Roy Christian, Sewastianik Tomasz, Saenz Ileana, Opiteck Gregory J, Stagg Sean, Maiers Martin, Nagorsen Dirk
Precision and Translational Medicine, Affini-T Therapeutics Inc, Watertown, Massachusetts, USA
Precision and Translational Medicine, Affini-T Therapeutics Inc, Watertown, Massachusetts, USA.
J Immunother Cancer. 2025 May 13;13(5):e011441. doi: 10.1136/jitc-2024-011441.
Understanding regional distribution of HLA frequencies is crucial for optimizing enrollment in HLA-restricted clinical trials and to promote trial diversity per the Food and Drug Administration's 2020 mandate. Using US HLA frequency data and census demographics we developed a method to create high-resolution HLA class 1 genotypic frequency maps. Analyzing HLA-A11:01 and HLA-B58:01 as alleles of interest, we found significant US regional variations. HLA-A11:01, which presents KRAS neoantigen mutations targeted by TCR T-cell therapies, showed 10-15% genotypic frequency (national average 11.2%), with western US states 1.5 times higher than average and local variations within California (10-19%). These insights can be used to guide clinical trial site selection, for example, in National Cancer Institute (NCI) cancer center catchment areas. For HLA-B58:01, which reacts pharmacogenetically with allopurinol and results in severe cutaneous adverse reactions, Mississippi had a high frequency among US states, which could be used to guide potential public safety campaigns. This method can identify regions with high HLA type representation, aiding efficient patient identification and enrollment for HLA-specific clinical trials and health-awareness efforts.
了解人类白细胞抗原（HLA）频率的区域分布对于优化HLA限制的临床试验入组以及按照美国食品药品监督管理局2020年的要求促进试验多样性至关重要。利用美国HLA频率数据和人口普查数据，我们开发了一种方法来创建高分辨率的HLA Ⅰ类基因频率图谱。分析感兴趣的等位基因HLA-A11:01和HLA-B58:01，我们发现美国存在显著的区域差异。HLA-A11:01可呈现TCR T细胞疗法靶向的KRAS新抗原突变，其基因频率为10%-15%（全国平均为11.2%），美国西部各州比平均水平高1.5倍，加利福尼亚州内部也存在局部差异（10%-19%）。这些见解可用于指导临床试验地点的选择，例如在国立癌症研究所（NCI）癌症中心的服务区域。对于与别嘌醇发生药物遗传学反应并导致严重皮肤不良反应的HLA-B58:01，密西西比州在美国各州中频率较高，这可用于指导潜在的公共安全宣传活动。这种方法可以识别HLA类型代表性高的区域，有助于高效识别患者并使其入组HLA特异性临床试验以及开展健康宣传工作。
