PO.ET02.07 · 实验与分子治疗
一项瘤内注射超高浓度一氧化氮(UNO)气体治疗皮肤及皮下实体瘤转移灶的1期研究
A phase 1 study of intratumoral ultra-high concentration nitric oxide (UNO) gas injection in cutaneous and subcutaneous solid tumor metastases
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摘要 Abstract
中文摘要
背景：瘤内给予超高浓度一氧化氮(UNO；>10,000 ppm)已在小鼠结肠癌和乳腺癌模型中显示出生存获益。UNO调节肿瘤免疫微环境，影响M1巨噬细胞、Tregs和CD8⁺ T细胞，并上调PD-1表达，从而增强免疫检查点抑制剂(ICIs)的活性。在临床前研究中，UNO联合抗PD-1、抗PD-L1或抗CTLA-4改善了肿瘤抑制，而在4T1荷乳腺瘤小鼠中，单用UNO的疗效超过了抗PD-1。
方法：本1期试验(NCT05351502)评估了在不可切除的皮肤或皮下实体瘤患者(浅表轴径4.5-30 mm)中单次瘤内注射UNO的安全性、最大耐受剂量(MTD)及推荐1b期剂量。UNO以25,000或50,000 ppm给药，使用23号针头水平穿过肿瘤以形成一个出口通道，然后回撤至病灶中心进行治疗。气体以0.2 L/min的速率瘤内递送5分钟。
结果：共入组10例接受过大量既往治疗的患者：鳞状细胞癌(n=2)、黑色素瘤(n=2)和乳腺癌(n=6)。患者平均接受过5.5线既往全身治疗和10.3项总的抗癌治疗。6例患者接受25,000 ppm UNO治疗，4例接受50,000 ppm治疗。总体而言，治疗耐受性良好；大多数治疗相关不良事件(AEs)为1级。1例严重不良事件(SAE，缺氧)发生于一次25,000 ppm给药期间，被判定为相关，但并非剂量限制性，且完全缓解。治疗后12周内无死亡发生。截至2025年10月1日，10例患者中有7例在单次UNO注射后19-37个月仍存活；1例患者于治疗后25个月死于疾病进展。2例三阴性乳腺癌患者无疾病状态。
结论：瘤内给予超高浓度UNO在不可切除实体瘤患者中可行且耐受性良好。在这一接受过大量既往治疗的人群中观察到的持久长期生存，支持对UNO进行进一步评估，包括与ICIs联合应用。
查看英文原文 English abstract
Background: Ultra-high concentration nitric oxide (UNO; >10,000 ppm) administered intratumorally has shown survival benefits in murine colon and breast cancer models. UNO modulates the tumor immune microenvironment, influencing M1 macrophages, Tregs, and CD8⁺ T cells, and upregulates PD-1 expression, thereby enhancing the activity of immune checkpoint inhibitors (ICIs). In preclinical studies, UNO combined with anti-PD-1, anti-PD-L1, or anti-CTLA-4 improved tumor inhibition, and UNO alone surpassed anti-PD-1 efficacy in 4T1 breast tumor-bearing mice.
Methods: This phase 1 trial (NCT05351502) evaluated the safety, maximum tolerated dose (MTD), and recommended phase 1b dose of a single intratumoral UNO injection in patients with unresectable cutaneous or subcutaneous solid tumors (superficial axis 4.5-30 mm). UNO was administered at 25,000 or 50,000 ppm using a 23-gauge needle inserted horizontally through the tumor to create an exit portal, then retracted to the lesion center for treatment. Gas was delivered intratumorally at 0.2 L/min for 5 minutes.
Results: Ten heavily pretreated patients were enrolled: squamous cell carcinoma (n=2), melanoma (n=2), and breast cancer (n=6). Patients received a mean of 5.5 prior systemic therapies and 10.3 total cancer-directed treatments. Six patients were treated with 25,000 ppm UNO and four with 50,000 ppm. Overall, treatment was well tolerated; most treatment-related adverse events (AEs) were grade 1. One serious (S)AE (hypoxia) that occurred during a 25,000 ppm administration, was considered related but was not dose-limiting and resolved fully. No deaths occurred within 12 weeks post-treatment. As of October 1, 2025, seven of ten patients remain alive 19-37 months post-single UNO injection; one patient died of disease progression 25 months post-treatment. Two patients with triple negative breast are disease free.
Conclusions: Intratumoral administration of ultra-high-concentration UNO was feasible and well tolerated in patients with unresectable solid tumors. Durable long-term survival observed in this heavily pretreated population supports further evaluation of UNO, including in combination with ICIs.
利益披露 Disclosure
A. Meirovitz, None..
S. Lisi, None..
K. Sheva, None..
D. Greenberg, None..
J. Jett, None.