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Using oncolytic viruses to ignite the tumour immune microenvironment in bladder cancer

Nature Reviews Urology volume 18, pages 543–555 (2021)Cite this article

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Abstract

The advent of immune checkpoint inhibition (ICI) has transformed the treatment paradigm for bladder cancer. However, despite the success of ICI in other tumour types, the majority of ICI-treated patients with bladder cancer failed to respond. The lack of efficacy in some patients could be attributed to a paucity of pre-existing immune reactive cells within the tumour immune microenvironment, which limits the beneficial effects of ICI. In this setting, strategies to attract lymphocytes before implementation of ICI could be helpful. Oncolytic virotherapy is thought to induce the release of damage-associated molecular patterns, eliciting a pro-inflammatory cytokine cascade and stimulating the activation of the innate immune system. Concurrently, oncolytic virotherapy-induced oncolysis leads to further release of neoantigens and subsequent epitope spreading, culminating in a robust, tumour-specific adaptive immune response. Combination therapy using oncolytic virotherapy with ICI has proven successful in a number of preclinical studies and is beginning to enter clinical trials for the treatment of both non-muscle-invasive and muscle-invasive bladder cancer. In this context, understanding of the mechanisms underpinning oncolytic virotherapy and its potential synergism with ICI will enable clinicians to effectively deploy oncolytic virotherapy, either as monotherapy or as combination therapy in the different clinical stages of bladder cancer.

Key points

  • Bladder cancer is uniquely accessible, enabling intravesical administration of anticancer agents to avoid drug sequestration and toxicity from off-target effects.

  • With advancing genetic engineering, oncolytic viruses can be modified to have enhanced antitumour specificity, immunogenicity and decreased toxicity.

  • Immunogenic cell death induced by oncolytic virotherapy can synergize with the effect of immune checkpoint inhibitors to achieve maximal cancer control.

  • Many types of oncolytic virus, including vaccinia virus, reovirus, herpesvirus, coxsackievirus and adenovirus, have demonstrated efficacy in preclinical studies, and some have entered clinical trials.

  • Neoadjuvant treatment of clinically localized muscle-invasive bladder cancer and adjuvant therapy of bacillus Calmette–Guérin-unresponsive carcinoma in situ represent two clinical scenarios ripe for the use of oncolytic virotherapy.

  • As the immunogenic and antitumour effects of intravesical treatment can propagate to distant sites, combining therapies that induce a strong but tolerable local response within the bladder followed by systemic amplification of the tumour-specific abscopal effects is an attractive strategy that is worthy of further clinical investigation.

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Fig. 1: Cancer homeostatic resistance mechanisms are exploited for oncolytic virus propagation.
Fig. 2: Oncolytic virus infection leads to immunogenic cell death.
Fig. 3: Combination oncolytic virus and immune checkpoint blockade leads to direct cytolysis and tumour-specific immune reactivity.

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References

  1. Morales, A., Eidinger, D. & Bruce, A. W. Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol. 116, 180–183 (1976).

    Article  CAS  PubMed  Google Scholar 

  2. Edge, R. E. et al. A let-7 MicroRNA-sensitive vesicular stomatitis virus demonstrates tumor-specific replication. Mol. Ther. 16, 1437–1443 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Martuza, R. L., Malick, A., Markert, J. M., Ruffner, K. L. & Coen, D. M. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 252, 854–856 (1991).

    Article  CAS  PubMed  Google Scholar 

  4. Toda, M., Martuza, R. L. & Rabkin, S. D. Tumor growth inhibition by intratumoral inoculation of defective herpes simplex virus vectors expressing granulocyte–macrophage colony-stimulating factor. Mol. Ther. 2, 324–329 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Lichty, B. D., Breitbach, C. J., Stojdl, D. F. & Bell, J. C. Going viral with cancer immunotherapy. Nat. Rev. Cancer 14, 559–567 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Breitbach, C. J. et al. Targeting tumor vasculature with an oncolytic virus. Mol. Ther. 19, 886–894 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Russell, S. J., Peng, K.-W. & Bell, J. C. Oncolytic virotherapy. Nat. Biotechnol. 30, 658–670 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tuve, S. et al. A new group B adenovirus receptor is expressed at high levels on human stem and tumor cells. J. Virol. 80, 12109–12120 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Uchida, H. et al. Effective treatment of an orthotopic xenograft model of human glioblastoma using an EGFR-retargeted oncolytic herpes simplex virus. Mol. Ther. 21, 561–569 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Nevins, J. R. The Rb/E2F pathway and cancer. Hum. Mol. Genet. 10, 699–703 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Savontaus, M. J., Sauter, B. V., Huang, T. G. & Woo, S. L. Transcriptional targeting of conditionally replicating adenovirus to dividing endothelial cells. Gene Ther. 9, 972–979 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Bommareddy, P. K., Shettigar, M. & Kaufman, H. L. Integrating oncolytic viruses in combination cancer immunotherapy. Nat. Rev. Immunol. 18, 498–513 (2018).

    Article  CAS  PubMed  Google Scholar 

  13. Norman, K. L., Farassati, F. & Lee, P. W. K. Oncolytic viruses and cancer therapy. Cytokine Growth Factor. Rev. 2, 271–282 (2001).

    Article  Google Scholar 

  14. Lilley, C. E., Carson, C. T., Muotri, A. R., Gage, F. H. & Weitzman, M. D. DNA repair proteins affect the lifecycle of herpes simplex virus 1. Proc. Natl Acad. Sci. USA 102, 5844–5849 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Morton, E. R. & Blaho, J. A. Herpes simplex virus blocks Fas-mediated apoptosis independent of viral activation of NF-κB in human epithelial HEp-2 cells. J. Interferon Cytokine Res. 27, 365–376 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Esfandiarei, M. et al. Protein kinase B/Akt regulates coxsackievirus B3 replication through a mechanism which is not caspase dependent. J. Virol. 78, 4289–4298 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Takaoka, A. et al. Integration of interferon-α/β signalling to p53 responses in tumour suppression and antiviral defence. Nature 424, 516–523 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Stanley, M. A., Pett, M. R. & Coleman, N. HPV: from infection to cancer. Biochem. Soc. Trans. 35, 1456–1460 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Jagus, R., Joshi, B. & Barber, G. N. PKR, apoptosis and cancer. Int. J. Biochem. Cell Biol. 31, 123–138 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Xia, T., Konno, H. & Barber, G. N. Recurrent loss of STING signaling in melanoma correlates with susceptibility to viral oncolysis. Cancer Res. 76, 6747–6759 (2016).

    Article  CAS  PubMed  Google Scholar 

  21. Kirn, D. H. & Thorne, S. H. Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer. Nat. Rev. Cancer 9, 64–71 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Nguyên, T. L. et al. Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis. Proc. Natl Acad. Sci. USA 105, 14981–14986 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhang, K. X. et al. Down-regulation of type I interferon receptor sensitizes bladder cancer cells to vesicular stomatitis virus-induced cell death. Int. J. Cancer 127, 830–838 (2010).

    CAS  PubMed  Google Scholar 

  24. Elde, N. C., Child, S. J., Geballe, A. P. & Malik, H. S. Protein kinase R reveals an evolutionary model for defeating viral mimicry. Nature 457, 485–489 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Annels, N. E. 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. 25, 5818–5831 (2019).

    Article  CAS  PubMed  Google Scholar 

  26. Burke, J. M. 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. 188, 2391–2397 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Packiam, V. T. et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: interim results. Urol. Oncol. 36, 440–447 (2018).

    Article  CAS  PubMed  Google Scholar 

  28. Gomella, L. G., Mastrangelo, M. J. & McCue, P. A. Maguire H. C., Mulholland S. G., Lattime E. C. Phase I study of intravesical vaccinia virus as a vector for gene therapy of bladder cancer. J. Urol. 166, 1291–1295 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Balar, A. V. Immune checkpoint blockade in metastatic urothelial cancer. J. Clin. Oncol. 35, 2109–2112 (2017).

    Article  CAS  PubMed  Google Scholar 

  30. FDA. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-bcg-unresponsive-high-risk-non-muscle-invasive-bladder-cancer (2020).

  31. Necchi, A. et al. Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an open-label, single-arm, phase II study. J. Clin. Oncol. 36, 3353–3360 (2018).

    Article  CAS  PubMed  Google Scholar 

  32. Curran, M. A., Montalvo, W., Yagita, H. & Allison, J. P. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl Acad. Sci. USA 107, 4275–4280 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sharma, P. et al. Nivolumab alone and with ipilimumab in previously treated metastatic urothelial carcinoma: checkmate 032 nivolumab 1 mg/kg plus ipilimumab 3 mg/kg expansion cohort results. J. Clin. Oncol. 37, 1608–1616 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. AstraZeneca. Update on phase III DANUBE trial for Imfinzi and tremelimumab in unresectable, stage IV bladder cancer. AstraZeneca https://www.astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-danube-trial-for-imfinzi-and-tremelimumab-in-unresectable-stage-iv-bladder-cancer-06032020.html (2020).

  35. Hato, S. V., Khong, A., de Vries, I. J. & Lesterhuis, W. J. Molecular pathways: the immunogenic effects of platinum-based chemotherapeutics. Clin. Cancer Res. 20, 2831–2837 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Galsky, M. D. et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 395, 1547–1557 (2020).

    Article  CAS  PubMed  Google Scholar 

  37. Merck. Merck provides update on phase 3 KEYNOTE-361 trial evaluating KEYTRUDA® (pembrolizumab) as monotherapy and in combination with chemotherapy in patients with advanced or metastatic urothelial carcinoma. Merck https://www.merck.com/news/merck-provides-update-on-phase-3-keynote-361-trial-evaluating-keytruda-pembrolizumab-as-monotherapy-and-in-combination-with-chemotherapy-in-patients-with-advanced-or-metastatic-urothelial-carc/ (2020).

  38. Xu, H. et al. Antitumor activity and treatment-related toxicity associated with nivolumab plus ipilimumab in advanced malignancies: a systematic review and meta-analysis. Front. Pharmacol. 10, 1300 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 515, 568–571 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 554, 544–548 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Garg, A. D., Dudek-Peric, A. M., Romano, E. & Agostinis, P. Immunogenic cell death. Int. J. Dev. Biol. 59, 131–140 (2015).

    Article  CAS  PubMed  Google Scholar 

  45. Kepp, O. et al. Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology 3, e955691 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Haag, F. et al. Extracellular NAD and ATP: Partners in immune cell modulation. Purinergic Signal. 3, 71–81 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gardai, S. J. et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell. 123, 321–334 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Spranger, S., Dai, D., Horton, B. & Gajewski, T. F. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31, 711–723.e4 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Cai, X., Chiu, Y.-H. & Chen, Z. J. The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. Mol. Cell 54, 289–296 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Kell, A. M. & Gale, M. Jr RIG-I in RNA virus recognition. Virology 479, 110–121 (2015).

    Article  PubMed  CAS  Google Scholar 

  51. Saha, D., Wakimoto, H. & Rabkin, S. D. Oncolytic herpes simplex virus interactions with the host immune system. Curr. Opin. Virol. 21, 26–34 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mihret, A., Mamo, G., Tafesse, M., Hailu, A. & Parida, S. Dendritic cells activate and mature after infection with Mycobacterium tuberculosis. BMC Res. Notes 4, 247 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Dai, P. et al. Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells. Sci. Immunol. 2, eaal1713 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Zamarin, D. et al. PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy. J. Clin. Invest. 128, 1413–1428 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Brode, S. & Macary, P. A. Cross-presentation: dendritic cells and macrophages bite off more than they can chew! Immunology 112, 345–351 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Nesslinger, N. J. et al. A viral vaccine encoding prostate-specific antigen induces antigen spreading to a common set of self-proteins in prostate cancer patients. Clin. Cancer Res. 16, 4046–4056 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Woller, N. et al. Viral infection of tumors overcomes resistance to PD-1-immunotherapy by broadening neoantigenome-directed T-cell responses. Mol. Ther. 23, 1630–1640 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Benencia, F., Courrèges, M. C., Fraser, N. W. & Coukos, G. Herpes virus oncolytic therapy reverses tumor immune dysfunction and facilitates tumor antigen presentation. Cancer Biol. Ther. 7, 1194–1205 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Smith-Garvin, J. E., Koretzky, G. A. & Jordan, M. S. T cell activation. Annu. Rev. Immunol. 27, 591–619 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Adachi, Y. et al. Distinct germinal center selection at local sites shapes memory B cell response to viral escape. J. Exp. Med. 212, 1709–1723 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Denton, A. E. et al. Type I interferon induces CXCL13 to support ectopic germinal center formation. J. Exp. Med. 216, 621–637 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Andtbacka, R. H. et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33, 2780–2788 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Liu, Z., Ravindranathan, R., Kalinski, P., Guo, Z. S. & Bartlett, D. L. Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy. Nat. Commun. 8, 1–12 (2017).

    CAS  Google Scholar 

  64. Shen, W., Patnaik, M. M., Ruiz, A., Russell, S. J. & Peng, K.-W. Immunovirotherapy with vesicular stomatitis virus and PD-L1 blockade enhances therapeutic outcome in murine acute myeloid leukemia. Blood. J. Am. Soc. Hematol. 127, 1449–1458 (2016).

    CAS  Google Scholar 

  65. Rajani, K. et al. Combination therapy with reovirus and anti-PD-1 blockade controls tumor growth through innate and adaptive immune responses. Mol. Ther. 24, 166–174 (2016).

    Article  CAS  PubMed  Google Scholar 

  66. Bourgeois-Daigneault, M.-C. et al. Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy. Sci. Transl Med. 10, eaao1641 (2018).

    Article  PubMed  CAS  Google Scholar 

  67. Rojas, J. J., Sampath, P., Hou, W. & Thorne, S. H. Defining effective combinations of immune checkpoint blockade and oncolytic virotherapy. Clin. Cancer Res. 21, 5543–5551 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Chesney, J. et al. Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. J. Clin. Oncol. 36, 1658 (2018).

    Article  CAS  PubMed  Google Scholar 

  69. Puzanov, I. et al. Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB–IV melanoma. J. Clin. Oncol. 34, 2619–2626 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ribas, A. et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell. 170, 1109–1119.e10 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kaufman, H. L. et al. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann. Surg. Oncol. 17, 718–730 (2010).

    Article  PubMed  Google Scholar 

  72. Haseley, A., Alvarez-Breckenridge, C., Chaudhury, A. R. & Kaur, B. Advances in oncolytic virus therapy for glioma. Recent. Pat. CNS Drug Discov. 4, 1–13 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Oyama, M. et al. Intravesical and intravenous therapy of human bladder cancer by the herpes vector G207. Hum. Gene Ther. 11, 1683–1693 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Hu, C. et al. Intravenous injections of the oncolytic virus M1 as a novel therapy for muscle-invasive bladder cancer. Cell Death Dis. 9, 274 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Li, X. et al. The efficacy of oncolytic adenovirus is mediated by T-cell responses against virus and tumor in Syrian hamster model. Clin. Cancer Res. 23, 239–249 (2017).

    Article  PubMed  CAS  Google Scholar 

  76. Ramesh, N. et al. Identification of pretreatment agents to enhance adenovirus infection of bladder epithelium. Mol. Ther. 10, 697–705 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Kamat, A. M. et al. Predicting response to intravesical bacillus Calmette-Guérin immunotherapy: are we there yet? A systematic review. Eur. Urol. 73, 738–748 (2018).

    Article  PubMed  Google Scholar 

  78. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Robertson, A. G. et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171, 540–556.e25 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Choi, W. et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25, 152–165 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Damrauer, J. S. et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc. Natl Acad. Sci. USA 111, 3110–3115 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Hedegaard, J. et al. Comprehensive transcriptional analysis of early-stage urothelial carcinoma. Cancer Cell 30, 27–42 (2016).

    Article  CAS  PubMed  Google Scholar 

  83. Harrington, K., Freeman, D. J., Kelly, B., Harper, J. & Soria, J. C. Optimizing oncolytic virotherapy in cancer treatment. Nat. Rev. Drug Discov. 18, 689–706 (2019).

    Article  CAS  PubMed  Google Scholar 

  84. Lee, S. S., Eisenlohr, L. C., McCue, P. A., Mastrangelo, M. J. & Lattime, E. C. Intravesical gene therapy: in vivo gene transfer using recombinant vaccinia virus vectors. Cancer Res. 54, 3325–3328 (1994).

    CAS  PubMed  Google Scholar 

  85. Potts, K. G. et al. Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti-tumor immunity with superior safety in bladder cancer models. EMBO Mol. Med. 9, 638–654 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Strong, J. E., Coffey, M. C., Tang, D., Sabinin, P. & Lee, P. W. The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. EMBO J. 17, 3351–3362 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hanel, E. G. et al. A novel intravesical therapy for superficial bladder cancer in an orthotopic model: oncolytic reovirus therapy. J. Urol. 172, 2018–2022 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Simpson, G. R. et al. Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer. Br. J. Cancer 106, 496–507 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Orvedahl, A. et al. HSV-1 ICP34. 5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1, 23–35 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Annels, N. E. et al. Oncolytic immunotherapy for bladder cancer using coxsackie A21 virus. Mol. Ther. Oncolytics 9, 1–12 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ramesh, N. et al. CG0070, a conditionally replicating granulocyte macrophage colony-stimulating factor–armed oncolytic adenovirus for the treatment of bladder cancer. Clin. Cancer Res. 12, 305–313 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Lichtenegger, E. et al. The oncolytic adenovirus XVir-N-31 as a novel therapy in muscle-invasive bladder cancer. Hum. Gene Ther. 30, 44–56 (2019).

    Article  CAS  PubMed  Google Scholar 

  93. Powles, T. et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat. Med. 25, 1706–1714 (2019).

    Article  CAS  PubMed  Google Scholar 

  94. Chang, S. S., Hassan, J. M., Cookson, M. S., Wells, N. & Smith, J. A. Jr. Delaying radical cystectomy for muscle invasive bladder cancer results in worse pathological stage. J. Urol. 170, 1085–1087 (2003).

    Article  PubMed  Google Scholar 

  95. Kamat, A. M. et al. Definitions, end points, and clinical trial designs for non-muscle-invasive bladder cancer: recommendations from the international bladder cancer group. J. Clin. Oncol. 34, 1935–1944 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Shabsigh, A. et al. Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur. Urol. 55, 164–174 (2009).

    Article  PubMed  Google Scholar 

  97. Li, R. et al. Systematic review of the therapeutic efficacy of bladder-preserving treatments for non-muscle-invasive bladder cancer following intravesical bacillus Calmette-Guérin. Eur. Urol. 78, 387–399 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  98. FDA. Bacillus Calmette-Guérin-Unresponsive Nonmuscle Invasive Bladder Cancer: Developing Drugs and Biologics for Treatment Guidance for Industry 1–10 (Office of Communications, Division of Drug Information, 2018).

  99. FDA. FDA/Merck, Sharpe & Dohme COMBINED Briefing Information for the December 17, 2019 Meeting of the Oncologic Drugs Advisory Committee (PM Session) (FDA, 2019).

  100. Knowles, M. A. & Hurst, C. D. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat. Rev. Cancer 15, 25–41 (2015).

    Article  CAS  PubMed  Google Scholar 

  101. FDA. Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products (FDA, 2015).

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Acknowledgements

This work has been supported in part by the Moffitt Cancer Center Schulze Award, the Campbell Family Foundation, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Cindy and Jon Gruden Fund, and the Chris Sullivan Fund.

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  1. Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Roger Li, Jingsong Zhang & Scott M. Gilbert

  2. Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Roger Li, José Conejo-Garcia & James J. Mulé

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R.L. and J.J.M. researched data for the article. R.L. contributed substantially to discussion of the content and wrote the manuscript. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Roger Li.

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R.L. declares positions on the clinical trial protocol committee for Cold Genesys and BMS, and scientific adviser and/or consultant positions at BMS and Fergene. J.C.-G. declares stock options and sponsored research from Compass Therapeutics and Anixa Bioscience, and receives consulting fees from Compass Therapeutics, Anixa Bioscience and Leidos. J.J.M. declares ownership interest (including patents) in Fulgent Genetics, Aleta Biotherapeutics, Cold Genesys, Myst Pharma and Tailored Therapeutics, and is a consultant and/or advisory board member for ONCoPEP, Cold Genesys, Morphogenesis, Mersana Therapeutics, GammaDelta Therapeutics, Myst Pharma, Tailored Therapeutics, Verseau Therapeutics, Iovance Biotherapeutics, Vault Pharma, Noble Life Sciences Partners, Fulgent Genetics, Orpheus Therapeutics, UbiVac, LLC, Vycellix and Aleta Biotherapeutics. The other authors declare no competing interests.

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Li, R., Zhang, J., Gilbert, S.M. et al. Using oncolytic viruses to ignite the tumour immune microenvironment in bladder cancer. Nat Rev Urol 18, 543–555 (2021). https://doi.org/10.1038/s41585-021-00483-z

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