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摘要: 肿瘤新生抗原是指由肿瘤细胞基因突变产生的特异性抗原,可激活CD4+ T和CD8+ T细胞产生免疫反应,抑制肿瘤生长。因肿瘤新生抗原未经历中枢性免疫耐受,故其免疫原性高。肿瘤新生抗原疫苗种类有DNA疫苗、RNA疫苗、树突状细胞疫苗及纳米疫苗等,是高度个体化疫苗,相对安全且副作用小。利用新一代测序技术和生物信息学技术鉴定和筛选新生抗原;利用佐剂或生物材料设计制备免疫原性更强的新生抗原疫苗。临床上肿瘤新生抗原疫苗可与免疫检查点抑制疗法、放疗、化疗等联合应用,为肿瘤患者提供个体化治疗方案。从肿瘤新生抗原的概念、肿瘤新生抗原疫苗的种类、设计制备方法以及临床应用等方面做一综述,以期为相关研究提供参考。Abstract: Tumor neoantigens, which are specific antigens produced by gene mutation in tumor cells, can activate CD4+ T and CD8+T cells to produce an immune response and inhibit tumor growth. The immunogenicity of neogenic antigens is high because they do not undergo central immune tolerance. Tumor neoantigen vaccines include DNA vaccines, RNA vaccines, dendritic cell vaccines and nano-vaccines, which are highly personalized with relatively safe with low side effects. Next-generation sequencing technology and bioinformatics technology are used to identify and screen neantigens; and adjuvants or biological materials are used to design and prepare more immunogenic neoantigen vaccines. Tumor neoantigen vaccine can be combined with immune checkpoint inhibition therapy, radiotherapy and chemotherapy to provide individualized treatment for tumor patients. This paper reviews the concept of tumor neoantigen, types of tumor neoantigen vaccines, design and preparation methods and clinical application, in order to provide some reference for related research.
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Keywords:
- tumor neoantigen /
- DNA vaccine /
- RNA vaccine /
- dendritic cell vaccine
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[1] Li L, Goedegebuure S P, Gillanders W E. Preclinical and clinical development of neoantigen vaccines[J].Ann Oncol, 2017, 28(Suppl 12):xii11-xii17.DOI: 10.1093/annonc/mdx681.
[2] Schumacher T N, Schreiber R D. Neoantigens in cancer immunotherapy[J].Science, 2015, 348(6230):69-74.
[3] Meler I, Gaudernack G, Gerritsen W, et al. Therapeutic vaccines for cancer:an overview of clinical trials[J].Nat Rev Clin Oncol, 2014, 11(9):509-524.
[4] Klebanoff C A, Acquavella N, Yu Z, et al. Therapeutic cancer vaccines:are we there yet?[J].Immunol Rev, 2011, 239(1):27-44.
[5] Wölfel T, Hauer M, Schneider J, et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma[J].Science, 1995, 269(5228):1281-1284.
[6] Tian H, He Y, Song X, et al. Nitrated T helper cell epitopes enhance the immunogenicity of HER2 vaccine and induce anti-tumor immunity[J].Cancer Lett, 2018, 430:79-87.
[7] Yarchoan M, Johnson B A, Lutz E R, et al. Targeting neoantigens to augment antitumour immunity[J].Nat Rev Cancer, 2017, 17(4):209-222.
[8] Fukushima S, Hirata S, Motomura Y, et al. Multiple antigen-targeted immunotherapy with α-galactosylceramide-loaded and genetically engineered dendritic cells derived from embryonic stem cells[J].J Immunother, 2009, 32(3):219-231.
[9] Rezaei T, Davoudian E, Khalili S, et al. Strategies in DNA vaccine for melanoma cancer[J].Pigment Cell Melanoma Res, 2021, 34(5):869-891.
[10] Gordy J T, Luo K, Kapoor A, et al. Treatment with an immature dendritic cell-targeting vaccine supplemented with IFN-α and an inhibitor of DNA methylation markedly enhances survival in a murine melanoma model[J].Cancer Immunol Immunother, 2020, 69(4):569-580.
[11] Gordy J T, Luo K, Zhang H, et al. Fusion of the dendritic cell-targeting chemokine MIP3α to melanoma antigen Gp100 in a therapeutic DNA vaccine significantly enhances immunogenicity and survival in a mouse melanoma model[J].J Immunother Cancer, 2016, 4:96.DOI: 10.1186/s40425-016-0189-y.
[12] Fassò M, Waitz R, Hou Y, et al. SPAS-1(stimulator of prostatic adenocarcinoma-specifific T cells)/SH3GLB2:a prostate tumor antigen identifified by CTLA-4 blockade[J].Proc Natl Acad Sci USA, 2008, 105(9):3509-3514.
[13] Xu S, Yang K, Li R, et al. mRNA vaccine era-mechanisms, drug platform and clinical prospection[J].Int J Mol Sci, 2020, 21(18):6582.DOI: 10.3390/ijms21186582.
[14] Stifter K, Dekhtiarenko I, Krieger J, et al. A tumor-specific neoepitope expressed in homologous/self or heterologous/viral antigens induced comparable effector CD8+ T-cell responses by DNA vaccination[J].Vaccine, 2020, 38(21):3711-3719.
[15] Sahin U, Oehm P, Derhovanessian E, et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma[J].Nature, 2020, 585(7823):107-112.
[16] Castle J C, Kreiter S, Diekmann J, et al. Exploiting the mutanome for tumor vaccination[J].Cancer Res, 2012, 72(5):1081-1091.
[17] Kreiter S, Vormehr M, van de Roemer N, et al. Mutant MHC class Ⅱ epitopes drive therapeutic immune responses to cancer[J].Nature, 2015, 520(7549):692-696.
[18] Sahin U, Türeci Ö. Personalized vaccines for cancer immunotherapy[J].Science, 2018, 359(6382):1355-1360.
[19] Peng M, Mo Y, Wang Y, et al. Neoantigen vaccine:an emerging tumor immunotherapy[J].Mol Cancer, 2019, 18(1):128.DOI: 10.1186/s12943-019-1055-6.
[20] Kadowaki N. Dendritic cells:a conductor of T cell differentiation[J].Allergol Int, 2007, 56(3):193-199.
[21] Fu C M, Zhou L, Mi Q S, et al. DC-based vaccines for cancer im munotherapy[J].Vaccines(Basel), 2020, 8(4):706.DOI: 10.3390/vaccines8040706Saito.
[22] Saito H, Kitagawa K, Yoneda T, et al. Combination of p53-DC vaccine and rAd-p53 gene therapy induced CTLs cytotoxic against p53-deleted human prostate cancer cells in vitro[J].Cancer Gene Ther, 2017, 24(7):289-296.
[23] Zhou L, Hou B, Wang D, et al. Engineering polymeric prodrug nanoplatform for vaccination immunotherapy of cancer[J].Nano Lett, 2020, 20(6):4393-4402.
[24] Sainz V, Moura L I F, Peres C, et al. α-Galactosylceramide and peptidebased nano-vaccine synergistically induced a strong tumor suppressive effect in melanoma[J].Acta Biomater, 2018, 76:193-207.
[25] Xu J, Lv J, Zhuang Q, et al. A general strategy towards personalized nanovaccines based on fluoropolymers for post-surgical cancer immunotherapy[J].Nat Nanotechnol, 2020, 15(12):1043-1052.
[26] Koh J, Kim S, Lee S N, et al. Therapeutic efficacy of cancer vaccine adjuvanted with nanoemulsion loaded with TLR7/8 agonist in lung cancer model[J].Nanomedicine, 2021, 37:102415.DOI: 10.1016/j.nano.2021.102415.
[27] Wen R, Umeano A C, Kou Y, et al. Nanoparticle systems for cancer vaccine[J].Nanomedicine(Lond), 2019, 14(5):627-648.
[28] Zhang R, Yuan F, Shu Y, et al. Personalized neoantigen-pulsed dendritic cell vaccines show superior immunogenicity to neoantigen-adjuvant vaccines in mouse tumor models[J].Cancer Immunol Immunother, 2020, 69(1):135-145.
[29] Bai P, Li Y, Zhou Q, et al. Immune-based mutation classification enables neoantigen prioritization and immune feature discovery in cancer immunotherapy[J].Oncoimmunology, 2021, 10(1):1868130.DOI: 10.1080/2162402X.2020.1868130.
[30] Yadav M, Jhunjhunwala S, Phung Q T, et al. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing[J].Nature, 2014, 515(7528):572-576.
[31] Ye X, Liang X, Chen Q, et al. Surgical tumor-derived personalized photothermal vaccine formulation for cancer immunotherapy[J].ACS Nano, 2019, 13(3):2956-2968.
[32] Gubin M M, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens[J].Nature, 2014, 515(7528):577-581.
[33] Ni Q, Zhang F, Liu Y, et al. A bi-adjuvant nanovaccine that potentiates immunogenicity of neoantigen for combination immunotherapy of colorectal cancer[J].Sci Adv, 2020, 6(12):eaaw6071.DOI: 10.1126/sciadv.aaw6071.
[34] Ott P A, Hu-Lieskovan S, Chmielowski B, et al. A phase Ib trial of personalized neoantigen therapy plus anti-PD-1 in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer[J].Cell, 2020, 183(2):347-362.e24.
[35] Tian H, Kang Y, Song X, et al. PDL1-targeted vaccine exhibits potent antitumor activity by simultaneously blocking PD1/PDL1 pathway and activating PDL1-specific immune responses[J].Cancer Lett, 2020, 476:170-182.
[36] Carreno B M, Magrini V, Becker-Hapak M, et al. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells[J].Science, 2015, 348(6236):803-808.
[37] Xu P, Luo H, Kong Y, et al. Cancer neoantigen:boosting immunotherapy[J].Biomed Pharmacother, 2020, 131:110640.DOI: 10.1016/j.biopha.2020.110640.
[38] Li F, Deng L, Jackson K R, et al. Neoantigen vaccination induces clinical and immunologic responses in non-small cell lung cancer patients harboring EGFR mutations[J].J Immunother Cancer, 2021, 9(7):e002531.DOI: 10.1136/jitc-2021-002531.
[39] Kinkead H L, Hopkins A, Lutz E, et al. Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer[J].JCI Insight, 2018, 3(20):e122857.DOI: 10.1172/jci.insight.122857.
[40] Li F, Chen C, Ju T, et al. Rapid tumor regression in an Asian lung cancer patient following personalized neo-epitope peptide vaccination[J].Oncoimmunology, 2016, 5(12):e1238539.DOI: 10.1080/2162402X.2016.1238539.
[41] Hu Z, Ott P A, Wu C J, et al. Towards personalized, tumourspecific, therapeutic vaccines for cancer[J].Nat Rev Immunol, 2018, 18(3):168-182.
[42] McGranahan N, Furness A J S, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade[J].Science, 2016, 351(6280):1463-1469.
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