mRNA疗法在肿瘤免疫治疗中的应用
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摘要
mRNA疗法以mRNA为制剂治疗疾病,是一种新兴的基因疗法,既可通过功能性蛋白的表达治疗基因缺陷性疾病或组织修复,又可通过抗原或抗体或受体的表达应用于免疫治疗,具有极大的应用价值。在肿瘤免疫治疗中,编码肿瘤相关抗原、特异性抗原、抗体或受体的mRNA进入细胞质后翻译成蛋白质,进而诱导特定免疫反应,实现疾病的预防与治疗。随着免疫治疗技术和mRNA的技术发展,针对恶性肿瘤和传染性疾病等的mRNA免疫治疗已步入临床应用阶段。本文将就mRNA的合成、纯化及修饰,基于mRNA的肿瘤免疫疗法、临床试验结果及开发新药所遇到的关键性机遇与挑战进行综述。
mRNA therapy, which involves the use of mRNAs as drugs for disease treatment, is a new kind of gene therapy. It can either treat diseases caused by gene deficiency or repair tissue through the expression of functional proteins, or be applied to immunotherapy through the expression of antigens, antibodies, or receptors, and is thus, of great value for various clinical applications. In tumor immunotherapy, mRNA that encodes tumor-related antigens, or specific antigens, antibodies, or receptors enters the cytoplasm and is translated into proteins, which then induce specific immune responses, thereby enabling disease prevention and treatment. With the development of immunotherapy and mRNA technologies, mRNA therapy for malignant tumors and infectious diseases has entered the stage of clinical applications. This review briefly introduces the synthesis, purification, and modification of mRNA, with emphasis on mRNA-based tumor immunotherapy, clinical trial results, and key opportunities and challenges in the development of new drugs.
mRNA therapy, which involves the use of mRNAs as drugs for disease treatment, is a new kind of gene therapy. It can either treat diseases caused by gene deficiency or repair tissue through the expression of functional proteins, or be applied to immunotherapy through the expression of antigens, antibodies, or receptors, and is thus, of great value for various clinical applications. In tumor immunotherapy, mRNA that encodes tumor-related antigens, or specific antigens, antibodies, or receptors enters the cytoplasm and is translated into proteins, which then induce specific immune responses, thereby enabling disease prevention and treatment. With the development of immunotherapy and mRNA technologies, mRNA therapy for malignant tumors and infectious diseases has entered the stage of clinical applications. This review briefly introduces the synthesis, purification, and modification of mRNA, with emphasis on mRNA-based tumor immunotherapy, clinical trial results, and key opportunities and challenges in the development of new drugs.
引文
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[3]Topalian SL,Drake CG,Pardoll DM.Immune checkpoint blockade:a common denominator approach to cancer therapy[J].Cancer Cell,2015,27(4):450-461.
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[10]Vaidyanathan S,Azizian KT,Haque A,et al.Uridine depletion and chemical modification increase cas9 mRNA activity and reduce immunogenicity without HPLC purification[J].Mol Ther Nucleic Acids,2018,12:530-542.
[11]Boccaletto P,Machnicka MA,Purta E,et al.MODOMICS:a database of RNA modification pathways.2017 update[J].Nucleic Acids Res,2018,46(D1):303-307.
[12]Li X,Ma S,Yi C.Pseudouridine:the fifth RNA nucleotide with renewed interests[J].Curr Opin Chem Biol,2016,33:108-116.
[13]Huber SM,van Delft P,Mendil L,et al.Formation and abundance of5-hydroxymethylcytosine in RNA[J].Chembiochem,2015,16(5):752-755.
[14]Song J,Yi C.Chemical Modifications to RNA:a new layer of gene expression regulation[J].ACS Chem Biol,2017,12(2):316-325.
[15]Kariko K,Muramatsu H,Ludwig J,et al.Generating the optimal mRNA for therapy:HPLC purification eliminates immune activation and improves translation of nucleoside-modified,protein-encoding mRNA[J].Nucleic Acids Res,2011,39(21):e142.
[16]Thess A,Grund S,Mui BL,et al.Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals[J].Mol Ther,2015,23(9):1456-1464.
[17]Vacchelli E,Vitale I,Eggermont A,et al.Trial watch:Dendritic cellbased interventions for cancer therapy[J].Oncoimmunology,2013,2(10):e25771.
[18]Mu LJ,Kyte JA,Kvalheim G,et al.Immunotherapy with allotumour mRNA-transfected dendritic cells in androgen-resistant prostate cancer patients[J].Br J Cancer,2005,93(7):749-756.
[19]Vik-Mo EO,Nyakas M,Mikkelsen BV,et al.Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma[J].Cancer Immunol Immunother,2013,62(9):1499-1509.
[20]Yadav M,Jhunjhunwala S,Phung QT,et al.Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing[J].Nature,2014,515(7528):572-576.
[21]Cheever MA,Allison JP,Ferris AS,et al.The prioritization of cancer antigens:a national cancer institute pilot project for the acceleration of translational research[J].Clin Cancer Res,2009,15(17):5323-5337.
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[23]Yarchoan M,Johnson BA 3rd,Lutz ER,et al.Targeting neoantigens to augment antitumour immunity[J].Nat Rev Cancer,2017,17(4):209-222.
[24]Matsushita H,Vesely MD,Koboldt DC,et al.Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting[J].Nature,2012,482(7385):400-404.
[25]Tran E,Robbins PF,Rosenberg SA.Final common pathway'of human cancer immunotherapy:targeting random somatic mutations[J].Nat Immunol,2017,18(3):255-262.
[26]Alexandrov LB,Nik-Zainal S,Wedge DC,et al.Signatures of mutational processes in human cancer[J].Nature,2013,500(7463):415-421.
[27]Wilgenhof S,Corthals J,Heirman C,et al.PhaseⅡstudy of autologous monocyte-derived mRNA electroporated dendritic cells(TriMixDC-MEL)plus ipilimumab in patients with pretreated advanced melanoma[J].J Clin Oncol,2016,34(12):1330-1338.
[28]Wilgenhof S,Van Nuffel AM,Benteyn D,et al.A phase IB study on intravenous synthetic mRNA electroporated dendritic cell immunotherapy in pretreated advanced melanoma patients[J].Ann Oncol,2013,24(10):2686-2693.
[29]Chen P,Liu X,Sun Y,et al.Dendritic cell targeted vaccines:Recent progresses and challenges[J].Hum Vaccin Immunother,2016,12(3):612-622.
[30]Aarntzen EH,Schreibelt G,Bol K,et al.Vaccination with mRNA-electroporated dendritic cells induces robust tumor antigen-specific CD4+and CD8+T cells responses in stage III and IV melanoma patients[J].Clin Cancer Res,2012,18(19):5460-5470.
[31]Anguille S,Van de Velde AL,Smits EL,et al.Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia[J].Blood,2017,130(15):1713-1721.
[32]Khoury HJ,Collins RH Jr,Blum W,et al.Immune responses and longterm disease recurrence status after telomerase-based dendritic cell immunotherapy in patients with acute myeloid leukemia[J].Cancer,2017,123(16):3061-3072.
[33]Batich KA,Reap EA,Archer GE,et al.Long-term survival in glioblastoma with cytomegalovirus pp65-targeted vaccination[J].Clin Cancer Res,2017,23(8):1898-1909.
[34]Reap EA,Suryadevara CM,Batich KA,et al.Dendritic cells enhance polyfunctionality of adoptively transferred T cells that target cytomegalovirus in glioblastoma[J].Cancer Res,2018,78(1):256-264.
[35]Pardi N,Hogan MJ,Pelc RS,et al.Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination[J].Nature,2017,543(7644):248-251.
[36]Sahin U,Derhovanessian E,Miller M,et al.Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer[J].Nature,2017,547(7662):222-226.
[37]Oberli MA,Reichmuth AM,Dorkin JR,et al.Lipid nanoparticle assisted mrna delivery for potent cancer immunotherapy[J].Nano Lett,2017,17(3):1326-1335.
[38]Robbins PF,Kassim SH,Tran TL,et al.A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor:long-term follow-up and correlates with response[J].Clin Cancer Res,2015,21(5):1019-1027.
[39]Schubert ML,Huckelhoven A,Hoffmann JM,et al.Chimeric antigen receptor t cell therapy targeting CD19-positive leukemia and lymphoma in the context of stem cell transplantation[J].Hum Gene Ther,2016,27(10):758-771.
[40]Beatty GL,Haas AR,Maus MV,et al.Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies[J].Cancer Immunol Res,2014,2(2):112-120.
[41]Svoboda J,Rheingold SR,Gill SI,et al.Nonviral RNA chimeric antigen receptor-modified T cells in patients with Hodgkin lymphoma[J].Blood,2018,132(10):1022-1026.
[42]Bertoletti A,Brunetto M,Maini MK,et al.T cell receptor-therapy in HBV-related hepatocellularcarcinoma[J].Oncoimmunology,2015,4(6):e1008354.
[43]Qasim W,Brunetto M,Gehring AJ,et al.Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells,targeting HBsAg in a liver transplant patient[J].J hepatol,2015,62(2):486-491.
[44]Szeto GL,Van Egeren D,Worku H,et al.Microfluidic squeezing for intracellular antigen loading in polyclonal B-cells as cellular vaccines[J].Sci Rep,2015,5:10276.
[45]Eggermont LJ,Paulis LE,Tel J,et al.Towards efficient cancer immunotherapy:advances in developing artificial antigen-presenting cells[J].Trends Biotechnol,2014,32(9):456-465.
[2]Kopp LM,Katsanis E.Targeted immunotherapy for pediatric solid tumors[J].Oncoimmunology,2016,5(3):e1087637.
[3]Topalian SL,Drake CG,Pardoll DM.Immune checkpoint blockade:a common denominator approach to cancer therapy[J].Cancer Cell,2015,27(4):450-461.
[4]Moore T,Wagner CR,Scurti GM,et al.Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells[J].Cancer Immunol Immunother,2018,67(2):311-325.
[5]Wang Y,Tang G,Xu L,et al.Construction of CD19-CAR retroviral vector and modification of its transduction of human T-lymphocytes[J].Zhonghua Xue Ye Xue Za Zhi,2015,36(4):331-336.
[6]Park JH,Riviere I,Gonen M,et al.Long-Term Follow-up of CD19CAR Therapy in Acute Lymphoblastic Leukemia[J].N Engl J Med,2018,378(5):449-459.
[7]Kallen KJ,Heidenreich R,Schnee M,et al.A novel,disruptive vaccination technology:self-adjuvanted RNActive((R))vaccines[J].Hum Vaccin Immunother,2013,9(10):2263-2276.
[8]Vallazza B,Petri S,Poleganov MA,et al.Recombinant messenger RNA technology and its application in cancer immunotherapy,transcript replacement therapies,pluripotent stem cell induction,and beyond[J].Wiley Interdiscip Rev RNA,2015,6(5):471-499.
[9]Sahin U,Kariko K,Tureci O.mRNA-based therapeutics--developing a new class of drugs[J].Nat Rev Drug Discov,2014,13(10):759-780.
[10]Vaidyanathan S,Azizian KT,Haque A,et al.Uridine depletion and chemical modification increase cas9 mRNA activity and reduce immunogenicity without HPLC purification[J].Mol Ther Nucleic Acids,2018,12:530-542.
[11]Boccaletto P,Machnicka MA,Purta E,et al.MODOMICS:a database of RNA modification pathways.2017 update[J].Nucleic Acids Res,2018,46(D1):303-307.
[12]Li X,Ma S,Yi C.Pseudouridine:the fifth RNA nucleotide with renewed interests[J].Curr Opin Chem Biol,2016,33:108-116.
[13]Huber SM,van Delft P,Mendil L,et al.Formation and abundance of5-hydroxymethylcytosine in RNA[J].Chembiochem,2015,16(5):752-755.
[14]Song J,Yi C.Chemical Modifications to RNA:a new layer of gene expression regulation[J].ACS Chem Biol,2017,12(2):316-325.
[15]Kariko K,Muramatsu H,Ludwig J,et al.Generating the optimal mRNA for therapy:HPLC purification eliminates immune activation and improves translation of nucleoside-modified,protein-encoding mRNA[J].Nucleic Acids Res,2011,39(21):e142.
[16]Thess A,Grund S,Mui BL,et al.Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals[J].Mol Ther,2015,23(9):1456-1464.
[17]Vacchelli E,Vitale I,Eggermont A,et al.Trial watch:Dendritic cellbased interventions for cancer therapy[J].Oncoimmunology,2013,2(10):e25771.
[18]Mu LJ,Kyte JA,Kvalheim G,et al.Immunotherapy with allotumour mRNA-transfected dendritic cells in androgen-resistant prostate cancer patients[J].Br J Cancer,2005,93(7):749-756.
[19]Vik-Mo EO,Nyakas M,Mikkelsen BV,et al.Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma[J].Cancer Immunol Immunother,2013,62(9):1499-1509.
[20]Yadav M,Jhunjhunwala S,Phung QT,et al.Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing[J].Nature,2014,515(7528):572-576.
[21]Cheever MA,Allison JP,Ferris AS,et al.The prioritization of cancer antigens:a national cancer institute pilot project for the acceleration of translational research[J].Clin Cancer Res,2009,15(17):5323-5337.
[22]Linette GP,Carreno BM.Neoantigen vaccines pass the immunogenicity test[J].Trends Mol Med,2017,23(10):869-871.
[23]Yarchoan M,Johnson BA 3rd,Lutz ER,et al.Targeting neoantigens to augment antitumour immunity[J].Nat Rev Cancer,2017,17(4):209-222.
[24]Matsushita H,Vesely MD,Koboldt DC,et al.Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting[J].Nature,2012,482(7385):400-404.
[25]Tran E,Robbins PF,Rosenberg SA.Final common pathway'of human cancer immunotherapy:targeting random somatic mutations[J].Nat Immunol,2017,18(3):255-262.
[26]Alexandrov LB,Nik-Zainal S,Wedge DC,et al.Signatures of mutational processes in human cancer[J].Nature,2013,500(7463):415-421.
[27]Wilgenhof S,Corthals J,Heirman C,et al.PhaseⅡstudy of autologous monocyte-derived mRNA electroporated dendritic cells(TriMixDC-MEL)plus ipilimumab in patients with pretreated advanced melanoma[J].J Clin Oncol,2016,34(12):1330-1338.
[28]Wilgenhof S,Van Nuffel AM,Benteyn D,et al.A phase IB study on intravenous synthetic mRNA electroporated dendritic cell immunotherapy in pretreated advanced melanoma patients[J].Ann Oncol,2013,24(10):2686-2693.
[29]Chen P,Liu X,Sun Y,et al.Dendritic cell targeted vaccines:Recent progresses and challenges[J].Hum Vaccin Immunother,2016,12(3):612-622.
[30]Aarntzen EH,Schreibelt G,Bol K,et al.Vaccination with mRNA-electroporated dendritic cells induces robust tumor antigen-specific CD4+and CD8+T cells responses in stage III and IV melanoma patients[J].Clin Cancer Res,2012,18(19):5460-5470.
[31]Anguille S,Van de Velde AL,Smits EL,et al.Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia[J].Blood,2017,130(15):1713-1721.
[32]Khoury HJ,Collins RH Jr,Blum W,et al.Immune responses and longterm disease recurrence status after telomerase-based dendritic cell immunotherapy in patients with acute myeloid leukemia[J].Cancer,2017,123(16):3061-3072.
[33]Batich KA,Reap EA,Archer GE,et al.Long-term survival in glioblastoma with cytomegalovirus pp65-targeted vaccination[J].Clin Cancer Res,2017,23(8):1898-1909.
[34]Reap EA,Suryadevara CM,Batich KA,et al.Dendritic cells enhance polyfunctionality of adoptively transferred T cells that target cytomegalovirus in glioblastoma[J].Cancer Res,2018,78(1):256-264.
[35]Pardi N,Hogan MJ,Pelc RS,et al.Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination[J].Nature,2017,543(7644):248-251.
[36]Sahin U,Derhovanessian E,Miller M,et al.Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer[J].Nature,2017,547(7662):222-226.
[37]Oberli MA,Reichmuth AM,Dorkin JR,et al.Lipid nanoparticle assisted mrna delivery for potent cancer immunotherapy[J].Nano Lett,2017,17(3):1326-1335.
[38]Robbins PF,Kassim SH,Tran TL,et al.A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor:long-term follow-up and correlates with response[J].Clin Cancer Res,2015,21(5):1019-1027.
[39]Schubert ML,Huckelhoven A,Hoffmann JM,et al.Chimeric antigen receptor t cell therapy targeting CD19-positive leukemia and lymphoma in the context of stem cell transplantation[J].Hum Gene Ther,2016,27(10):758-771.
[40]Beatty GL,Haas AR,Maus MV,et al.Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies[J].Cancer Immunol Res,2014,2(2):112-120.
[41]Svoboda J,Rheingold SR,Gill SI,et al.Nonviral RNA chimeric antigen receptor-modified T cells in patients with Hodgkin lymphoma[J].Blood,2018,132(10):1022-1026.
[42]Bertoletti A,Brunetto M,Maini MK,et al.T cell receptor-therapy in HBV-related hepatocellularcarcinoma[J].Oncoimmunology,2015,4(6):e1008354.
[43]Qasim W,Brunetto M,Gehring AJ,et al.Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells,targeting HBsAg in a liver transplant patient[J].J hepatol,2015,62(2):486-491.
[44]Szeto GL,Van Egeren D,Worku H,et al.Microfluidic squeezing for intracellular antigen loading in polyclonal B-cells as cellular vaccines[J].Sci Rep,2015,5:10276.
[45]Eggermont LJ,Paulis LE,Tel J,et al.Towards efficient cancer immunotherapy:advances in developing artificial antigen-presenting cells[J].Trends Biotechnol,2014,32(9):456-465.