PO.CL01.06 · 临床研究
nelmastobart疗效的生物标志物：结直肠癌中BTN1A1表达与肿瘤微环境动态
Biomarkers of nelmastobart efficacy: BTN1A1 expression and tumor microenvironment dynamics in colorectal cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：Butyrophilin 1A1（BTN1A1）是一种在多种肿瘤和免疫细胞群中表达的免疫调节蛋白，在塑造肿瘤微环境（TME）中发挥作用。我们此前的组织芯片（TMA）分析表明，结直肠癌中BTN1A1高表达与瘤内CD8⁺ T细胞浸润减少相关，提示BTN1A1在促进免疫抑制性TME中的作用。Nelmastobart（一种靶向BTN1A1的抗体）的1期临床研究显示出可接受的安全性和初步抗肿瘤活性。此外，正在进行的STCUBE-IIT 1b/2期试验（ClinicalTrials.gov：NCT05990543）的早期结果提示BTN1A1表达与治疗应答之间存在潜在关联。为进一步研究BTN1A1的生物学意义并识别可靠的、可预测Nelmastobart疗效的生物标志物，我们使用CellDIVE平台对入组STCUBE-IIT 1b/2期临床试验的患者基线肿瘤标本进行了深度多重组织分析。
方法：使用CellDIVE多重成像系统分析基线结直肠肿瘤组织。定量分析包括BTN1A1、CD8、FoxP3以及其他TME和肿瘤内在标志物。在应答者与无应答者之间比较TME组成和空间组织。整合基线BTN1A1表达和通路活性评分，以评估其与客观缓解率（ORR）和无进展生存期（PFS）的相关性。主要终点为BTN1A1表达与免疫细胞组成之间的关联；次要终点考察可预测Nelmastobart应答的复合分子特征。
结果：BTN1A1高表达与较低的瘤内CD8⁺ T细胞浸润和增多的免疫抑制性细胞群相关。整合分析显示，将耗竭性CD8⁺ T细胞丰度和空间分布与肿瘤内在DNA损伤修复活性相结合，比单独BTN1A1表达与治疗应答的相关性更强。
结论：BTN1A1表达与结直肠癌TME中关键的免疫学改变相关。相较于单独使用BTN1A1，整合耗竭性CD8⁺ T细胞特征和肿瘤DNA损伤相关修复活性的复合生物标志物为Nelmastobart应答提供了更优的预测价值。这些发现支持采用多维生物标志物策略来优化BTN1A1靶向治疗，并有必要在更大的临床队列中进行验证。
查看英文原文 English abstract
Background: Butyrophilin 1A1 (BTN1A1) is an immune regulatory protein expressed in various tumors and immune cell populations, playing a role in shaping the tumor microenvironment (TME). Our previous tissue microarray (TMA) analysis demonstrated that high BTN1A1 expression in colorectal cancer is associated with reduced intratumoral CD8⁺ T-cell infiltration, suggesting BTN1A1's role in promoting an immunosuppressive TME. The Phase 1 clinical study of Nelmastobart, a BTN1A1-targeting antibody, showed acceptable safety and preliminary antitumor activity. Additionally, early findings from the ongoing STCUBE-IIT Phase 1b/2 trial (ClinicalTrials.gov: NCT05990543) suggest a potential link between BTN1A1 expression and therapeutic response. To further investigate the biological significance of BTN1A1 and identify reliable biomarkers predictive of Nelmastobart efficacy, we conducted a deep, multiplexed tissue analysis using the CellDIVE platform on baseline tumor specimens from patients enrolled in the STCUBE-IIT Phase 1b/2 clinical trial.
Methods: Baseline colorectal tumor tissues were analyzed using the CellDIVE multiplex imaging system. Quantitative profiling included BTN1A1, CD8, FoxP3, and additional TME- and tumor-intrinsic markers. TME composition and spatial organization were compared between responders and non-responders. Baseline BTN1A1 expression and pathway activity scores were integrated to assess correlations with objective response rate (ORR) and progression-free survival (PFS). The primary endpoint was the association between BTN1A1 expression and immune cell composition; the secondary endpoint examined composite molecular features predictive of response to Nelmastobart.
Results: High BTN1A1 expression was associated with lower intratumoral CD8⁺ T-cell infiltration and increased immunosuppressive cellular populations. Integrated analyses revealed that combining exhausted CD8⁺ T-cell abundance and spatial distribution with tumor-intrinsic DNA damage repair activity more strongly correlated with treatment response than BTN1A1 expression alone.
Conclusions: BTN1A1 expression is linked to key immunological alterations in the colorectal cancer TME. A composite biomarker incorporating exhausted CD8⁺ T-cell features and tumor DNA damage-related repair activity provides superior predictive value for Nelmastobart response compared with BTN1A1 alone. These findings support a multidimensional biomarker strategy for optimizing BTN1A1-targeted therapies and warrant validation in larger clinical cohorts.
利益披露 Disclosure
B. Hong, None..
A. Park, None..
Y. Kim, None..
C. Wu, None..
S. Lee, None..
J. Park, None..
S. S. Yoo, None.