Detecting HLA loss of heterozygosity within a standard diagnostic sequencing workflow for prognostic and therapeutic opportunities.

Autor: Lozac'hmeur A; Tempus AI Inc., Chicago, IL, USA., Danek T; Tempus AI Inc., Chicago, IL, USA., Yang Q; Tempus AI Inc., Chicago, IL, USA., Rosasco MG; Tempus AI Inc., Chicago, IL, USA., Welch JS; A2 Biotherapeutics, Agoura Hills, CA, USA., Go WY; A2 Biotherapeutics, Agoura Hills, CA, USA., Ng EW; A2 Biotherapeutics, Agoura Hills, CA, USA., Mardiros A; A2 Biotherapeutics, Agoura Hills, CA, USA., Maloney DG; Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Garon EB; David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Kirtane K; Moffitt Cancer Center, Tampa, FL, USA., Simeone DM; Moores Cancer Center, UC San Diego Health, San Diego, CA, USA., Molina JR; Mayo Clinic, Rochester, MN, USA., Salahudeen AA; University of Illinois at Chicago College of Medicine, Departments of Medicine, Biochemistry & Molecular Genetics, Chicago, IL, USA., Stein MM; Tempus AI Inc., Chicago, IL, USA. publications@tempus.com., Hecht JR; David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Jazyk: angličtina
Zdroj: NPJ precision oncology [NPJ Precis Oncol] 2024 Aug 05; Vol. 8 (1), pp. 174. Date of Electronic Publication: 2024 Aug 05.
DOI: 10.1038/s41698-024-00665-z
Abstrakt: To enable interrogation of tumor HLA LOH as a clinical diagnostic for precision oncology, we developed and validated an assay that detects HLA LOH within the context of an FDA-approved clinical diagnostic test, Tempus xT CDx. Validation was conducted via: (1) analytical evaluation of 17 archival patient samples and 42 cell line admixtures and (2) independent clinical evaluation of LOH prevalence in the HLA-A gene (HLA-A LOH) across 10,982 patients. To evaluate the prognostic relevance of HLA-A LOH we assessed 256 immunotherapy-treated non-small cell lung cancer (NSCLC) patients. To determine the feasibility of prospectively identifying and enrolling HLA-A LOH patients into a clinical trial, we established BASECAMP-1 (NCT04981119). We observed a positive predictive agreement of 97% and a negative predictive agreement of 100% in samples with ≥ 40% tumor purity. We observed HLA-A LOH in 16.1% of patients (1771/10,982), comparable to previous reports. HLA-A LOH was associated with longer survival among NSCLC adenocarcinoma patients (HR = 0.60, 95% CI [0.37, 0.96], p = 0.032) with a trend towards shorter survival among squamous cell patients (HR = 1.64, 95% CI [0.80, 3.41], p = 0.183). In 20 months, we prospectively screened 1720 subjects using the Tempus AWARE program, identifying 26 HLA-A*02 LOH patients at 8 sites, with 14 (54%) enrolled into BASECAMP-1. In conclusion, we developed and validated an investigational assay that detects tumor HLA LOH within an FDA-approved clinical diagnostic test, enabling HLA LOH utilization in diagnostic, prognostic, and therapeutic applications.
(© 2024. The Author(s).)
Databáze: MEDLINE
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