Abstract 7277: Comprehensivegenomic tumor profiling identifies functional neoantigens to predict adjuvant chemotherapy benefit and optimize personalized immunotherapy in colorectal cancer

Abstract Background: Adjuvant chemotherapy benefits only ∼20% of patients with stage III colorectal cancer (CRC), underscoring the need for more precise and individualized treatment strategies. While neoantigen-based immunotherapies show promise, their integration with chemotherapy remains poorly understood. In this study, we analyzed neoantigen landscapes in 66 resectable CRC patients receiving adjuvant chemotherapy and evaluated their association with relapse risk. To further assess neoantigen-specific T-cell responses, we also characterized T cells reactive to neoantigens derived from different neoantigen sources to evaluate their therapeutic potential. Methods: Fresh-frozen tumor tissue and peripheral blood were collected from 66 stage II/III CRC patients who underwent curative resection followed by FOLFOX and were monitored for ≥18 months. Clinical responses were assessed using RECIST. Our comprehensive genomic profiling workflow integrated DNA, RNA, and TCR sequencing to characterize somatic mutations, transcriptomic features, and TCR repertoires. Neoantigens derived from SNVs, indels, and gene fusions were predicted using NetMHCpan, PRIME, and DeepImmuno. Ex vivo immunogenicity was assessed by ELISpot using long synthetic peptides and patient-derived PBMCs (n = 7). Neoantigen-specific T cells were further characterized using 10x Genomics single-cell RNA/TCR sequencing. Results: Gene fusion-derived neoantigens (GFNs) exhibited broader and more variable HLA-binding affinities than SNV/indel-derived neoantigens, with significant enrichment in high-affinity binders (≤1% rank). GFN burden was inversely correlated with SNV/indel burden, indicating that GFNs represent an independent neoantigen source—particularly in tumors with low mutational load. Notably, only GFN burden, when integrated with tumor microenvironment (TME) scores, significantly differentiated chemotherapy responders from non-responders. The resulting Fusion-TCR Immune Composite Score (FTICS) correlated strongly with progression-free survival (PFS) and demonstrated robust prognostic performance (AUC = 0.70). Moreover, GFNs-specific T cell responses were observed in 57.1% of tested patients, comparable to responses against SNV/Indel-derived neoantigens. CD8+ T cells showed stronger activation and cytotoxicity against GFNs compared with co-detected SNV-derived neoantigens. Conclusion: Our findings highlight the clinical utility of integrated immunogenomic tumor profiling in expanding neoantigen discovery beyond SNVs and indels, which can potentially guide adjuvant chemotherapy and improve personalized immunotherapy outcomes. Citation Format: Le Son Tran, Bui Que Tran Nguyen. Comprehensivegenomic tumor profiling identifies functional neoantigens to predict adjuvant chemotherapy benefit and optimize personalized immunotherapy 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 7277.