STING Agonist VB-85247 Induces Durable Antitumor Immune Responses by Intravesical Administration in a Non-Muscle-Invasive Bladder Cancer.

Abstract

Bacillus Calmette-Guérin (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 IFN 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. In this study, we developed 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 agonists, 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 efficacious in the model. The efficacious dose was well tolerated and induced an immune response with immunologic memory that protected from rechallenge without further treatment. Activation of the STING pathway via VB-85247 induced upregulation of inflammatory cytokines IFNα/β, TNFα, IL6, 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-PD-1 antibody treatment. Together, these preclinical data support the potential utility of VB-85247 for treating BCG-unresponsive patients with NMIBC and for enhancing the clinical benefit of potential of anti-PD-1 in bladder cancer. Based on these data, VB-85247 is being advanced into clinical development. Significance: STING agonist VB-85247 administered by the intravesical route achieves prolonged tumor regression, induces immunologic memory, and provides additive benefits to anti-PD-1 treatment in non-muscle invasive bladder cancer.