Development of novel targeted therapies for multiple myeloma
Basic Information
Description
The overarching goal of this study was to characterize and develop strategies to harness the immunomodulatory properties of the NF-kB inhibitor IT848 for multiple myeloma (MM) therapy. IT848 is a novel small molecule NF-κB inhibitor that we recently developed as a joint effort with our biotech partner ImmuneTarget Inc. IT848 is a direct inhibitor of NF-κB transcriptional activity that demonstrates on-target specificity and dose-dependent efficacy against MM cells in vitro. Moreover, we observed that NF-κB inhibition with IT848 resulted in downregulation of PD-L1 in 5TGM1 MM cells. In vivo studies revealed a favorable pharmacokinetics and toxicology profile, as well as potent antimyeloma activity in a) a cell line-based xenograft model and b) in combination with anti-PD-1 therapy in an immunocompetent mouse model of MM. The latter effect that was associated with modulation of immunosuppressive bone marrow microenvironment by reducing bone marrow infiltration by regulatory T cells. In addition to direct NF-κB inhibitory effects, IT848 treatment altered the redox homeostasis of MM cells through depletion of the reduced glutathione pool, selectively inducing oxidative stress in MM but not in healthy cells. Our findings suggest that while treatment with high-doses of IT848 displays antimyeloma activity even in the absence of a functional immune system, harnessing the immunomodulary effects of IT848 in immunocompetent individuals promises synergistic therapeutic effects at lower doses in the absence of major toxicities.
