Abstract A001: Prevalence of Common HLA Class I Alleles in a Spanish Oncology Cohort Prescreened for Early-Phase Trials: Implications for Broadening Access to HLA-Restricted Therapies

Abstract Background: HLA-restricted immunotherapies—including engineered T-cell receptors, TCR-mimic antibodies and peptide–HLA-directed bispecifics—are an expanding pillar of precision oncology. Development has historically centred on HLA-A*02:01 because it is common in individuals of European ancestry and is supported by an extensive knowledge base. However, emerging population studies show that this single allele captures only a subset of patients, raising concerns about trial eligibility, data generalisability and therapeutic equity. Comprehensive, high-resolution HLA reference maps are therefore essential for designing multi-allele or supertype-based platforms able to reach broader patient populations. Methods: We analyzed HLA class I genotypes from 355 unique patients who underwent molecular prescreening for early-phase clinical trials at a national referral centre. Typing was performed as part of routine eligibility assessments to support inclusion in trials with HLA-based selection criteria. All raw allele strings—including high-resolution forms (e.g., A*02:01:01G) and occasional ambiguous entries (e.g., A*03:XX)—were collated and collapsed to four-digit resolution (first two numeric fields). All alleles were retained for descriptive analysis. Each locus (A, B, and C) was analyzed separately, and the number of patients carrying at least one copy of each allele—regardless of zygosity—was calculated. The ten most frequent alleles across all loci were then identified. Results: Among 355 prescreened patients, the most prevalent HLA class I allele was HLA-A*02:01, present in 129 individuals (36.3%). Other frequently observed alleles included HLA-A*01:01 (n = 65, 18.3%), HLA-A*03:01 (n = 51, 14.4%), HLA-A*24:02 (n = 46, 13.0%), HLA-C*05:01 (n = 43, 12.1%), HLA-C*04:01 (n = 42, 11.8%), HLA-A*29:02 (n = 41, 11.5%), HLA-C*07:01 (n = 40, 11.3%), HLA-A*30:02 (n = 33, 9.3%), and HLA-A*11:01 (n = 28, 7.9%). This distribution confirms the predominance of A*02:01 but also reveals substantial representation of other A-locus alleles and multiple C-locus alleles. Ambiguous four-digit entries were rare in this dataset and did not influence allele ranking, reflecting improved standardisation in molecular prescreening workflows. Overall, 64% of patients carried at least one of the top-ranked non-A*02:01 alleles, highlighting the immunogenetic diversity relevant to HLA-restricted trial eligibility and antigen design. Conclusions: Our findings demonstrate that while HLA-A*02:01 remains the most frequent allele, a broad spectrum of alternative class I alleles are highly prevalent and, taken together, outnumber A*02:01 carriers. These results support the strategic expansion of HLA-targeted immunotherapy beyond A*02:01, with an emphasis on rational multi-allele and supertype-based design. Furthermore, the high-resolution typing achieved across this cohort underscores both the feasibility and the clinical relevance of embedding immunogenetic profiling into early-phase trial pipelines to promote broader and more equitable access to HLA-restricted therapies. Citation Format: Paula Villalba-Cuesta, Tatiana Hernandez, Bernard Doger de Spéville, Manuel Pedregal, Ester Garcia-Lorenzo, Victor Moreno. Prevalence of Common HLA Class I Alleles in a Spanish Oncology Cohort Prescreened for Early-Phase Trials: Implications for Broadening Access to HLA-Restricted Therapies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A001.