Dataset Information

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

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.

SUBMITTER: Iafolla MAJ

PROVIDER: S-EPMC7853183 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Iafolla Marco A J MAJ Yang Cindy C Chandran Vinod V Pintilie Melania M Li Quan Q Bedard Philippe L PL Hansen Aaron A Lheureux Stephanie S Spreafico Anna A Razak Albiruni A AA Hakgor Sevan S Giesler Amanda A Pugh Trevor J TJ Siu Lillian L LL

JNCI cancer spectrum 20201229 1

<h4>Background</h4>Human leukocyte antigen class 1 (HLA-1)-dependent immune activity is linked to autoimmune diseases. HLA-1-dependent CD8<sup>+</sup> 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.<h4>Methods</h4>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 inv ...[more]

PMID: 33554038

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Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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