PO.CTP01.01 · 进行中的临床试验
UCL70802（一种LACO-Stim装甲型抗CD70 CART细胞疗法）在转移性透明细胞肾细胞癌（mccRCC）患者中的首次人体1期研究
First-in-human phase I study of UCL70802, a LACO-Stim armored Anti-CD70 CART cell therapy, in patients with metastatic clear cell renal cell carcinoma (mccRCC)
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：UCL70802是一种新型自体CART产品，经工程改造以共表达抗CD70 CAR和淋巴细胞-APC-共刺激分子（LACO-Stim），旨在通过双重机制靶向CD70阳性肿瘤：经CAR结合直接裂解肿瘤，以及经LACO-Stim实现全身免疫激活。LACO-Stim通过CD40和CD28提供共刺激，增强T细胞和APC功能，重塑肿瘤微环境，并促进抗肿瘤免疫。
方法：纳入标准治疗失败的CD70阳性mccRCC患者。主要终点包括安全性、剂量限制性毒性和最大耐受剂量。次要终点涵盖药代动力学及按RECIST v1.1评估的抗肿瘤应答。
结果：截至2025年12月30日，共治疗6例患者。安全性分析显示4例患者出现可控的1-2级细胞因子释放综合征（CRS），2例患者出现3级CRS（1天内恢复至2级）。治疗相关不良事件（TRAE）包括淋巴细胞减少（100%）、红斑（100%）和水肿（83.3%）。所有3级或以上TRAE均为与淋巴细胞清除相关的血液学毒性。未观察到DLT。除1例接受0.6×10⁶/kg剂量（DL1）的患者外，所有剂量水平均观察到抗肿瘤活性。在2×10⁶/kg剂量水平（DL3），3例患者中有2例达到部分缓解（PR）。1例患者达到确认的PR（-68.9%）。另1例患者在第1个月（M1）出现肿瘤缩小（-17.3%），并在第2个月（M2）达到PR（-32.3%）。剂量与CAR-T暴露之间存在相关性。在DL3，中位峰值CAR拷贝数（Cmax）达到37750拷贝/μg，远高于DL2。值得注意的是，DL2中一例患者暴露量较低，Cmax为1,368拷贝/μg DNA，却实现了持续的肿瘤缩小。尽管在M1时CAR拷贝已不可检测，但肿瘤缩小持续了超过六个月，肿瘤缩减从M1的-17.4%增加至M6的-26.5%。这表明在抗CD70 CAR-T细胞诱导初始抗肿瘤应答之后，通过LACO-Stim分子激活的先天免疫系统维持了持续的活性。
结论：UCL70802在mccRCC患者中显示出可控的安全性特征和有前景的初步抗肿瘤活性。其双重机制——将CAR介导的直接靶向与经LACO-Stim的全身免疫激活相结合——可能有助于克服传统CAR-T疗法所见的耐药性。剂量爬坡仍在继续，以进一步评估疗效和安全性。
查看英文原文 English abstract
Background: UCL70802 is a novel autologous CART product engineered to co-express an anti-CD70 CAR and a Lymphocyte-APC-Co-stimulator (LACO-Stim) molecule, designed to target CD70-positive tumors through dual mechanisms: direct tumor lysis via CAR engagement and systemic immune activation via LACO-Stim. LACO-Stim provides co-stimulation through CD40 and CD28, enhancing T cell and APC function, remodeling the tumor microenvironment, and promoting anti-tumor immunity.
Methods: Eligible patients with CD70 positive mccRCC who failed standard therapies were enrolled. Primary endpoints included safety, dose-limiting toxicities, and maximum tolerated dose. Secondary endpoints covered pharmacokinetics and antitumor response per RECIST v1.1.
Results: As of December 30, 2025, 6 patients were treated. Safety analysis showed manageable Grade 1-2 cytokine release syndrome (CRS) in 4 patients and Grade 3 CRS in 2 patients (recover to Grade 2 in 1 day). Treatment-related adverse events (TRAEs) included lymphopenia (100%), erythema (100%), and edema (83.3%). All Grade 3 or higher TRAEs were hematological toxicities associated with the lymphodepletion. NO DLTs were observed. Anti-tumor activity was observed across all dose levels except one patient with the dose of 0.6×10⁶/kg (DL1). At the dose level of 2×10⁶/kg (DL3), 2 out of 3 patients achieved a partial response (PR). One patient achieved a conformed PR (-68.9%). The other patient experienced a tumor shrinkage at M1(-17.3%) and achieved PR at M2 (-32.3%). There is a correlation between dose and CAR-T exposure. In DL3, the median peak CAR copy number (Cmax) reached 37750 copies/μg, which is much higher than in DL2. Notably, one patient at DL2 demonstrated mild exposure with C max of 1,368 copies/μg DNA yet achieved sustained tumor shrinkage. Although CAR copies were undetectable at M1, tumor shrinkage persisted for over six months, with tumor reduction increasing from -17.4% at M1 to -26.5% at M6. This indicates that after the initial antitumor response induced by anti-CD70 CAR-T cells, sustained activity was maintained by the innate immune system activated via the LACO-Stim molecule.
Conclusions: UCL70802 demonstrated a manageable safety profile and promising preliminary antitumor activity in mccRCC patients. Its dual mechanism -combining direct CAR-mediated targeting with systemic immune activation via LACO-Stim-may help overcome resistance seen with conventional CAR-T therapies. Dose escalation continues to further assess efficacy and safety.
利益披露 Disclosure
X. Gan, None..
W. Li, None..
W. Zhang, None..
J. Ding, None..
J. Hu, None..
C. Wu, None..
L. Lu, None..
C. Han, None..
X. Liu, None..
Y. Zhao, None..
L. Wang, None.