溶瘤病毒及其在肿瘤治疗中的应用
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摘要
溶瘤病毒在肿瘤治疗中具有重要应用潜力。它能诱导机体抗肿瘤免疫反应,这是其产生疗效的重要基础之一。溶瘤病毒的安全性和靶向性在逐渐提高,但最终疗效尚不令人满意。溶瘤病毒未来的发展方向之一是与其他肿瘤疗法联合,尤其是与免疫疗法,如免疫检查点抑制剂、免疫调节细胞因子(集落刺激因子、白细胞介素、干扰素和趋化因子等)、共刺激分子、嵌合抗原受体T细胞(CAR-T)和双特异性T细胞衔接蛋白(BiTE)等联合。降低机体抗病毒免疫是另一个重要方向。本文从溶瘤病毒概念、发展历程、种类、机制、安全性、靶向性,以及提高疗效策略等几方面分别进行阐述。
Oncolytic viruses play an important role in tumor therapy. Their safety and selectivity are gradually improving,but the ultimate efficacy is not satisfactory,which has become a key bottleneck limiting their development. Oncolytic viruses can induce antitumor immune response in the body,which is an important basis for their efficacy. One of the future directions for the therapeutic application of oncolytic viruses is its combination with other tumor therapies,especially with the immunotherapy,including the immuno-checkpoint inhibitors,immuno-regulatory cytokines(such as colony-stimulating factors,interleukins,interferons and chemokines),costimulatory molecules,CAR-T and bispecific T-cell engagers(BiTE). In addition,reducing the body′s antiviral immunity is another important direction. The concept,history,species,mechanism,safety and selectivity of oncolytic viruses as well as the therapeutic strategies for improving their efficacy are reviewed in this paper.
Oncolytic viruses play an important role in tumor therapy. Their safety and selectivity are gradually improving,but the ultimate efficacy is not satisfactory,which has become a key bottleneck limiting their development. Oncolytic viruses can induce antitumor immune response in the body,which is an important basis for their efficacy. One of the future directions for the therapeutic application of oncolytic viruses is its combination with other tumor therapies,especially with the immunotherapy,including the immuno-checkpoint inhibitors,immuno-regulatory cytokines(such as colony-stimulating factors,interleukins,interferons and chemokines),costimulatory molecules,CAR-T and bispecific T-cell engagers(BiTE). In addition,reducing the body′s antiviral immunity is another important direction. The concept,history,species,mechanism,safety and selectivity of oncolytic viruses as well as the therapeutic strategies for improving their efficacy are reviewed in this paper.
引文
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[2]Dock G.The influence of complicating diseases upon leukaemia[J].Am J Med Sci,1904,127(4):563-592.
[3]邓洪新,魏于全.肿瘤基因治疗的研究现状和展望[J].中国肿瘤生物治疗杂志,2015,22(2):170-176.
[4]Pol J,Kroemer G,Galluzzi L.First oncolytic virus approved for melanoma immunotherapy[J].OncoImmunology,2016,5:1-3.
[5]Wei D,Xu J,Liu X,et al.Fighting cancer with viruses:oncolytic virus therapy in China[J].Human Gene Ther,2017,29(2):151-159.
[6]Kirn DH,Thorne SH.Targeted and armed oncolytic poxviruses:a novel multi-mechanistic therapeutic class for cancer[J].Nat Rev Cancer,2009,9(1):64-71.
[7]Efferson CL,Tsuda N,Kawano K,et al.Prostate tumor cells infected with a recombinant influenza virus expressing a truncated NS1 protein activate cytolytic CD8+cells to recognize noninfected tumor cells[J].J Virol,2006,80(1):383-394.
[8]Lin Y,Zhang H,Liang J,et al.Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers[J].Proc Nat Acad Sci USA,2014,111(42):4504-4512.
[9]Garant KA,Shmulevitz M,Pan L,et al.Oncolytic reovirus induces intracellular redistribution of Ras to promote apoptosis and progeny virus release[J].Oncogene,2016,35(6):771-782.
[10]Kaufman HL,Kohlhapp FJ,Zloza A.Oncolytic viruses:a new class of immunotherapy drugs[J].Nat Rev Drug Discov,2015,14(9):642.
[11]Vile RG.How to train your oncolytic virus:the immunological sequel[J].Mol Ther J Am Soci Gene Ther,2014,22(11):1881-1884.
[12]Zamarin D,Holmgaard RB,Subudhi SK,et al.Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy[J].Sci Translat Med,2014,226(6):226-232.
[13]Bommareddy PK,Shettigar M,Kaufman HL.Integrating oncolytic viruses in combination cancer immunotherapy[J].Nat Rev Immunol,2018,18(8):498-513.
[14]Slaney CY,Darcy PK.Releasing the brake on oncolytic viral therapy[J].Clin Cancer Res,2015,21(24):5417-5419.
[15]Poppers J,Mulvey M,Khoo D,et al.Inhibition of PKR activation by the proline-rich RNA binding domain of the herpes simplex virus type 1 Us11 protein[J].J Virol,2000,74(23):11215-11221.
[16]Kaufman HL,Kim DW,Deraffele G,et al.Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stageⅢc andⅣmelanoma[J].Ann Surg Oncol,2010,17(3):718-730.
[17]Kaufman HL,Bines SD.OPTIM Trial:a phaseⅢtrial of an oncolytic herpes virus encoding GM-CSF for unresectable stageⅢorⅣmelanoma[J].Fut Oncol,2010,6(6):941-949.
[18]夏忠军,常建华,张力,等.基因工程腺病毒(H101)瘤内注射联合化疗治疗头颈部及食管鳞癌的Ⅲ期临床研究[J].癌症,2004,23(12):1666-1670.
[19]Lin XJ,Li QJ,Lao XM,et al.Transarterial injection of recombinant human type-5 adenovirus H101 in combination with transarterial chemoembolization(TACE)improves overall and progressive-free survival in unresectable hepatocellular carcinoma(HCC)[J].BMC Cancer,2015,15(1):707.
[20]杨帆,卢斌,胡春燕,等.胸腔内注射重组人5型腺病毒治疗晚期肺癌恶性胸腔积液的疗效观察[J].实用医学杂志,2013,29(17):2885-2886.
[21]肖斌,金震东,李兆申,等.瘤内注射重组溶瘤病毒联合吉西他滨化疗治疗中晚期胰腺癌l9例疗效观察[J].中华胰腺病杂志,2011,11(3):163-166.
[22]Scholl SM,Balloul JM,Le GG,et al.Recombinant vaccinia virus encoding human MUC1 and IL2 as immunotherapy in patients with breast cancer[J].J Immunother,2000,23(5):570-580.
[23]Cole DJ,Wilson MC,Baron PL,et al.PhaseⅠstudy of recombinant CEA vaccinia virus vaccine with post vaccination CEA peptide challenge[J].Human Gene Ther,1996,7(11):1381-1394.
[24]Gulley JL,Arlen PM,Tsang KY,et al.Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinoma[J].Clin Cancer Res,2008,14(10):3060-3069.
[25]Heo J,Reid T,Ruo L,et al.Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer[J].Nat Med,2013,19(3):329-336.
[26]Shafren DR,Au GG,Nguyen T,et al.Systemic therapy of malignant human melanoma tumors by a common cold-producing enterovirus,coxsackie virus a21[J].Clin Cancer Res,2004,10(1):53-60.
[27]Miyamoto S,Inoue H,Nakamura T,et al.Coxsackie virus B3 is an oncolytic virus with immunostimulatory properties that is active against lung adenocarcinoma[J].Cancer Res,2012,72(10):2609-2621.
[28]Andtbacka RH.Final data from CALM:a phaseⅡstudy of Coxsackie virus A21(CVA21)oncolytic virus immunotherapy in patients with advanced melanoma[J].J Clin Oncol,2015,33:S9030.
[29]Bluming A,Ziegler JL.Regression of Burkitt′s lymphoma in association with measles infection[J].Lancet,1971,298(7715):105-106.
[30]Pasquinucci G.Possible effect of measles on leukaemia[J].Lancet,1971,297(7690):136.
[31]Taqi AM,Abdurrahman MB,Yakubu AM,et al.Regression of Hodgkin′s disease after measles[J].Lancet,1981,317(8229):1112.
[32]D?rig,Ruth E,Marcil,et al.The human CD46 molecule is a receptor for measles virus(Edmonston strain)[J].Cell,1993,75(2):295-305.
[33]Platanias LC.Mechanisms of type-Ⅰ-and type-Ⅱ-interferon mediated signalling[J].Nat Rev Immunol,2005,5(5):375.
[34]Farassati F,Yang AD,Lee PW.Oncogenes in Ras signalling pathway dictate host-cell permissiveness to herpes simplex virus1[J].Nat Cell Biol,2001,3(8):745-750.
[35]Pan W,Bodempudi V,Esfandyari T,et al.Utilizing Ras signaling pathway to direct selective replication of herpes simplex virus-1[J].PLoS One,2009,4(8):e6514.
[36]Parato KA,Breitbach CJ,Le BF,et al.The oncolytic poxvirus JX-594 selectively replicates in and destroys cancer cells driven by genetic pathways commonly activated in cancers[J].Mol Ther,2012,20(4):749-758.
[37]Cheng PH,Rao XM,Duan X,et al.Virotherapy targeting cyclin E overexpression in tumors with adenovirus-enhanced cancerselective promoter[J].J Mol Med,2015,93(2):211-223.
[38]Deweese TL,Van d PH,Li S,et al.A phaseⅠtrial of CV706,a replication-competent,PSA selective oncolytic adenovirus,for the treatment of locally recurrent prostate cancer following radiation therapy[J].Cancer Res,2001,61(20):7464-7472.
[39]Post DE,Sandberg EM,Kyle MM,et al.Targeted cancer gene therapy using a hypoxia inducible factor dependent oncolytic adenovirus armed with interleukin-4[J].Cancer Res,2007,67(14):6872.
[40]Hikichi M,Kidokoro M,Haraguchi T,et al.MicroRNA regulation of glycoprotein B5R in oncolytic vaccinia virus reduces viral pathogenicity without impairing its antitumor efficacy[J].Mol Ther,2011,19(6):1107.
[41]Morrison J,Briggs SS,Green N,et al.Virotherapy of ovarian cancer with polymer-cloaked adenovirus retargeted to the epidermal growth factor receptor[J].Mol Ther,2008,16(2):244-251.
[42]Zhang H,Lin Y,Li K,et al.Naturally existing oncolytic virus M1 is nonpathogenic for the nonhuman primates after multiple rounds of repeated intravenous injections[J].Human Gene Ther,2016,27(9):700-711.
[43]Kasai K,Nakashima H,Fang L,et al.Toxicology and biodistribution studies for MGH2.1,an oncolytic virus that expresses two prodrug-activating genes,in combination with prodrugs[J].Mol Ther Nucleic Acids,2013,2(8):e113.
[44]Cheng X,Wang W,Xu Q,et al.Genetic modification of oncolytic newcastle disease virus for cancer therapy[J].J Virol,2016,90(11):5343-5352.
[45]Pesonen S,Diaconu I,Kangasniemi L,et al.Oncolytic immunotherapy of advanced solid tumors with a CD40L-expressing replicating adenovirus:assessment of safety and immunologic responses in patients[J].Cancer Res,2012,72(7):1621-1631.
[46]Bustos M.A blood-tumor barrier limits gene transfer to experimental liver cancer:the effect of vasoactive compounds[J].Gene Ther,2000,7(21):1824-1832.
[47]Eisenberg DP,Carpenter SG,Adusumilli PS,et al.Hyperthermia potentiates oncolytic herpes viral killing of pancreatic cancer through a heat shock protein pathway[J].Surgery,2010,148(2):325-334.
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