肿瘤新抗原在恶性肿瘤治疗和预后分析中的应用
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摘要
近年来随着二代测序技术,特别是全外显子测序和生物信息技术的进步,肿瘤的精准免疫治疗得到了很大发展;肿瘤新抗原的研究更是为肿瘤的免疫治疗提供了新的研究方向.本文基于近十年来关于肿瘤新抗原的研究,系统介绍精准医疗时代肿瘤新抗原在恶性肿瘤治疗上的作用和可能的应用,以及肿瘤新抗原研究中可能遇到的挑战.
In the last decade, there have been an endless number of cancer therapy strategies, and the study of tumor neoantigens provides a new direction for cancer immune therapy. With the development of deep sequencing, especially whole-exome sequencing, great opportunities have been provided to precise immune therapy of malignant tumors. This article systematically summarizes the research on tumor neoantigens in the past ten years and the challenges most likely to be encountered, describes the role of neoantigens in the treatment of malignant tumors, and discusses their possible clinical applications.
In the last decade, there have been an endless number of cancer therapy strategies, and the study of tumor neoantigens provides a new direction for cancer immune therapy. With the development of deep sequencing, especially whole-exome sequencing, great opportunities have been provided to precise immune therapy of malignant tumors. This article systematically summarizes the research on tumor neoantigens in the past ten years and the challenges most likely to be encountered, describes the role of neoantigens in the treatment of malignant tumors, and discusses their possible clinical applications.
引文
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2 Kawashima I,Tsai V,Southwood S,Takesako K,Sette A,Celis E.Identification of HLA-A3-restricted cytotoxic T lymphocyte epitopes from carcinoembryonic antigen and HER-2/neu by primary in vitro immunization with peptide-pulsed dendritic cells.Cancer Res 1999;59:431-435[PMID:9927058]
3 Liu CC,Yang H,Zhang R,Zhao JJ,Hao DJ.Tumourassociated antigens and their anti-cancer applications.Eur JCancer Care(Engl)2017;26[PMID:26853428 DOI:10.1111/ecc.12446]
4 Gubin MM,Artyomov MN,Mardis ER,Schreiber RD.Tumor neoantigens:building a framework for personalized cancer immunotherapy.J Clin Invest 2015;125:3413-3421[PMID:26258412 DOI:10.1172/jci80008]
5 Blankenstein T,Leisegang M,Uckert W,Schreiber H.Targeting cancer-specific mutations by T cell receptor gene therapy.Curr Opin Immunol 2015;33:112-119[PMID:25728991 DOI:10.1016/j.coi.2015.02.005]
6 Whitehurst AW.Cause and consequence of cancer/testis antigen activation in cancer.Annu Rev Pharmacol Toxicol2014;54:251-272[PMID:24160706 DOI:10.1146/annurevpharmtox-011112-140326]
7 Arum CJ,Anderssen E,Viset T,Kodama Y,Lundgren S,Chen D,Zhao CM.Cancer immunoediting from immunosurveillance to tumor escape in microvillus-formed niche:a study of syngeneic orthotopic rat bladder cancer model in comparison with human bladder cancer.Neoplasia2010;12:434-442[PMID:20563246]
8 Interleukin-2:sunrise for immunotherapy?Lancet 1989;1:308[PMID:2563463]
9 Rosenberg SA,Spiess P,Lafreniere R.A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes.Science 1986;233:1318-1321[PMID:3489291DOI:10.1126/science.3489291]
10 Muzzey D,Evans EA,Lieber C.Understanding the Basics of NGS:From Mechanism to Variant Calling.Curr Genet Med Rep 2015;3:158-165[PMID:26566462 DOI:10.1007/s40142-015-0076-8]
11 Chang YS,Huang HD,Yeh KT,Chang JG.Evaluation of whole exome sequencing by targeted gene sequencing and Sanger sequencing.Clin Chim Acta 2017;471:222-232[PMID:28624499 DOI:10.1016/j.cca.2017.06.015]
12 Rosenberg SA,Yang JC,Sherry RM,Kammula US,Hughes MS,Phan GQ,Citrin DE,Restifo NP,Robbins PF,Wunderlich JR,Morton KE,Laurencot CM,Steinberg SM,White DE,Dudley ME.Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy.Clin Cancer Res 2011;17:4550-4557[PMID:21498393 DOI:10.1158/1078-0432.ccr-11-0116]
13 Lu YC,Yao X,Li YF,El-Gamil M,Dudley ME,Yang JC,Almeida JR,Douek DC,Samuels Y,Rosenberg SA,Robbins PF.Mutated PPP1R3B is recognized by T cells used to treat a melanoma patient who experienced a durable complete tumor regression.J Immunol 2013;190:6034-6042[PMID:23690473 DOI:10.4049/jimmunol.1202830]
14 Robbins PF,Lu YC,El-Gamil M,Li YF,Gross C,Gartner J,Lin JC,Teer JK,Cliften P,Tycksen E,Samuels Y,Rosenberg SA.Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells.Nat Med 2013;19:747-752[PMID:23644516 DOI:10.1038/nm.3161]
15 Tran E,Turcotte S,Gros A,Robbins PF,Lu YC,Dudley ME,Wunderlich JR,Somerville RP,Hogan K,Hinrichs CS,Parkhurst MR,Yang JC,Rosenberg SA.Cancer immunotherapy based on mutation-specific CD4+T cells in a patient with epithelial cancer.Science 2014;344:641-645[PMID:24812403 DOI:10.1126/science.1251102]
16 Tran E,Ahmadzadeh M,Lu YC,Gros A,Turcotte S,Robbins PF,Gartner JJ,Zheng Z,Li YF,Ray S,Wunderlich JR,Somerville RP,Rosenberg SA.Immunogenicity of somatic mutations in human gastrointestinal cancers.Science 2015;350:1387-1390[PMID:26516200 DOI:10.1126/science.aad1253]
17 Tran E,Robbins PF,Lu YC,Prickett TD,Gartner JJ,Jia L,Pasetto A,Zheng Z,Ray S,Groh EM,Kriley IR,Rosenberg SA.T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer.N Engl J Med 2016;375:2255-2262[PMID:27959684DOI:10.1056/NEJMoa1609279]
18 Keilholz U,Weber J,Finke JH,Gabrilovich DI,Kast WM,Disis ML,Kirkwood JM,Scheibenbogen C,Schlom J,Maino VC,Lyerly HK,Lee PP,Storkus W,Marincola F,Worobec A,Atkins MB.Immunologic monitoring of cancer vaccine therapy:results of a workshop sponsored by the Society for Biological Therapy.J Immunother 2002;25:97-138[PMID:12074049 DOI:10.1097/00002371-200203000-00001]
19 Tjoa BA,Murphy GP.Development of dendritic-cell based prostate cancer vaccine.Immunol Lett 2000;74:87-93[PMID:10996633 DOI:10.1016/S0165-2478(00)00254-6]
20 Palucka K,Banchereau J.Dendritic-cell-based therapeutic cancer vaccines.Immunity 2013;39:38-48[PMID:23890062DOI:10.1016/j.immuni.2013.07.004]
21 Zhou H,Luo YP,Kaplan CD,Krüger,JA,Lee SH,Xiang R,Reisfeld RA.A DNA-based cancer vaccine enhances lymphocyte cross talk by engaging the NKG2D receptor.Blood 2006,107:3251-3257[DOI:10.1182/blood-2005-10-4231]
22 Mc Namara MA,Nair SK,Holl EK.RNA-Based Vaccines in Cancer Immunotherapy.J Immunol Res 2015;2015:794528[PMID:26665011 DOI:10.1155/2015/794528]
23 Iwasa S,Yamada Y,Heike Y,Shoji H,Honma Y,Komatsu N,Matsueda S,Yamada A,Morita M,Yamaguchi R,Tanaka N,Kawahara A,Kage M,Shichijo S,Sasada T,Itoh K.Phase I study of a new cancer vaccine of ten mixed peptides for advanced cancer patients.Cancer Sci 2016;107:590-600[PMID:26920496 DOI:10.1111/cas.12919]
24 Cheever MA,Allison JP,Ferris AS,Finn OJ,Hastings BM,Hecht TT,Mellman I,Prindiville SA,Viner JL,Weiner LM,Matrisian LM.The prioritization of cancer antigens:a national cancer institute pilot project for the acceleration of translational research.Clin Cancer Res 2009;15:5323-5337[PMID:19723653 DOI:10.1158/1078-0432.ccr-09-0737]
25 Ott PA,Hu Z,Keskin DB,Shukla SA,Sun J,Bozym DJ,Zhang W,Luoma A,Giobbie-Hurder A,Peter L,Chen C,Olive O,Carter TA,Li S,Lieb DJ,Eisenhaure T,Gjini E,Stevens J,Lane WJ,Javeri I,Nellaiappan K,Salazar AM,Daley H,Seaman M,Buchbinder EI,Yoon CH,Harden M,Lennon N,Gabriel S,Rodig SJ,Barouch DH,Aster JC,Getz G,Wucherpfennig K,Neuberg D,Ritz J,Lander ES,Fritsch EF,Hacohen N,Wu CJ.An immunogenic personal neoantigen vaccine for patients with melanoma.Nature 2017;547:217-221[PMID:28678778DOI:10.1038/nature22991]
26 Sahin U,Derhovanessian E,Miller M,Kloke BP,Simon P,L?wer M,Bukur V,Tadmor AD,Luxemburger U,Schr?rs B,Omokoko T,Vormehr M,Albrecht C,Paruzynski A,Kuhn AN,Buck J,Heesch S,Schreeb KH,Müller F,Ortseifer I,Vogler I,Godehardt E,Attig S,Rae R,Breitkreuz A,Tolliver C,Suchan M,Martic G,Hohberger A,Sorn P,Diekmann J,Ciesla J,Waksmann O,Brück AK,Witt M,Zillgen M,Rothermel A,Kasemann B,Langer D,Bolte S,Diken M,Kreiter S,Nemecek R,Gebhardt C,Grabbe S,H?ller C,Utikal J,Huber C,Loquai C,Türeci?.Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer.Nature 2017;547:222-226[PMID:28678784 DOI:10.1038/nature23003]
27 Hellmann MD,Snyder A.Making It Personal:Neoantigen Vaccines in Metastatic Melanoma.Immunity 2017;47:221-223[PMID:28813655 DOI:10.1016/j.immuni.2017.08.001]
28 Sonntag K,Hashimoto H,Eyrich M,Menzel M,Schubach M,D?cker D,Battke F,Courage C,Lambertz H,Handgretinger R,Biskup S,Schilbach K.Immune monitoring and TCRsequencing of CD4 T cells in a long term responsive patient with metastasized pancreatic ductal carcinoma treated with individualized,neoepitope-derived multipeptide vaccines:a case report.J Tran Med 2018;16:23[DOI:10.1186/s12967-018-1382-1]
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