PO.CL01.05 · 临床研究

装甲型TIL GT201在晚期实体瘤中诱导强效的肿瘤特异性TCR扩增和持久的抗肿瘤应答

Armored TIL GT201 induces potent tumor-specific TCR expansion and durable antitumor responses in advanced solid tumor

编号 5257 展板 23 时间 4/21 09:00–12:00 区域 Section 42 主讲 Yiyang Tan

分会场 Biomarkers Predictive of Therapeutic Benefit 5

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作者与单位 Authors & Affiliations

Pin Wang¹, Rong Zhou², Yong Han², Zhengxiang Han³, Weijia Fang⁴, Kai Chen⁵, Youguo Chen⁵, Liqing Ma⁶, Lili Lu⁶, Derun Shen⁶, Jiahui Jin⁶, Yiyang Tan⁶, Ke Liu⁶, Zhenjiang Liu⁶, Jingman Wang⁶, Zhao Xu⁶, Jingwei Sun⁶, Jun Cui⁶, Jing Yu⁶, Yue He², Yarong Liu⁶

¹University of Southern California, Los Angeles, CA,²Department of Oral Maxillofacial & Head and Neck Oncology, Shanghai Ninth People‘s Hospital, Shanghai, China,³Oncology Department, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China,⁴Department of Medical Oncology, the First Affiliated Hospital, Zhejiang University, Hangzhou, China,⁵The First Affiliated Hospital of Soochow University, Suzhou, China,⁶Grit Biotechnology, Shanghai, China

摘要 Abstract

中文摘要

背景：肿瘤浸润淋巴细胞(TIL)治疗已在实体瘤中显示出活性，但仍受制于T细胞耗竭和免疫抑制性肿瘤微环境。GT201是一种经工程化改造的细胞因子装甲型TIL产品，表达膜结合型IL-15(mbIL-15)，旨在增强TIL的持久性和抗肿瘤功能。一项多中心、开放标签、单臂探索性临床研究启动，以评估GT201在晚期实体瘤患者中的安全性、耐受性和初步疗效。方法：主要终点是根据CTCAE v5.0评估耐受性和安全性特征。次要终点包括按RECIST v1.1评估的总缓解率(ORR)、疾病控制率(DCR)等初步疗效指标，以及GT201的药代动力学。探索性终点包括纵向肿瘤活检和外周血采样，通过单细胞RNA/TCR测序和批量TCR测序进行分析，以追踪克隆动态并识别肿瘤特异性TCRs。结果：截至2025年11月4日，共入组12例患者(中位年龄52.5岁；中位既往两线治疗)。GT201表现出良好的安全性特征：大多数AEs为1-2级，而≥3级事件归因于清淋化疗或IL-2支持，并在14天内缓解。初步疗效信号令人鼓舞，ORR为58.3%(7/12)，DCR为83.3%(10/12)，包括两例完全缓解(16.7%)和五例部分缓解(41.7%)。相关多组学分析显示，表达mbIL-15的细胞在输注后肿瘤样本中富集，其相应的TCRs经历了显著的克隆扩增。一个假定的肿瘤特异性T细胞亚群(输注前后肿瘤样本中4-1BB⁺CD8⁺，具有高效应/耗竭和低干性特征)在制备过程中被优先扩增，并在应答者的外周血中于第7-28天之间显示出明显的扩增峰值。该亚群在基线时稀少，并在无应答者中表现出极少的扩增。相比之下，“仅TIL”型TCRs(即存在于输注产品中但输注前不存在的克隆型)在任何患者的外周血中均未扩增。结论：GT201在晚期实体瘤患者中表现出可控的安全性特征和令人鼓舞的早期疗效，正在进行的入组将进一步阐明临床结局。整合的多组学分析表明，应答患者在制备和输注后期间肿瘤特异性TCRs的扩增，与临床获益的相关性强于仅TIL型TCRs的扩增。持续的纵向采样和对假定肿瘤特异性克隆型的功能验证，将是确立其作为GT201治疗应答生物标志物效用的关键。

查看英文原文 English abstract

Background: Tumor-infiltrating lymphocyte (TIL) therapy has demonstrated activity in solid tumors but remains constrained by T-cell exhaustion and an immunosuppressive tumor microenvironment. GT201 is an engineered, cytokine-armored TIL product expressing membrane-bound IL-15 (mbIL-15) designed to enhance TIL persistence and antitumor function. A multi-center, open-label, single-arm exploratory clinical study was initiated to evaluate the safety, tolerability, and preliminary efficacy of GT201 in patients with advanced solid tumor. Method: The primary endpoint was to evaluate the tolerance and safety profile according to CTCAE v5.0. Secondary endpoints included preliminary efficacy measures such as overall response rate (ORR), disease control rate (DCR), assessed per RECIST v1.1, as well as pharmacokinetics of GT201. Exploratory endpoint included longitudinal tumor biopsies and peripheral blood sampling, analyzed by single-cell RNA/TCR sequencing and bulk TCR sequencing to track clonal dynamics and identify tumor-specific TCRs. Result: As of November 4, 2025, twelve patients were enrolled (median age 52.5 years; median of two prior lines of therapy). GT201 demonstrated a favorable safety profile: most AEs were Grade 1-2, while Grade ≥3 events were attributable to lymphodepleting chemotherapy or IL-2 support and resolved within 14 days. Preliminary efficacy signals were encouraging, with an ORR of 58.3% (7/12) and a DCR of 83.3% (10/12), including two complete responses (16.7%) and five partial responses (41.7%). Correlative multi-omics profiling revealed that mbIL-15-expressing cells were enriched in post-infusion tumor samples, and their corresponding TCRs underwent marked clonal expansion. A putative tumor-specific T-cell subset (4-1BB⁺CD8⁺ with high effector/exhaustion and low stemness signatures in tumor samples pre- and post-infusion) was preferentially expanded during manufacturing and showed a pronounced expansion peak in peripheral blood between Days 7-28 in responders. This subset was scarce at baseline and exhibited minimal expansion in non-responders. In contrast, “TIL-only” TCRs, which were clonotypes present in the infused product but absent pre-infusion, did not expand in peripheral blood in any patient. Conclusion: GT201 exhibited a manageable safety profile and encouraging early efficacy in patients with advanced solid tumor, with ongoing enrollment to further inform clinical outcomes. Integrated multi-omics analyses indicate that expansion of tumor-specific TCRs, during both manufacturing and post-infusion in responding patients, correlates more strongly with clinical benefit than expansion of TIL-only TCRs. Continued longitudinal sampling and functional validation of putative tumor-specific clonotypes will be essential to establish their utility as biomarkers of response in GT201 therapy.

利益披露 Disclosure

P. Wang, Grit Biotechnology Employment, Stock, Stock Option. TCR CURE Biopharma Technology Co., Ltd Stock. Shanghai Simnova Biotechnology Co., Ltd. Stock. R. Zhou, None.. Y. Han, None.. Z. Han, None.. W. Fang, None.. K. Chen, None.. Y. Chen, None.. L. Ma, None.. L. Lu, None.. D. Shen, None.. J. Jin, None.. Y. Tan, None.. K. Liu, None.. Z. Liu, None.. J. Wang, None.. Z. Xu, None.. J. Sun, None.. J. Cui, None.. J. Yu, None.. Y. He, None.. Y. Liu, None.

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