基于核酸适配体的肿瘤免疫治疗进展
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摘要
肿瘤免疫治疗是通过调节机体的免疫功能来控制和杀伤肿瘤的一种治疗手段。针对免疫检查点的治疗等一系列临床突破使得肿瘤的免疫治疗受到了广泛重视。目前,抗体治疗和过继性细胞治疗是肿瘤免疫治疗的主要方式,但是这些方法仍具有副作用较强,实体瘤治疗难以实现,治疗费用高昂等缺点。因此改进和发展更加高效、安全、低成本的新技术仍十分必要。适配体是利用指数富集的配体系统进化技术筛选得到的单链寡核苷酸,有核酸"抗体"之称。适配体具有低免疫原性、组织穿透力强、易于化学合成与修饰等优势,且与其靶标的结合具有较好亲和力和特异性,可像抗体一样实现肿瘤的免疫治疗。对适配体在肿瘤免疫治疗相关技术中的新应用作一综述,主要包括基于免疫检查点的抗肿瘤作用、双特异性适配体的肿瘤免疫治疗、适配体靶向递送siRNA的肿瘤免疫治疗和适配体联合抗体的肿瘤免疫治疗等方面。
Tumor immunotherapy is aimed to inhibit the proliferation of tumor cell and kill the tumors through regulating the immunity of the body. In recent years,tumor immunotherapy has gained great progress in clinical practice,especially in the aspect of blocking the immune check point. The main methods for tumor immunotherapy are antibody therapy and adoptive cellular therapy. However,there are some shortages in the present immunotherapy,such as high side effects and high cost for treatment. Therefore,it is necessary to develop new methods that are efficient,safe and low cost. Aptamers are signal-strand DNA or RNA oligonucleotides obtained throughout systematic evolution of ligands by exponential enrichment( SELEX). The aptamers are similar to antibody,which can bind to their targets with high affinity and specificity. Moreover,aptamers have the advantages of low immunogenicity,penetrating tissues easily,convenient chemical synthesis and modification,and have the potential to take the similar role as the antibody for tumor immunotherapy.Presents the new applications of aptamers in cancer immunotherapy was reviewed,mainly including immune checkpoint immunotherapy,bispecific aptamer immunotherapy,aptamer-targeting siRNA immunotherapy and antibody-aptamer combination immunotherapy.
Tumor immunotherapy is aimed to inhibit the proliferation of tumor cell and kill the tumors through regulating the immunity of the body. In recent years,tumor immunotherapy has gained great progress in clinical practice,especially in the aspect of blocking the immune check point. The main methods for tumor immunotherapy are antibody therapy and adoptive cellular therapy. However,there are some shortages in the present immunotherapy,such as high side effects and high cost for treatment. Therefore,it is necessary to develop new methods that are efficient,safe and low cost. Aptamers are signal-strand DNA or RNA oligonucleotides obtained throughout systematic evolution of ligands by exponential enrichment( SELEX). The aptamers are similar to antibody,which can bind to their targets with high affinity and specificity. Moreover,aptamers have the advantages of low immunogenicity,penetrating tissues easily,convenient chemical synthesis and modification,and have the potential to take the similar role as the antibody for tumor immunotherapy.Presents the new applications of aptamers in cancer immunotherapy was reviewed,mainly including immune checkpoint immunotherapy,bispecific aptamer immunotherapy,aptamer-targeting siRNA immunotherapy and antibody-aptamer combination immunotherapy.
引文
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[2] Yee C. Adoptive T cell therapy:points to consider. Curr Opin Immunol,2018,51:197-203.
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[5]Arabi F,Torabi-Rahvar M,Shariati A,et al. Antigenic targets of CAR T cell therapy. A retrospective view on clinical trials. Exp Cell Res,2018,369(1):1-10.
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[7] Khalil D N,Smith E L,Brentjens R J,et al. The future of cancer treatment:immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol,2016,13(5):273-290.
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[9] Almagro J C,Daniels-Wells T R,Perez-Tapia S M,et al.Progress and challenges in the design and clinical development of antibodies for cancer therapy. Front Immunol,2017,8:1751.
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[11]Nasiri H,Valedkarimi Z,Aghebati-Maleki L,et al. Antibodydrug conjugates:Promising and efficient tools for targeted cancer therapy. J Cell Physiol,2018,233(9):6441-6457.
[12] Krishnamurthy A,Jimeno A. Bispecific antibodies for cancer therapy:A review. Pharmacol Ther,2018,185:122-134.
[13] Kontermann R E,Brinkmann U. Bispecific antibodies. Drug Discov Today,2015,20(7):838-847.
[14]Klebanoff C A,Rosenberg S A,Restifo N P. Prospects for geneengineered T cell immunotherapy for solid cancers. Nat Med,2016,22(1):26-36.
[15]Lyons J M,Schwimer J E,Anthony C T,et al. The role of VEGF pathways in human physiologic and pathologic angiogenesis. J Surg Res,2010,159(1):517-527.
[16] Groff K,Brown J,Clippinger A J. Modern affinity reagents:Recombinant antibodies and aptamers. Biotechnol Adv,2015,33(8):1787-1798.
[17]Lee A,Sun S,Sandler A,et al. Recent progress in therapeutic antibodies for cancer immunotherapy. Curr Opin Chem Biol,2018,44:56-65.
[18]Zhou Z,Liu M,Jiang J. The potential of aptamers for cancer research. Anal Biochem,2018,549:91-95.
[19] Soldevilla M M,Villanueva H,Pastor F. Aptamers:A feasible technology in cancer immunotherapy. J Immunol Res,2016,2016:1083738.
[20]Hu P P. Recent advances in aptamers targeting immune system.Inflammation,2017,40(1):295-302.
[21]Kim M,Kim D M,Kim K S,et al. Applications of cancer cellspecific aptamers in targeted delivery of anticancer therapeutic agents. Molecules,2018,23(4):830.
[22] Pastor F. Aptamers:A new technological platform in cancer immunotherapy. Pharmaceuticals 2016,9(4):64.
[23] Wu X,Shaikh A B,Yu Y,et al. Potential diagnostic and therapeutic applications of oligonucleotide aptamers in breast cancer. Int J Mol Sci,2017,18(9):1851.
[24]Ghahremani F,Shahbazi-Gahrouei D,Amirhosein Kefayat,et al.AS1411 aptamer conjugated gold nanoclusters as a targeted radiosensitizer for megavoltage radiation therapy of 4T1 breast cancer cells. RSC Advances,2018,8(8):4249-4258.
[25] Ai J,Ga L,Wang Y. A dual-targeting AS1411-folic acid fluorescent nanocomposite for cancer cell and drug delivery.Analytical Methods,2018,10(17):1949-1951.
[26]Yoon S,Huang K W,Reebye V,et al. Aptamer-drug conjugates ofactive metabolites of nucleoside analogs and cytotoxic agents inhibit pancreatic tumor cell growth. Mol Ther Nucleic Acids,2017,6:80-88.
[27] Kong D H,Kim M R,Jang J H,et al. A review of antiangiogenic targets for monoclonal antibody cancer therapy. Int J Mol Sci,2017,18(8):1786.
[28]Zhang X,Peng L,Liang Z,et al. Effects of aptamer to U87-EGFRvIII cells on the proliferation, radiosensitivity, and radiotherapy of glioblastoma cells. Mol Ther Nucleic Acids,2018,10:438-449.
[29]Morita Y,Leslie M,Kameyama H,et al. Aptamer therapeutics in cancer:Current and future. Cancers 2018,10(3):80.
[30]Prodeus A,Abdul-Wahid A,Fischer N W,et al. Targeting the PD-1/PD-L1 immune evasion axis with DNA aptamers as a novel therapeutic strategy for the treatment of disseminated cancers. Mol Ther Nucleic Acids,2015,4:e237.
[31] Wang H,Lam C H,Li X,et al. Selection of PD1/PD-L1 Xaptamers. Biochimie,2018,145:125-130.
[32]Lai W Y,Huang B T,Wang J W,et al. A novel PD-L1-targeting antagonistic DNA aptamer with antitumor effects. Mol Ther Nucleic Acids,2016,5(12):e397.
[33]Huang B T,Lai W Y,Chang Y C,et al. A CTLA-4 antagonizing DNA aptamer with antitumor effect. Mol Ther Nucleic Acids,2017,8:520-528.
[34] Pratico E D,Sullenger B A,Nair S K. Identification and characterization of an agonistic aptamer against the T cell costimulatory receptor, OX40. Nucleic Acid Ther,2013,23(1):35-43.
[35]Dollins C M,Nair S,Boczkowski D,et al. Assembling OX40aptamers on a molecular scaffold to create a receptor-activating aptamer. Chem Biol,2008,15(7):675-682.
[36] Liu X,Yan H,Liu Y,et al. Targeted cell-cell interactions by DNA nanoscaffold-templated multivalent bispecific aptamers.Small,2011,7(12):1673-1682.
[37] Rajagopalan A,Berezhnoy A,Schrand B,et al. Aptamertargeted attenuation of IL-2 signaling in CD8+T cells enhances antitumor immunity. Mol Ther,2017,25(1):54-61.
[38]Schrand B,Berezhnoy A,Brenneman R,et al. Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy. Cancer Immunol Res,2014,2(9):867-877.
[39] Pastor F,Kolonias D,Mcnamara J O,et al. Targeting 4-1BB costimulation to disseminated tumor lesions with bi-specific oligonucleotide aptamers. Mol Ther,2011,19(10):1878-1886.
[40] Pastor F. Tumor-targeted costimulation by using bi-specific aptamers. Cancer Cell Microenviron,2016,3:e1333.
[41] Soldevilla M M,Villanueva H,Casares N,et al. MRP1-CD28bi-specific oligonucleotide aptamers:target costimulation to drugresistant melanoma cancer stem cells. Oncotarget,2016,7(17):23182-23196.
[42] O’donnell J S,Smyth M J,Teng M W L. PD1 functions by inhibiting CD28-mediated co-stimulation. Clin Transl Immunology,2017,6(5):e138.
[43] Khedri M, Rafatpanah H, Abnous K, et al. Cancer immunotherapy via nucleic acid aptamers. Int Immunopharmacol,2015,29(2):926-936.
[44] Alshaer W,Hillaireau H,Vergnaud J,et al. Aptamer-guided siRNA-loaded nanomedicines for systemic gene silencing in CD-44expressing murine triple-negative breast cancer model. J Control Release,2018,271:98-106.
[45]De Almeida C E B,Alves L N,Rocha H F,et al. Aptamer delivery of siRNA,radiopharmaceutics and chemotherapy agents in cancer. Int J Pharm,2017,525(2):334-342.
[46] Berezhnoy A, Castro I, Levay A, et al. Aptamer-targeted inhibition of m TOR in T cells enhances antitumor immunity. J Clin Invest,2014,124(1):188-197.
[47]Heo K,Min S W,Sung H J,et al. An aptamer-antibody complex(oligobody)as a novel delivery platform for targeted cancer therapies. J Control Release,2016,229:1-9.
[48]Hu Z,He J,Gong W,et al. TLS11a aptamer/CD3 antibody antitumor system for liver cancer. J Biomed Nanotechnol,2018,14(9):1645-1653.
[49] Keefe A D,Pai S,Ellington A. Aptamers as therapeutics. Nat Rev Drug Discov,2010,9(7):537-550.
[2] Yee C. Adoptive T cell therapy:points to consider. Curr Opin Immunol,2018,51:197-203.
[3]Ligtenberg M A,Pico De Coana Y,Shmushkovich T,et al. Selfdelivering RNAi targeting PD-1 improves tumor-specific T cell functionality for adoptive cell therapy of malignant melanoma. Mol Ther,2018,26(6):1482-1493.
[4] Vormittag P, Gunn R, Ghorashian S, et al. A guide to manufacturing CAR T cell therapies. Curr Opin Biotechnol,2018,53:164-181.
[5]Arabi F,Torabi-Rahvar M,Shariati A,et al. Antigenic targets of CAR T cell therapy. A retrospective view on clinical trials. Exp Cell Res,2018,369(1):1-10.
[6] Ramello M C,Haura E B,Abate-Daga D. CAR-T cells and combination therapies:What’s next in the immunotherapy revolution. Pharmacol Res,2018,129:194-203.
[7] Khalil D N,Smith E L,Brentjens R J,et al. The future of cancer treatment:immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol,2016,13(5):273-290.
[8]Simpson A,Caballero O. Monoclonal antibodies for the therapy of cancer. BMC Proceedings,2014,8(Suppl 4):6.
[9] Almagro J C,Daniels-Wells T R,Perez-Tapia S M,et al.Progress and challenges in the design and clinical development of antibodies for cancer therapy. Front Immunol,2017,8:1751.
[10]Thomas A,Teicher B A,Hassan R. Antibody-drug conjugates for cancer therapy. The Lancet Oncology,2016,17(6):e254-e262.
[11]Nasiri H,Valedkarimi Z,Aghebati-Maleki L,et al. Antibodydrug conjugates:Promising and efficient tools for targeted cancer therapy. J Cell Physiol,2018,233(9):6441-6457.
[12] Krishnamurthy A,Jimeno A. Bispecific antibodies for cancer therapy:A review. Pharmacol Ther,2018,185:122-134.
[13] Kontermann R E,Brinkmann U. Bispecific antibodies. Drug Discov Today,2015,20(7):838-847.
[14]Klebanoff C A,Rosenberg S A,Restifo N P. Prospects for geneengineered T cell immunotherapy for solid cancers. Nat Med,2016,22(1):26-36.
[15]Lyons J M,Schwimer J E,Anthony C T,et al. The role of VEGF pathways in human physiologic and pathologic angiogenesis. J Surg Res,2010,159(1):517-527.
[16] Groff K,Brown J,Clippinger A J. Modern affinity reagents:Recombinant antibodies and aptamers. Biotechnol Adv,2015,33(8):1787-1798.
[17]Lee A,Sun S,Sandler A,et al. Recent progress in therapeutic antibodies for cancer immunotherapy. Curr Opin Chem Biol,2018,44:56-65.
[18]Zhou Z,Liu M,Jiang J. The potential of aptamers for cancer research. Anal Biochem,2018,549:91-95.
[19] Soldevilla M M,Villanueva H,Pastor F. Aptamers:A feasible technology in cancer immunotherapy. J Immunol Res,2016,2016:1083738.
[20]Hu P P. Recent advances in aptamers targeting immune system.Inflammation,2017,40(1):295-302.
[21]Kim M,Kim D M,Kim K S,et al. Applications of cancer cellspecific aptamers in targeted delivery of anticancer therapeutic agents. Molecules,2018,23(4):830.
[22] Pastor F. Aptamers:A new technological platform in cancer immunotherapy. Pharmaceuticals 2016,9(4):64.
[23] Wu X,Shaikh A B,Yu Y,et al. Potential diagnostic and therapeutic applications of oligonucleotide aptamers in breast cancer. Int J Mol Sci,2017,18(9):1851.
[24]Ghahremani F,Shahbazi-Gahrouei D,Amirhosein Kefayat,et al.AS1411 aptamer conjugated gold nanoclusters as a targeted radiosensitizer for megavoltage radiation therapy of 4T1 breast cancer cells. RSC Advances,2018,8(8):4249-4258.
[25] Ai J,Ga L,Wang Y. A dual-targeting AS1411-folic acid fluorescent nanocomposite for cancer cell and drug delivery.Analytical Methods,2018,10(17):1949-1951.
[26]Yoon S,Huang K W,Reebye V,et al. Aptamer-drug conjugates ofactive metabolites of nucleoside analogs and cytotoxic agents inhibit pancreatic tumor cell growth. Mol Ther Nucleic Acids,2017,6:80-88.
[27] Kong D H,Kim M R,Jang J H,et al. A review of antiangiogenic targets for monoclonal antibody cancer therapy. Int J Mol Sci,2017,18(8):1786.
[28]Zhang X,Peng L,Liang Z,et al. Effects of aptamer to U87-EGFRvIII cells on the proliferation, radiosensitivity, and radiotherapy of glioblastoma cells. Mol Ther Nucleic Acids,2018,10:438-449.
[29]Morita Y,Leslie M,Kameyama H,et al. Aptamer therapeutics in cancer:Current and future. Cancers 2018,10(3):80.
[30]Prodeus A,Abdul-Wahid A,Fischer N W,et al. Targeting the PD-1/PD-L1 immune evasion axis with DNA aptamers as a novel therapeutic strategy for the treatment of disseminated cancers. Mol Ther Nucleic Acids,2015,4:e237.
[31] Wang H,Lam C H,Li X,et al. Selection of PD1/PD-L1 Xaptamers. Biochimie,2018,145:125-130.
[32]Lai W Y,Huang B T,Wang J W,et al. A novel PD-L1-targeting antagonistic DNA aptamer with antitumor effects. Mol Ther Nucleic Acids,2016,5(12):e397.
[33]Huang B T,Lai W Y,Chang Y C,et al. A CTLA-4 antagonizing DNA aptamer with antitumor effect. Mol Ther Nucleic Acids,2017,8:520-528.
[34] Pratico E D,Sullenger B A,Nair S K. Identification and characterization of an agonistic aptamer against the T cell costimulatory receptor, OX40. Nucleic Acid Ther,2013,23(1):35-43.
[35]Dollins C M,Nair S,Boczkowski D,et al. Assembling OX40aptamers on a molecular scaffold to create a receptor-activating aptamer. Chem Biol,2008,15(7):675-682.
[36] Liu X,Yan H,Liu Y,et al. Targeted cell-cell interactions by DNA nanoscaffold-templated multivalent bispecific aptamers.Small,2011,7(12):1673-1682.
[37] Rajagopalan A,Berezhnoy A,Schrand B,et al. Aptamertargeted attenuation of IL-2 signaling in CD8+T cells enhances antitumor immunity. Mol Ther,2017,25(1):54-61.
[38]Schrand B,Berezhnoy A,Brenneman R,et al. Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy. Cancer Immunol Res,2014,2(9):867-877.
[39] Pastor F,Kolonias D,Mcnamara J O,et al. Targeting 4-1BB costimulation to disseminated tumor lesions with bi-specific oligonucleotide aptamers. Mol Ther,2011,19(10):1878-1886.
[40] Pastor F. Tumor-targeted costimulation by using bi-specific aptamers. Cancer Cell Microenviron,2016,3:e1333.
[41] Soldevilla M M,Villanueva H,Casares N,et al. MRP1-CD28bi-specific oligonucleotide aptamers:target costimulation to drugresistant melanoma cancer stem cells. Oncotarget,2016,7(17):23182-23196.
[42] O’donnell J S,Smyth M J,Teng M W L. PD1 functions by inhibiting CD28-mediated co-stimulation. Clin Transl Immunology,2017,6(5):e138.
[43] Khedri M, Rafatpanah H, Abnous K, et al. Cancer immunotherapy via nucleic acid aptamers. Int Immunopharmacol,2015,29(2):926-936.
[44] Alshaer W,Hillaireau H,Vergnaud J,et al. Aptamer-guided siRNA-loaded nanomedicines for systemic gene silencing in CD-44expressing murine triple-negative breast cancer model. J Control Release,2018,271:98-106.
[45]De Almeida C E B,Alves L N,Rocha H F,et al. Aptamer delivery of siRNA,radiopharmaceutics and chemotherapy agents in cancer. Int J Pharm,2017,525(2):334-342.
[46] Berezhnoy A, Castro I, Levay A, et al. Aptamer-targeted inhibition of m TOR in T cells enhances antitumor immunity. J Clin Invest,2014,124(1):188-197.
[47]Heo K,Min S W,Sung H J,et al. An aptamer-antibody complex(oligobody)as a novel delivery platform for targeted cancer therapies. J Control Release,2016,229:1-9.
[48]Hu Z,He J,Gong W,et al. TLS11a aptamer/CD3 antibody antitumor system for liver cancer. J Biomed Nanotechnol,2018,14(9):1645-1653.
[49] Keefe A D,Pai S,Ellington A. Aptamers as therapeutics. Nat Rev Drug Discov,2010,9(7):537-550.