THE STING AGONIST VB-85247 INDUCES DURABLE ANTITUMOR IMMUNE RESPONSES BY INTRAVESICAL ADMINISTRATION IN A NON-MUSCLE INVASIVE BLADDER CANCER.

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Bacillus Calmette-Guerin (BCG) is the current standard of care for non-muscle invasive bladder cancer (NMIBC), but recurrence is common. Additional therapeutic options are a major unmet medical need for treating unresponsive patients. Stimulator of Interferon Genes (STING) plays a central role in mounting innate and adaptive immune responses to tumor cells, and activation of STING is a promising immunotherapeutic approach. Here, we developed the STING agonist VB-85247 for treating NMIBC by intravesical delivery as a strategy to provide a sustained period of exposure to bladder cancer cells while avoiding potential issues associated with intratumoral injection of STING agonist, which to date have shown only limited clinical efficacy. VB-85247 induced complete response in an orthotopic NMIBC model in contrast to treatment with BCG, which was not efficasious in the model. The efficacious dose was well tolerated and induced an immune response with immunologic memory which protected from re-challenge without further treatment. Activation of the STING pathway via VB-85247 induced upregulation of inflammatory cytokines IFN-/β, TNF-, IL-6 and CXCL10, along with maturation and activation of dendritic cells. In addition, VB-85247 provided a therapeutic benefit in combination with immune checkpoint blockade using anti-PD1 antibody treatment. Together, these preclinical data support the potential utility of VB-85247 for treating BCG-unresponsive NMIBC patients and for enhancing the clinical benefit of potential of anti-PD1 in bladder cancer. Based on these data, VB-85247 is being advanced into clinical development.