Smac Mimetic and Combination Immunotherapy for the Treatment of Urothelial Cell Carcinoma

Abstract

The inhibitors of apoptosis (IAP) proteins regulate cell death signaling cascades. Smac mimetic (SM) compounds are antagonists of these proteins and are being evaluated for their anti-cancer efficacy and immunomodulatory effects. Here, I adopted an orthotopic murine model of urothelial carcinoma (MB49) resistant to prominent immune-stimulating therapies BCG mycobacterium and PD-1/PD-L1 checkpoint blockade. I found treatment with a monovalent SM, LCL161, generated T lymphocyte-dependent cures of MB49, retaining potent anti-tumour immune memory and significantly improving overall survival benefit. Separately, I report SM treatment modulates multiple components comprising the cellular adaptive immune response. Specifically, I found SM promoting the expansion of antigen-presenting cells (APCs) in vitro and enabling T lymphocyte priming in vivo. I evaluated SM in combination with concurrent immune checkpoint blockade. The combination of SM with a monoclonal antibody targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4, 9h10 clone) potentiated anticancer immunity, curing all tested subjects of MB49. I verified Fc receptor-dependent intratumoural regulatory T cell depletion as a required mechanism for enhancing survival probability with the combination of SM and anti-CTLA-4. The further evaluation of mechanisms responsible for SMs stimulating immunity will promote their clinical application for cancer therapy.