Antigen mimicry as an effective strategy to induce CSPG4-targeted immunity in dogs with oral melanoma: a veterinary trial.
Animals
Antigens, Neoplasm
/ immunology
Cancer Vaccines
/ immunology
Chondroitin Sulfate Proteoglycans
/ immunology
Dog Diseases
/ drug therapy
Dogs
Melanoma
/ drug therapy
Membrane Proteins
/ immunology
Molecular Mimicry
/ immunology
Mouth Neoplasms
/ therapy
Phylogeny
Prospective Studies
Melanoma, Cutaneous Malignant
Immunogenicity, Vaccine
Immunotherapy, Active
Melanoma
Translational Medical Research
Vaccination
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
accepted:
26
04
2022
entrez:
17
5
2022
pubmed:
18
5
2022
medline:
20
5
2022
Statut:
ppublish
Résumé
Melanoma is the most lethal form of skin cancer in humans. Conventional therapies have limited efficacy, and overall response is still unsatisfactory considering that immune checkpoint inhibitors induce lasting clinical responses only in a low percentage of patients. This has prompted us to develop a vaccination strategy employing the tumor antigen chondroitin sulfate proteoglycan (CSPG)4 as a target. To overcome the host's unresponsiveness to the self-antigen CSPG4, we have taken advantage of the conservation of CSPG4 sequence through phylogenetic evolution, so we have used a vaccine, based on a chimeric DNA molecule encompassing both human (Hu) and dog (Do) portions of CSPG4 (HuDo-CSPG4). We have tested its safety and immunogenicity (primary objectives), along with its therapeutic efficacy (secondary outcome), in a prospective, non-randomized, veterinary clinical trial enrolling 80 client-owned dogs with surgically resected, CSPG4-positive, stage II-IV oral melanoma. Vaccinated dogs developed anti-Do-CSPG4 and Hu-CSPG4 immune response. Interestingly, the antibody titer in vaccinated dogs was significantly associated with the overall survival. Our data suggest that there may be a contribution of the HuDo-CSPG4 vaccination to the improvement of survival of vaccinated dogs as compared with controls treated with conventional therapies alone. HuDo-CSPG4 adjuvant vaccination was safe and immunogenic in dogs with oral melanoma, with potential beneficial effects on the course of the disease. Thanks to the power of naturally occurring canine tumors as predictive models for cancer immunotherapy response, these data may represent a basis for the translation of this approach to the treatment of human patients with CSPG4-positive melanoma subtypes.
Sections du résumé
BACKGROUND
Melanoma is the most lethal form of skin cancer in humans. Conventional therapies have limited efficacy, and overall response is still unsatisfactory considering that immune checkpoint inhibitors induce lasting clinical responses only in a low percentage of patients. This has prompted us to develop a vaccination strategy employing the tumor antigen chondroitin sulfate proteoglycan (CSPG)4 as a target.
METHODS
To overcome the host's unresponsiveness to the self-antigen CSPG4, we have taken advantage of the conservation of CSPG4 sequence through phylogenetic evolution, so we have used a vaccine, based on a chimeric DNA molecule encompassing both human (Hu) and dog (Do) portions of CSPG4 (HuDo-CSPG4). We have tested its safety and immunogenicity (primary objectives), along with its therapeutic efficacy (secondary outcome), in a prospective, non-randomized, veterinary clinical trial enrolling 80 client-owned dogs with surgically resected, CSPG4-positive, stage II-IV oral melanoma.
RESULTS
Vaccinated dogs developed anti-Do-CSPG4 and Hu-CSPG4 immune response. Interestingly, the antibody titer in vaccinated dogs was significantly associated with the overall survival. Our data suggest that there may be a contribution of the HuDo-CSPG4 vaccination to the improvement of survival of vaccinated dogs as compared with controls treated with conventional therapies alone.
CONCLUSIONS
HuDo-CSPG4 adjuvant vaccination was safe and immunogenic in dogs with oral melanoma, with potential beneficial effects on the course of the disease. Thanks to the power of naturally occurring canine tumors as predictive models for cancer immunotherapy response, these data may represent a basis for the translation of this approach to the treatment of human patients with CSPG4-positive melanoma subtypes.
Identifiants
pubmed: 35580930
pii: jitc-2021-004007
doi: 10.1136/jitc-2021-004007
pmc: PMC9114861
pii:
doi:
Substances chimiques
Antigens, Neoplasm
0
Cancer Vaccines
0
Chondroitin Sulfate Proteoglycans
0
Membrane Proteins
0
Types de publication
Clinical Trial, Veterinary
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDCR NIH HHS
ID : R01 DE028172
Pays : United States
Informations de copyright
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: No, there are no competing interests.
Références
Int J Cancer. 1981 Sep 15;28(3):293-300
pubmed: 7033148
Vet J. 2011 Nov;190(2):e26-e30
pubmed: 21482159
Vet Comp Oncol. 2017 Dec;15(4):1487-1502
pubmed: 28120417
Vet Comp Oncol. 2021 Jun;19(2):311-352
pubmed: 33427378
J Clin Invest. 1990 Dec;86(6):2136-44
pubmed: 2254463
Oncoimmunology. 2012 May 1;1(3):316-325
pubmed: 22737607
J Vet Med Sci. 2016 Jun 1;78(5):845-50
pubmed: 26781703
FEBS J. 2005 Oct;272(20):5101-9
pubmed: 16218944
Immunology. 1987 Feb;60(2):181-6
pubmed: 3817870
Vet Sci. 2019 Feb 12;6(1):
pubmed: 30759787
Expert Opin Biol Ther. 2014 Oct;14(10):1427-42
pubmed: 25023219
Immunol Today. 1995 Oct;16(10):487-94
pubmed: 7576053
Vet Clin North Am Small Anim Pract. 2019 Sep;49(5):xiii-xiv
pubmed: 31345517
Am J Vet Res. 2011 Dec;72(12):1631-8
pubmed: 22126691
Cancer Cell. 2018 Jan 8;33(1):151
pubmed: 29316429
Clin Cancer Res. 2003 Apr;9(4):1284-90
pubmed: 12684396
Nat Commun. 2019 Jan 21;10(1):353
pubmed: 30664638
Cancer Res. 1992 May 1;52(9):2497-503
pubmed: 1373670
Vet Radiol Ultrasound. 2020 Jul;61(4):471-480
pubmed: 32323424
Vet Comp Oncol. 2013 Sep;11(3):219-29
pubmed: 23909996
Clin Cancer Res. 1995 Jul;1(7):705-13
pubmed: 9816036
J Pathol. 2019 Apr;247(5):539-551
pubmed: 30511391
Vet Comp Oncol. 2021 Dec;19(4):651-660
pubmed: 33751759
CA Cancer J Clin. 2020 Jan;70(1):7-30
pubmed: 31912902
Cancer Immunol Immunother. 2019 Nov;68(11):1839-1853
pubmed: 31222484
Curr Top Microbiol Immunol. 2017;405:99-122
pubmed: 25294003
Sci Rep. 2020 Oct 27;10(1):18311
pubmed: 33110170
Theranostics. 2015 Feb 15;5(5):530-44
pubmed: 25767619
Int J Mol Sci. 2018 Mar 10;19(3):
pubmed: 29534457
J Transl Med. 2017 Jul 1;15(1):151
pubmed: 28668095
Nat Rev Cancer. 2007 Sep;7(9):707-13
pubmed: 17700704
Genes (Basel). 2019 Jun 30;10(7):
pubmed: 31262050
Vet J. 2017 Mar;221:38-47
pubmed: 28283079
Int J Cancer. 2004 Sep 20;111(5):720-6
pubmed: 15252841
Clin Cancer Res. 2014 Jul 15;20(14):3753-62
pubmed: 24874834
Cancer Res. 2005 Aug 1;65(15):6976-83
pubmed: 16061683
Int J Mol Sci. 2020 Mar 30;21(7):
pubmed: 32235439
J Immunol. 1981 Aug;127(2):505-9
pubmed: 6166672
Clin Cancer Res. 2012 Oct 1;18(19):5352-63
pubmed: 22893632
Int J Mol Sci. 2018 Jan 30;19(2):
pubmed: 29385676
Cancer Immunol Res. 2020 Aug;8(8):1039-1053
pubmed: 32532810
Cancers (Basel). 2020 Oct 20;12(10):
pubmed: 33092131
Adv Cancer Res. 2010;109:73-121
pubmed: 21070915
Annu Rev Pathol. 2014;9:239-71
pubmed: 24460190
PLoS One. 2012;7(4):e35005
pubmed: 22506061
Am Surg. 2016 Jan;82(1):1-5
pubmed: 26802836
Cancer Res. 2010 Apr 1;70(7):2604-12
pubmed: 20332241
Ther Adv Med Oncol. 2019 Jun 06;11:1758835919855491
pubmed: 31217827
Curr Oncol. 2013 Apr;20(2):e150-60
pubmed: 23559882
J Small Anim Pract. 2017 Jan;58(1):10-16
pubmed: 28094857
Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):466-70
pubmed: 1731316
Vet Comp Oncol. 2017 Sep;15(3):996-1013
pubmed: 27146852
Vaccine. 2006 May 22;24(21):4582-5
pubmed: 16188351
Clin Cancer Res. 2013 Sep 15;19(18):4941-50
pubmed: 24021875
Cancers (Basel). 2020 Jun 08;12(6):
pubmed: 32521631