Predicting Toxicity and Response to Pembrolizumab Through Germline Genomic HLA Class 1 Analysis.
Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized
/ adverse effects
CD8-Positive T-Lymphocytes
/ immunology
Female
HLA-A Antigens
/ genetics
HLA-B Antigens
/ genetics
HLA-C Antigens
/ genetics
Heterozygote
Histocompatibility Antigens Class I
/ genetics
Humans
Immune Checkpoint Inhibitors
/ adverse effects
Leukocytes, Mononuclear
Male
Middle Aged
Neoplasms
/ drug therapy
Exome Sequencing
/ methods
Young Adult
Journal
JNCI cancer spectrum
ISSN: 2515-5091
Titre abrégé: JNCI Cancer Spectr
Pays: England
ID NLM: 101721827
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
13
02
2020
revised:
05
05
2020
accepted:
03
12
2020
entrez:
8
2
2021
pubmed:
9
2
2021
medline:
9
2
2021
Statut:
epublish
Résumé
Human leukocyte antigen class 1 (HLA-1)-dependent immune activity is linked to autoimmune diseases. HLA-1-dependent CD8 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. 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, HLA-C heterozygosity may predict decreased response to pembrolizumab. Prospective validation is required.
Sections du résumé
Background
Human leukocyte antigen class 1 (HLA-1)-dependent immune activity is linked to autoimmune diseases. HLA-1-dependent CD8
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,
Conclusions
HLA-C heterozygosity may predict decreased response to pembrolizumab. Prospective validation is required.
Identifiants
pubmed: 33554038
doi: 10.1093/jncics/pkaa115
pii: pkaa115
pmc: PMC7853183
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
HLA-A Antigens
0
HLA-B Antigens
0
HLA-C Antigens
0
Histocompatibility Antigens Class I
0
Immune Checkpoint Inhibitors
0
pembrolizumab
DPT0O3T46P
Banques de données
ClinicalTrials.gov
['NCT02644369']
Types de publication
Clinical Trial, Phase II
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press.
Références
Science. 2015 Dec 11;350(6266):1387-90
pubmed: 26516200
Lancet Oncol. 2015 Apr;16(4):375-84
pubmed: 25795410
Cell. 2016 Mar 24;165(1):35-44
pubmed: 26997480
Ann Oncol. 2017 Feb 1;28(2):368-376
pubmed: 27687304
Int Rev Cytol. 2007;256:139-89
pubmed: 17241907
BMC Med Genomics. 2019 Jul 25;12(Suppl 6):107
pubmed: 31345234
JCI Insight. 2018 Dec 20;3(24):
pubmed: 30568030
Cell. 2019 Aug 8;178(4):933-948.e14
pubmed: 31398344
J Allergy Clin Immunol. 2017 Jan;139(1):335-346.e3
pubmed: 27372564
Oncogene. 2008 Oct 6;27(45):5869-85
pubmed: 18836468
Nature. 2014 Nov 27;515(7528):577-81
pubmed: 25428507
Cell. 2017 Nov 30;171(6):1259-1271.e11
pubmed: 29107330
J Immunother Cancer. 2019 Mar 13;7(1):72
pubmed: 30867072
Cell. 2017 Nov 2;171(4):934-949.e16
pubmed: 29033130
J Clin Oncol. 2008 Aug 20;26(24):3913-5
pubmed: 18711176
Science. 2015 Apr 3;348(6230):124-8
pubmed: 25765070
Lancet Oncol. 2016 Dec;17(12):e542-e551
pubmed: 27924752
Nat Rev Drug Discov. 2015 Jun;14(6):374-5
pubmed: 26027531
Rev Immunogenet. 2000;2(3):433-48
pubmed: 11256749
Anticancer Res. 2004 May-Jun;24(3a):1525-8
pubmed: 15274319
N Engl J Med. 2015 Jun 25;372(26):2509-20
pubmed: 26028255
Cancer Immunol Immunother. 2008 Feb;57(2):197-206
pubmed: 17622526
J Clin Oncol. 2017 Mar;35(7):785-792
pubmed: 28068177
Nat Biotechnol. 2015 Nov;33(11):1152-8
pubmed: 26372948
BMC Med. 2016 May 05;14:73
pubmed: 27151159
Int J Mol Sci. 2017 Oct 12;18(10):
pubmed: 29023417
N Engl J Med. 2016 Dec 8;375(23):2255-2262
pubmed: 27959684
Nat Commun. 2016 Jan 29;7:10582
pubmed: 26822383
Proc Natl Acad Sci U S A. 2016 May 24;113(21):5999-6004
pubmed: 27162338
Nat Rev Immunol. 2001 Oct;1(1):41-9
pubmed: 11905813
Oncotarget. 2016 Nov 8;7(45):72961-72977
pubmed: 27662664
Lancet. 1975 Jun 28;1(7922):1406-9
pubmed: 49564
Sci Transl Med. 2018 Jul 18;10(450):
pubmed: 30021886
N Engl J Med. 2015 Jul 2;373(1):23-34
pubmed: 26027431
Ann Oncol. 2016 Apr;27(4):559-74
pubmed: 26715621
Int J Cancer. 2014 Jan 1;134(1):102-13
pubmed: 23784959
Sci Immunol. 2016 Sep;1(3):
pubmed: 27868107
N Engl J Med. 2015 Jul 9;373(2):123-35
pubmed: 26028407
N Engl J Med. 2015 Jun 25;372(26):2521-32
pubmed: 25891173
Eur J Cancer. 2019 Jan;107:8-14
pubmed: 30529903
Nat Immunol. 2007 Mar;8(3):239-45
pubmed: 17304234
J Clin Oncol. 2018 Apr 1;36(10):942-950
pubmed: 29394125
J Clin Oncol. 1988 May;6(5):868-70
pubmed: 3367190
Nat Rev Immunol. 2009 Aug;9(8):568-80
pubmed: 19629084
Curr Opin Pharmacol. 2015 Aug;23:32-8
pubmed: 26047524
Oncoimmunology. 2017 Feb 6;6(2):e1171447
pubmed: 28344859
Nat Genet. 2015 Feb;47(2):172-9
pubmed: 25559196
Science. 2018 Feb 2;359(6375):582-587
pubmed: 29217585
JAMA Oncol. 2018 Mar 1;4(3):374-378
pubmed: 28975219
Eur J Immunol. 2002 Apr;32(4):972-81
pubmed: 11920563
Transl Lung Cancer Res. 2015 Oct;4(5):560-75
pubmed: 26629425