Abstract 7722: Biomarkers of nelmastobart efficacy: BTN1A1 expression and tumor microenvironment dynamics in colorectal cancer

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. Citation Format: Bong-Ki Hong, Soohyeon Lee, Andrew H. Park, Young-Seung Kim, Chunai Wu, Seung-Hoon Lee, Jong-Su Park, Stephen S. Yoo. Biomarkers of nelmastobart efficacy: BTN1A1 expression and tumor microenvironment dynamics in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7722.