596 Oncolytic virotherapy combined with nivolumab elicits complete responses in muscle-invasive bladder cancer in association with the formation of tertiary lymphoid structures

<h3>Background</h3> Cretostimogene grenadenorepvec (C) is a replication-competent oncolytic adenovirus engineered to target RB deficient tumor cells. It has previously demonstrated safety and efficacy against BCG-exposed high risk non-muscle invasive bladder cancer through tumor lysis and anti-tumor immune activation. We tested the safety and efficacy of C in combination with Nivolumab (N) as neoadjuvant therapy for MIBC in cisplatin-ineligible patients in this study (NCT04610671). <h3>Methods</h3> Cisplatin-ineligible pts with MIBC (cT2-4a, N≤1) were enrolled. Pts received 6 weekly intravesical cretostimogene (1x10¹²vp) and N (480mg) at wks 2 and 6, followed by radical cystectomy (RC). The primary objective was safety as measured by CTCAEv5.0. Secondary objective was to assess pathologic complete response (pCR) (pT0N0) and 1yr recurrence free survival (EFS). Exploratory objectives included the assessment of biomarkers, local and systemic measures of immune activation. <h3>Results</h3> Between Nov 2020 and Feb 2023, 21 pts were enrolled with clinico-characterstics (table 1). Treatment was stopped after 1 infusion of C in 1 pt due to treatment unrelated adverse event (AE). No dose limiting toxicity was encountered. Combination treatment achieved a pathologic complete response rate of 42.1%, which was associated with baseline free E2F activity and tumor mutational burden, but not PD-L1 status. Although T cell infiltration was broadly induced following intravesical oncolytic virotherapy, the formation and maturation of tertiary lymphoid structures (TLSs) were specifically associated with complete response, emphasizing the importance of adaptive humoral immune responses. <h3>Conclusions</h3> Neoadjuvant C+N is safe and efficacious in cisplatin-ineligible MIBC pts with clinical response association with TLSs, warranting additional study in the neoadjuvant therapeutic setting. NCT04610671. <h3>Trial Registration</h3> NCT04610671. <h3>Ethics Approval</h3> We have obtained ethics approval from the Moffitt IRB. <h3>Consent</h3> Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.