Cross-Reactivity and Functionality of Approved Human Immune Checkpoint Blockers in Dogs.
PD-1/PD-L1
T cells
cancer immunotherapy
canine cancer
checkpoint blockade
combination therapy
immunophenotyping
response biomarker
translational cancer research
veterinary oncology
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
13 Feb 2021
13 Feb 2021
Historique:
received:
17
01
2021
revised:
05
02
2021
accepted:
10
02
2021
entrez:
6
3
2021
pubmed:
7
3
2021
medline:
7
3
2021
Statut:
epublish
Résumé
Rodent cancer models have limitations in predicting efficacy, tolerability and accompanying biomarkers of ICIs in humans. Companion dogs suffering from neoplastic diseases have gained attention as a highly relevant translational disease model. Despite successful reports of PD-1/PD-L1 blockade in dogs, no compounds are available for veterinary medicine. Here, we assessed suitability of seven FDA-approved human ICIs to target CTLA-4 or PD-1/PD-L1 in dogs. Cross-reactivity and blocking potential was assessed using ELISA and flow cytometry. Functional responses were assessed on peripheral blood mononuclear cells (PBMCs) derived from healthy donors ( Four candidates showed cross-reactivity and two blocked the interaction of canine PD-1 and PD-L1. Of those, only atezolizumab significantly increased cytokine production of healthy and patient derived PBMCs in vitro. Especially lymphoma patient PBMCs responded with increased cytokine production. In other types of cancer, response to atezolizumab appeared to correlate with a lower frequency of CD8 T cells. Cross-functionality of atezolizumab encourages reverse translational efforts using (combination) immunotherapies in companion dog tumor patients to benefit both veterinary and human medicine.
Sections du résumé
BACKGROUND
BACKGROUND
Rodent cancer models have limitations in predicting efficacy, tolerability and accompanying biomarkers of ICIs in humans. Companion dogs suffering from neoplastic diseases have gained attention as a highly relevant translational disease model. Despite successful reports of PD-1/PD-L1 blockade in dogs, no compounds are available for veterinary medicine.
METHODS
METHODS
Here, we assessed suitability of seven FDA-approved human ICIs to target CTLA-4 or PD-1/PD-L1 in dogs. Cross-reactivity and blocking potential was assessed using ELISA and flow cytometry. Functional responses were assessed on peripheral blood mononuclear cells (PBMCs) derived from healthy donors (
RESULTS
RESULTS
Four candidates showed cross-reactivity and two blocked the interaction of canine PD-1 and PD-L1. Of those, only atezolizumab significantly increased cytokine production of healthy and patient derived PBMCs in vitro. Especially lymphoma patient PBMCs responded with increased cytokine production. In other types of cancer, response to atezolizumab appeared to correlate with a lower frequency of CD8 T cells.
CONCLUSIONS
CONCLUSIONS
Cross-functionality of atezolizumab encourages reverse translational efforts using (combination) immunotherapies in companion dog tumor patients to benefit both veterinary and human medicine.
Identifiants
pubmed: 33668625
pii: cancers13040785
doi: 10.3390/cancers13040785
pmc: PMC7918463
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Swiss Cancer Research Foundation
ID : KFS-3852-02-2016
Organisme : Swiss Cancer Research Foundation
ID : KFS-4146-02-2017
Organisme : Novartis Stiftung für Medizinisch-Biologische Forschung
ID : #16C231
Références
Neurosurg Focus. 2021 Feb;50(2):E5
pubmed: 33524948
Molecules. 2019 Mar 26;24(6):
pubmed: 30917623
Nucleic Acids Res. 2016 Jul 8;44(W1):W147-53
pubmed: 27190236
J Immunother Cancer. 2016 Dec 20;4:97
pubmed: 28031824
PLoS One. 2020 Jul 2;15(7):e0235518
pubmed: 32614928
Clin Cancer Res. 2020 Jun 15;26(12):2827-2837
pubmed: 32376655
Front Immunol. 2016 Nov 23;7:521
pubmed: 27933061
Cell Res. 2020 Jun;30(6):507-519
pubmed: 32467593
Ann Oncol. 2018 Jan 1;29(1):84-91
pubmed: 29228097
N Engl J Med. 2015 Jan 22;372(4):311-9
pubmed: 25482239
Nat Rev Cancer. 2020 Dec;20(12):727-742
pubmed: 32934365
Vet Immunol Immunopathol. 2014 Jan 15;157(1-2):31-41
pubmed: 24268690
In Vivo. 2016 May-Jun;30(3):195-204
pubmed: 27107075
MAbs. 2016;8(2):216-28
pubmed: 26736022
Reprod Domest Anim. 2017 Apr;52 Suppl 2:137-147
pubmed: 27862405
PLoS One. 2014 Jun 10;9(6):e98415
pubmed: 24915569
Blood. 2019 Oct 24;134(17):1406-1414
pubmed: 31467059
Toxins (Basel). 2010 Aug;2(8):2177-97
pubmed: 22069679
Vet Comp Oncol. 2018 Sep;16(3):352-360
pubmed: 29380929
Sci Transl Med. 2020 Mar 11;12(534):
pubmed: 32161104
J Hematol Oncol. 2019 Sep 5;12(1):92
pubmed: 31488176
Cell Death Differ. 2015 Feb;22(2):237-46
pubmed: 25190142
Front Oncol. 2018 Jul 25;8:285
pubmed: 30090763
Vet Res. 2014 Jan 23;45:6
pubmed: 24456537
N Engl J Med. 2018 May 17;378(20):1947-1948
pubmed: 29768155
Blood. 2010 Oct 28;116(17):3268-77
pubmed: 20628145
Sci Rep. 2017 Aug 21;7(1):8951
pubmed: 28827658
Front Immunol. 2018 Feb 05;9:133
pubmed: 29459862
AAPS J. 2019 Mar 13;21(3):39
pubmed: 30868312
Sci Rep. 2020 Oct 27;10(1):18311
pubmed: 33110170
Immunity. 2020 Jan 14;52(1):17-35
pubmed: 31940268
Nat Med. 2018 Nov;24(11):1773-1775
pubmed: 29967347
Mol Cell. 2020 Jun 18;78(6):1002-1018
pubmed: 32559422
Eur J Cancer. 2019 Aug;117:14-31
pubmed: 31229946
Nat Med. 2019 Dec;25(12):1822-1832
pubmed: 31806905
J Immunother Cancer. 2019 Nov 27;7(1):325
pubmed: 31775882
Cancer Immunol Res. 2019 Jul;7(7):1175-1187
pubmed: 31160277
J Transl Med. 2012 Nov 21;10:234
pubmed: 23171444
Cancer Immunol Res. 2014 Sep;2(9):846-56
pubmed: 24872026
PLoS One. 2018 Jul 24;13(7):e0201222
pubmed: 30040869
Vet Comp Oncol. 2017 Jun;15(2):534-549
pubmed: 26842912
Blood. 2019 Jul 4;134(1):22-29
pubmed: 30952672
Neoplasia. 2020 Dec;22(12):778-788
pubmed: 33142242
Oncotarget. 2017 Mar 28;8(13):20558-20571
pubmed: 28423552
PLoS One. 2015 Jun 19;10(6):e0129954
pubmed: 26091536
Cytometry A. 2020 Oct;97(10):1024-1027
pubmed: 32583607
Vet Comp Oncol. 2017 Dec;15(4):1487-1502
pubmed: 28120417
Front Immunol. 2018 Apr 27;9:841
pubmed: 29755462
Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):944-949
pubmed: 28096333
Front Immunol. 2020 Jan 17;10:2935
pubmed: 32010120
Cell Rep. 2017 May 9;19(6):1189-1201
pubmed: 28494868
PLoS One. 2016 Sep 09;11(9):e0161779
pubmed: 27610613
Vet Pathol. 1991 Mar;28(2):131-8
pubmed: 2063514