Abstract 5356: Targeted in vivo delivery of NF-κB decoy oligodeoxynucleotide augments efficacy of radiation therapy against B-cell lymphomas

Abstract

Abstract Despite recent advances in the treatment of non-Hodgkin B-cell lymphoma (BCL), significant numbers of patients relapse or remain refractory to current therapies. Treatment resistance in BCL is associated with survival signaling via NF-κB transcription factor. While NF-κB is an attractive molecular target in BCL and many other human cancers, as a transcription factor it remains undruggable. Here, we describe a B-cell-selective NF-κB inhibitor consisting of a NF-κB-specific decoy oligodeoxynucleotide (dODN) conjugated to a type B CpG ODN sequence targeting Toll-like receptor-9 (TLR9)-expressing B-cell lymphoma cells. Bc-NFκBdODN showed efficient uptake by human diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), such as U2932, OCI-Ly3 and Jeko1, respectively. In addition, we confirmed that Bc-NFκBdODN inhibited nuclear translocation and DNA-binding activity of NF-κB together with the expression of CCND2 and MYC target genes. In vitro Bc-NFκBdODN enhanced direct and ionizing radiation-induced cytotoxicity in lymphoma cells. In xenotransplanted models of human U2932 and Ly3 lymphomas, local injections of Bc-NFκBdODN reduced NF-κB activity in whole tumors and effectively arrested lymphoma progression when combined with a single, local 3Gy or 10Gy dose of radiation. In immune-competent mice, intratumoral treatment with Bc-NFκBdODN abrogated growth of directly treated as well as distant A20 lymphomas and triggered CD8+ T cell-mediated anti-tumor immune responses. Bc-NFκBdODN but not control Bc-scrambled oligonucleotides downregulated PD-1 expression on CD8+ and CD4+ T cells, while reducing Treg percentage in tumor draining lymph nodes (TDLN). Bc-NFκBdODN treatment also downregulated PD-L1 on tumor-associated myeloid cells and reduced percentage of tumor-infiltrating M-MDSCs. Our results underscore clinical relevance of NF-κB-specific decoy strategy, which can restore efficacy of standard radiation therapy to benefit patients with resistant or relapsed BCL. Citation Format: Zhuoran zhang, Xingli Zhao, Dayson Moreira, Yu-Lin Su, Piotr Swiderski, Stephen Forman, Larry Kwak, Marcin Kortylewski. Targeted in vivo delivery of NF-κB decoy oligodeoxynucleotide augments efficacy of radiation therapy against B-cell lymphomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5356.