Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA; Department of Hematology, Tianjin Union Medical Center, Tianjin People's Hospital, Tianjin, China; Department of Oncology, Tianjin Union Medical Center, Tianjin People's Hospital, Tianjin, China.
Mol Ther. 2021 Mar 3;29(3):1214-1225. doi: 10.1016/j.ymthe.2020.11.026. Epub 2020 Nov 26.
Despite recent advances, non-Hodgkin's B cell lymphoma patients often relapse or remain refractory to therapy. Therapeutic resistance is often associated with survival signaling via nuclear factor κB (NF-κB) transcription factor, an attractive but undruggable molecular target. In this study, we describe a bipartite inhibitor comprising a NF-κB-specific decoy DNA tethered to a CpG oligodeoxynucleotide (ODN) 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 3-Gy 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 of Bc-NFκBdODN to mice bearing disseminated A20 lymphoma induced complete regression and extended survival of most of the treated mice. 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.
尽管最近取得了进展，但非霍奇金氏 B 细胞淋巴瘤患者经常复发或对治疗产生耐药性。治疗耐药性通常与核因子 κB（NF-κB）转录因子的生存信号有关，这是一个有吸引力但难以成药的分子靶点。在这项研究中，我们描述了一种由 NF-κB 特异性诱饵 DNA 与靶向表达 Toll 样受体-9 的 B 细胞淋巴瘤细胞的 CpG 寡脱氧核苷酸（ODN）组成的二聚体抑制剂。Bc-NFκBdODN 分别有效地被人弥漫性大 B 细胞（U2932、OCI-Ly3）、伯基特（RaJi）和套细胞（Jeko1）淋巴瘤摄取。我们证实 Bc-NFκBdODN 抑制 NF-κB 核易位和 DNA 结合，导致 CCND2 和 MYC 下调。Bc-NFκBdODN 在体外增强了淋巴瘤细胞的放射敏感性。在异种移植的人类淋巴瘤中，Bc-NFκBdODN 的局部注射降低了整个肿瘤中的 NF-κB 活性。当与局部 3Gy 剂量的辐射联合使用时，Bc-NFκBdODN 有效地阻止了 OCI-Ly3 淋巴瘤的进展。在免疫功能正常的小鼠中，Bc-NFκBdODN 的肿瘤内注射抑制了直接治疗和远处 A20 淋巴瘤的生长，这是由于全身 CD8 T 细胞依赖性免疫反应的结果。最后，Bc-NFκBdODN 对患有弥散性 A20 淋巴瘤的小鼠进行全身给药，诱导大多数治疗小鼠的完全消退并延长了它们的存活时间。我们的结果强调了这种策略作为单一疗法的临床相关性，并支持放射治疗以造福于耐药或复发的 B 细胞淋巴瘤患者。
