Despite recent advances, non-Hodgkin B-cell lymphoma patients often relapse or remain refractory to therapy. Therapeutic resistance is often associated with survival signaling via NF-κB transcription factor, an attractive but undruggable molecular target. Here, we describe a bi-partite inhibitor comprising a NF-κB-specific decoy DNA tethered to a CpG oligodeoxynucleotide targeting Toll-like receptor-9 expressing B-cell lymphoma cells. The Bc-NFκBdODN showed efficient uptake by human diffuse large B-cell (U2932, OCI-Ly3), Burkitt (RaJi) and mantle cell (Jeko1) lymphomas, respectively. We confirmed that Bc-NFκBdODN inhibited NF-κB nuclear translocation and DNA-binding, resulting in CCND2 and MYC downregulation. Bc-NFκBdODN enhanced radiosensitivity of lymphoma cells in vitro. In xenotransplanted human lymphoma, local injections of Bc-NFκBdODN reduced NF-κB activity in whole tumors. When combined with a local 3Gy dose of radiation, Bc-NFκBdODN effectively arrested OCI-Ly3 lymphoma progression. In immunocompetent mice, intratumoral injections of Bc-NFκBdODN suppressed growth of directly treated and distant A20 lymphomas, as a result of systemic CD8 T cell-dependent immune responses. Finally, systemic administration Bc-NFκBdODN to mice bearing disseminated A20 lymphoma induced complete regression and extended survival of the majority of treated. Our results underscore clinical relevance of this strategy as monotherapy and in support of radiation therapy to benefit patients with resistant or relapsed B-cell lymphoma.
Copyright © 2020. Published by Elsevier Inc.