Washington University School of Medicine, St. Louis, Missouri.
Medical University of South Carolina, Charleston, South Carolina.
Clin Cancer Res. 2021 Jun 15;27(12):3339-3350. doi: 10.1158/1078-0432.CCR-20-4575. Epub 2021 Apr 8.
N-803 is an IL15 receptor superagonist complex, designed to optimize persistence and trans-presentation, thereby activating and expanding natural killer (NK) cells and CD8 T cells. Monoclonal antibodies (mAbs) direct Fc receptor-bearing immune cells, including NK cells, to recognize and eliminate cancer targets. The ability of IL15R agonists to enhance tumor-targeting mAbs in patients has not been reported previously.
Relapsed/refractory patients with indolent non-Hodgkin lymphoma were treated with rituximab and intravenous or subcutaneous N-803 on an open-label, dose-escalation phase I study using a 3+3 design (NCT02384954). Primary endpoint was maximum tolerated dose. Immune correlates were performed using multidimensional analysis via mass cytometry and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) which simultaneously measures protein and single-cell RNA expression.
This immunotherapy combination was safe and well tolerated and resulted in durable clinical responses including in rituximab-refractory patients. Subcutaneous N-803 plus rituximab induced sustained proliferation, expansion, and activation of peripheral blood NK cells and CD8 T cells, with increased NK cell and T cells present 8 weeks following last N-803 treatment. CITE-seq revealed a therapy-altered NK cell molecular program, including enhancement of AP-1 transcription factor. Furthermore, the monocyte transcriptional program was remodeled with enhanced MHC expression and antigen-presentation genes.
N-803 combines with mAbs to enhance tumor targeting in patients, and warrants further investigation in combination with immunotherapies.
N-803 是一种白细胞介素 15（IL15）受体超激动剂复合物，旨在优化其持久性和转呈作用，从而激活和扩增自然杀伤（NK）细胞和 CD8 T 细胞。单克隆抗体（mAbs）指导 Fc 受体表达的免疫细胞，包括 NK 细胞，识别并消除癌症靶标。IL15R 激动剂增强患者中肿瘤靶向 mAbs 的能力以前尚未报道过。
复发/难治性惰性非霍奇金淋巴瘤患者接受利妥昔单抗和静脉或皮下注射 N-803 的开放性、剂量递增 I 期研究（NCT02384954），采用 3+3 设计。主要终点是最大耐受剂量。免疫相关性通过使用多维分析通过质谱流式细胞术和转录物和表位的细胞索引测序（CITE-seq）进行评估，该方法同时测量蛋白质和单细胞 RNA 表达。
该免疫治疗联合方案安全且耐受良好，可产生持久的临床反应，包括在利妥昔单抗耐药患者中。皮下注射 N-803 联合利妥昔单抗诱导外周血 NK 细胞和 CD8 T 细胞的持续增殖、扩增和激活，在最后一次 N-803 治疗后 8 周时，NK 细胞和 T 细胞持续存在。CITE-seq 揭示了治疗改变的 NK 细胞分子程序，包括增强 AP-1 转录因子。此外，单核细胞转录程序被重塑，MHC 表达和抗原呈递基因增强。
N-803 与 mAbs 联合使用可增强患者的肿瘤靶向作用，值得进一步与免疫疗法联合进行研究。
