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Systemic delivery of tannic acid-ferric-masked oncolytic adenovirus reprograms tumor microenvironment for improved therapeutic efficacy in glioblastoma

Cancer Gene Therapy volume 31, pages 1804–1817 (2024)Cite this article

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Abstract

Glioblastoma (GBM) represents the most aggressive primary brain tumor, and urgently requires effective treatments. Oncolytic adenovirus (OA) shows promise as a potential candidate for clinical antitumor therapy, including in the treatment of GBM. Nevertheless, the systemic delivery of OA continues to face challenges, leading to significantly compromised antitumor efficacy. In this study, we developed an innovative approach by encapsulating CXCL11-armed OA with tannic acid and Fe3+ (TA-Fe3+) to realize the systemic delivery of OA. The nanocarrier’s ability to protect the OA from elimination by host immune response was evaluated in vitro and in vivo. We evaluated the antitumor effect and safety profile of OA@TA-Fe3+ in a GBM-bearing mice model. OA@TA-Fe3+ effectively safeguarded the virus from host immune clearance and extended its circulation in vivo. After targeting tumor sites, TA-Fe3+ could dissolve and release Fe3+ and OA. Fe3+-induced O2 production from H2O2 relieved the hypoxic state, and promoted OA replication, leading to a remarkable alteration of tumor immune microenvironment and enhancement in antitumor efficacy. Moreover, the systemic delivery of OA@TA-Fe3+ was safe without inflammation or organ damage. Our findings demonstrated the promising potential of systemically delivering the engineered OA for effective oncolytic virotherapy against GBM.

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Fig. 1: Characterization of OA@TA-Fe3+ nanoparticles.
Fig. 2: The evaluation of infection, replication, and cytotoxicity of OA@TA-Fe3+ in vitro.
Fig. 3: The immune response evaluation and biodistribution of systemic administration of OA@TA-Fe3+ nanoparticles.
Fig. 4: Hypoxia alleviation and OA replication enhancing ability of OA@TA-Fe3+.
Fig. 5: In vivo antitumor efficacy in an hPBMC humanized mouse GBM model.
Fig. 6: Immunohistochemical analysis of tumor sections.
Fig. 7: Evaluation of the chemokine, cytokines, and infiltration of T cells in tumor microenvironment.

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All data generated and analyzed during this study are available on request.

References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.

    Article  CAS  PubMed  Google Scholar 

  2. Tan AC, Ashley DM, López GY, Malinzak M, Friedman HS, Khasraw M. Management of glioblastoma: state of the art and future directions. CA Cancer J Clin. 2020;70:299–312.

    Article  PubMed  Google Scholar 

  3. Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2016;15:660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ghajar-Rahimi G, Kang K-D, Totsch SK, Gary S, Rocco A, Blitz S, et al. Clinical advances in oncolytic virotherapy for pediatric brain tumors. Pharmacol Ther. 2022;239:108193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yuan B, Wang G, Tang X, Tong A, Zhou L. Immunotherapy of glioblastoma: recent advances and future prospects. Hum Vaccin Immunother. 2022;18:2055417.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Harrington K, Freeman DJ, Kelly B, Harper J, Soria J-C. Optimizing oncolytic virotherapy in cancer treatment. Nat Rev Drug Discov. 2019;18:689–706.

    Article  CAS  PubMed  Google Scholar 

  7. Heo J, Reid T, Ruo L, Breitbach CJ, Rose S, Bloomston M, et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med. 2013;19:329–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang G, Zhang Z, Zhong K, Wang Z, Yang N, Tang X, et al. CXCL11-armed oncolytic adenoviruses enhance CAR-T cell therapeutic efficacy and reprogram tumor microenvironment in glioblastoma. Mol Ther. 2023;31:134–53.

    Article  CAS  PubMed  Google Scholar 

  9. Thambi T, Hong J, Yoon A-R, Yun C-O. Challenges and progress toward tumor-targeted therapy by systemic delivery of polymer-complexed oncolytic adenoviruses. Cancer Gene Ther. 2022;29:1321–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Tannock IF, Romel L, et al. a controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med. 2000;6:879–85.

    Article  CAS  PubMed  Google Scholar 

  11. Hecht JR, Bedford R, Abbruzzese JL, Lahoti S, Reid TR, Soetikno RM, et al. A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma. Clin Cancer Res. 2003;9:555–61.

    CAS  PubMed  Google Scholar 

  12. Ferguson MS, Lemoine NR, Wang Y. Systemic delivery of oncolytic viruses: hopes and hurdles. Adv Virol. 2012;2012:805629.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Nemunaitis J, Cunningham C, Buchanan A, Blackburn A, Edelman G, Maples P, et al. Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity. Gene Ther. 2001;8:746–59.

    Article  CAS  PubMed  Google Scholar 

  14. Reid T, Galanis E, Abbruzzese J, Sze D, Andrews J, Romel L, et al. Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial. Gene Ther. 2001;8:1618–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Small EJ, Carducci MA, Burke JM, Rodriguez R, Fong L, van Ummersen L, et al. A phase I trial of intravenous CG7870, a replication-selective, prostate-specific antigen-targeted oncolytic adenovirus, for the treatment of hormone-refractory, metastatic prostate cancer. Mol Ther. 2006;14:107–17.

    Article  CAS  PubMed  Google Scholar 

  16. Reid TR, Freeman S, Post L, McCormick F, Sze DY. Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-FU/leucovorin. Cancer Gene Ther. 2005;12:673–81.

    Article  CAS  PubMed  Google Scholar 

  17. Reid T, Galanis E, Abbruzzese J, Sze D, Wein LM, Andrews J, et al. Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints. Cancer Res. 2002;62:6070–9.

    CAS  PubMed  Google Scholar 

  18. Martinez-Quintanilla J, Seah I, Chua M, Shah K. Oncolytic viruses: overcoming translational challenges. J Clin Invest. 2019;129:1407–18.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wong HH, Lemoine NR, Wang Y. Oncolytic viruses for cancer therapy: overcoming the obstacles. Viruses. 2010;2:78–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vassilaki N, Frakolaki E. Virus-host interactions under hypoxia. Microbes Infect. 2017;19:193–203.

    Article  CAS  PubMed  Google Scholar 

  21. Shen BH, Hermiston TW. Effect of hypoxia on Ad5 infection, transgene expression and replication. Gene Ther. 2005;12:902–10.

    Article  CAS  PubMed  Google Scholar 

  22. Schmid M, Ernst P, Honegger A, Suomalainen M, Zimmermann M, Braun L, et al. Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control. Nat Commun. 2018;9:450.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Mu M, Chen H, Fan R, Wang Y, Tang X, Mei L, et al. A tumor-specific ferric-coordinated epigallocatechin-3-gallate cascade nanoreactor for glioblastoma therapy. J Adv Res. 2021;34:29–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang X, Sun C, Li P, Wu T, Zhou H, Yang D, et al. Vaccine engineering with dual-functional mineral shell: a promising strategy to overcome preexisting immunity. Adv Mater. 2016;28:694–700.

    Article  CAS  PubMed  Google Scholar 

  25. Chen J, Gao P, Yuan S, Li R, Ni A, Chu L, et al. Oncolytic adenovirus complexes coated with lipids and calcium phosphate for cancer gene therapy. ACS Nano. 2016;10:11548–60.

    Article  CAS  PubMed  Google Scholar 

  26. Mu M, Liang X, Zhao N, Chuan D, Chen B, Zhao S, et al. Boosting ferroptosis and microtubule inhibition for antitumor therapy via a carrier-free supermolecule nanoreactor. J Pharm Anal. 2023;13:99–109.

    Article  PubMed  Google Scholar 

  27. Xue C-C, Li M-H, Zhao Y, Zhou J, Hu Y, Cai K-Y, et al. Tumor microenvironment-activatable Fe-doxorubicin preloaded amorphous CaCO(3) nanoformulation triggers ferroptosis in target tumor cells. Sci Adv. 2020;6:eaax1346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang L, Wan S-S, Li C-X, Xu L, Cheng H, Zhang X-Z. An adenosine triphosphate-responsive autocatalytic fenton nanoparticle for tumor ablation with self-supplied H(2)O(2) and acceleration of Fe(III)/Fe(II) conversion. Nano Lett. 2018;18:7609–18.

    Article  CAS  PubMed  Google Scholar 

  29. Chen J, Chen F, Zhang L, Yang Z, Deng T, Zhao Y, et al. Self-assembling porphyrins as a single therapeutic agent for synergistic cancer therapy: a one stone three birds strategy. ACS Appl Mater Interfaces. 2021;13:27856–67.

    Article  CAS  PubMed  Google Scholar 

  30. Pan C, Ou M, Cheng Q, Zhou Y, Yu Y, Li Z, et al. Z-scheme heterojunction functionalized pyrite nanosheets for modulating tumor microenvironment and strengthening photo/chemodynamic therapeutic effects. Adv Funct Mater. 2020;30:1906466.

    Article  CAS  Google Scholar 

  31. Ge X, Pan M-H, Wang L, Li W, Jiang C, He J, et al. Hypoxia-mediated mitochondria apoptosis inhibition induces temozolomide treatment resistance through miR-26a/Bad/Bax axis. Cell Death Dis. 2018;9:1128.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lichty BD, Breitbach CJ, Stojdl DF, Bell JC. Going viral with cancer immunotherapy. Nat Rev Cancer. 2014;14:559–67.

    Article  CAS  PubMed  Google Scholar 

  33. Guo ZS, Liu Z, Bartlett DL. Oncolytic immunotherapy: dying the right way is a key to eliciting potent antitumor immunity. Front Oncol. 2014;4:74.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol. 2017;17:97–111.

    Article  CAS  PubMed  Google Scholar 

  35. Fang Y-Z, Yang S, Wu G. Free radicals, antioxidants, and nutrition. Nutrition. 2002;18:872–9.

    Article  CAS  PubMed  Google Scholar 

  36. Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov. 2009;8:579–91.

    Article  CAS  PubMed  Google Scholar 

  37. Liu C, Liu B, Zhao J, Di Z, Chen D, Gu Z, et al. Nd(3+)-sensitized upconversion metal-organic frameworks for mitochondria-targeted amplified photodynamic therapy. Angew Chem Int Ed Engl. 2020;59:2634–8.

    Article  CAS  PubMed  Google Scholar 

  38. Lin L-S, Huang T, Song J, Ou X-Y, Wang Z, Deng H, et al. Synthesis of copper peroxide nanodots for H(2)O(2) self-supplying chemodynamic therapy. J Am Chem Soc. 2019;141:9937–45.

    Article  CAS  PubMed  Google Scholar 

  39. Yang B, Chen Y, Shi J. Reactive oxygen species (ROS)-based nanomedicine. Chem Rev. 2019;119:4881–985.

    Article  CAS  PubMed  Google Scholar 

  40. Ranji-Burachaloo H, Gurr PA, Dunstan DE, Qiao GG. Cancer treatment through nanoparticle-facilitated fenton reaction. ACS Nano. 2018;12:11819–37.

    Article  CAS  PubMed  Google Scholar 

  41. Tang Z, Liu Y, He M, Bu W. Chemodynamic therapy: tumour microenvironment-mediated Fenton and Fenton-like reactions. Angew Chem Int Ed Engl. 2019;58:946–56.

    Article  CAS  PubMed  Google Scholar 

  42. Liu C, Cao Y, Cheng Y, Wang D, Xu T, Su L, et al. An open source and reduce expenditure ROS generation strategy for chemodynamic/photodynamic synergistic therapy. Nat Commun. 2020;11:1735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hamilton NHR, Mahalingam S, Banyer JL, Ramshaw IA, Thomson SA. A recombinant vaccinia virus encoding the interferon-inducible T-cell alpha chemoattractant is attenuated in vivo. Scand J Immunol. 2004;59:246–54.

    Article  CAS  PubMed  Google Scholar 

  44. Moon EK, Wang L-CS, Bekdache K, Lynn RC, Lo A, Thorne SH, et al. Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines. Oncoimmunology. 2018;7:e1395997.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Hensbergen PJ, Wijnands PGJTB, Schreurs MWJ, Scheper RJ, Willemze R, Tensen CP. The CXCR3 targeting chemokine CXCL11 has potent antitumor activity in vivo involving attraction of CD8+ T lymphocytes but not inhibition of angiogenesis. J Immunother. 2005;28:343–51.

    Article  CAS  PubMed  Google Scholar 

  46. Ménard S, Tomasic G, Casalini P, Balsari A, Pilotti S, Cascinelli N, et al. Lymphoid infiltration as a prognostic variable for early-onset breast carcinomas. Clin Cancer Res. 1997;3:817–9.

    PubMed  Google Scholar 

  47. Zhu X, Li C, Lu Y, Liu Y, Wan D, Zhu D, et al. Tumor microenvironment-activated therapeutic peptide-conjugated prodrug nanoparticles for enhanced tumor penetration and local T cell activation in the tumor microenvironment. Acta Biomater. 2021;119:337–48.

    Article  CAS  PubMed  Google Scholar 

  48. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. 2005;102:18538–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yokoda R, Nagalo BM, Vernon B, Oklu R, Albadawi H, DeLeon TT, et al. Oncolytic virus delivery: from nano-pharmacodynamics to enhanced oncolytic effect. Oncolytic Virother. 2017;6:39–49.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Huang L-L, Li X, Zhang J, Zhao QR, Zhang MJ, Liu A-A, et al. MnCaCs-biomineralized oncolytic virus for bimodal imaging-guided and synergistically enhanced anticancer therapy. Nano Lett. 2019;19:8002–9.

    Article  CAS  PubMed  Google Scholar 

  51. Lv P, Liu X, Chen X, Liu C, Zhang Y, Chu C, et al. Genetically engineered cell membrane nanovesicles for oncolytic adenovirus delivery: a versatile platform for cancer virotherapy. Nano Lett. 2019;19:2993–3001.

    Article  CAS  PubMed  Google Scholar 

  52. Hong J, Yun C-O. Overcoming the limitations of locally administered oncolytic virotherapy. BMC Biomed Eng. 2019;1:17.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Lee C-H, Kasala D, Na Y, Lee MS, Kim SW, Jeong JH, et al. Enhanced therapeutic efficacy of an adenovirus-PEI-bile-acid complex in tumors with low coxsackie and adenovirus receptor expression. Biomaterials. 2014;35:5505–16.

    Article  CAS  PubMed  Google Scholar 

  54. Xia M, Luo D, Dong J, Zheng M, Meng G, Wu J, et al. Graphene oxide arms oncolytic measles virus for improved effectiveness of cancer therapy. J Exp Clin Cancer Res. 2019;38:408.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Nosaki K, Hamada K, Takashima Y, Sagara M, Matsumura Y, Miyamoto S, et al. A novel, polymer-coated oncolytic measles virus overcomes immune suppression and induces robust antitumor activity. Mol Ther oncolytics. 2016;3:16022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Walker S, Busatto S, Pham A, Tian M, Suh A, Carson K, et al. Extracellular vesicle-based drug delivery systems for cancer treatment. Theranostics. 2019;9:8001–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Evgin L, Kottke T, Tonne J, Thompson J, Huff AL, van Vloten J, et al. Oncolytic virus-mediated expansion of dual-specific CAR T cells improves efficacy against solid tumors in mice. Sci Transl Med. 2022;14:eabn2231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank our colleagues for stimulating discussions.

Funding

We declare that this work was supported by funding from the National Natural Science Foundation of China (82073404), 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYJC21003), National Key Research and Development Program of China (2023YFC3403303 and 2023YFC3403304), the Frontiers Medical Center, Tianfu Jincheng Laboratory Foundation (TFJC2023010006) and the Postdoctor Research Fund of West China Hospital, Sichuan University (2024HXBH132).

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  1. These authors contributed equally: Guoqing Wang, Min Mu, Zongliang Zhang.

Authors and Affiliations

  1. Department of Ophthalmology, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, PR China

    Guoqing Wang & Fang Lu

  2. Laboratory of Liquid Biopsy and Single Cell Research, Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, PR China

    Min Mu

  3. State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China

    Zongliang Zhang, Yongdong Chen, Nian Yang, Kunhong Zhong, Yanfang Li, Gang Guo & Aiping Tong

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Contributions

GW, MM, and ZZ designed and conducted the experiments and wrote the paper. YC, KZ, YL, and NY performed the data analysis. FL, GG, and AT designed the experiments and supervised the research. All authors discussed the results and commented on the paper.

Corresponding authors

Correspondence to Fang Lu, Gang Guo or Aiping Tong.

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The authors declare no competing interests.

Ethics approval and consent to participate

All animal’s experiments have been approved by the Biomedical Ethics Committee of West China Hospital (2018-061). All methods were performed in accordance with the relevant guidelines and regulations. All PBMC samples from healthy donors as well as tumor samples obtained from GBM patients were approved by Sichuan University West China Hospital Biomedical Ethics Committee. All healthy donors and GBM patients provided written informed consent.

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Wang, G., Mu, M., Zhang, Z. et al. Systemic delivery of tannic acid-ferric-masked oncolytic adenovirus reprograms tumor microenvironment for improved therapeutic efficacy in glioblastoma. Cancer Gene Ther 31, 1804–1817 (2024). https://doi.org/10.1038/s41417-024-00839-8

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