Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Nuclear Medicine, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Signal Transduct Target Ther. 2024 Mar 6;9(1):62. doi: 10.1038/s41392-024-01782-8.
Natural killer T cell lymphoma (NKTCL) is highly aggressive, with advanced stage patients poorly responding to intensive chemotherapy. To explore effective and safe treatment for newly diagnosed advanced stage NKTCL, we conducted a phase II study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab (NCT04096690). Twenty-two patients with a median age of 51 years (range, 24-74) were enrolled and treated with induction treatment of pegaspargase 2500 IU/m intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days, followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days. The complete response and overall response rate after induction treatment were 59% (95%CI, 43-79%) and 68% (95%CI, 47-84%), respectively. With a median follow-up of 30 months, the 2 year progression-free and overall survival rates were 68% (95%CI, 45-83%) and 86% (95%CI, 63-95%), respectively. The most frequently grade 3/4 adverse events were neutropenia (32%, n = 7) and hypofibrinogenemia (18%, n = 4), which were manageable and led to no discontinuation of treatment. Tumor proportion score of PD-L1, peripheral blood high-density lipoprotein cholesterol, and apolipoprotein A-I correlated with good response, while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment. In conclusion, the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed, advanced stage NKTCL. Dysregulated lipid profile and immunosuppressive signature contributed to treatment resistance, providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.
自然杀伤 T 细胞淋巴瘤（NKTCL）侵袭性高，晚期患者对强化化疗反应不佳。为了探索新诊断的晚期 NKTCL 的有效和安全治疗方法，我们进行了一项 II 期研究，评估抗代谢药物培门冬酶联合 PD-1 抗体信迪利单抗（NCT04096690）的疗效。22 例患者的中位年龄为 51 岁（范围，24-74 岁），接受了为期 6 个周期、21 天为 1 个周期的诱导治疗，培门冬酶 2500IU/m 肌内注射，第 1 天；信迪利单抗 200mg 静脉注射，第 2 天。随后进行 28 个周期、21 天为 1 个周期的维持治疗，信迪利单抗 200mg。诱导治疗后的完全缓解率和总缓解率分别为 59%（95%CI，43-79%）和 68%（95%CI，47-84%）。中位随访 30 个月时，2 年无进展生存率和总生存率分别为 68%（95%CI，45-83%）和 86%（95%CI，63-95%）。最常见的 3/4 级不良事件为中性粒细胞减少（32%，n=7）和低纤维蛋白原血症（18%，n=4），均可管理且未导致治疗中断。肿瘤 PD-L1 比例评分、外周血高密度脂蛋白胆固醇和载脂蛋白 A-I 与良好反应相关，而肿瘤浸润淋巴细胞和外周 Treg 细胞中的 PD-1 与培门冬酶联合信迪利单抗治疗的不良反应相关。总之，无化疗方案培门冬酶联合信迪利单抗对新诊断的晚期 NKTCL 有效且安全。脂质代谢紊乱和免疫抑制特征与治疗耐药相关，为 NKTCL 的脂肪酸代谢和 CTLA-4 双重靶向治疗提供了一种替代治疗方法。
