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Predicting Toxicity and Response to Pembrolizumab Through Germline Genomic HLA Class 1 Analysis
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| Zeitschriftentitel: | JNCI Cancer Spectrum |
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| Personen und Körperschaften: | , , , , , , , , , , , , , |
| In: | JNCI Cancer Spectrum, 5, 2021, 1 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Oxford University Press (OUP)
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| Schlagwörter: |
| Zusammenfassung: | <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Human leukocyte antigen class 1 (HLA-1)–dependent immune activity is linked to autoimmune diseases. HLA-1–dependent CD8+ T cells are required for immune checkpoint blockade antitumor activity. It is unknown if HLA-1 genotype is predictive of toxicity to immune checkpoint blockade.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Patients with advanced solid tumors stratified into 5 cohorts received single agent pembrolizumab (anti-programmed cell death-1) 200 mg intravenously every 3 weeks in an investigator-initiated phase II trial (Investigator-Initiated Phase II Study of Pembrolizumab Immunological Response Evaluation study, NCT02644369). Germline whole-exome sequencing of peripheral blood mononuclear cells was performed using the Illumina HiSeq2500 platform. HLA-1 haplotypes were predicted from whole-exome sequencing using HLAminer and HLAVBSeq. Heterozygosity of HLA-A, -B, and -C, individual HLA-1 alleles, and HLA haplotype dimorphism at positions −21 M and −21 T of the HLA-A and -B leader sequence were analyzed as predictors of toxicity defined as grade 2 or greater immune-related adverse events and clinical benefit defined as complete or partial response, or stable disease for 6 or more cycles of pembrolizumab. Statistical significance tests were 2-sided.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>In the overall cohort of 101 patients, the frequency of toxicity and clinical benefit from pembrolizumab was 22.8% and 25.7%, respectively. There was no association between any of the HLA-1 loci or alleles with toxicity. HLA-C heterozygosity had an association with decreased clinical benefit relative to HLA-C homozygosity when controlling for cohort (odds ratio = 0.28, 95% confidence interval = 0.09 to 0.91, P = .04). HLA-A and -B haplotype −21 M/T dimorphism and heterozygosity of HLA-A, -B, and -C were not predictive of outcomes.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>HLA-C heterozygosity may predict decreased response to pembrolizumab. Prospective validation is required.</jats:p> </jats:sec> |
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| ISSN: |
2515-5091
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| DOI: | 10.1093/jncics/pkaa115 |