肿瘤细胞治疗研究
英文原题：Nemvaleukin alfa, a modified interleukin-2 cytokine, as monotherapy and with pembrolizumab in patients with advanced solid tumors (ARTISTRY-1).
Nemvaleukin alfa, a modified interleukin-2 cytokine, as monotherapy and with pembrolizumab in patients with advanced solid tumors (ARTISTRY-1).
Nemvaleukin耐受性良好，并在经过大量预治疗的晚期实体瘤中显示出有前景的抗肿瘤活性。Nemvaleukin的2/3期研究正在进行中。
Nemvaleukin alfa（nemvaleukin，ALKS 4230）是一种新型工程化细胞因子，选择性结合中等亲和力白细胞介素-2受体，优先激活CD8+ T细胞和NK 细胞，对调节性T细胞的扩增极小，从而降低与高亲和力白细胞介素-2受体激活相关的毒性风险。nemvaleukin的临床结局尚不明确。ARTISTRY-1研究了nemvaleukin在晚期实体瘤患者中的安全性、推荐的2期剂量（RP2D）和抗肿瘤活性。
这是一项三部分、开放标签的1/2期研究：A部分为剂量递增单药治疗，B部分为剂量扩展单药治疗，C部分为与pembrolizumab联合治疗。该研究在7个国家的32个中心开展。入组成年晚期实体瘤患者，接受静脉注射nemvaleukin，每日一次，第1-5天给药（21天为一个周期），剂量为0.1-10 µg/kg/天（A部分），或按RP2D给药（B部分），或与pembrolizumab联合给药（C部分）。主要终点为RP2D选择与剂量限制性毒性（A部分），以及总缓解率（ORR）与安全性（B部分和C部分）。
2016年7月至2023年3月，共入组并治疗243例患者（A、B、C部分分别为46例、74例和166例）。未达到最大耐受剂量。RP2D确定为6 µg/kg/天。nemvaleukin单药治疗的ORR为10%（7/68；95% CI 4至20），其中7例部分缓解（黑色素瘤，n=4；肾细胞癌，n=3）。nemvaleukin治疗后观察到显著的CD8 + T细胞和NK 细胞扩增，以及轻微的调节性T细胞扩增。nemvaleukin联合pembrolizumab治疗的ORR为13%（19/144；95% CI 8至20），其中5例完全缓解和14例部分缓解；6例缓解见于PD-(L)1抑制剂已获批的肿瘤类型，5例见于PD-(L)1抑制剂未获批的肿瘤类型。3例缓解见于铂耐药卵巢癌患者。B部分和C部分中最常见的3-4级治疗相关不良事件（TRAEs）分别为中性粒细胞减少症（49%，21%）和贫血（10%，11%）；每个部分各有4%的患者因TRAEs而停药。
BACKGROUND: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds to the intermediate-affinity interleukin-2 receptor, preferentially activating CD8 + T cells and natural killer cells, with minimal expansion of regulatory T cells, thereby mitigating the risk of toxicities associated with high-affinity interleukin-2 receptor activation. Clinical outcomes with nemvaleukin are unknown. ARTISTRY-1 investigated the safety, recommended phase 2 dose (RP2D), and antitumor activity of nemvaleukin in patients with advanced solid tumors. METHODS: This was a three-part, open-label, phase 1/2 study: part A, dose-escalation monotherapy, part B, dose-expansion monotherapy, and part C, combination therapy with pembrolizumab. The study was conducted at 32 sites in 7 countries. Adult patients with advanced solid tumors were enrolled and received intravenous nemvaleukin once daily on days 1-5 (21-day cycle) at 0.1-10 µg/kg/day (part A), or at the RP2D (part B), or with pembrolizumab (part C). Primary endpoints were RP2D selection and dose-limiting toxicities (part A), and overall response rate (ORR) and safety (parts B and C). RESULTS: From July 2016 to March 2023, 243 patients were enrolled and treated (46, 74, and 166 in parts A, B, and C, respectively). The maximum tolerated dose was not reached. RP2D was determined as 6 µg/kg/day. ORR with nemvaleukin monotherapy was 10% (7/68; 95% CI 4 to 20), with seven partial responses (melanoma, n=4; renal cell carcinoma, n=3). Robust CD8 + T and natural killer cell expansion, and minimal regulatory T cell expansion were observed following nemvaleukin treatment. ORR with nemvaleukin plus pembrolizumab was 13% (19/144; 95% CI 8 to 20), with 5 complete and 14 partial responses; 6 responses were in PD-(L)1 inhibitor-approved and five in PD-(L)1 inhibitor-unapproved tumor types. Three responses were in patients with platinum-resistant ovarian cancer. The most common grade 3-4 treatment-related adverse events (TRAEs) in parts B and C, respectively, were neutropenia (49%, 21%) and anemia (10%, 11%); 4% of patients in each part discontinued due to TRAEs. CONCLUSIONS: Nemvaleukin was well tolerated and demonstrated promising antitumor activity across heavily pretreated advanced solid tumors. Phase 2/3 studies of nemvaleukin are ongoing. TRIAL REGISTRATION NUMBER: NCT02799095.
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