A Tumor-Targeted Replicating Oncolytic Adenovirus Ad-TD-nsIL12 as a Promising Therapeutic Agent for Human Esophageal Squamous Cell Carcinoma
Zifang Zhang, Chunyang Zhang, Jinxin Miao, Zhizhong Wang, Zhimin Wang, Zhenguo Cheng, Pengju Wang, Louisa S Chard Dunmall, Nicholas R Lemoine, Yaohe Wang, Zifang Zhang, Chunyang Zhang, Jinxin Miao, Zhizhong Wang, Zhimin Wang, Zhenguo Cheng, Pengju Wang, Louisa S Chard Dunmall, Nicholas R Lemoine, Yaohe Wang
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in China and existing therapies have been unable to significantly improve prognosis. Oncolytic adenoviruses (OAds) are novel promising anti-tumor drugs and have been evaluated in several cancers including ESCC. However, the antitumour efficacy of the first generation OAds (H101) as single agent is limited. Therefore, more effective OAds are needed. Our previous studies demonstrated that the novel oncolytic adenovirus Ad-TD-nsIL12 (human adenovirus type 5 with E1ACR2, E1B19K, E3gp19K-triple deletions)harboring human non-secretory IL-12 had significant anti-tumor effect, with no toxicity, in a Syrian hamster pancreatic cancer model. In this study, we evaluated the anti-tumor effect of Ad-TD-nsIL12 in human ESCC. The cytotoxicity of Ad-TD-nsIL12, H101 and cisplatin were investigated in two newly established patient-derived tumor cells (PDCs) and a panel of ESCC cell lines in vitro. A novel adenovirus-permissive, immune-deficient Syrian hamster model of PDCs subcutaneous xenograft was established for in vivo analysis of efficacy. The results showed that Ad-TD-nsIL12 was more cytotixic to and replicated more effectively in human ESCC cell lines than H101. Compared with cisplatin and H101, Ad-TD-nsIL12 could significantly inhibit tumor growth and tumor angiogenesis as well as enhance survival rate of animals with no side effects. These findings suggest that Ad-TD-nsIL12 has superior anti-tumor potency against human ESCC with a good safety profile.
Keywords: Ad-TD-nsIL12; ESCC; Syrian hamster model; antitumour efficacy; oncolytic adenovirus.
Conflict of interest statement
The authors declare no conflict of interest.
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References
- Zeng H., Zheng R., Zhang S., Zuo T., Xia C., Zou X., Chen W. Esophageal cancer statistics in China, 2011: Estimates based on 177 cancer registries. Thorac. Cancer. 2015;7:232–237. doi: 10.1111/1759-7714.12322.
- He L., Jin-Hu F., You-Lin Q. Epidemiology, etiology, and prevention of esophageal squamous cell carcinoma in China. Cancer Biol. Med. 2017;14:33–41. doi: 10.20892/j.issn.2095-3941.2016.0093.
- Chang J., Tan W., Ling Z., Xi R., Shao M., Chen M., Luo Y., Zhao Y., Liu Y., Huang X., et al. Genomic analysis of oesophageal squamous-cell carcinoma identifies alcohol drinking-related mutation signature and genomic alterations. Nat. Commun. 2017;8:15290. doi: 10.1038/ncomms15290.
- Russell L., Peng K.-W. The emerging role of oncolytic virus therapy against cancer. Chin. Clin. Oncol. 2018;7:16. doi: 10.21037/cco.2018.04.04.
- Dolgin E. Oncolytic viruses get a boost with first FDA-approval recommendation. Nat. Rev. Drug Discov. 2015;14:369–371. doi: 10.1038/nrd4643.
- Marelli G., Howells A., Lemoine N.R., Wang Y. Oncolytic Viral Therapy and the Immune System: A Double-Edged Sword Against Cancer. Front. Immunol. 2018;9:866. doi: 10.3389/fimmu.2018.00866.
- Lei J., Li Q.-H., Yang J.-L., Liu F., Wang L., Xu W.-M., Zhao W.-X. The antitumor effects of oncolytic adenovirus H101 against lung cancer. Int. J. Oncol. 2015;47:555–562. doi: 10.3892/ijo.2015.3045.
- Lin X., Li Q.-J., Lao X.-M., Yang H., Li S. Transarterial injection of recombinant human type-5 adenovirus H101 in combination with transarterial chemoembolization (TACE) improves overall and progressive-free survival in unresectable hepatocellular carcinoma (HCC) BMC Cancer. 2015;15:707. doi: 10.1186/s12885-015-1715-x.
- Liang M. Oncorine, the World First Oncolytic Virus Medicine and its Update in China. Curr. Cancer Drug Targets. 2018;18:171–176. doi: 10.2174/1568009618666171129221503.
- Wang Y., Hallden G., Hill R.P., Anand A., Liu T.-C., Francis J., A Brooks G., Lemoine N.R., Kirn D.H. E3 gene manipulations affect oncolytic adenovirus activity in immunocompetent tumor models. Nat. Biotechnol. 2003;21:1328–1335. doi: 10.1038/nbt887.
- Ma J., Li N., Zhao J., Lu J., Ma Y., Zhu Q., Dong Z., Liu K., Ming L. Histone deacetylase inhibitor trichostatin A enhances the antitumor effect of the oncolytic adenovirus H101 on esophageal squamous cell carcinoma in vitro and in vivo. Oncol. Lett. 2017;13:4868–4874. doi: 10.3892/ol.2017.6069.
- Wang P., Li X., Wang J., Gao D., Li Y., Li H., Chu Y., Zhang Z., Liu H., Jiang G., et al. Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent. Nat. Commun. 2017;8:1395. doi: 10.1038/s41467-017-01385-8.
- Mansurov A., Ishihara J., Hosseinchi P., Potin L., Marchell T.M., Ishihara A., Williford J.-M., Alpar A.T., Raczy M.M., Gray L.T., et al. Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours. Nat. Biomed. Eng. 2020;4:531–543. doi: 10.1038/s41551-020-0549-2.
- Nguyen H.-M., Guz-Montgomery K., Saha D. Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy. Cells. 2020;9:400. doi: 10.3390/cells9020400.
- Song H.-N., Lee C., Kim S.T., Kim S.Y., Kim N.K., Jang J., Kang M., Jang H., Ahn S., Kim S.H., et al. Molecular characterization of colorectal cancer patients and concomitant patient-derived tumor cell establishment. Oncotarget. 2016;7:19610–19619. doi: 10.18632/oncotarget.7526.
- Lee J.-K., Liu Z., Sa J.K., Shin S., Wang J., Bordyuh M., Cho H.J., Elliott O., Chu T., Choi S.W., et al. Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy. Nat. Genet. 2018;50:1399–1411. doi: 10.1038/s41588-018-0209-6.
- Miao J.X., Wang J.Y., Li H.Z., Guo H.R., Dunmall L.S.C., Zhang Z.X., Cheng Z.G., Gao D.L., Dong J.Z., Wang Z.D. Promising xenograft animal model recapitulating the features of human pancreatic cancer. World J. Gastroenterol. 2020;26:4802–4816. doi: 10.3748/wjg.v26.i32.4802.
- Toth K., Lee S.R., Ying B., Spencer J.F., Tollefson A.E., Sagartz J.E., Kong I.-K., Wang Z., Wold W.S.M. STAT2 Knockout Syrian Hamsters Support Enhanced Replication and Pathogenicity of Human Adenovirus, Revealing an Important Role of Type I Interferon Response in Viral Control. PLOS Pathog. 2015;11:e1005084. doi: 10.1371/journal.ppat.1005084.
- Ayyoob K., Masoud K., Vahideh K., Asadi J. Authentication of newly established human esophageal squamous cell carcinoma cell line (YM-1) using short tandem repeat (STR) profiling method. Tumor Biol. 2015;37:3197–3204. doi: 10.1007/s13277-015-4133-4.
- Wen J., Zheng B., Hu Y., Zhang X., Yang H., Luo K.J., Zhang X., Li Y.F., Fu J.H. Establishment and biological analysis of the EC109/CDDP multidrug-resistant esophageal squamous cell carcinoma cell line. Oncol. Rep. 2009;22:65–71.
- Hagihara Y., Sakamoto A., Tokuda T., Yamashita T., Ikemoto S., Kimura A., Haruta M., Sasagawa K., Ohta J., Takayama K., et al. Photoactivatable oncolytic adenovirus for optogenetic cancer therapy. Cell Death Dis. 2020;11:1–9. doi: 10.1038/s41419-020-02782-6.
- Martin D.K., Uckermann O., Bertram A., Liebner C., Hendruschk S., Sitoci-Ficici K.H., Schackert G., Lord E.M., Temme A., Kirsch M. Differential growth inhibition of cerebral metastases by anti-angiogenic compounds. Anticancer. Res. 2014;34:3293–3302.
- Xu J., Bai Y., Xu N., Li E., Wang B., Wang J., Li X., Wang X., Yuan X. Tislelizumab Plus Chemotherapy as First-line Treatment for Advanced Esophageal Squamous Cell Carcinoma and Gastric/Gastroesophageal Junction Adenocarcinoma. Clin. Cancer Res. 2020;26:4542–4550. doi: 10.1158/1078-0432.CCR-19-3561.
- Wold W.S., Toth K. Chapter three--Syrian hamster as an animal model to study oncolytic adenoviruses and to evaluate the efficacy of antiviral compounds. Adv. Cancer Res. 2012;115:69–92.
- Yang C., Zhang J., Ding M., Xu K., Li L., Mao L., Zheng J. Ki67 targeted strategies for cancer therapy. Clin. Transl. Oncol. 2017;20:570–575. doi: 10.1007/s12094-017-1774-3.
- Wong R.J., Chan M.-K., Yu Z., Ghossein R.A., Ngai I., Adusumilli P.S., Stiles B.M., Shah J., Singh B., Fong Y. Angiogenesis Inhibition by an Oncolytic Herpes Virus Expressing Interleukin 12. Clin. Cancer Res. 2004;10:4509–4516. doi: 10.1158/1078-0432.CCR-04-0081.
- Wei D., Xu J., Liu X.-Y., Chen Z., Bian H. Fighting Cancer with Viruses: Oncolytic Virus Therapy in China. Hum. Gene Ther. 2018;29:151–159. doi: 10.1089/hum.2017.212.
- Shaw A.R., Suzuki M. Immunology of Adenoviral Vectors in Cancer Therapy. Mol. Ther. - Methods Clin. Dev. 2019;15:418–429. doi: 10.1016/j.omtm.2019.11.001.
- Ma G., Kawamura K., Li Q., Okamoto S., Suzuki N., Kobayashi H., Liang M., Tada Y., Tatsumi K., Hiroshima K., et al. Combinatory cytotoxic effects produced by E1B-55kDa-deleted adenoviruses and chemotherapeutic agents are dependent on the agents in esophageal carcinoma. Cancer Gene Ther. 2010;17:803–813. doi: 10.1038/cgt.2010.37.
- Cheng P.-H., Wechman S.L., McMasters K.M., Zhou H.S. Oncolytic Replication of E1b-Deleted Adenoviruses. Viruses. 2015;7:5767–5779. doi: 10.3390/v7112905.
- Öberg D., Yanover E., Adam V., Sweeney K., Costas C., Lemoine N.R., Halldén G. Improved potency and selectivity of an oncolytic E1ACR2 and E1B19K deleted adenoviral mutant in prostate and pancreatic cancers. Clin. Cancer Res. 2010;16:541–543. doi: 10.1158/1078-0432.CCR-09-1960.
- Mao L.-J., Kan Y., Li B.-H., Ma S., Liu Y., Yang D.-L., Yang C. Combination Therapy of Prostate Cancer by Oncolytic Adenovirus Harboring Interleukin 24 and Ionizing Radiation. Front. Oncol. 2020;10:421. doi: 10.3389/fonc.2020.00421.
- Cicchelero L., Denies S., Haers H., Vanderperren K., Stock E., Van Brantegem L., De Rooster H., Sanders N.N. Intratumoural interleukin 12 gene therapy stimulates the immune system and decreases angiogenesis in dogs with spontaneous cancer. Vet. Comp. Oncol. 2016;15:1187–1205. doi: 10.1111/vco.12255.
- Lu X. Impact of IL-12 in Cancer. Curr. Cancer Drug targets. 2017;17:682–697. doi: 10.2174/1568009617666170427102729.
- Lasek W., Zagozdzon R., Jakobisiak M. Interleukin 12: Still a promising candidate for tumor immunotherapy? Cancer Immunol. Immunother. 2014;63:419–435. doi: 10.1007/s00262-014-1523-1.
- Freytag S.O., Barton K.N., Zhang Y. Efficacy of oncolytic adenovirus expressing suicide genes and interleukin-12 in preclinical model of prostate cancer. Gene Ther. 2013;20:1131–1139. doi: 10.1038/gt.2013.40.
- O Freytag S., Zhang Y., Siddiqui F. Preclinical toxicology of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for prostate cancer. Mol. Ther. Oncolytics. 2015;2:15006. doi: 10.1038/mto.2015.6.
- Fredebohm J., Boettcher M., Eisen C., Gaida M.M., Heller A., Keleg S., Tost J., Greulich-Bode K.M., Hotz-Wagenblatt A., Lathrop M., et al. Establishment and Characterization of a Highly Tumourigenic and Cancer Stem Cell Enriched Pancreatic Cancer Cell Line as a Well Defined Model System. PLoS ONE. 2012;7:e48503. doi: 10.1371/journal.pone.0048503.
- Ohkura Y., Ueno M., Udagawa H. Risk factors for febrile neutropenia and effectiveness of primary prophylaxis with pegfilgrastim in patients with esophageal cancer treated with docetaxel, cisplatin, and 5-fluorouracil. World J. Surg. Oncol. 2019;17:125. doi: 10.1186/s12957-019-1665-x.
- Bortolanza S., Alzuguren P., Buñuales M., Qian C., Prieto J., Hernandez-Alcoceba R. Human adenovirus replicates in immunocompetent models of pancreatic cancer in Syrian hamsters. Hum. Gene Ther. 2007;18:681–690. doi: 10.1089/hum.2007.017.
- Li X., Wang P., Li H., Du X., Liu M., Huang Q., Wang Y., Wang S. The Efficacy of Oncolytic Adenovirus Is Mediated by T-cell Responses against Virus and Tumor in Syrian Hamster Model. Clin. Cancer Res. 2016;23:239–249. doi: 10.1158/1078-0432.CCR-16-0477.
- Milanovic M., Fan D.N.Y., Belenki D., Däbritz J.H.M., Zhao Z., Yu Y., Dörr J.R., Dimitrova L., Lenze D., Barbosa I.A.M., et al. Senescence-associated reprogramming promotes cancer stemness. Nat. Cell Biol. 2018;553:96–100. doi: 10.1038/nature25167.
- Saunders N.A., Simpson F., Thompson E.W., Hill M.M., Endo-Munoz L., Leggatt G., Minchin R.F., Guminski A. Role of intratumoural heterogeneity in cancer drug resistance: Molecular and clinical perspectives. EMBO Mol. Med. 2012;4:675–684. doi: 10.1002/emmm.201101131.
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