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BackgroundMicrobial immunotherapy, in the form of intravesical Bacillus Calmette-Guérin (BCG), is the standard-of-care for non-muscle invasive bladder cancer (NMIBC). BCG therapy is associated with significant side-effects, high disease recurrence and progression rates, and product supply shortages, leaving a significant unmet medical need for bladder cancer patients.1 2 We sought to establish the preclinical safety and efficacy of live-attenuated Salmonella enterica Typhi strain ZH9 (ΔaroC, ΔssaV) as a novel microbial immunotherapy.MethodsTherapeutic efficacy of intravesical ZH9 was established in the murine orthotopic, syngeneic MB49 bladder tumor model. Tumor-bearing animals were treated with a single intravesical dose of ZH9 or OncoTice BCG and long-term survival comparisons were evaluated by log-rank (Mantel-Cox) test. ZH9 interaction with urothelial cancer cells was investigated using in vitro invasion assays and flow cytometry staining for intracellular Salmonella common antigen (CSA-1) and propidium iodide for cell death. Local immune responses were analyzed by flow cytometry staining of disaggregated mouse bladders.ResultsMice treated with a single intravesical dose of ZH9 2 days after MB49 tumor inoculation demonstrated significant survival benefit compared to vehicle treated (median survival 49.5 vs. 31 days, p=0.003) and BCG treated animals (median survival 49.5 vs. 27.5 days, pConclusionsLive-attenuated Salmonella strain ZH9 demonstrated a significant survival benefit over the standard-of-care OncoTice BCG in an orthotopic bladder cancer model. ZH9 demonstrated direct tumour cell killing in vitro and induction of robust cellular immune responses in vivo. Preclinical studies indicate significant therapeutic potential of intravesical ZH9 as a novel microbial immunotherapy in bladder cancer.ReferencesLiu Y, Lu J, Huang Y, Ma L. Clinical spectrum of complications induced by intravesical immunotherapy of Bacillus Calmette-Guérin for bladder cancer. J Oncol 2019 March 10;2019:6230409.vanRhijn BW, Burger M, Lotan Y, et al. Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol 2009 September;56(3):430–42.Ethics ApprovalThe studies were conducted under approval from Pennsylvania State College of Medicine Institutional Animal Care and Use Committee approval number 47682, or with approval of the Cantonal Veterinary Office of Canton de Vaud, Switzerland. |
