• Continuous rituximab may lower CD20 in B-cell non-Hodgkin lymphoma (B-NHL) • Chidamide can enhance rituximab cytotoxicity in rituximab-resistance B-NHL cells • 177 LuLu-DOTAGA-rituximab has been developed for radioimmunotherapy (RIT) • RIT combined with chidamide showed potential for rituximab-resistance B-NHL therapy Rituximab resistance in B-cell non-Hodgkin lymphoma (RR B-NHL) involves decreased CD20 expression, limiting the efficacy of CD20-targeting radioimmunotherapy (RIT). Since the histone deacetylase inhibitor chidamide enhances CD20 expression, we investigated its potential to improve the effectiveness of rituximab and a novel rituximab-based RIT in RR Raji cells. RR Raji cells were generated via one-week rituximab exposure, then treated with chidamide for 24 hours to upregulate CD20. Cell death was measured following exposure to a rituximab-serum mixture. Additionally, a radioimmunoconjugate was synthesized using DOTAGA-anhydride and lutetium-177 ( 177 Lu) for in vitro RIT on these cells. Chidamide modestly increased CD20 expression ( p =0.655) but significantly enhanced cell death with the rituximab-serum mixture ( p =0.000), improving cytotoxicity. The synthesized 177 LuLu-DOTAGA-rituximab achieved clinical-grade quality (>98% radiochemical purity; >96% stability at 144 hours). RIT using this conjugate caused significantly higher cell death in chidamide-treated RR Raji cells compared to the control (without chidamide) groups ( p < 0.0001). This in vitro proof-of-concept study demonstrates that chidamide may enhance the cytotoxic effect of a novel ¹⁷⁷LuLu-DOTAGA-rituximab in RR Raji cells. Despite limitations (a single cell line and an exploratory design), this finding supports the biological plausibility and feasibility of this combination therapy, warranting further in vivo validation.
Ridwansyah et al. (2026) studied this question.