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Predicting Toxicity and Response to Pembrolizumab Through Germline Genomic HLA Class 1 Analysis

2020; Oxford University Press; Volume: 5; Issue: 1 Linguagem: Inglês

10.1093/jncics/pkaa115

2515-5091

Marco Iafolla, Cindy Yang, Vinod Chandran, Melania Pintilie, Quan Li, Philippe L. Bédard, Aaron R. Hansen, Stéphanie Lheureux, Anna Spreafico, Albiruni Abdul Razak, Sevan Hakgor, Amanda Giesler, Trevor J. Pugh, Lillian L. Siu,

T-cell and B-cell Immunology

Abstract 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 antitumor activity. It is unknown if HLA-1 genotype is predictive of toxicity to immune checkpoint blockade. Methods 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. Results 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. Conclusions HLA-C heterozygosity may predict decreased response to pembrolizumab. Prospective validation is required.