tumors[J]. CHINESE JOURNAL OF MEDICINAL GUIDE, 2022, 24(11): 1062-1067.

参考文献

[1]Wu R，Forget MA，Chacon J，et al.Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes for metastatic melanoma: current status and future outlook[J].Cancer J，2012，18(2):160-175.
     [2]Rosenberg SA，Packard BS，Aebersold PM，et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report[J].N Engl J Med，1988，319(25):1676-1680.
     [3]Piersma SJ，Jordanova ES，van Poelgeest MI， et al. High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer[J].Cancer Res，2007，67(1):354-361.
     [4]Farhood B，Najafi M，Mortezaee K.CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review[J].J Cell Physiol，2019，234(6):8509-8521.
     [5]Moreno V，Hernandez T，de Miguel M，et al.Adoptive cell therapy for solid tumors: Chimeric antigen receptor T cells and beyond[J]. Curr Opin Pharmacol，2021，59:70-84.
     [6]Eberlein TJ，Rosenstein M，Rosenberg SA.Regression of a disseminated syngeneic solid tumor by systemic transfer of lymphoid cells expanded in interleukin 2[J].J Exp Med，1982，156(2):385-397.
     [7]Rosenberg SA，Spiess P，Lafreniere R.A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes[J].Science，1986，233(4770):1318-1321.
     [8]梁锐，李蕾蕾，王志强.肿瘤浸润性淋巴细胞在实体瘤的临床研究进展[J].中国肿瘤临床，2021，48(22):1168-1172.
     [9]Zitvogel L，Galluzzi L，Kepp O，et al.Type Ⅰ interferons in anticancer immunity[J]. Nat Rev Immunol，2015，15(7):405-414.
     [10]Saberian C，Amaria RN，Najjar AM，et al. Randomized phase Ⅱ trial of lymphodepletion plus adoptive cell transfer of tumor-infiltrating lymphocytes， with or without dendritic cell vaccination， in patients with metastatic melanoma[J].J Immunother Cancer，2021，9(5):e002449.
     [11]Hall M，Liu H，Malafa M，et al. Expansion of tumor-infiltrating lymphocytes (TIL) from human pancreatic tumors[J].J Immunother Cancer，2016，4:61.
     [12]Friese C，Harbst K，Borch TH，et al.CTLA-4 blockade boosts the expansion of tumor-reactive CD8+ tumor-infiltrating lymphocytes in ovarian cancer[J].Sci Rep，2020，10(1):3914.
     [13]Tavera RJ，Forget MA，Kim YU，et al.Utilizing T-cell activation signals 1，2，and 3 for tumor-infiltrating lymphocytes (TIL) expansion: the advantage over the sole use of interleukin-2 in cutaneous and uveal melanoma[J]. J Immunother，2018，41(9):399-405.
     [14]Aydin AM，Bunch BL，Beatty M， et al. The factors affecting expansion of reactive tumor infiltrating lymphocytes (TIL) from bladder cancer and potential therapeutic applications[J]. Front Immunol，2021，12:628063.
     [15]Schumacher TN， Schreiber RD. Neoantigens in cancer immunotherapy[J]. Science，2015，348(6230):69-74.
     [16]van den Berg JH， Heemskerk B， van Rooij N， et al. Tumor infiltrating lymphocytes (TIL) therapy in metastatic melanoma: boosting of neoantigen-specific T cell reactivity and long-term follow-up[J].J Immunother Cancer，2020，8(2):e000848.
     [17]Dafni U，Michielin O，Lluesma SM，et al.Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis[J].Ann Oncol，2019，30(12):1902-1913.
     [18]Chandran SS，Somerville RPT，Yang JC，et al.Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes:a single-centre，two-stage， single-arm， phase 2 study[J].Lancet Oncol，2017，18(6):792-802.
     [19]Sarnaik AA，Hamid O，Khushalani NI，et al. Lifileucel， a tumor-infiltrating lymphocyte therapy， in metastatic melanoma[J].J Clin Oncol，2021，39(24):2656-2666.
     [20]Harel M，Ortenberg R，Varanasi SK，et al.Proteomics of melanoma response to immunotherapy reveals mitochondrial dependence[J].Cell，2019，179(1):236-250.e18.
     [21]Creelan BC，Wang C，Teer JK，et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial[J]. Nat Med，2021，27(8):1410-1418.
     [22]Stevanovi S，Helman SR，Wunderlich JR，et al.A phase Ⅱ study of tumor-infiltrating lymphocyte therapy for human papillomavirus-associated epithelial cancers[J].Clin Cancer Res，2019，25(5):1486-1493.
     [23]Stevanovi S， Pasetto A， Helman SR， et al. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer[J].Science，2017，356(6334):200-205.
     [24]Aoki Y，Takakuwa K，Kodama S，et al.Use of adoptive transfer of tumor-infiltrating lymphocytes alone or in combination with cisplatin-containing chemotherapy in patients with epithelial ovarian cancer[J].Cancer Res，1991，51(7):1934-1939.
     [25]Fujita K，Ikarashi H，Takakuwa K，et al. Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes[J].Clin Cancer Res，1995，1(5):501-507.
     [26]华祖德，陆静，李慧芳，等.卵巢癌肿瘤浸润淋巴细胞的临床研究[J].中华妇产科杂志，1996，31(9):44-46.
     [27]Kradin RL，Kurnick JT，Lazarus DS，et al.Tumour-infiltrating lymphocytes and interleukin-2 in treatment of advanced cancer[J].Lancet, 1989，1(8638):577-580.
     [28]Figlin RA，Pierce WC，Kaboo R，et al.Treatment of metastatic renal cell carcinoma with nephrectomy， interleukin-2 and cytokine-primed or CD8+ selected tumor infiltrating lymphocytes from primary tumor[J].J Urol，1997，158(3 Pt 1):740-745.
     [29]Fabbri M，Ridolfi R，Maltoni R，et al. Tumor infiltrating lymphocytes and continuous infusion interleukin-2 after metastasectomy in 61 patients with melanoma， colorectal and renal carcinoma[J].Tumori，2000，86(1):46-52.
     [30]张一心，汪晓莺，刘继斌，等.肝癌术后应用白介素12及白介素2诱导的自体肿瘤浸润淋巴细胞的临床观察[J].中华医学杂志，2008，88(14):973-976.
     [31]Zacharakis N， Huq LM， Seitter SJ， et al. Breast cancers are immunogenic: immunologic analyses and a phase Ⅱ pilot clinical trial using mutation-reactive autologous lymphocytes[J].J Clin Oncol，2022，40(16):1741-1754.
     [32]Wolf B，Zimmermann S，Arber C，et al. Safety and tolerability of adoptive cell therapy in cancer[J]. Drug Saf，2019，42(2):315-334.
     [33]Rosenberg SA， Yang JC， Sherry RM， et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy[J]. Clin Cancer Res，2011，17(13):4550-4557.
     [34]Cruz CR，Hanley PJ，Liu H，et al.Adverse events following infusion of T cells for adoptive immunotherapy: a 10-year experience[J].Cytotherapy，2010，12(6):743-749.
     [35]Wang DY，Salem JE，Cohen JV，et al.Fatal toxic effects associated with immune checkpoint inhibitors: asystematic review and Meta-analysis[J].JAMA Oncol，2018，4(12):1721-1728.
     [36]Martins F，Sofiya L，Sykiotis GP，et al. Adverse effects of immune-checkpoint inhibitors: epidemiology， management and surveillance[J].Nat Rev Clin Oncol，2019，16(9):563-580.
     [37]Xu C，Chen YP，Du XJ，et al. Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis[J]. BMJ，2018，363:k4226.
     [38]Goldstein BL，Gedmintas L，Todd DJ.Drug-associated polymyalgia rheumatica/giant cell arteritis occurring in two patients after treatment with ipilimumab， an antagonist of ctla-4[J]. Arthritis Rheumatol，2014，66(3):768-769.
     [39]Haanen JBAG， Carbonnel F， Robert C， et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis， treatment and follow-up[J].Ann Oncol， 2017，28(suppl_4):iv119-iv142.
     [40]Puzanov I， Diab A， Abdallah K， et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group[J].J Immunother Cancer，2017，5(1):95.
     [41]Dougan M， Luoma AM， Dougan SK， et al. Understanding and treating the inflammatory adverse events of cancer immunotherapy[J].Cell，2021，184(6):1575-1588.
     [42]Titov A，Zmievskaya E，Ganeeva I，et al.Adoptive immunotherapy beyond CAR T-Cells[J]. Cancers (Basel)，2021，13(4):743.
     [43]Bedognetti D，Spivey TL，Zhao Y，et al. CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2[J].Br J Cancer，2013，109(9):2412-2423.
     [44]Mikucki ME， Fisher DT， Matsuzaki J， et al. Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints[J]. Nat Commun，2015，6:7458.
     [45]van Kooyk Y， van de Wiel-van Kemenade P， Weder P， et al.Enhancement of LFA-1-mediated cell adhesion by triggering through CD2 or CD3 on T lymphocytes[J]. Nature， 1989，342(6251):811-813.
     [46]Burbach BJ， Medeiros RB， Mueller KL， et al. T-cell receptor signaling to integrins[J]. Immunol Rev， 2007，218:65-81.
     [47]Mirenda V， Jarmin SJ， David R， et al. Physiologic and aberrant regulation of memory T-cell trafficking by the costimulatory molecule CD28[J]. Blood，2007，109(7):2968-2977.
     [48]Sackstein R，Schatton T，Barthel SR.T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy[J]. Lab Invest，2017，97(6):669-697.
     [49]Cameron BJ，Gerry AB，Dukes J，et al.Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells[J].Sci Transl Med，2013，5(197):197ra103.
     [50]Morgan RA， Chinnasamy N， Abate-Daga D， et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy[J]. J Immunother，2013，36(2):133-151.
     [51]Stevanovi S，Draper LM，Langhan MM，et al.Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells[J].J Clin Oncol，2015，33(14):1543-1550.
     [52]Sarnaik A，Khushalani NI，Chesney JA，et al. Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144， lifileucel) in advanced metastatic melanoma patients who progressed on multiple prior therapies including anti-PD-1[J].J Clin Oncol，2019，37(15_suppl):2518.
     [53]Atkins MB， Lotze MT， Dutcher JP， et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993[J]. J Clin Oncol，1999，17(7):2105-2116.
     [54]Schwartz RN，Stover L，Dutcher JP.Managing toxicities of high-dose interleukin-2[J]. Oncology (Williston Park)，2002，16(11 Suppl 13):11-20.
     [55]Lotze MT，Matory YL，Rayner AA，et al.Clinical effects and toxicity of interleukin-2 in patients with cancer[J]. Cancer，1986，58(12):2764-2772.
     [56]Yao X， Ahmadzadeh M， Lu YC， et al.Levels of peripheral CD4(+)FoxP3(+) regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer[J]. Blood，2012，119(24):5688-5696.
     [57]Ellebaek E，Iversen TZ，Junker N，et al.Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients[J]. J Transl Med，2012，10:169.
     [58]Andersen R，Donia M，Borch TH，et al.Adoptive cell therapy with tumor infiltrating lymphocytes and intermediate dose IL-2 for metastatic melanoma[J].J Immuno Ther Cancer， 2014，2:S3.
     [59]Robbins PF，Dudley ME，Wunderlich J，et al.Cutting edge: persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy[J].J Immunol，2004，173(12):7125-7130.
     [60]Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy[J].Science，2013，342(6165):1432-1433.
     [61]June CH，O′Connor RS，Kawalekar OU，et al.CAR T cell immunotherapy for human cancer[J]. Science，2018，359(6382):1361-1365.
     [62]Ribas A，Wolchok JD.Cancer immunotherapy using checkpoint blockade[J].Science，2018，359(6382):1350-1355.
     [63]Wang Z，Ahmed S，Labib M，et al.Efficient recovery of potent tumour-infiltrating lymphocytes through quantitative immunomagnetic cell sorting[J].Nat Biomed Eng，2022， 6(2):108-117.
     [64]Lvgren T，Wolodarski M，Wickstrm S，et al.Complete and long-lasting clinical responses in immune checkpoint inhibitor-resistant， metastasized melanoma treated with adoptive T cell transfer combined with DC vaccination[J].Oncoimmunology，2020，9(1):1792058.

快速检索引用检索图表检索高级检索