Yunhong Huang, Yuan Yang, Yunfei Hu, Jingling Tang, Kai Liao, Liyun Wu, Haiyan Jiang, Honglin Liu, Jindan Shen, Xiaoyang Li, Yang Xue, Yuan Wang, Kunqiao Yang, Rongjie Gu, Yuan Cheng
Natural killer (NK) cell dysfunction contributes to tumor resistance, particularly in antibody-dependent cell-mediated cytotoxicity. This study evaluated a fully chemically defined system for expanding high-purity NK (hpNK) cells and their clinical application. In preclinical studies, hpNK demonstrated strong antibody-dependent cell-mediated cytotoxicity activity in combination with rituximab. An exploratory clinical trial involving 19 patients with relapsed/refractory diffuse large B-cell lymphoma assessed the safety and preliminary clinical efficacy of combining allogeneic hpNK (shiheleucel) with anti-CD20 antibody and chemotherapy. Among 17 patients treated, no dose-limiting toxicity was observed. Among the 12 patients who underwent at least 1 postbaseline positron emission tomography and computed tomography efficacy assessment, the investigator-assessed objective response rate was 75.0% (9/12), including 7 complete responses and 2 partial responses. Median progression-free survival was 24 weeks, with median overall survival not reached at the time of analysis. Shiheleucel demonstrated a manageable safety profile and preliminary clinical activity, warranting further evaluation in larger controlled studies. SIGNIFICANCE STATEMENT: This study demonstrates that a fully chemically defined expansion system can generate high-purity natural killer (NK) cells with potent antibody-dependent cell-mediated cytotoxicity activity in preclinical settings. In an exploratory clinical trial combining allogeneic NK cell therapy with anti-CD20 antibody and chemotherapy to treat relapsed/refractory diffuse large B-cell lymphoma provided a manageable safety profile and evidence of clinical activity. These findings support further investigation of antibody-dependent cell-mediated cytotoxicity-driven NK cell-based allogeneic cell therapy.