Abstract 3745: Allele-specific HLA LOH frequencies and survival outcomes in cancer: a real-world analysis

作者：Tomasz Sewastianik, Christian Roy, Michael V. Gormally, Meagan Montesion, Patrick J. Halvey, Aastha Jindal, Christopher A. Klebanoff, Gregory J. Opiteck, Dirk Nagorsen · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/1538-7445.am2025-3745 · 研究领域：Cancer Immunotherapy and Biomarkers、T-cell and B-cell Immunology、Immunotherapy and Immune Responses

Abstract While immunotherapies have revolutionized cancer treatment, the unpredictability and the limited durability of clinical responses continue to pose challenges to achieving broader success in treating solid tumors. Therapies involving T cell receptor (TCR)-HLA:peptide interactions have shown promise, including the first-in-class FDA approval of afami-cel in 2024, but concerns have been raised whether their response rate will be negatively affected by HLA loss of heterozygosity (LOH) as a mechanism of resistance. Therefore, it is important to understand the frequencies and the potential impact which HLA LOH has on overall survival. Given the heterogeneity of HLA genes as well as multiple modalities relying on a specific HLA allele for their mechanism of action, allele-specific, in addition to allele-agnostic, analyses may help explain variance in treatment outcomes. We analyzed a real-world genomic dataset of 78, 418 cases (Montesion et al.), that were heterozygous for one or more HLA class I loci, to assess HLA LOH frequencies in paired groups of frequent HLA-A alleles and hotspot mutations. We also used an orthogonal dataset from MSK IMPACT and AACR Genie BPC to examine the impact of LOH on survival in colorectal cancer (CRC; n=579) and lung adenocarcinoma (LUAD; n=610) patients. Allele-agnostic HLA LOH was detected in 16.6% of all Montesion et al. cases. Rates varied by cancer type but had no impact on the survival from diagnosis in CRC or LUAD patients treated with ...