vedomostiregmedРегуляторные исследования и экспертиза лекарственных средствRegulatory Research and Medicine Evaluation3034-30623034-3453Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/1991-2919-2021-11-148-159vedomostiregmed-374Research ArticleОБЗОРЫREVIEWSВысокотехнологические лекарственные препараты на основе онколитических вирусов (часть 1: разработка и регистрация в КНР)Advanced Therapy Medicines Based on Oncolytic Viruses (Part I: Development and Authorisation of Products in China)https://orcid.org/0000-0002-9585-3545МельниковаЕ. В.MelnikovaE. V.

Мельникова Екатерина Валерьевна, кандидат биологических наук,

Петровский б-р, д. 8, стр. 2, Москва, 127051

Ekaterina V. Melnikova, Cand. Sci. (Biol.),

8/2 Petrovsky Blvd, Moscow 127051

MelnikovaEV@expmed.ruhttps://orcid.org/0000-0001-8377-9205РачинскаяО. А.RachinskayaO. A.

Рачинская Ольга Анатольевна, кандидат биологических наук,

Петровский б-р, д. 8, стр. 2, Москва, 127051

Olga A. Rachinskaya, Cand. Sci. (Biol.),

8/2 Petrovsky Blvd, Moscow 127051

Rachynskaya@expmed.ruhttps://orcid.org/0000-0003-4891-973XМеркуловВ. А.MerkulovV. A.

Меркулов Вадим Анатольевич, доктор медицинских наук, профессор,

Петровский б-р, д. 8, стр. 2, Москва, 127051

Vadim A. Merkulov, Dr. Sci. (Med.), Professor,

8/2 Petrovsky Blvd, Moscow 127051

 

Merkulov@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation202130082021113148159Copyright © Мельникова Е.В., Рачинская О.А., Меркулов В.А., 20212021Мельникова Е.В., Рачинская О.А., Меркулов В.А.Melnikova E.V., Rachinskaya O.A., Merkulov V.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.vedomostincesmp.ru/jour/article/view/374

Одним из перспективных направлений при поиске инновационных препаратов для лечения онкологических заболеваний является применение онколитических (природных или генетически модифицированных) вирусов (ОЛВ) для избирательного действия на опухолевые клетки и их уничтожения, особенно в составе комбинированной терапии. В настоящее время официально разрешены к медицинскому применению три препарата на основе ОЛВ: два в Китайской Народной Республике (КНР) и один в США и Европейском союзе. Цель работы – анализ материалов, касающихся особенностей разработки препаратов на основе онколитических вирусов, проведения доклинических и клинических исследований, а также их регистрации в КНР. Был проведен анализ данных, представленных в свободном доступе на сайтах производителей препаратов, в публичных докладах и нормативной документации регуляторных органов КНР, в международных реестрах клинических исследований и научных публикациях. Препараты Gendicine® (SiBiono GeneTech Co., LTD) и Oncorine® (Shanghai Sunway Biotech Co., LTD) разрабатывались и были разрешены в КНР для использования в клинической практике в составе комбинированной терапии. Отмечена значительная продолжительность разработки препаратов (до момента начала регистрационных процедур препарат Gendicine® изучался в течение 14 лет), сложность дизайна доклинических исследований и возможность применения препаратов для нескольких нозологий с различной локализацией опухолей. Выявленные особенности разработки и регистрации в КНР препаратов на основе онколитических вирусов могут быть использованы в регуляторной практике Российской Федерации.

One of the promising areas in the development of innovative products for the treatment of cancer is the use of oncolytic (native or genetically modified) viruses (OLVs) for selective targeting of tumour cells and their destruction, especially as part of combination therapy. At present, there are three OLV-based products approved for medical use (two in China and one in the USА and EU). The aim of the study was to analyse data on specific aspects of OLV-based products’ development, preclinical and clinical research, and authorisation process in China. The authors analysed data freely available on the manufacturers’ websites, in public reports and documents of the Chinese regulatory authorities, in international clinical trial registries, and scientific publications. The products Gendicine® (SiBiono GeneTech Co., Ltd.) and Oncorine® (Shanghai Sunway Biotech Co., Ltd.) were originally developed and approved in China for clinical use as part of combination therapy. The analysis demonstrated long product development periods (Gendicine had been studied for 14 years before the start of the authorisation procedures), complex preclinical trial designs, and potential use of the products for several medical conditions with different tumour localisation. The identified specific aspects of OVL-based products’ development and authorisation in China could be taken into account in the regulatory practice of the Russian Federation.

терапия онкологических заболеванийонколитические вирусыгенетические модификациидоклинические исследованияклинические исследованиярегистрация препаратовcancer therapyoncolytic virusesgenetic modificationspreclinical trialsclinical trialsmarketing authorisationРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00005-21-00 на проведение прикладных научных исследований (номер государственного учета НИР 121021800098-4).The study reported in this publication was carried out as part of a publicly funded research project No. 056-00005-21-00 and was supported by the Scientific Centre for Expert Evaluation of Medicinal Products (R&D public accounting No. 121021800098-4).ReferencesArab A, Behravan N, Razazn A, Barati N, Mosaffa F, Nicastro J, et al. The viral approach to breast cancer immunotherapy. J Cell Physiol. 2019;234(2):1257–67. https://doi.org/10.1002/jcp.27150Arab A, Behravan N, Razazn A, Barati N, Mosaffa F, Nicastro J, et al. The viral approach to breast cancer immunotherapy. J Cell Physiol. 2019;234(2):1257–67. https://doi.org/10.1002/jcp.27150Packiriswamy N, Upreti D, Zhou Y, Khan R, Miller A, Diaz RM, et al. Oncolytic measles virus therapy enhances tumor antigen-specific T-cell responses in patients with multiple myeloma. Leukemia. 2020;34(12):3310–22. https://doi.org/10.1038/s41375-020-0828-7Packiriswamy N, Upreti D, Zhou Y, Khan R, Miller A, Diaz RM, et al. Oncolytic measles virus therapy enhances tumor antigen-specific T-cell responses in patients with multiple myeloma. Leukemia. 2020;34(12):3310–22. https://doi.org/10.1038/s41375-020-0828-7Yang X, Huang B, Deng L, Hu Z. Progress in gene therapy using oncolytic vaccinia virus as vectors. J Cancer Res Clin Oncol. 2018;144(12): 2433–40. https://doi.org/10.1007/s00432-018-2762-xYang X, Huang B, Deng L, Hu Z. Progress in gene therapy using oncolytic vaccinia virus as vectors. J Cancer Res Clin Oncol. 2018;144(12): 2433–40. https://doi.org/10.1007/s00432-018-2762-xWei D, Xu J, Liu X-Y, Chen Z-N, Bian H. Fighting cancer with viruses: oncolytic virus therapy in China. Hum Gene Ther. 2018;29(2):151–9. https://doi.org/10.1089/hum.2017.212Wei D, Xu J, Liu X-Y, Chen Z-N, Bian H. Fighting cancer with viruses: oncolytic virus therapy in China. Hum Gene Ther. 2018;29(2):151–9. https://doi.org/10.1089/hum.2017.212Taguchi S, Fukuhara H, Todo T. Oncolytic virus therapy in Japan: progress in clinical trials and future perspectives. Jpn J Clin Oncol. 2019;49(3):201–9. https://doi.org/10.1093/jjco/hyy170Taguchi S, Fukuhara H, Todo T. Oncolytic virus therapy in Japan: progress in clinical trials and future perspectives. Jpn J Clin Oncol. 2019;49(3):201–9. https://doi.org/10.1093/jjco/hyy170Fu L-Q, Wang S-B, Cai M-H, Wang X-J, Chen J-Y, Tong X-M, et al. Recent advances in oncolytic virus-based cancer therapy. Virus Res. 2019;270:197675. https://doi.org/10.1016/j.virusres.2019.197675Fu L-Q, Wang S-B, Cai M-H, Wang X-J, Chen J-Y, Tong X-M, et al. Recent advances in oncolytic virus-based cancer therapy. Virus Res. 2019;270:197675. https://doi.org/10.1016/j.virusres.2019.197675Haines BB, Denslow A, Grzesik P, Lee JS, Farkaly T, Hewett J, et al. ONCR-177, an oncolytic HSV-1 designed to potently activate systemic antitumor immunity. Cancer Immunol Res. 2021;9(3):291–308. https://doi.org/10.1158/2326-6066.cir-20-0609Haines BB, Denslow A, Grzesik P, Lee JS, Farkaly T, Hewett J, et al. ONCR-177, an oncolytic HSV-1 designed to potently activate systemic antitumor immunity. Cancer Immunol Res. 2021;9(3):291–308. https://doi.org/10.1158/2326-6066.cir-20-0609Lan Q, Xia S, Wang Q, Xu W, Huang H, Jiang S, Lu L. Development of oncolytic virotherapy: from genetic modification to combination therapy. Front Med. 2020;14(2):160–184. https://doi.org/10.1007/s11684-020-0750-4Lan Q, Xia S, Wang Q, Xu W, Huang H, Jiang S, Lu L. Development of oncolytic virotherapy: from genetic modification to combination therapy. Front Med. 2020;14(2):160–184. https://doi.org/10.1007/s11684-020-0750-4Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res. 2014;2(4):295–300. https://doi.org/10.1158/2326-6066.cir-14-0015Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res. 2014;2(4):295–300. https://doi.org/10.1158/2326-6066.cir-14-0015Wang P, Li X, Wang J, Gao D, Li Y, Li H, et al. Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent. Nat Commun. 2017;8(1):1395. https://doi.org/10.1038/s41467-017-01385-8Wang P, Li X, Wang J, Gao D, Li Y, Li H, et al. Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent. Nat Commun. 2017;8(1):1395. https://doi.org/10.1038/s41467-017-01385-8Samson A, Scott KJ, Taggart D, West EJ, Wilson E, Nuovo GJ, et al. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci Transl Med. 2018;10(422):eaam7577. https://doi.org/10.1126/scitranslmed.aam7577Samson A, Scott KJ, Taggart D, West EJ, Wilson E, Nuovo GJ, et al. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci Transl Med. 2018;10(422):eaam7577. https://doi.org/10.1126/scitranslmed.aam7577Geletneky K, Hajda J, Angelova AL, Leuchs B, Capper D, Bartsch AJ, et al. Oncolytic H-1 parvovirus shows safety and signs of immunogenic activity in a first phase I/IIa glioblastoma trial. Mol Ther. 2017;25(12):2620–34. https://doi.org/10.1016/j.ymthe.2017.08.016Geletneky K, Hajda J, Angelova AL, Leuchs B, Capper D, Bartsch AJ, et al. Oncolytic H-1 parvovirus shows safety and signs of immunogenic activity in a first phase I/IIa glioblastoma trial. Mol Ther. 2017;25(12):2620–34. https://doi.org/10.1016/j.ymthe.2017.08.016Bourgeois-Daigneault MC, Roy DG, Aitken AS, El Sayes N, Martin NT, Varette O, et al. Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy. Sci Transl Med. 2018;10(422):eaao1641. https://doi.org/10.1126/scitranslmed.aao1641Bourgeois-Daigneault MC, Roy DG, Aitken AS, El Sayes N, Martin NT, Varette O, et al. Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy. Sci Transl Med. 2018;10(422):eaao1641. https://doi.org/10.1126/scitranslmed.aao1641Bommareddy PK, Shettigar M, Kaufman HL. Integrating oncolytic viruses in combination cancer immunotherapy. Nat Rev Immunol. 2018;18(8):498–513. https://doi.org/10.1038/s41577-018-0014-6Bommareddy PK, Shettigar M, Kaufman HL. Integrating oncolytic viruses in combination cancer immunotherapy. Nat Rev Immunol. 2018;18(8):498–513. https://doi.org/10.1038/s41577-018-0014-6Foreman PM, Friedman GK, Cassady KA, Markert JM. Oncolytic virotherapy for the treatment of malignant glioma. Neurotherapeutics. 2017;14(2):333–44. https://doi.org/10.1007/s13311-017-0516-0Foreman PM, Friedman GK, Cassady KA, Markert JM. Oncolytic virotherapy for the treatment of malignant glioma. Neurotherapeutics. 2017;14(2):333–44. https://doi.org/10.1007/s13311-017-0516-0Alessandrini F, Menotti L, Avitabile E, Appolloni I, Ceresa D, Marubbi D, et al. Eradication of glioblastoma by immuno-virotherapy with a retargeted oncolytic HSV in a preclinical model. Oncogene. 2019;38(23):4467–79. https://doi.org/10.1038/s41388-019-0737-2Alessandrini F, Menotti L, Avitabile E, Appolloni I, Ceresa D, Marubbi D, et al. Eradication of glioblastoma by immuno-virotherapy with a retargeted oncolytic HSV in a preclinical model. Oncogene. 2019;38(23):4467–79. https://doi.org/10.1038/s41388-019-0737-2Li JM, Kao KC, Li LF, Yang TM, Wu CP, Horng YM, et al. MicroRNA-145 regulates oncolytic herpes simplex virus-1 for selective killing of human non-small cell lung cancer cells. Virol J. 2013;10(1):241. https://doi.org/10.1186/1743-422x-10-241Li JM, Kao KC, Li LF, Yang TM, Wu CP, Horng YM, et al. MicroRNA-145 regulates oncolytic herpes simplex virus-1 for selective killing of human non-small cell lung cancer cells. Virol J. 2013;10(1):241. https://doi.org/10.1186/1743-422x-10-241Eriksson E, Milenova I, Wenthe J, Stahle M, Leja-Jarblad J, Ullenhag G, et al. Shaping the tumor stroma and sparking immune activation by CD40 and 4–1BB signaling induced by an armed oncolytic virus. Clin Cancer Res. 2017;23(19):5846–57. https://doi.org/10.1158/1078-0432.ccr-17-0285Eriksson E, Milenova I, Wenthe J, Stahle M, Leja-Jarblad J, Ullenhag G, et al. Shaping the tumor stroma and sparking immune activation by CD40 and 4–1BB signaling induced by an armed oncolytic virus. Clin Cancer Res. 2017;23(19):5846–57. https://doi.org/10.1158/1078-0432.ccr-17-0285Pearl TM, Markert JM, Cassady KA, Ghonime MG. Oncolytic virus-based cytokine expression to improve immune activity in brain and solid tumors. Mol Ther Oncolytics. 2019;13:14–21. https://doi.org/10.1016/j.omto.2019.03.001Pearl TM, Markert JM, Cassady KA, Ghonime MG. Oncolytic virus-based cytokine expression to improve immune activity in brain and solid tumors. Mol Ther Oncolytics. 2019;13:14–21. https://doi.org/10.1016/j.omto.2019.03.001Foloppe J, Kempf J, Futin N, Kintz J, Cordier P, Pichon C, et al. The enhanced tumor specificity of TG6002, an armed oncolytic vaccinia virus deleted in two genes involved in nucleotide metabolism. Mol Ther Oncolytics. 2019;14:1–14. https://doi.org/10.1016/j.omto.2019.03.005Foloppe J, Kempf J, Futin N, Kintz J, Cordier P, Pichon C, et al. The enhanced tumor specificity of TG6002, an armed oncolytic vaccinia virus deleted in two genes involved in nucleotide metabolism. Mol Ther Oncolytics. 2019;14:1–14. https://doi.org/10.1016/j.omto.2019.03.005Grigg C, Blake Z, Gartrell R, Sacher A, Taback B, Saenger Y. Talimogene laherparepvec (T-Vec) for the treatment of melanoma and other cancers. Semin Oncol. 2016;43(6):638–46. https://doi.org/10.1053/j.seminoncol.2016.10.005Grigg C, Blake Z, Gartrell R, Sacher A, Taback B, Saenger Y. Talimogene laherparepvec (T-Vec) for the treatment of melanoma and other cancers. Semin Oncol. 2016;43(6):638–46. https://doi.org/10.1053/j.seminoncol.2016.10.005Hamid O, Hoffner B, Gasal E, Hong J, Carvajal RD. Oncolytic immunotherapy: unlocking the potential of viruses to help target cancer. Cancer Immunol Immunother. 2017;66(10):1249–64. https://doi.org/10.1007/s00262-017-2025-8Hamid O, Hoffner B, Gasal E, Hong J, Carvajal RD. Oncolytic immunotherapy: unlocking the potential of viruses to help target cancer. Cancer Immunol Immunother. 2017;66(10):1249–64. https://doi.org/10.1007/s00262-017-2025-8Robinson S, Galanis E. Potential and clinical translation of oncolytic measles viruses. Expert Opin Biol Ther. 2017;17(3):353–63. https://doi.org/10.1080/14712598.2017.1288713Robinson S, Galanis E. Potential and clinical translation of oncolytic measles viruses. Expert Opin Biol Ther. 2017;17(3):353–63. https://doi.org/10.1080/14712598.2017.1288713Doniņa S, Strēle I, Proboka G, Auziņš J, Alberts P, Jonsson B, et al. Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study. Melanoma Res. 2015;25(5):421–26. https://doi.org/10.1097/cmr.0000000000000180Doniņa S, Strēle I, Proboka G, Auziņš J, Alberts P, Jonsson B, et al. Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study. Melanoma Res. 2015;25(5):421–26. https://doi.org/10.1097/cmr.0000000000000180Peng Z. Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers. Hum Gene Ther. 2005;16(9):1016–27. https://doi.org/10.1089/hum.2005.16.1016Peng Z. Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers. Hum Gene Ther. 2005;16(9):1016–27. https://doi.org/10.1089/hum.2005.16.1016Husain SR, Han J, Au P, Shannon K, Puri RK. Gene therapy for cancer: regulatory considerations for approval. Cancer Gene Ther. 2015;22(12):554–63. https://doi.org/10.1038/cgt.2015.58Husain SR, Han J, Au P, Shannon K, Puri RK. Gene therapy for cancer: regulatory considerations for approval. Cancer Gene Ther. 2015;22(12):554–63. https://doi.org/10.1038/cgt.2015.58Zhang WW, Li L, Li D, Liu J, Li X, Li W, et al. The first approved gene therapy product for cancer Ad-p53 (gendicine): 12 years in the clinic. Human Gene Ther. 2018;29(2):160–79. https://doi.org/10.1089/hum.2017.218Zhang WW, Li L, Li D, Liu J, Li X, Li W, et al. The first approved gene therapy product for cancer Ad-p53 (gendicine): 12 years in the clinic. Human Gene Ther. 2018;29(2):160–79. https://doi.org/10.1089/hum.2017.218Zhang SW, Xiao SW, Liu CQ, Sun Y, Su X, Li DM, et al. Treatment of head and neck squamous cell carcinoma by recombinant adenovirus-p53 combined with radiotherapy: a phase II clinical trial of 42 cases. Zhonghua Yi Xue Za Zhi. 2003;83(23):2023–8. PMID: 14703408Zhang SW, Xiao SW, Liu CQ, Sun Y, Su X, Li DM, et al. Treatment of head and neck squamous cell carcinoma by recombinant adenovirus-p53 combined with radiotherapy: a phase II clinical trial of 42 cases. Zhonghua Yi Xue Za Zhi. 2003;83(23):2023–8. PMID: 14703408Chen CB, Pan JJ, Xu LY. Recombinant adenovirus p53 agent injection combined with radiotherapy in treatment of nasopharyngeal carcinoma: a phase II clinical trial. Zhonghua Yi Xue Za Zhi. 2003;83(23):2033–5. PMID: 14703410Chen CB, Pan JJ, Xu LY. Recombinant adenovirus p53 agent injection combined with radiotherapy in treatment of nasopharyngeal carcinoma: a phase II clinical trial. Zhonghua Yi Xue Za Zhi. 2003;83(23):2033–5. PMID: 14703410Han DM, Huang ZG, Zhang W, Yu ZK, Wang Q, Ni X, et al. Effectiveness of recombinant adenovirus p53 injection on laryngeal cancer: phase I clinical trial and follow up. Zhonghua Yi Xue Za Zhi. 2003;83(23):2029-32. PMID: 14703409Han DM, Huang ZG, Zhang W, Yu ZK, Wang Q, Ni X, et al. Effectiveness of recombinant adenovirus p53 injection on laryngeal cancer: phase I clinical trial and follow up. Zhonghua Yi Xue Za Zhi. 2003;83(23):2029-32. PMID: 14703409Liu J, Lv D, Wang H, Zou J, Chen F, Yang H. Recombinant adenovirus-p53 enhances the therapeutic effect of surgery and chemoradiotherapy combination in hypopharyngeal squamous cell carcinomas patients. Medicine (Baltimore). 2018;97(35):e12193. https://doi.org/10.1097/md.0000000000012193Liu J, Lv D, Wang H, Zou J, Chen F, Yang H. Recombinant adenovirus-p53 enhances the therapeutic effect of surgery and chemoradiotherapy combination in hypopharyngeal squamous cell carcinomas patients. Medicine (Baltimore). 2018;97(35):e12193. https://doi.org/10.1097/md.0000000000012193Li Y, Li L-J, Wang L-J, Zhang Z, Gao N, Liang C-Y, et al. Selective intra-arterial infusion of rAd-p53 with chemotherapy for advanced oral cancer: a randomized clinical trial. BMC Med. 2014;12:16. https://doi.org/10.1186/1741-7015-12-16Li Y, Li L-J, Wang L-J, Zhang Z, Gao N, Liang C-Y, et al. Selective intra-arterial infusion of rAd-p53 with chemotherapy for advanced oral cancer: a randomized clinical trial. BMC Med. 2014;12:16. https://doi.org/10.1186/1741-7015-12-16Geng J, Xiao S, Zhang S, Liu Ch, Li Y, Fang JJ, et al. Clinical effectiveness of recombinant adenovirus-p53 combined with radiotherapy in advanced soft tissue sarcoma: A report of 37 cases. J Clin Oncol. 2014;32(15):e21514. https://dx.doi.org/10.1200/jco.2014.32.15_suppl.e21514Geng J, Xiao S, Zhang S, Liu Ch, Li Y, Fang JJ, et al. Clinical effectiveness of recombinant adenovirus-p53 combined with radiotherapy in advanced soft tissue sarcoma: A report of 37 cases. J Clin Oncol. 2014;32(15):e21514. https://dx.doi.org/10.1200/jco.2014.32.15_suppl.e21514Xiao SW, Xu Y-Z, Xiao B-F, Jiang J, Liu C-Q, Fang Z-W, et al. Recombinant adenovirus-p53 gene therapy for advanced unresectable soft-tissue sarcomas. Hum Gene Ther. 2018;29(6):699–707. https://doi.org/10.1089/hum.2017.103Xiao SW, Xu Y-Z, Xiao B-F, Jiang J, Liu C-Q, Fang Z-W, et al. Recombinant adenovirus-p53 gene therapy for advanced unresectable soft-tissue sarcomas. Hum Gene Ther. 2018;29(6):699–707. https://doi.org/10.1089/hum.2017.103Su X, Chen W-J, Xiao S-W, Li X-F, Xu G, Pan J-J, Zhang S-W. Effect and safety of recombinant adenovirus-p53 transfer combined with radiotherapy on long-term survival of locally advanced cervical cancer. Hum Gene Ther. 2016;27(12):1008–14. https://doi.org/10.1089/hum.2016.043Su X, Chen W-J, Xiao S-W, Li X-F, Xu G, Pan J-J, Zhang S-W. Effect and safety of recombinant adenovirus-p53 transfer combined with radiotherapy on long-term survival of locally advanced cervical cancer. Hum Gene Ther. 2016;27(12):1008–14. https://doi.org/10.1089/hum.2016.043Qu H, Xia Y, Li X. Recombinant human p53 adenovirus injection (rAd-p53) combined with chemotherapy for 4 cases of high-grade serous ovarian cancer. Curr Gene Ther. 2020;20(4):313–20. https://doi.org/10.2174/1566523220666200826100245Qu H, Xia Y, Li X. Recombinant human p53 adenovirus injection (rAd-p53) combined with chemotherapy for 4 cases of high-grade serous ovarian cancer. Curr Gene Ther. 2020;20(4):313–20. https://doi.org/10.2174/1566523220666200826100245Shen A, Liu S, Yu W, Deng H, Li Q. P53 gene therapy-based transarterial chemoembolization for unresectable hepatocellular carcinoma: a prospective cohort study. J Gastroenterol Hepatol. 2015;30(11):1651–6. https://doi.org/10.1111/jgh.13009Shen A, Liu S, Yu W, Deng H, Li Q. P53 gene therapy-based transarterial chemoembolization for unresectable hepatocellular carcinoma: a prospective cohort study. J Gastroenterol Hepatol. 2015;30(11):1651–6. https://doi.org/10.1111/jgh.13009Liu Y, Zhang Y, Bautista D, Tang S, Zhou J, Li C, Zhao G. Trans-arterial p53-gene-embolization with gelatin sponge microparticles for hepatocellular carcinoma with BCLC stage B: single-center experience. Cell Biochem Biophys. 2015;71(1):99–104. https://doi.org/10.1007/s12013-014-0167-2Liu Y, Zhang Y, Bautista D, Tang S, Zhou J, Li C, Zhao G. Trans-arterial p53-gene-embolization with gelatin sponge microparticles for hepatocellular carcinoma with BCLC stage B: single-center experience. Cell Biochem Biophys. 2015;71(1):99–104. https://doi.org/10.1007/s12013-014-0167-2Zhou J, Zhang Y, Zhao G, Liu Y, Li C, Tang S, et al. The preliminary study of recombinant adenovirus p53 combined with transarterial embolization with particles for advanced hepatocellular carcinoma. Zhonghua Yi Xue Za Zhi. 2014;94(9):660–3. PMID: 24842203Zhou J, Zhang Y, Zhao G, Liu Y, Li C, Tang S, et al. The preliminary study of recombinant adenovirus p53 combined with transarterial embolization with particles for advanced hepatocellular carcinoma. Zhonghua Yi Xue Za Zhi. 2014;94(9):660–3. PMID: 24842203Yang J, Wang X, Zheng G. A primary report of recombinant adeno-viral human p53 gene (rad-p53) in combination with concurrent radio-chemothrepy in patients with t4n0-2m0 stage non-small cell lung cancer in elderly. Chinese Journal of Coal Industry Medicine. 2013;(10):1586–9.Yang J, Wang X, Zheng G. A primary report of recombinant adeno-viral human p53 gene (rad-p53) in combination with concurrent radio-chemothrepy in patients with t4n0-2m0 stage non-small cell lung cancer in elderly. Chinese Journal of Coal Industry Medicine. 2013;(10):1586–9.Garber K. China approves world's first oncolytic virus therapy for cancer treatment. J Natl Cancer Inst. 2006;98(5):298–300. https://doi.org/10.1093/jnci/djj111Garber K. China approves world's first oncolytic virus therapy for cancer treatment. J Natl Cancer Inst. 2006;98(5):298–300. https://doi.org/10.1093/jnci/djj111Lichtenstein DL, Toth K, Doronin K, Tollefson AE, Wold WSM. Functions and mechanisms of action of the adenovirus E3 proteins. Int Rev Immunol. 2004;23(1–2):75–111. https://doi.org/10.1080/08830180490265556Lichtenstein DL, Toth K, Doronin K, Tollefson AE, Wold WSM. Functions and mechanisms of action of the adenovirus E3 proteins. Int Rev Immunol. 2004;23(1–2):75–111. https://doi.org/10.1080/08830180490265556Liang M. Oncorine, the world first oncolytic virus medicine and its update in China. Curr Cancer Drug Targets. 2018;18(2):171–76. https://doi.org/10.2174/1568009618666171129221503Liang M. Oncorine, the world first oncolytic virus medicine and its update in China. Curr Cancer Drug Targets. 2018;18(2):171–76. https://doi.org/10.2174/1568009618666171129221503Yuan Z-Y, Zhang L, Li S, Qian X-Z, Guan Z-Z. Safety of an E1B deleted adenovirus administered intratumorally to patients with cancer. Ai Zheng. 2003;22(3):310–3. PMID: 12654194Yuan Z-Y, Zhang L, Li S, Qian X-Z, Guan Z-Z. Safety of an E1B deleted adenovirus administered intratumorally to patients with cancer. Ai Zheng. 2003;22(3):310–3. PMID: 12654194Lu W, Zheng S, Li X-F, Huang J-J, Zheng X, Li Z. Intra-tumor injection of H101, a recombinant adenovirus, in combination with chemotherapy in patients with advanced cancers: а pilot phase II clinical trial. World J Gastroenterol. 2004;10(20):3634–8. https://doi.org/10.3748/wjg.v10.i24.3634Lu W, Zheng S, Li X-F, Huang J-J, Zheng X, Li Z. Intra-tumor injection of H101, a recombinant adenovirus, in combination with chemotherapy in patients with advanced cancers: а pilot phase II clinical trial. World J Gastroenterol. 2004;10(20):3634–8. https://doi.org/10.3748/wjg.v10.i24.3634Xia Z-J, Chang J-H, Zhang L, Jiang W-Q, Guan Z-Z, Liu J-W, et al. Phase III randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus. Ai Zheng. 2004;23(12):1666–70. PMID: 15601557Xia Z-J, Chang J-H, Zhang L, Jiang W-Q, Guan Z-Z, Liu J-W, et al. Phase III randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus. Ai Zheng. 2004;23(12):1666–70. PMID: 15601557He C, Zhang Y, Lin X. Increased overall survival and decreased cancer-specific mortality in patients with hepatocellular carcinoma treated by transarterial chemoembolization and human adenovirus type-5 combination therapy: a competing risk analysis. J Gastrointest Surg. 2018;22(6):989–97. https://doi.org/10.1007/s11605-018-3703-3He C, Zhang Y, Lin X. Increased overall survival and decreased cancer-specific mortality in patients with hepatocellular carcinoma treated by transarterial chemoembolization and human adenovirus type-5 combination therapy: a competing risk analysis. J Gastrointest Surg. 2018;22(6):989–97. https://doi.org/10.1007/s11605-018-3703-3He C-B, Lao X-M, Lin X-J. Transarterial chemoembolization combined with recombinant human adenovirus type 5 H101 prolongs overall survival of patients with intermediate to advanced hepatocellular carcinoma: a prognostic nomogram study. Chin J Cancer. 2017;36(1):59. https://doi.org/10.1186/s40880-017-0227-2He C-B, Lao X-M, Lin X-J. Transarterial chemoembolization combined with recombinant human adenovirus type 5 H101 prolongs overall survival of patients with intermediate to advanced hepatocellular carcinoma: a prognostic nomogram study. Chin J Cancer. 2017;36(1):59. https://doi.org/10.1186/s40880-017-0227-2Xiao B, Jin Z-D, Li Z-S, Du Y-Q, Wu R-P, Zhou J. Intra-tumoral injection of E1B gene-deleted adenovirus combined with gemcitabine for unresectable pancreatic carcinoma: 19 cases analysis. Chinese Journal of Pancreatology. 2011;11(3). https://doi.org/10.3760/cma.j.issn.1674-1935.2011.03.004Xiao B, Jin Z-D, Li Z-S, Du Y-Q, Wu R-P, Zhou J. Intra-tumoral injection of E1B gene-deleted adenovirus combined with gemcitabine for unresectable pancreatic carcinoma: 19 cases analysis. Chinese Journal of Pancreatology. 2011;11(3). https://doi.org/10.3760/cma.j.issn.1674-1935.2011.03.004

The authors declare that there are no conflicts of interest present.