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. 2025 Jan 1;11(1):74-76.
doi: 10.1001/jamaoncol.2024.5364.

Next-Generation Sequencing for HLA Genotype Screening and Matching to HLA-Restricted Therapies

Michael V Gormally  1 , Monica F Chen  1 , Anne Marie Noronha  2 , Kristalla Panageas  1 , Maggie Reynolds  1 , Kaelyn Kohlasch  1 , Bryan Novak  1 , Tatiana Kee-Velez  1 , Nikeysha Clarke  1 , Michael Eubank  2 , Cynthia Chu  2 , Clare Wilhelm  1 , Amanda Blouin  3 , Chrisann Kyi  1 , Claire Friedman  1 , Charles M Rudin  1 , Mark G Kris  1 , Ronak Shah  2 , David Aggen  1 , Sandra D'Angelo  1 , Alexander N Shoushtari  1 , Michael F Berger  2   3   4 , Chaitanya Bandlamudi  2 , Christopher A Klebanoff  1   4 , Alexander Drilon  1 , Adam J Schoenfeld  1 , Mark T A Donoghue  2
Affiliations

Next-Generation Sequencing for HLA Genotype Screening and Matching to HLA-Restricted Therapies

Michael V Gormally et al. JAMA Oncol. .
No abstract available

Plain language summary

This case series evaluates whether human leukocyte antigen (HLA) genotype could be inferred from standard next-generation sequencing, comparing concordance with confirmatory whole-exome sequencing and assessing if this assisted in matching patients to clinical trials.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Gormally reported a patent for TCR therapeutics licensed to Affini-T Therapeutics. Dr Chen reported grants from Memorial Sloan Kettering Cancer Center (MSKCC) and personal fees from Monica F Chen Candel Therapeutics; stock in Nordisk, Doximity, Quest, and Figs. Dr Friedman reported financial support from Immunocore, Merck, Eli Lily, Marengo Therapeutics, Puma Biotechnology, Hotspot Therapeutics, AstraZeneca, and Bristol Myers Squibb. Dr Rudin reported personal fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Jazz, and Harpoon Therapeutics SAB; and licensing/royalties for DLL3-directed therapeutics. Dr Kris reported personal fees from AstraZeneca, Bristol Myers Squibb, Sanofi, Pfizer, Merus, Daicchi Sankyo; nonfinancial support from Genentech. Dr Shah is part owner of Krelytics LLC. Dr Aggen reported support from Adaptimmune, University of Illinois, Seattle Genetics, Bristol Myers Squibb, Century Therapeutics, Curio Science, and Astellas. Dr D'Angelo reported personal fees from Adaptimmune, GI Innovation, Incyte, Medendi, and Piper Sandler & Co. Dr Shoushtari reported personal fees from Bristol Myers Squibb, Immunocore, Erasca, and Novartis; grants from multiple institutions. Dr Berger reported personal fees from Eli Lilly, AstraZeneca, and Paige.ai; intellectual property rights (SOPHiA Genetics). Dr Klebanoff reported grants from NIH, MSKCC, and several other organizations; personal fees from multiple biotech companies; and patents for TCRs licensed to various companies. Dr Drilon reported personal fees from numerous pharmaceutical companies, royalties from Wolters Kluwer and UpToDate, and a patent for Selpercatinib-Osimertinib. Dr Schoenfeld reported personal fees from J&J, KSQ Therapeutics, BMS, Merck, AstraZeneca, and several other companies; grants from AffiniT, Achilles Therapeutics, GSK, Harpoon, and PACTpharma. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Growth of Human Leukocyte Antigen (HLA)–Restricted Therapeutic Trials
This bar chart reports the annual cumulative number of HLA-restricted therapeutic clinical trials worldwide for any malignant indication. Their incidence has been increasing over the past 2 decades. Each annual bar is shaded to convey the discrete contribution from each HLA-restricted therapeutic class to the cumulative count. Classes include T-cell receptor (TCR) engineered adoptive cell therapy (ACT), TCR fusion protein, and vaccine. The total annual number of new trial registrations across all therapeutic classes is provided in the balloon plot below each bar with larger circles indicating larger numbers. The search criteria is provided in the eMethods in Supplement 1.
Figure 2.
Figure 2.. Human Leukocyte Antigen (HLA) Genotyping From MSK-IMPACT Improves Clinical Trial Screening Efficiency for HLA-Restricted Therapeutics
These bar charts report the allele frequencies for the 20 most abundant (A) HLA-A, (B) HLA-B, and (C) HLA-C alleles across the MSK-IMPACT institutional cohort, with data available for investigational HLA genotyping in 58 236 patients. D, This bar chart shows the percentages of patients with potentially actionable alterations before implementing investigational HLA genotyping (29%, defined as tumor mutational burden > 10, microsatellite instability–high, alteration with OncoKB Therapeutic level 1 or level 2) and after (91%; additionally inclusive of patients with an HLA-eligible genotype for a HLA-restricted trial). The percentages of patients with potentially actionable alterations including HLA-eligible genotypes by racial category including Asian (n = 4486), Black or African American (n = 4034), and White patients (n = 44 434), from a total 58 236 patients. HLA alleles used as criteria for an HLA-restricted phase 1 trial include A*02:01, A*01:01, A*02:05, A*02:06, A*11:01, A*24:02, A*68:01, B*58:01, C*01:02, C*07:02, C*08:01, and C*08:02. The process for investigational HLA genotyping and actionability analysis is detailed in the eMethods in Supplement 1.
See this image and copyright information in PMC

References

    1. Hassel JC, Piperno-Neumann S, Rutkowski P, et al. Three-year overall survival with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2023;389(24):2256-2266. doi: 10.1056/NEJMoa2304753 - DOI - PMC - PubMed
    1. Hong DS, Van Tine BA, Biswas S, et al. Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial. Nat Med. 2023;29(1):104-114. doi: 10.1038/s41591-022-02128-z - DOI - PMC - PubMed
    1. Shukla SA, Rooney MS, Rajasagi M, et al. Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes. Nat Biotechnol. 2015;33(11):1152-1158. doi: 10.1038/nbt.3344 - DOI - PMC - PubMed
    1. Szolek A, Schubert B, Mohr C, Sturm M, Feldhahn M, Kohlbacher O. OptiType: precision HLA typing from next-generation sequencing data. Bioinformatics. 2014;30(23):3310-3316. doi: 10.1093/bioinformatics/btu548 - DOI - PMC - PubMed
    1. Lee H, Kingsford C. Kourami: graph-guided assembly for novel human leukocyte antigen allele discovery. Genome Biol. 2018;19(1):16. doi: 10.1186/s13059-018-1388-2 - DOI - PMC - PubMed