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

Author:

Iafolla Marco A J1ORCID,Yang Cindy23,Chandran Vinod45ORCID,Pintilie Melania6,Li Quan5,Bedard Philippe L1,Hansen Aaron1,Lheureux Stephanie1,Spreafico Anna1,Razak Albiruni A1,Hakgor Sevan1,Giesler Amanda1,Pugh Trevor J237ORCID,Siu Lillian L1

Affiliation:

1. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

3. Princess Margaret Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

4. Krembil Research Institute, University Health Network

5. Faculty of Medicine, Memorial University, St. John’s, Newfoundland and Labrador, Canada

6. Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

7. Ontario Institute for Cancer Research, Toronto, Ontario, Canada

Abstract

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.

Funder

Princess Margaret Cancer Foundation and Merck

Terry Fox Research Institute

Ontario Institute for Cancer Research

Princess Margaret Cancer Foundation

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

Reference54 articles.

1. Cancer immunotherapy: the beginning of the end of cancer?;Farkona;BMC Med,2016

2. Combinations with checkpoint inhibitors at wavefront of cancer immunotherapy;Cully;Nat Rev Drug Discov,2015

3. PD-1/PD-L1 inhibitors;Sunshine;Curr Opin Pharmacol,2015

4. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma;Larkin;N Engl J Med,2015

5. Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities;Villadolid;Transl Lung Cancer Res,2015

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