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Although its exact mechanism of action is unknown, BCG significantly reduces this risk in responding patients but is mainly associated with toxic side-effects in those facing treatment resistance. Methods that allow the identification of BCG responders are, therefore, urgently needed. Methods: Fluorescently labelled UM-UC-3 cells and dissociated patient tumor samples were used to establish zebrafish tumor xenograft (ZTX) models. Changes in the relative primary tumor size and cell dissemination to the tail were evaluated via fluorescence microscopy at three days post-implantation. The data were compared to the treatment outcomes of the corresponding patients. Toxicity was evaluated based on gross morphological evaluation of the treated zebrafish larvae. Results: BCG-induced toxicity was avoided by removing the water-soluble fraction of the BCG formulation prior to use. BCG treatment via co-injection with the tumor cells resulted in significant and dose-dependent primary tumor size regression. Heat-inactivation of BCG decreased this effect, while intravenous BCG injections were ineffective. ZTX models were successfully established for six of six patients based on TUR-B biopsies. In two of these models, significant tumor regression was observed, which, in both cases, corresponded to the treatment response in the patients. Conclusions: The observed BCG-related anti-tumor effect indicates that ZTX models might predict the BCG response and thereby improve treatment planning. More experiments and clinical studies are needed, however, to elucidate the BCG mechanism and estimate the predictive value.<\/jats:p>","DOI":"10.3390\/cells12030508","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T04:25:28Z","timestamp":1675657528000},"page":"508","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Novel Zebrafish Patient-Derived Tumor Xenograft Methodology for Evaluating Efficacy of Immune-Stimulating BCG Therapy in Urinary Bladder Cancer"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7652-4551","authenticated-orcid":false,"given":"Saskia","family":"Kowald","sequence":"first","affiliation":[{"name":"Department of Health, Medicine and Care, Division of Diagnostics and Specialist Medicine, Link\u00f6ping University, SE-58185 Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ylva","family":"Huge","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, Division of Urology, Link\u00f6ping University, SE-58185 Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Decky","family":"Tandiono","sequence":"additional","affiliation":[{"name":"BioReperia AB, SE-58213 Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6505-3096","authenticated-orcid":false,"given":"Zaheer","family":"Ali","sequence":"additional","affiliation":[{"name":"BioReperia AB, SE-58213 Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9310-2433","authenticated-orcid":false,"given":"Gabriela","family":"Vazquez-Rodriguez","sequence":"additional","affiliation":[{"name":"BioReperia AB, SE-58213 Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Erkstam","sequence":"additional","affiliation":[{"name":"BioReperia AB, SE-58213 Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Fahlgren","sequence":"additional","affiliation":[{"name":"BioReperia AB, SE-58213 Link\u00f6ping, Sweden"},{"name":"Department of Biomedical and Clinical Sciences, Division of Cell Biology, Link\u00f6ping University, SE-58185 Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3675-3050","authenticated-orcid":false,"given":"Amir","family":"Sherif","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences, Division of Urology, Link\u00f6ping University, SE-58185 Link\u00f6ping, Sweden"},{"name":"Department of Surgery and Perioperative Sciences, Urology and Andrology, Ume\u00e5 University, SE-90187 Ume\u00e5, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihai","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, SE-17165 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2338-357X","authenticated-orcid":false,"given":"Lasse D.","family":"Jensen","sequence":"additional","affiliation":[{"name":"Department of Health, Medicine and Care, Division of Diagnostics and Specialist Medicine, Link\u00f6ping University, SE-58185 Link\u00f6ping, Sweden"},{"name":"BioReperia AB, SE-58213 Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nrclinonc.2017.166","article-title":"Tumour heterogeneity and resistance to cancer therapies","volume":"15","author":"Shaw","year":"2018","journal-title":"Nat. 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