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/m² 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) 具有高度侵袭性，晚期患者对强化化疗反应不佳。为了探索新诊断的晚期 NKTCL 的有效和安全的治疗方法，我们进行了抗代谢药物培门冬酶联合 PD-1 抗体信迪利单抗 (NCT04096690) 的 II 期研究。入组 22 名中位年龄为 51 岁（范围为 24-74 岁）的患者，并接受第 1 天肌肉注射培门冬酶 2500 IU/m ²和第 2 天静脉注射信迪利单抗 200 mg 的诱导治疗，共 6 个周期，共 21 天，随后信迪利单抗 200 mg 维持治疗，共 28 个周期，每次 21 天。诱导治疗后的完全缓解率和总体缓解率分别为 59% (95% CI, 43-79%) 和 68% (95% CI, 47-84%)。中位随访时间为 30 个月，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 级不良事件是中性粒细胞减少症（32%，n  = 7）和低纤维蛋白原血症（18%，n  = 4），这些事件是可以控制的，不会导致治疗中断。PD-L1、外周血高密度脂蛋白胆固醇和载脂蛋白 AI 的肿瘤比例评分与良好的反应相关，而肿瘤浸润淋巴细胞和外周 Treg 细胞上的 PD-1 与培门冬酶联合信迪利单抗治疗反应较差。总之，非化疗方案培加斯冬酶加信迪利单抗对于新诊断的晚期 NKTCL 是有效且安全的。血脂失调和免疫抑制信号导致治疗耐药，为 NKTCL 提供了一种双重靶向脂肪酸代谢和 CTLA-4 的替代治疗方法。