胶质母细胞瘤免疫治疗研究进展
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摘要
免疫治疗旨在提高机体对肿瘤的免疫应答。如今所采用的主要手段包括提高机体部分的免疫应答或针对靶向抗原刺激机体产生相应的免疫应答。其中,后者通常将重新启动免疫应答的细胞引入体内使免疫系统直接作用于靶标抗原。临床上,主要将免疫治疗应用于黑素瘤和前列腺瘤等实体瘤的治疗中。中枢神经系统曾被认为是免疫特免区,然而近年来大量的研究表明脑部的免疫系统处于高水平活化状态并能够与脑部肿瘤相互作用。因此,研究并利用这种免疫作用对于恶性脑部肿瘤的治疗十分重要。针对近年来恶性胶质母细胞瘤的免疫治疗进展进行了总结,并对中枢神经系统和胶质母细胞瘤的免疫机制、免疫治疗疫苗及T细胞疗法在肿瘤治疗中的研究进行了详细的介绍,以期为发展出更为有效的靶向治疗手段进而大幅提高GBM患者的生存时间带来新的思路。
Immunotherapy aims to increase the body's immune response to tumors. The primary means used today include increasing the immune response in the body part or generating a corresponding immune response against the targeted antigen stimulating organism. Among them, the latter usually introduces cells that restart the immune response into the body to directly act on the target antigen by the immune system. Clinically, immunotherapy is mainly applied to the treatment of solid tumors such as melanoma and prostate tumor. The central nervous system was once thought to be an immune privilege zone, but in recent years a large number of studies have shown that the brain's immune system is at a high level of activation and can interact with brain tumors. Therefore, research and use of this immune function is very important for the development of treatment of malignant brain tumors. This article summarized recent advances in immunotherapy for malignant glioblastoma, and provided a detailed introduction to the immunological mechanisms of central nervous system and glioblastoma, immunotherapy vaccines, and T cell therapy in cancer therapy.
Immunotherapy aims to increase the body's immune response to tumors. The primary means used today include increasing the immune response in the body part or generating a corresponding immune response against the targeted antigen stimulating organism. Among them, the latter usually introduces cells that restart the immune response into the body to directly act on the target antigen by the immune system. Clinically, immunotherapy is mainly applied to the treatment of solid tumors such as melanoma and prostate tumor. The central nervous system was once thought to be an immune privilege zone, but in recent years a large number of studies have shown that the brain's immune system is at a high level of activation and can interact with brain tumors. Therefore, research and use of this immune function is very important for the development of treatment of malignant brain tumors. This article summarized recent advances in immunotherapy for malignant glioblastoma, and provided a detailed introduction to the immunological mechanisms of central nervous system and glioblastoma, immunotherapy vaccines, and T cell therapy in cancer therapy.
引文
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[17] Jiang G M,Tan Y,Wang H,et al..The relationship between autophagy and the immune system and its applications for tumor immunotherapy[J].Mol.Cancer,2019,18(1):17.
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[26] Js H,Eh J,My K,et al..Glioma-secreted soluble factors stimulate microglial activation:The role of interleukin-1β and tumor necrosis factor-α[J].J.Neuroimmunol.,2016,298:165-171.
[27] Valentini D,Rao M,Meng Q,et al..Identification of neoepitopes recognized by tumor-infiltrating lymphocytes (TILs) from patients with glioma[J].Oncotarget,2018,9(28):19469-19480.
[28] Kapp K,Volz B,Curran M A,et al..EnanDIM - a novel family of L-nucleotide-protected TLR9 agonists for cancer immunotherapy[J].J.Immunother.Cancer,2019,7(1):5.
[29] Neidert M C,Schoor O,Trautwein C,et al..Natural HLA class I ligands from glioblastoma:Extending the options for immunotherapy[J].J.Neuro Oncol.,2013,111(3):285-294.
[30] Marian Christoph N,Oliver S,Claudia T,et al..Natural HLA class I ligands from glioblastoma:Extending the options for immunotherapy[J].J.Neuro Oncol.,2013,111(3):285-294.
[31] Wong A J,Ruppert J M,Bigner S H,et al..Structural alterations of the epidermal growth factor receptor gene in human gliomas[J].Proc.Natl.Acade.Sci.USA,1992,89(7):2965-2969.
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[33] Theresa S,Lukas B,Stefan P,et al..A vaccine targeting mutant IDH1 induces antitumour immunity[J].Nature,2014,512(7514):324-327.
[34] Diplas B H,He X,Brosnancashman J A,et al..The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma[J].Nat.Commun.,2018,9(1):2087-2098.
[35] Landi D,Hegde M,Ahmed N.Human cytomegalovirus antigens in malignant gliomas as targets for adoptive cellular therapy[J].Front.Oncol.,2014,4:338.
[36] Rampling R,Peoples S,Mulholland P J,et al..A cancer research UK first time in human phase I trial of IMA950 (novel multi peptide therapeutic vaccine) in patients with newly diagnosed glioblastoma[J].Clin.Cancer Res.Off.J.Am.Assoc.Cancer Res.,2016,22(19):4776.
[37] Hua G,Yan Y,Guo L,et al..Prognostic role of HSPs in human gastrointestinal cancer:A systematic review and meta-analysis[J].Oncotargets Ther.,2018,11:351-359.
[38] Wruck F,Avellaneda M J,Koers E J,et al..Protein folding mediated by trigger factor and Hsp70:New insights from single-molecule approaches[J].J.Mol.Biol.,2018,430(4):438-449.
[39] Crane C A,Han S J,Ahn B,et al..Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 kD chaperone protein[J].Clin.Cancer Res.Off.J.Am.Assoc.Cancer Res.,2013,19(1):205-214.
[40] Bloch O,Crane C A,Fuks Y,et al..Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma:A phase II,single-arm trial[J].Neuro Oncol.,2014,16(2):274-279.
[41] Choi P J,Tubbs R S,Oskouian R J.Emerging cellular therapies for glioblastoma multiforme[J].Cureus,2018,10(3):e2305.
[42] Sayegh E T,Oh T,Fakurnejad S,et al..Vaccine therapies for patients with glioblastoma[J].J.Neuro Oncol.,2014,119(3):531-546.
[43] Schirrmacher V,Haas C,R,Ahlert T,et al..Human tumor cell modification by virus infection:An efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus[J].Gene Ther.,1999,6(1):63-73.
[44] Hans H S,Matteo M B,Philipp B,et al..Antitumor vaccination of patients with glioblastoma multiforme:A pilot study to assess feasibility,safety,and clinical benefit[J].J.Clin.Oncol.,2004,22(21):4272-4281.
[45] Berzofsky J A,Terabe M,Trepel J B,et al..Cancer vaccine strategies:Translation from mice to human clinical trials[J].Cancer Immunol.Immunother.,2018,67(12):1863-1869.
[46] Santos P M,Butterfield L H.Dendritic cell-based cancer vaccines[J].J.Immunol.,2018,200(2):443.
[47] Slovin S F.Sipuleucel-T:When and for whom to recommend it[J].Oncology,2017,31(12):900.
[48] Prins R M,Horacio S,Vera K,et al..Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy[J].Clin.Cancer Res.Off.J.Am.Assoc.Cancer Res.,2011,17(6):1603.
[49] Liau L M,Ashkan K,Tran D D,et al..First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma[J].J.Transl.Med.,2018,16(1):142.
[50] Phuphanich,Surasak,Rudnick,et al..Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma[J].Cancer Immunol.Immunother.,2013,62(1):125-135.
[51] Hdeib A,Sloan A.Immunotherapy for malignant primary brain tumors with ICT-107,a dendritic cell vaccine[J].Expert Opin.Orphan Drugs,2017,5(1):85-89.
[52] Rahman M,Dastmalchi F,Karachi A,et al..The role of CMV in glioblastoma and implications for immunotherapeutic strategies[J].OncoImmunology,2019,8(1):e1514921.
[53] Liu Z,Poiret T,Meng Q,et al..Epstein-barr virus- and cytomegalovirus-specific immune response in patients with brain cancer[J].J.Transl.Med.,2018,16(1):182.
[54] Prins R M,Cloughesy T F,Liau L M.Cytomegalovirus immunity after vaccination with autologous glioblastoma lysate[J].New England J.Med.,2008,359(5):539-41.
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