Updated oncolytic viruses for the treatment of bladder cancer: a systematic review
-
Fatemeh Khatami
,
Abdolreza Mohammadi
,
Kayhan Azadmanesh
,
Roham Deyhimfar
,
Helia Azodian Ghajar
,
Parsa Nikoofar
,
Seyed Mohammad Kazem Aghamir
Abstract
Background and Objectives: Bladder cancer (BCa) is the most prevalent malignancy of the urinary tract and is often diagnosed at a late stage. Recurrence remains a major challenge for current treatment strategies. Over the past decade, the antitumor potential of oncolytic viruses (OVs) has been increasingly recognized, with several studies evaluating their safety and efficacy in BCa treatment. In this systematic review, we present clinical trials and animal studies to comprehensively evaluate the safety and therapeutic efficiency of various OVs in BCa.
Materials and Methods: After receiving the PROSPERO registration code, four electronic databases PubMed, Web of Science, Scopus, and Embase, were systematically searched to identify studies evaluating the safety and treatment potential of OVs in BCa. Two reviewers independently conducted the screening process, and data from clinical trials and animal studies were systematically extracted into Excel for subsequent synthesis and reporting. All steps of this systematic review adhered to the guidelines outlined in the Cochrane Handbook for Systematic Reviews of Interventions, upholding high standards of methodological rigor and transparency.
Results: The initial search strategy yielded 1,061 records. After removing duplicates, 809 articles were screened for relevance. Following the exclusion of 761 studies, 48 were deemed eligible for data extraction, comprising 17 clinical trials and 29 animal studies. Various oncolytic viruses were investigated, either as monotherapies or in combination with other agents, including Vaccinia virus, Adenovirus, Oncolytic adenovirus ONYX, Coxsackievirus A21 (CVA21), oncolytic CVA21 (V937), attenuated measles virus (MV-NIS virus), recombinant adenovirus (rAd), and a serotype 5 adenovirus engineered to express GM-CSF. All studies reported their most effective doses administered within safe parameters.
Conclusion: The common virus was the non-replicative recombinant adenovirus serotype 5 (Ad5), which encodes human interferon alfa-2b (IFNα2b) a cytokine with anti-tumor properties. It is administered via intravesical instillation and has received FDA approval.
2. Black AJ, Black PC. Variant histology in bladder cancer: diagnostic and clinical implications. Transl Cancer Res 2020; 9: 6565-6575.
3. Sanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME, et al. Bladder cancer. Nat Rev Dis Primers 2017; 3: 17022.
4. Chang SS, Boorjian SA, Chou R, Clark PE, Daneshmand S, Konety BR, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol 2016; 196: 1021-1029.
5. Holzbeierlein JM, Bixler BR, Buckley DI, Chang SS, Holmes R, James AC, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline: 2024 Amendment. J Urol 2024; 211: 533-538.
6. Hu X, Li G, Wu S. Advances in Diagnosis and Therapy for Bladder Cancer. Cancers (Basel) 2022; 14: 3181.
7. McNall S, Hooper K, Sullivan T, Rieger-Christ K, Clements M. Treatment Modalities for Non-Muscle Invasive Bladder Cancer: An Updated Review. Cancers (Basel) 2024; 16: 1843.
8. Alouini S. Risk Factors Associated with Urothelial Bladder Cancer. Int J Environ Res Public Health 2024; 21: 954.
9. Kitamura H, Nishiyama N. Oncolytic virus therapy for nonmuscle-invasive bladder cancer: current status and future directions. Curr Opin Urol 2025; 35: 629-635.
10. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71.
11. McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C. PRESS Peer Review of Electronic Search Strategies: 2015 Guideline Statement. J Clin Epidemiol 2016; 75: 40-46.
12. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010; 25: 603-605.
13. Pinton P. Gene Therapy for BCG-Unresponsive Non-Muscle Invasive Bladder Cancer: Current Evidence and Future Directions. Cancers (Basel) 2025; 17: 3631.
14. Tyson MD, Uchio EM, Nam JK, Joshi SS, Bivalacqua TJ, Steinberg GD, et al. Final results: Bond-003 cohort c-phase 3, single-arm study of intravesical cretostimogene grenadenorepvec for high-risk bcg-unresponsive non-muscle invasive bladder cancer with carcinoma in situ. J Urol 2025; 213(5S2): e1.
15. Burke JM, Lamm DL, Meng MV, Nemunaitis JJ, Stephenson JJ, Arseneau JC, et al. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. J Urol 2012; 188: 2391-2397.
16. Peng Y, Bai J, Li W, Su Z, Cheng X. Advancements in p53-Based Anti-Tumor Gene Therapy Research. Molecules 2024; 29: 5315.
17. Chen GX, Zhang S, He XH, Liu SY, Ma C, Zou XP. Clinical utility of recombinant adenoviral human p53 gene therapy: current perspectives. Onco Targets Ther 2014; 7: 1901-1909.
18. Hemminki O, Parviainen S, Juhila J, Turkki R, Linder N, Lundin J, et al. Immunological data from cancer patients treated with Ad5/3-E2F-Δ24-GMCSF suggests utility for tumor immunotherapy. Oncotarget 2015; 6: 4467-4481.
19. Skelding KA, Barry RD, Shafren DR. Enhanced oncolysis mediated by Coxsackievirus A21 in combination with doxorubicin hydrochloride. Invest New Drugs 2012; 30: 568-581.
20. Relph K, Arif M, Pandha H, Annels N, Simpson GR. Analysis of ICAM-1 Expression on Bladder Carcinoma Cell Lines and Infectivity and Oncolysis by Coxsackie Virus A21. Methods Mol Biol 2023; 2684: 319-327.
21. Messing E. Intravesical Coxsackievirus A21 Therapy for Non-Muscle Invasive Bladder Cancer. Bladder Cancer 2020; 6: 97-98.
22. Annels NE, Arif M, Simpson GR, Denyer M, Moller-Levet C, Mansfield D, et al. Oncolytic Immunotherapy for Bladder Cancer Using Coxsackie A21 Virus. Mol Ther Oncolytics 2018; 9: 1-12.
23. Annels NE, Mansfield D, Arif M, Ballesteros-Merino C, Simpson GR, Denyer M, et al. Phase I Trial of an ICAM-1-Targeted Immunotherapeutic-Coxsackievirus A21 (CVA21) as an Oncolytic Agent Against Non Muscle-Invasive Bladder Cancer. Clin Cancer Res 2019; 25: 5818-5831.
24. Yun CO, Hong J, Yoon AR. Current clinical landscape of oncolytic viruses as novel cancer immunotherapeutic and recent preclinical advancements. Front Immunol 2022; 13: 953410.
25. Michaud É, Mansure JJ, Kassouf W. Integrating novel immunotherapeutic approaches in organ-preserving therapies for bladder cancer. Br J Pharmacol 2026; 183: 1215-1232.
26. Ekrami E, Ghanbari P, Othman EM, Szalay AA. The 16th international oncolytic virotherapy conference: from in vitro to clinical studies, novel approaches in cancer therapy meeting report. Front Immunol 2025; 16: 1554767.
27. Smelser WW, Wang J, Ogden KM, Chang SS, Kirschner AN. Intravesical oncolytic virotherapy and immunotherapy for non-muscle-invasive bladder cancer mouse model. BJU Int 2023; 132: 298-306.
28. Colbert L, Jia Y, Sharma A, Hu J, Xu Z, Suzman DL, et al. FDA Approval Summary: Nadofaragene Firadenovec-vncg for Bacillus Calmette-Guérin-Unresponsive Non-Muscle-Invasive Bladder Cancer. Clin Cancer Res 2025; 31: 1182-1185.
29. Kikuchi E, Hayakawa N, Fukumoto K, Shigeta K, Matsumoto K. Bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer: Its definition and future therapeutic strategies. Int J Urol 2020; 27: 108-116.
30. Wang F, Zhang G, Xu T, Ma J, Wang J, Liu S, et al. High and selective cytotoxicity of ex vivo expanded allogeneic human natural killer cells from peripheral blood against bladder cancer: implications for natural killer cell instillation after transurethral resection of bladder tumor. J Exp Clin Cancer Res 2024; 43: 24.
31. Aires I, Parada B, Ferreira R, Oliveira PA. Recent animal models of bladder cancer and their application in drug discovery: an update of the literature. Expert Opin Drug Discov 2025; 20: 295-315.
32. Hirigoyen U, Guilbaud C, Krejbich M, Fouet M, Fresquet J, Arnaud B, et al. Oncolytic viruses alter the biogenesis of tumor extracellular vesicles and influence their immunogenicity. Mol Ther Oncol 2024; 32: 200887.
33. Guo J, Xiong S, Zhang X, Gong W, Si Y, Ma D, et al. Preclinical Efficacy and Safety of an Oncolytic Adenovirus KD01 for the Treatment of Bladder Cancer. Pharmaceuticals (Basel) 2025; 18: 511.
34. Li W, Ji T, Ye J, Xiong S, Si Y, Sun X, Li F, Dai Z. Ferroptosis enhances the therapeutic potential of oncolytic adenoviruses KD01 against cancer. Cancer Gene Ther 2025; 32: 403-417.
| Files | ||
| Issue | Vol 18 No 4 (2026) | |
| Section | Review Article(s) | |
| Keywords | ||
| Bladder tumors Oncolytic viruses Urology | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
