Publication Date:
2020-12-29
Description:
Background 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 (ICB) anti-tumor activity. It is unknown if HLA-1 genotype is predictive of toxicity to ICB. Methods Patients with advanced solid tumors stratified into five cohorts received single agent pembrolizumab (anti-PD-1) 200 mg IV every 3 weeks in an investigator-initiated phase II trial (INSPIRE study, NCT02644369). Germline whole exome sequencing (WES) of peripheral blood mononuclear cells was performed using the Illumina HiSeq2500 platform. HLA-1 haplotypes were predicted from WES 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 immune-related adverse events; and clinical benefit (CB) defined as complete or partial response, or stable disease for ≥ 6 cycles of pembrolizumab. Statistical significance tests were two-sided. Results In the overall cohort of 101 patients, the frequency of toxicity and CB 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 CB relative to HLA-C homozygosity when controlling for cohort (OR = 0.28, 95% CI 0.09–0.91, p = .04). HLA-A and -B haplotype -21 M/T dimorphism and heterozygosity of HLA-A, -B and -C were not predictive of outcomes. Conclusions HLA-C heterozygosity may predict decreased response to pembrolizumab. Prospective validation is required.
Electronic ISSN:
2515-5091
Topics:
Chemistry and Pharmacology
,
Medicine
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