Smac mimetics synergize with an -CTLA-4 antibody variant that depletes Tregs
Tarun Sanda1,2, Shawn Beug2, Eric LaCasse2, Robert Korneluk1,2 1University of Ottawa, Canada, 2Children's Hospital of Eastern Ontario Research Institute, Canada
Smac mimetics (SMs) are small molecules that target the Inhibitor of Apoptosis (IAPs) proteins and possess pro-apoptotic and NF-B stimulating activities. SMs are currently in clinical trials as monotherapies and in combination with immune checkpoint inhibitors such as -PD-1 and -PD-L1. We recently discovered that the combination of SMs and -CTLA-4 cures mice bearing bladder cancer. The synergy was most pronounced using a variant of -CTLA-4 capable of depleting immunosuppressive regulatory T cells (Tregs) in the tumor microenvironment (TME). Furthermore, we observed a significant increase in antigen-presenting cells and associated uptake of tumor antigens within the TME. This finding is indicative of a pronounced processing and presentation of antigens to the T cell compartment, an immune cell subset necessary for combination efficacy. Our preliminary data also suggests that SMs selectively induce the proliferation of antigen-specific CD8+ T cells in response to antigenic stimulation, a finding indicative of enhanced T cell priming. Overall, our findings indicate that SMs potentiate the generation of an antigen-specific response, which is aided by the ablation of suppressive Tregs.
Funded by the CIHR, CCSRI and Ottawa Regional Cancer Foundation.
Credits: None available.
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