You have accessJournal of UrologyCME1 May 2022PD53-11 DIVERGENT THERAPEUTIC OUTCOMES OF STING AGONIST ADU-S100 IN INTRATUMORAL AND INTRAVESICAL TREATMENT REGIMENS IN SYNGENEIC MURINE MB49 AND IN THE N-METHYL-N-NITROSOUREA (MNU) RAT MODEL OF UROTHELIAL CARCINOMA Alok Kumar Singh, Kara Lombardo, Monali Praharaj, James Liu, Russel Becker, Kelly Harris, Max Kates, David McConkey, Andres Matoso, William R. Bishai, and Trinity Jude Bivalacqua Alok Kumar SinghAlok Kumar Singh More articles by this author , Kara LombardoKara Lombardo More articles by this author , Monali PraharajMonali Praharaj More articles by this author , James LiuJames Liu More articles by this author , Russel BeckerRussel Becker More articles by this author , Kelly HarrisKelly Harris More articles by this author , Max KatesMax Kates More articles by this author , David McConkeyDavid McConkey More articles by this author , Andres MatosoAndres Matoso More articles by this author , William R. BishaiWilliam R. Bishai More articles by this author , and Trinity Jude BivalacquaTrinity Jude Bivalacqua More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002630.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: STING agonist ADU-S100 as an intratumoral (IT) therapeutic regimen shows excellent CD8+T cells-mediated antitumor immunity. Rapid absorption from IT sites, short terminal half-life and treatment related adverse outcomes caused withdrawal of ADU-S100 from clinical trials. We developed BCG-STING, a preclinical candidate for non-muscle invasive bladder cancer (NMIBC) that overexpresses a STING agonist (c-di-AMP). BCG-STING confers superior antitumor immunity over BCG-WT by increasing tumor infiltrating CD4+ and CD8+ T cells and inflammatory macrophages. Due to similarities in the mechanism of action, we compared antitumor efficacy of BCG-STING with ADU-S100 in an IT as well as intravesical (IV) dosing regimen. METHODS: Syngeneic MB49 flank tumors in C57BL/6 female mice were given IT treatment of BCG-WT, BCG-STING (5x106CFU) or ADU-S100 (100, 50 or 25 mg). End-point measurements included tumor volume and flow-cytometry based tumor immune infiltrate analyses (at 100 μg). MNU carcinogen rat model of NMIBC and the standard IV administration regimen was used for BCG-WT or BCG-STING (5x106 CFU, 6x weekly) or ADU-S100 (25 μg, 6x weekly). Histopathological analyses of MNU rat bladders were performed for tumor involvement index (TII) and pathological tumor staging. RESULTS: IT administration of ADU-S100 in MB49 tumor showed greatest tumor regression over BCG-WT or BCG-STING even at lowest dose (25 μg). ADU-S100 caused strongest infiltration of TNF-α+MHCII+F4/80+CD11b+ macrophages and IFN-γ+CD8+ T cells as compared to BCG-STING or BCG-WT. We did observe a significant increase in immunosuppressive IL-10+ and ARG-1+ Ly6C(hi)Ly6G(-) monocytic myeloid-derived suppressor cells (M-MDSCs) in MB49 tumors treated with ADU-S100 and BCG-WT, but not BCG-STING. In contrast to MB49 model, lV induction course of BCG-STING in MNU rat model showed the greatest antitumor effects with only 5% residual TII compared to 30% in ADU-S100 or 42% in BCG-WT. Tumor staging revealed residual T1 (50%), CIS (25%) and Ta (25%) tumors in ADU-S100 group, while BCG-WT treated group showed a lower degree of invasion to the lamina propria with CIS (50%), T1 (25%) and Ta (25%) residual tumors. BCG-STING IV therapy resulted in 60% of rat bladders showing complete tumor regression while 40% had minimal residual non-invasive tumors. CONCLUSIONS: The divergent therapeutic outcomes of IT vs IV treatment regimens of ADU-S100 over BCG-STING or BCG-WT in different urothelial carcinoma models indicate the critical role of tumor microenvironment and dosing regimens on relative efficacy. Induction of immunosuppressive M-MDSCs by ADU-S100 or BCG-WT suggests unique advantages of BCG-STING. The therapeutic targeting of M-MDSCs as combination may improve therapeutic efficacies of BCGs. Source of Funding: National Institute of Health, Maryland Tedco, Willowcroft Foundation, and Cigarette Restitution Fund © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e914 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alok Kumar Singh More articles by this author Kara Lombardo More articles by this author Monali Praharaj More articles by this author James Liu More articles by this author Russel Becker More articles by this author Kelly Harris More articles by this author Max Kates More articles by this author David McConkey More articles by this author Andres Matoso More articles by this author William R. Bishai More articles by this author Trinity Jude Bivalacqua More articles by this author Expand All Advertisement PDF downloadLoading ...
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