CART细胞疗法新兴治疗的前沿进展

摘要/Abstract

摘要： 细胞治疗领域因其高度精准化和个性化的优势，已成为未来人类医学发展的热门方向。细胞治疗是指应用人的自体、同种异体或异种（非人体）的细胞，经体外操作后回输（或植入）人体的治疗方法。其中嵌合抗原受体T细胞免疫疗法（CART细胞疗法）是近几年兴起的过继性细胞免疫治疗，主要通过将嵌合抗原受体的特异性与T细胞的免疫作用相结合，再经过特异性识别对恶性肿瘤细胞进行杀伤。鉴于其潜力和优势，这项技术也在不断改进，扩展到其它疾病领域的应用，即新兴治疗，本研究梳理了CART细胞疗法的发展背景及其结构组成和演变过程；主要概述了CART细胞疗法新兴治疗应用进展，包括应用实体瘤新靶点的第2代CART细胞疗法、联合免疫检查点抑制剂治疗实体瘤的CART细胞疗法、第3代CART细胞疗法、第4代CART细胞疗法和治疗非肿瘤疾病的CART细胞疗法；探讨了CART细胞疗法新兴治疗面临的4个主要问题：敌对免疫抑制性肿瘤微环境（TME）、免疫抑制细胞、实体瘤异质性和免疫检查点；同时聚焦这些问题给出了解决策略：CART细胞联合免疫检查点抑制剂来解决免疫抑制和免疫逃逸的问题，以及纳米颗粒药物涂覆CART细胞膜的方法来提升抗肿瘤能力和靶向能力；最后提出展望：以CART细胞疗法为代表的各种嵌合抗原受体免疫细胞疗法的应用范围将会越来越广阔，将给人类肿瘤等疾病的治疗带来重大突破，以期为我国细胞疗法研究领域的专家学者提供参考。

关键词: font-size:medium, ">细胞治疗；嵌合抗原受体；CART；实体瘤；免疫疗法

Abstract: The field of cell therapy has become a hot direction for the development of human medicine due to its advantage of high precision and personalization. Cell therapy refers to the therapy that use human autologous， allogeneic， or xenogeneic (nonhuman) cells， after in vitro operation， and then infused (or implanted) into the human body. Chimeric antigen receptor T cell immunotherapy (CART cell therapy) is adoptive cellular immunotherapy emerging in recent years， which mainly combines the specificity of chimeric antigen receptors with the immune function of T cells and then kills malignant tumor cells after specific recognition. Given its potential and advantages， this technology is also constantly being improved and extended to applications in other disease areas， namely emerging therapies. This study reviews the background， structural composition， and evolution of CART cell therapy， and mainly summarizes the emerging therapeutic application progress of CART cell therapy， which includes the secondgeneration CART cell therapy using new solid tumor targets， CART cell therapy combined with immune checkpoint inhibitors for solid tumors， the thirdgeneration CART cell therapy， the fourthgeneration CART cell therapy， and CART cell therapy for nontumor diseases. Four major problems in the emerging therapies of CART cell therapy are discussed： hostile immunosuppressive tumor microenvironment (TME)， immunosuppressive cells， solid tumor heterogeneity， and immune checkpoints. At the same time， the study focused on these problems and provided solutions： CART cells combined with immune checkpoint inhibitors to solve the problem of immune suppression and immune escape， and nanoparticles coated with drugs to improve the antitumor ability and targeting ability of CART cells. Finally， it is proposed that the application range of various chimeric antigen receptor immune cell therapies (represented by CART cell therapy) will be broader and broader， and will bring a breakthrough in the treatment of human tumors and other diseases. It is hoped to provide a reference for experts and scholars in the field of cell therapy in China.

Key words: font-size:medium, ">Cell therapy； Chimeric antigen receptor；CART；Solid tumor；Immunotherapy

中图分类号:

粆香, 高鹏翼, 郑浩呈, 李贺, 秦瑜, 王铁山. CART细胞疗法新兴治疗的前沿进展[J]. 中国医药导刊, 2022, 24(10): 974-982.

CHAO Xiang, GAO Pengyi, ZHENG Haocheng, LI He, QIN Yu, WANG Tieshan. The Frontier Progress of Emerging Therapies of CART Cell Therapy[J]. CHINESE JOURNAL OF MEDICINAL GUIDE, 2022, 24(10): 974-982.

参考文献

[1]Gross G，Waks T，Eshhar Z.Expression of immunoglobulinTcell receptor chimeric molecules as functional receptors with antibodytype specificity[J].Proc Natl Acad Sci USA，1989，86(24)：1002410028.
     [2]Maher J， Brentjens RJ， Gunset G， et al. Human Tlymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor[J].Nat Biotechnol， 2002，20(1)：7075.
     [3]Imai C， Mihara K， Andreansky M， et al. Chimeric receptors with 41BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia[J].Leukemia， 2004，18(4)：676684.
     [4]Hombach AA，Rappl G，Abken H.Arming cytokineinduced killer cells with chimeric antigen receptors： CD28 outperforms combined CD28OX40“superstimulation” [J].Mol Ther，2013，21：22682277.
     [5]Carpenito C， Milone MC， Hassan R， et al. Control of large， established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains[J].Proc Natl Acad Sci U S A， 2009，106(9)：33603365.
     [6]Zhong XS，Matsushita M，Plotkin J，et al.Chimeric antigen receptors combining 41BB and CD28 signaling domains augment PI3kinase/AKT/BclXL activation and CD8+ T cellmediated tumor eradication[J].Mol Ther，2010，18：413420.
     [7]Tammana S， Huang X， Wong M， et al. 41BB and CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against Bcell malignancies[J]. Hum Gene Ther， 2010，21(1)：7586.
     [8]PegramHJ，Park JH，Brentjens RJ.CD28z CARs and armored CARs[J].Cancer J，2014，20：127133.
     [9]Brentjens RJ， Davila ML， Riviere I， et al. CD19targeted T cells rapidly induce molecular remissions in adults with chemotherapyrefractory acute lymphoblastic leukemia[J]. Sci Transl Med， 2013，5(177)：177ra38.
     [10]Mullard A.FDA approves first CAR T therapy[J].Nat Rev Drug Discov，2017，16(10)：669.
     [11]Keir ME， Butte MJ， Freeman GJ，et al. PD1 and its ligands in tolerance and immunity[J]. Annu Rev Immunol， 2008，26：677704.
     [12]Liu M， Wang X， Li W， et al. Targeting PDL1 in nonsmall cell lung cancer using CAR T cells[J]. Oncogenesis， 2020，9(8)：72.
     [13]Qin L， Zhao R， Chen D， et al. Chimeric antigen receptor T cells targeting PDL1 suppress tumor growth[J]. Biomark Res， 2020，8：19.
     [14]Bajor M， GraczykJarzynka A， Marhelava K， et al. PDL1 CAR effector cells induce selfamplifying cytotoxic effects against target cells[J]. J Immunother Cancer， 2022，10(1)：e002500.
     [15]Liao Q， Mao Y， He H， et al. PDL1 chimeric costimulatory receptor improves the efficacy of CART cells for PDL1positive solid tumors and reduces toxicity in vivo[J]. Biomark Res，2020，8(1)：57.
     [16]Scholl S， Beuzeboc P， Pouillart P. Targeting HER2 in other tumor types[J]. Ann Oncol，2001，12(Suppl 1)：S81S87.
     [17]Ahmed N， Brawley VS， Hegde M， et al. Human epidermal growth factor receptor 2 (HER2) specific chimeric antigen receptormodified T cells for the immunotherapy of HER2Positive sarcoma[J]. J Clin Oncol，2015，33(15)：16881696.
     [18]Hegde M， Joseph SK， Pashankar F， et al. Tumor response and endogenous immune reactivity after administration of HER2 CAR T cells in a child with metastatic rhabdomyosarcoma[J]. Nat Commun， 2020，11(1)：3549.
     [19]Song Y， Tong C， Wang Y， et al. Effective and persistent antitumor activity of HER2directed CART cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo[J]. Protein Cell， 2018，9(10)：867878.
     [20]Feng K， Liu Y， Guo Y， et al. Phase I study of chimeric antigen receptor modified T cells in treating HER2positive advanced biliary tract cancers and pancreatic cancers[J]. Protein Cell， 2018，9(10)：838847.
     [21]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.
     [22]Groh V， Steinle A， Bauer S，et al. Recognition of stressinduced MHC molecules by intestinal epithelial gammadelta T cells [J]. Science， 1998， 279： 17371740.
     [23]Watson N， Spendiove I， Madjd Z，et al. Expression of the stressrelated MHC class I chainrelated protein MICA is an indicator of good prognosis in colorectal cancer patients [J]. Int J Cancer， 2006， 118： 14451452.
     [24]Spear P， Barber A， RyndaApple A，et al. NKG2D CAR Tcell therapy inhibits the growth of NKG2D ligand heterogeneous tumors[J]. Immunol Cell Biol. 2013，91(6)：435440.
     [25]Han Y， Xie W， Song DG， et al. Control of triplenegative breast cancer using ex vivo selfenriched， costimulated NKG2D CAR T cells[J]. J Hematol Oncol，2018，11(1)：92.
     [26]Deng X， Gao F， Li N， et al. Antitumor activity of NKG2D CART cells against human colorectal cancer cells in vitro and in vivo[J]. Am J Cancer Res，2019，9(5)：945958.
     [27]Yang D， Sun B， Dai H， et al. T cells expressing NKG2D chimeric antigen receptors efficiently eliminate glioblastoma and cancer stem cells[J]. J Immunother Cancer，2019，7(1)：171.
     [28]Sun B， Yang D， Dai H， et al. Eradication of hepatocellular carcinoma by NKG2Dbased CART cells[J]. Cancer Immunol Res，2019，7(11)：18131823.
     [29]Wang J， Liu X， Ji J， et al. Orthotopic and heterotopic murine models of pancreatic cancer exhibit different immunological microenvironments and different responses to immunotherapy[J]. Front Immunol，2022，13：863346.
     [30]Van Seggelen H， Hammill JA， DvorkinGheva A， et al. T Cells Engineered With Chimeric Antigen Receptors Targeting NKG2D Ligands Display Lethal Toxicity in Mice[J]. Mol Ther，2015，23(10)：16001610.
     [31]Hirsch FR，Scagliotti GV，Mulshine JL，et al.Lung cancer： current therapies and new targeted treatments[J].Lancet，2017，389(10066)：299311.
     [32]Siegel RL，Miller KD，Jemal A.Cancer statistics[J].CA Cancer J Clin，2020，70(1)：730.
     [33]Chen Z，Fillmore CM，Hammerman PS， et al.Nonsmallcell lung cancers：a heterogeneous set of diseases[J].Nat Rev Cancer，2014，14(8)：535546.
     [34]Li H，Huang Y，Jiang DQ，et al.Antitumor activity of EGFRspecific CAR T cells against nonsmallcell lung cancer cells in vitro and in mice[J].Cell Death Dis，2018，9(2)：177.
     [35]Hu Z，Zheng X，Jiao D，et al.LunXCAR T cells as a targeted therapy fornonsmall cell lung cancer[J].Mol Ther Oncolytics，2020，17：361370.
     [36]Liu J，Yang S，Cao B，et al.Targeting B7H3 via chimeric antigen receptor T cells and bispecific killer cell engagers augments antitumor response of cytotoxic lymphocytes[J].J Hematol Oncol，2021，14(1)：21.
     [37]Qi C，Gong J，Li J，et al.Claudin18.2specific CAR T cells in gastrointestinal cancers：phase 1 trial interim results[J].Nat Med，2022，28(6)：11891198.
     [38]Shi D，Shi Y，Kaseb AO，et al.Chimeric antigen receptorglypican3 Tcell therapy for advanced hepatocellular carcinoma：results of phase I trials[J].Clin Cancer Res，2020，26(15)：39793989.
     [39]Chmielewski M，Hahn O，Rappl G，et al.T cells that target carcinoembryonic antigen eradicate orthotopic pancreatic carcinomas without inducing autoimmune colitis in mice[J].Gastroenterology，2012，143(4)：10951107.e2.
     [40]Beatty GL，O′Hara MH，Lacey SF，et al.Activity of mesothelinspecific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial[J].Gastroenterology， 2018，155(1)：2932.
     [41]Schfer D，Tomiuk S，Küster LN，et al.Identification of CD318， TSPAN8 and CD66c as target candidates for CAR T cell based immunotherapy of pancreatic adenocarcinoma[J].Nat Commun，2021，12(1)：1453.
     [42]Wang D，Starr R，Chang WC，et al.Chlorotoxindirected CAR T cells for specific and effective targeting of glioblastoma[J].Sci Transl Med，2020，12(533)：eaaw2672.
     [43]Majzner RG，Ramakrishna S，Yeom KW，et al.GD2CAR T cell therapy for H3K27Mmutated diffuse midline gliomas[J].Nature，2022，603(7903)：934941.
     [44]MarinAcevedo JA， Kimbrough EO， Lou Y. Next generation of immune checkpoint inhibitors and beyond[J]. J Hematol Oncol，2021，14(1)：45.
     [45]Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy[J]. Nat Rev Cancer， 2012，12(4)：252264.
     [46]Vinay DS， Ryan EP， Pawelec G， et al. Immune evasion in cancer： mechanistic basis and therapeutic strategies[J]. Semin Cancer Biol， 2015， 35(Suppl 1)：S185S198.
     [47]Grosser R， Cherkassky L， Chintala N， et al. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors[J]. Cancer Cell，2019，36(5)：471482.
     [48]Gulati P，Rühl J，Kannan A，et al.Aberrant lck signal via CD28 costimulation augments antigenspecific functionality and tumor control by redirected T cells with PD1 blockade in humanized mice[J].Clin Cancer Res，2018，24(16)：39813993.
     [49]Adusumilli PS，Zauderer MG，Rivière I，et al.A phase I trial of regional mesothelintargeted CAR Tcell therapy in patients with malignant pleural disease，in combination with the antiPD1 agent pembrolizumab[J].Cancer Discov，2021，11(11)：27482763.
     [50]Lv J，Zhao R，Wu D，et al.Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer[J].J Hematol Oncol，2019，12(1)：18.
     [51]Gao H，Li K，Tu H，et al.Development of T cells redirected to glypican3 for the treatment of hepatocellular carcinoma[J].Clin Cancer Res，2014，20(24)：64186428.
     [52]Batra SA，Rathi P，Guo L，et al.Glypican3specific CAR T cells coexpressing IL15 and IL21 have superior expansion and antitumor activity against hepatocellular carcinoma[J].Cancer Immunol Res，2020，8(3)：309320.
     [53]Li H，Harrison EB，Li H，et al.Targeting brain lesions of nonsmall cell lung cancer by enhancing CCL2mediated CART cell migration[J].Nat Commun，2022，13(1)：2154.
     [54]Koneru M，Purdon TJ，Spriggs D，et al.IL12 secreting tumortargeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo[J].Oncoimmunology，2015，4(3)：e994446.
     [55]Li T，Wang J.Therapeutic effect of dual CART targeting PDL1 and MUC16 antigens on ovarian cancer cells in mice[J].BMC Cancer，2020，20(1)：678.
     [56]Sangsuwannukul T，Supimon K，Sujjitjoon J，et al.Antitumour effect of the fourthgeneration chimeric antigen receptor T cells targeting CD133 against cholangiocarcinoma cells[J].Int Immunopharmacol，2020，89(Pt B)：107069.
     [57]Wang Y，Wang J，Yang X，et al.Chemokine receptor CCR2b enhanced antitumor function of chimeric antigen receptor T cells targeting mesothelin in a nonsmallcell lung carcinoma model[J].Front Immunol，2021，12：628906.
     [58]Rurik JG，Tombácz I，Yadegari A，et al.CAR T cells produced in vivo to treat cardiac injury[J].Science，2022，375(6576)：9196.
     [59]Merrill JT，Neuwelt CM，Wallace DJ，et al.Efficacy and safety of rituximab in moderatelytoseverely active systemic lupus erythematosus： the randomized， doubleblind， phase II/III systemic lupus erythematosus evaluation of rituximab trial[J].Arthritis Rheum，2010，62：222233.
     [60]Jin X， Xu Q， Pu C，et al.Therapeutic efficacy of antiCD19 CART cells in a mouse model of systemic lupus erythematosus[J].Cell Mol Immunol， 2021，18(8)：18961903.
     [61]Mougiakakos D，Krnke G，Vlkl S，et al.CD19targeted CAR T cells in refractory systemic lupus erythematosus[J].N Engl J Med，2021，385(6)：567569.
     [62]AnthonyGonda K，Bardhi A，Ray A，et al.Multispecific antiHIV duoCART cells display broad in vitro antiviral activity and potent in vivo elimination of HIVinfected cells in a humanized mouse model[J].Sci Transl Med，2019，11(504)：eaav5685.
     [63]Herzig E，Kim KC，Packard TA，et al.Attacking latent HIV with convertibleCART cells， a highly adaptable killing platform[J].Cell，2019，179(4)：880894.
     [64]Maldini CR，Claiborne DT，Okawa K，et al.Dual CD4based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo[J].Nat Med，2020，26(11)：17761787.
     [65]Maldini CR，Gayout K，Leibman RS，et al.HIVresistant and HIVspecific CARmodified CD4+T cells mitigate HIV disease progression and confer CD4+T cell help in vivo[J].Mol Ther，2020，28(7)：15851599.
     [66]Liu B，Zhang W，Xia B，et al.Broadly neutralizing antibodyderived CAR T cells reduce viral reservoir in individuals infected with HIV1[J].J Clin Invest，2021，131(19)：e150211.
     [67]Krebs K，Bttinger N，Huang LR，et al.T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice[J].Gastroenterology，2013，145(2)：456465.
     [68]Sautto GA，Wisskirchen K，Clementi N，et al.Chimeric antigen receptor (CAR)engineered T cells redirected against hepatitis C virus (HCV) E2 glycoprotein[J].Gut，2016，65(3)：512523.
     [69]Theocharis AD，Skandalis SS，Gialeli C，et al. Extracellular matrix structure[J].Adv Drug Deliv Rev，2016，97：427.
     [70]Bernfield M，Gtte M，Park PW，et al.Functions of cell surface heparan sulfate proteoglycans[J].Annu Rev Biochem，1999，68：729777.
     [71]Digre A， Singh K， Abrink M， et al. Overexpression of heparanase enhances T lymphocyte activities and intensifies the inflammatory response in a model of murine rheumatoid arthritis[J].Sci Rep，2017，7：46229.
     [72]Cairns RA，Harris IS，Mak TW.Regulation of cancer cell metabolism[J].Nat Rev Cancer，2011，11：8595.
     [73]Balkwill FR，Capasso M，Hagemann T.The tumor microenvironment at a glance[J].J Cell Sci，2012，125：55915596.
     [74]Hanahan D，Weinberg RA.Hallmarks of cancer： the next generation[J].Cell，2011，144：646674.
     [75]Linterman MA，Pierson W，Lee SK，et al.Foxp3+ follicular regulatory T cells control the germinal center response[J].Nat Med，2011，17：975982.
     [76]Sakaguchi S，Yamaguchi T，Nomura T，et al.Regulatory T cells and immune tolerance[J].Cell，2008，133：775787.
     [77]Pandiyan P，Zheng L，Ishihara S，et al.CD4CD25 Foxp3+ regulatory T cells induce cytokine deprivationmediated apoptosis of effector CD4+T cells[J].Nat Immunol，2007，8：13531362.
     [78]Porter DL，Levine BL，Kalos M，et al.Chimeric antigen receptormodified T cells in chronic lymphoid leukemia[J].N Engl J Med，2011，365：725733.
     [79]Grupp SA，Kalos M，Barrett D，et al.Chimeric antigen receptormodified T cells for acute lymphoid leukemia[J].N Engl J Med，2013，368：15091518.
     [80]Maude SL，Frey N，Shaw PA，et al. Chimeric antigen receptor T cells for sustained remissions in leukemia[J].N Engl J Med，2014，371：15071517.
     [81]Porter DL，Hwang WT，Frey NV，et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia[J].Sci Transl Med，2015，7：303ra139.
     [82]JamalHanjani M，Quezada SA，Larkin J，et al.Translational implications of tumor heterogeneity[J].Clin Cancer Res，2015，21：12581266.
     [83]Sharma P，Allison JP.Immune checkpoint targeting in cancer therapy： toward combination strategies with curative potential[J].Cell，2015，161：205214.
     [84]Bradshaw JD，Lu P，Leytze G，et al. Interaction of the cytoplasmic tail of CTLA4 (CD152) with a clathrinassociated protein is negatively regulated by tyrosine phosphorylation[J].Biochemistry，1997，36：1597515982.
     [85]高春晓，魏训东，黄卫，等.纳米药物对肿瘤免疫微环境的影响[J].中国药学杂志，2021，56(19)：15461550.
     [86]Ma W，Zhu D，Li J，et al.Coating biomimetic nanoparticles with chimeric antigen receptor T cellmembrane provides high specificity for hepatocellular carcinoma photothermal therapy treatment[J].Theranostics，2020，10(3)：12811295.
     [87]Zhu L，Liu J，Zhou G，et al.Remodeling of tumor microenvironment by tumortargeting nanozymes enhances immune activation of CAR T cells for combination therapy[J].Small，2021，17(43)：e2102624.

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