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A single-arm phase I\/II study was conducted with 44 patients with NMIBC who were unresponsive to BCG treatment. Primary outcomes were pathological complete response (pCR) and relapse-free survival (RFS). Secondary outcomes comprised response duration and therapy safety. Patients\u2019 mean age was 65 years; 59.1% of them were refractory, 31.8% relapsed, and 9.1% were intolerant to BCG. Moreover, the pCR rate after 24 months reached 72.7% (95% CI), whereas the mean RFS reached 21.4 months. Mean response duration in the pCR group was 14.3 months. No patient developed muscle-invasive or metastatic disease during treatment. Treatment-related adverse events occurred in 77.3% of patients, mostly grade 1\u20132 events. OncoTherad\u00ae activated the innate immune system through toll-like receptor 4, leading to increased interferon signaling. This activation played a crucial role in activating CX3CR1+ CD8 T cells, decreasing immune checkpoint molecules, and reversing immunosuppression in the bladder microenvironment. OncoTherad\u00ae has proved to be a safe and effective therapeutic option for patients with BCG-unresponsive NMIBC, besides showing likely advantages in tumor relapse prevention processes.<\/jats:p>","DOI":"10.3390\/ijms242417535","type":"journal-article","created":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T11:26:52Z","timestamp":1702639612000},"page":"17535","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["OncoTherad\u00ae (MRB-CFI-1) Nanoimmunotherapy: A Promising Strategy to Treat Bacillus Calmette\u2013Gu\u00e9rin-Unresponsive Non-Muscle-Invasive Bladder Cancer: Crosstalk among T-Cell CX3CR1, Immune Checkpoints, and the Toll-Like Receptor 4 Signaling Pathway"],"prefix":"10.3390","volume":"24","author":[{"given":"Jo\u00e3o Carlos Cardoso","family":"Alonso","sequence":"first","affiliation":[{"name":"Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), Universidade Estadual de Campinas (UNICAMP), Campinas 13083-865, S\u00e3o Paulo, Brazil"},{"name":"Paul\u00ednia Municipal Hospital, Paul\u00ednia 13140-000, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9373-6989","authenticated-orcid":false,"given":"Bianca Ribeiro","family":"de Souza","sequence":"additional","affiliation":[{"name":"Obstetrics & Gynecology Department, Ovarian Cancer Research Group University of British Columbia, Vancouver, BC V6Z 2K8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2939-3501","authenticated-orcid":false,"given":"Ianny Brum","family":"Reis","sequence":"additional","affiliation":[{"name":"Diagnosis and Surgery Department, Dentistry School, S\u00e3o Paulo State University (UNESP), Araraquara 14801-903, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela Cardoso","family":"de Arruda Camargo","sequence":"additional","affiliation":[{"name":"Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), Universidade Estadual de Campinas (UNICAMP), Campinas 13083-865, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), Universidade Estadual de Campinas (UNICAMP), Campinas 13083-865, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Izabel","family":"de Barros Fraz\u00e3o Salmazo","sequence":"additional","affiliation":[{"name":"Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), Universidade Estadual de Campinas (UNICAMP), Campinas 13083-865, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana Mattoso","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), Universidade Estadual de Campinas (UNICAMP), Campinas 13083-865, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Ronaldo","family":"de Castro Roston","sequence":"additional","affiliation":[{"name":"Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), Universidade Estadual de Campinas (UNICAMP), Campinas 13083-865, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8829-6704","authenticated-orcid":false,"given":"Paulo Henrique Ferreira","family":"Caria","sequence":"additional","affiliation":[{"name":"Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), Universidade Estadual de Campinas (UNICAMP), Campinas 13083-865, S\u00e3o Paulo, 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current knowledge database","volume":"136","author":"Faguet","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Celada Luis, G., Albers Acosta, E., de la Fuente, H., Velasco Balanza, C., Arroyo Correas, M., Romero-Laorden, N., Alfranca, A., and Olivier G\u00f3mez, C. (2023). A Comprehensive Analysis of Immune Response in Patients with Non-Muscle-Invasive Bladder Cancer. Cancers, 15.","DOI":"10.3390\/cancers15051364"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1046\/j.1464-410x.1998.00628.x","article-title":"The early clinical course of primary Ta and T1 bladder cancer: A proposed prognostic index","volume":"81","author":"Allard","year":"1998","journal-title":"Br. J. Urol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"181987","DOI":"10.1155\/2012\/181987","article-title":"Bladder cancer immunotherapy: BCG and beyond","volume":"2012","author":"Askeland","year":"2012","journal-title":"Adv. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.juro.2013.07.102","article-title":"Defining progression in nonmuscle invasive bladder cancer: It is time for a new, standard definition","volume":"191","author":"Lamm","year":"2014","journal-title":"J. Urol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.eururo.2021.08.010","article-title":"European Association of Urology Guidelines on Non-Muscle-Invasive Bladder Cancer (Ta, T1, and Carcinoma in situ)","volume":"81","author":"Babjuk","year":"2022","journal-title":"Eur. Urol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.eururo.2005.12.031","article-title":"Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: A combined analysis of 2596 patients from seven EORTC trials","volume":"49","author":"Sylvester","year":"2006","journal-title":"Eur. Urol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.eururo.2009.06.028","article-title":"Recurrence and progression of disease in non-muscle-invasive bladder cancer: From epidemiology to treatment strategy","volume":"56","author":"Burger","year":"2009","journal-title":"Eur. Urol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1080\/14737140.2022.2046466","article-title":"Evolution of immunotherapy in the treatment of non-muscle-invasive bladder cancer","volume":"22","author":"Lobo","year":"2022","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"eabn4118","DOI":"10.1126\/scitranslmed.abn4118","article-title":"Non-muscle-invasive bladder cancer molecular subtypes predict differential response to intravesical Bacillus Calmette-Gu\u00e9rin","volume":"15","author":"Laajala","year":"2023","journal-title":"Sci. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.euo.2020.02.006","article-title":"Evidence-Based Assessment of Current and Emerging Bladder-Sparing Therapies for Non-Muscle-Invasive Bladder Cancer after Bacillus Calmette-Guerin Therapy: A Systematic Review and Meta-Analysis","volume":"3","author":"Kamat","year":"2020","journal-title":"Eur. Urol. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1097\/JU.0000000000001422","article-title":"T1 Substaging of Nonmuscle Invasive Bladder Cancer is Associated with Bacillus Calmette-Gu\u00e9rin Failure and Improves Patient Stratification at Diagnosis","volume":"205","author":"Hoedemaeker","year":"2021","journal-title":"J. Urol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.eururo.2018.06.024","article-title":"Treatment Strategy for Newly Diagnosed T1 High-Grade Bladder Urothelial Carcinoma: New Insights and Updated Recommendations","volume":"74","author":"Klaassen","year":"2018","journal-title":"Eur. Urol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.eururo.2014.11.031","article-title":"Therapeutic options in high-risk non-muscle-invasive bladder cancer during the current worldwide shortage of bacille Calmette-Gu\u00e9rin","volume":"67","author":"Mostafid","year":"2015","journal-title":"Eur. Urol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.imlet.2020.04.002","article-title":"Toll-like receptors: Triggers of regulated cell death and promising targets for cancer therapy","volume":"223","author":"Yang","year":"2020","journal-title":"Immunol. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"104192","DOI":"10.1016\/j.phrs.2019.03.001","article-title":"Harnessing the immune system to fight cancer with Toll-like receptor and RIG-I-like receptor agonists","volume":"154","author":"Bourquin","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1038\/s41467-021-21619-0","article-title":"T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors","volume":"12","author":"Yamauchi","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.smim.2003.10.003","article-title":"TLR signaling pathways","volume":"16","author":"Takeda","year":"2004","journal-title":"Semin. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/microbiolspec.MCHD-0040-2016","article-title":"Toll-like receptor signaling and its inducible proteins","volume":"4","author":"Satoh","year":"2016","journal-title":"Microbiol. Spectr."},{"key":"ref_21","unstructured":"F\u00e1varo, W.J., and Dur\u00e1n-Caballero, N.E. (2023). Process of Obtaining a Nanostructured Complex (CFI-1), Associated to Nanostructured CFI-1 with a Protein (MRB-CFI-1) and Its Use. (PIBR10.2017.012768.0), Brazil Patent."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"012022","DOI":"10.1088\/1742-6596\/1323\/1\/012022","article-title":"New therapeutic perspective for bladder cancer in dogs: Toxicological and clinical effects of oncotherad nanostructured immunotherapy","volume":"1323","author":"Tizziani","year":"2019","journal-title":"J. Phys. Conf. Ser."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"012018","DOI":"10.1088\/1742-6596\/1323\/1\/012018","article-title":"OncoTherad: A new nanobiological response modifier, its toxicological and anticancer activities","volume":"1323","author":"Dias","year":"2019","journal-title":"J. Phys. Conf. Ser."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e16000","DOI":"10.1200\/JCO.2019.37.15_suppl.e16000","article-title":"Single-arm phase I\/II study of the safety and efficacy of OncoTherad immunomodulator in patients BCG-refractory or relapsed non-muscle invasive bladder cancer","volume":"37","author":"Iantas","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e16004","DOI":"10.1200\/JCO.2019.37.15_suppl.e16004","article-title":"Role of OncoTherad immunotherapy in the regulation of toll-like receptors-mediated immune system and RANK\/RANKL signaling: New therapeutic perspective for non-muscle invasive bladder cancer","volume":"37","author":"Iantas","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"101762","DOI":"10.1016\/j.tice.2022.101762","article-title":"OncoTherad\u00ae (MRB-CFI-1) nano-immunotherapy reduced tumoral progression in non-muscle invasive bladder cancer through activation of Toll-like signaling pathway","volume":"76","author":"Reis","year":"2022","journal-title":"Tissue Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"101988","DOI":"10.1016\/j.tice.2022.101988","article-title":"New synthetic nano-immunotherapy (OncoTherad\u00ae) for non-muscle invasive bladder cancer: Its synthesis, characterization and anticancer property","volume":"80","author":"Alonso","year":"2023","journal-title":"Tissue Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5025","DOI":"10.1007\/s00432-022-04449-5","article-title":"OncoTherad\u00ae is an immunomodulator of biological response that downregulate RANK\/RANKL signaling pathway and PD-1\/PD-L1 immune checkpoint in non-muscle invasive bladder cancer","volume":"149","author":"Reis","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_29","unstructured":"F\u00e1varo, W.J., and Dur\u00e1n-Caballero, N.E. (2021). Method for Producing a Nanostructured Complex (CFI-1), a Protein-Associated Nanostructured Complex (MRB-CFI-1) and Use. (16\/617,493), U.S. Patent."},{"key":"ref_30","unstructured":"F\u00e1varo, W.J., and Dur\u00e1n-Caballero, N.E. (2023). Method for Producing a Nanostructured Complex (CFI-1), a Protein-Associated Nanostructured Complex (MRB-CFI-1) and Use. (17\/236,839), U.S. Patent."},{"key":"ref_31","unstructured":"F\u00e1varo, W.J., and Dur\u00e1n-Caballero, N.E. (2023). Method for Producing a Nanostructured Complex (CFI-1), a Protein-Associated Nanostructured Complex (MRB-CFI-1) and Use. (17\/236,848), U.S. Patent."},{"key":"ref_32","unstructured":"F\u00e1varo, W.J., and Dur\u00e1n-Caballero, N.E. (2023). Method for Producing a Nanostructured Complex (CFI-1), a Protein-Associated Nanostructured Complex (MRB-CFI-1) and Use. (17\/236,861), U.S. Patent."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"707025","DOI":"10.3389\/fvets.2021.707025","article-title":"Current Status of Canine Melanoma Diagnosis and Therapy: Report from a Colloquium on Canine Melanoma Organized by ABROVET (Brazilian Association of Veterinary Oncology)","volume":"8","author":"Ferreira","year":"2021","journal-title":"Front. Vet. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3892\/ijmm.2021.4844","article-title":"Vitamin D, zinc and glutamine: Synergistic action with OncoTherad immunomodulator in interferon signaling and COVID-19 (Review)","volume":"47","author":"Name","year":"2021","journal-title":"Int. J. Mol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"101747","DOI":"10.1016\/j.tice.2022.101747","article-title":"Effects of combined OncoTherad immunotherapy and probiotic supplementation on modulating the chronic inflammatory process in colorectal carcinogenesis","volume":"75","author":"Reis","year":"2022","journal-title":"Tissue Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"110723","DOI":"10.1016\/j.intimp.2023.110723","article-title":"A novel therapeutic strategy for non-muscle invasive bladder cancer: OncoTherad\u00ae immunotherapy associated with platelet-rich plasma","volume":"123","author":"Oliveira","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1200\/JCO.2021.39.6_suppl.462","article-title":"Modulation of the RANK\/RANKL\/OPG system and FOXP3+ regulatory T cells in the tumor microenvironment of noninvasive bladder cancer after intravesical oncotherad immunotherapy associated with platelet-rich plasma","volume":"39","author":"Reis","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.eururo.2019.08.016","article-title":"European Association of Urology Guidelines on Non-Muscle-Invasive Bladder Cancer (TaT1 and Carcinoma In Situ)\u20142019 Update","volume":"76","author":"Babjuk","year":"2019","journal-title":"Eur. Urol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"329","DOI":"10.6004\/jnccn.2020.0011","article-title":"Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology","volume":"18","author":"Flaig","year":"2020","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.urolonc.2021.05.015","article-title":"Non-muscle-invasive bladder cancer: An overview of potential new treatment options","volume":"39","author":"Shore","year":"2021","journal-title":"Urol. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.eururo.2011.05.045","article-title":"Long-term cancer-specific survival in patients with high-risk, non-muscle-invasive bladder cancer and tumour progression: A systematic review","volume":"60","author":"Witjes","year":"2011","journal-title":"Eur. Urol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"E284","DOI":"10.1111\/j.1464-410X.2010.09980.x","article-title":"Early vs. delayed radical cystectomy for \u2018high-risk\u2019 carcinoma not invading bladder muscle: Delay of cystectomy reduces cancer-specific survival","volume":"108","author":"Thomas","year":"2011","journal-title":"BJU Int."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1016\/j.juro.2016.01.087","article-title":"The timing of radical cystectomy for bacillus Calmette-Gu\u00e9rin failure: Comparison of outcomes and risk factors for prognosis","volume":"195","author":"Haas","year":"2016","journal-title":"J. Urol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2147\/ITT.S202006","article-title":"Bacillus Calmette-Gu\u00e9rin (BCG) Therapy for Bladder Cancer: An Update","volume":"9","year":"2020","journal-title":"Immunotargets Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.eururo.2020.04.066","article-title":"Treatment of High-Grade Non-Muscle-Invasive Bladder Carcinoma by Standard Number and Dose of BCG Instillations versus Reduced Number and Standard Dose of BCG Instillations: Results of the European Association of Urology Research Foundation Randomised Phase III Clinical Trial \u201cNIMBUS\u201d","volume":"78","author":"Grimm","year":"2020","journal-title":"Eur. Urol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.euf.2019.04.002","article-title":"Recurrence Rate and Cost Consequence of the Shortage of Bacillus Calmette-Gu\u00e9rin Connaught Strain for Bladder Cancer Patients","volume":"7","author":"Ourfali","year":"2021","journal-title":"Eur. Urol. Focus"},{"key":"ref_47","unstructured":"US Food and Drug Administration (2020, October 27). Highlights of Prescribing Information: Keytruda (Pembrolizumab), Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2020\/125514s066lbl.pdf."},{"key":"ref_48","unstructured":"US Food and Drug Administration (2020, November 03). Highlights of Prescribing Information: Valstar (Valrubicin), Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2016\/020892s019lbl.pdf."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1200\/JCO.2015.64.4070","article-title":"Definitions, End Points, and Clinical Trial Designs for Non-Muscle-Invasive Bladder Cancer: Recommendations from the International Bladder Cancer Group","volume":"34","author":"Kamat","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1038\/nrurol.2017.16","article-title":"BCG-unresponsive non-muscle-invasive bladder cancer: Recommendations from the IBCG","volume":"4","author":"Kamat","year":"2017","journal-title":"Nat. Rev. Urol."},{"key":"ref_51","unstructured":"(2018, February 27). US Food and Drug Administration, Available online: https:\/\/www.fda.gov\/media\/101468\/download."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"313","DOI":"10.3233\/BLC-179023","article-title":"Bladder sparing therapy for BCG failures-I\u2014Intravesical immunotherapy","volume":"3","author":"Messing","year":"2017","journal-title":"Bladder Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/S0022-5347(05)67799-3","article-title":"Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group","volume":"163","author":"Steinberg","year":"2000","journal-title":"J. Urol."},{"key":"ref_54","first-page":"494","article-title":"Pilot study of intravesical alfa-2b interferon for treatment of bladder carcinoma in situ following BCG failure [abstract]","volume":"155","author":"Williams","year":"1996","journal-title":"J. Urol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1097\/01.ju.0000136446.37840.0a","article-title":"Interim results from a national multicenter phase II trial of combination bacillus Calmette-Guerin plus interferon alfa-2b for superficial bladder cancer","volume":"172","author":"Lilli","year":"2004","journal-title":"J. Urol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.1200\/JCO.2005.05.2720","article-title":"Phase II trial of intravesical gemcitabine in bacille Calmette-Gu\u00e9rin-refractory transitional cell carcinoma of the bladder","volume":"24","author":"Dalbagni","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1016\/S0022-5347(01)61607-0","article-title":"5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma","volume":"161","author":"Lundholm","year":"1999","journal-title":"J. Urol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"5041","DOI":"10.1200\/JCO.2020.38.15_suppl.5041","article-title":"Pembrolizumab (pembro) for the treatment of patients with bacillus Calmette-Gu\u00e9rin (BCG) unresponsive, high-risk (HR) non\u2013muscle-invasive bladder cancer (NMIBC): Over two years follow-up of KEYNOTE-057","volume":"38","author":"Balar","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5022","DOI":"10.1200\/JCO.2020.38.15_suppl.5022","article-title":"Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816)","volume":"38","author":"Black","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4561","DOI":"10.1200\/JCO.2019.37.15_suppl.4561","article-title":"Preliminary phase 2 clinical results of IL-15R\u03b1Fc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) patients","volume":"37","author":"Chamie","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_61","unstructured":"Dickstein, R.W.N., Cowan, B., Dunshee, C., Franks, M., Wolk, F., Belkoff, L., Castellucci, S., Holzbeierlein, J., Kulkarni, G., and Weizer, A. (2018, January 20\u201321). VISTA, phase 3 trial of vicinium, an EpCAM-targeted pseudomonas exotoxin, in BCG-unresponsive non-muscle invasive bladder cancer. Proceedings of the Global Congress on Bladder Cancer 2018, Madrid, Spain."},{"key":"ref_62","unstructured":"Sesen Bio (2019, October 27). Sesen Bio Reports Positive, Preliminary Data Update from Phase 3 VISTA Trial for High-Risk Non-Muscle Invasive Bladder Cancer [Press Release]. Available online: https:\/\/ir.sesenbio.com\/news-releases\/news-release-details\/sesen-bio-reports-positive-preliminary-data-update-phase-3-vista."},{"key":"ref_63","first-page":"e72","article-title":"PD03-02Phase 3 results of vicinium in BCG-unresponsive non-muscle invasive bladder cancer","volume":"203","author":"Shore","year":"2020","journal-title":"J. Urol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1200\/JCO.2020.38.6_suppl.442","article-title":"SUO Clinical Trials Consortium. Safety and efficacy of intravesical nadofaragene firadenovec for patients with high-grade, BCG unresponsive nonmuscle invasive bladder cancer (NMIBC): Results from a phase III trial","volume":"38","author":"Boorjian","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_65","unstructured":"Tizziani, S.H.S. (2019). Nova Perspectiva Terap\u00eautico Para o Carcinoma Urotelial de Bexiga em C\u00e3es: Efeitos Toxicol\u00f3gicos e Cl\u00ednicos da Imunoterapia Com Oncotherad (MRB-CFI-1). [Mestrado Disserta\u00e7\u00e3o, Universidade Estadual de Campinas]."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S0302-2838(03)00371-3","article-title":"Maintenance Bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: Results from a European Organization for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial","volume":"44","author":"Sylvester","year":"2003","journal-title":"Eur. Urol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00345-006-0112-0","article-title":"Treatment options for BCG failures","volume":"24","year":"2006","journal-title":"World J. Urol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2314","DOI":"10.1016\/j.juro.2007.09.003","article-title":"Guideline for the management of non-muscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update","volume":"178","author":"Hall","year":"2007","journal-title":"J. Urol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1097\/01.ju.0000073852.24341.4a","article-title":"Immune mechanisms in Bacillus Calmette-Guerin immunotherapy for superficial bladder cancer","volume":"170","author":"Brandau","year":"2003","journal-title":"J. Urol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1200\/JCO.2019.37.7_suppl.350","article-title":"Keynote 057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-gu\u00e9rin (BCG)","volume":"37","author":"Balar","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e12818","DOI":"10.1111\/sji.12818","article-title":"Toll-like receptors: The role in bladder cancer development, progression and immunotherapy","volume":"90","author":"Nowroozi","year":"2019","journal-title":"Scand. J. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1038\/mi.2013.72","article-title":"From infection to immunotherapy: Host immune responses to bacteria at the bladder mucosa","volume":"6","author":"Ingersoll","year":"2013","journal-title":"Mucosal Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.juro.2006.08.078","article-title":"Human bladder carcinoma is dominated by T-regulatory cells and Th1 inhibitory cytokines","volume":"177","author":"Loskog","year":"2007","journal-title":"J. Urol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"351","DOI":"10.2217\/imt.15.122","article-title":"Future directions in bladder cancer immunotherapy: Towards adaptive immunity","volume":"8","author":"Smith","year":"2016","journal-title":"Immunotherapy"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1038\/35074122","article-title":"IFN gamma and Lymphocytes Prevent Primary Tumour Development and Shape Tumour Immunogenicity","volume":"410","author":"Shankaran","year":"2001","journal-title":"Nature"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.ccr.2004.08.012","article-title":"Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression","volume":"6","author":"Luo","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Lu, J.L., Xia, Q.D., Sun, Y., Xun, Y., Hu, H.L., Liu, C.Q., Sun, J.X., Xu, J.Z., Hu, J., and Wang, S.G. (2021). Toll-Like Receptor 4 as a Favorable Prognostic Marker in Bladder Cancer: A Multi-Omics Analysis. Front. Cell. Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.651560"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3548","DOI":"10.1016\/j.vaccine.2010.03.007","article-title":"IFN-gamma-mediated upmodulation of MHC class I expression activates tumor-specific immune response in a mouse model of prostate cancer","volume":"28","author":"Martini","year":"2010","journal-title":"Vaccine"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1475-2867-11-33","article-title":"IFN-\u03b3, IL-17 and TGF-\u03b2 involvement in shaping the tumor microenvironment: The significance of modulating such cytokines in treating malignant solid tumors","volume":"11","author":"Alshaker","year":"2011","journal-title":"Cancer Cell Int."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.7150\/ijbs.4694","article-title":"Interferon-gamma-induced nitric oxide inhibits the proliferation of murine renal cell carcinoma cells","volume":"8","author":"Tate","year":"2012","journal-title":"Int. J. Biol. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.immuni.2014.10.017","article-title":"STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors","volume":"41","author":"Woo","year":"2014","journal-title":"Immunity"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.immuni.2010.07.008","article-title":"Follicular dendritic cell makes environmental sense","volume":"33","author":"Deshane","year":"2010","journal-title":"Immunity"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.smim.2009.05.005","article-title":"Modulation of adaptive immunity with Toll-like receptors","volume":"21","author":"Manicassamy","year":"2009","journal-title":"Semin. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1097\/00000478-199812000-00001","article-title":"The World Health Organization\/International Society of Urologic Pathology consensus classification of urothelial (transitional) neoplasms of the urinary bladder","volume":"22","author":"Epstein","year":"1998","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_85","unstructured":"(2020, October 27). National Cancer Institute, Available online: https:\/\/ctep.cancer.gov\/protocoldevelopment\/electronic_applications\/docs\/CTCAE_v5_Quick_Reference_8.5\u00d711.pdf."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17535\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:39:46Z","timestamp":1760132386000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17535"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,15]]},"references-count":85,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242417535"],"URL":"https:\/\/doi.org\/10.3390\/ijms242417535","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,15]]}}}