MHC-restricted phosphopeptide antigens: preclinical validation and first-in-humans clinical trial in participants with high-risk melanoma.
Adaptor Proteins, Signal Transducing
/ genetics
Adult
Aged
Aged, 80 and over
Animals
Antigens, Neoplasm
/ genetics
CD8-Positive T-Lymphocytes
/ immunology
Cancer Vaccines
/ administration & dosage
Cell Line, Tumor
Female
Guanine Nucleotide Exchange Factors
/ genetics
HLA-A2 Antigen
/ genetics
Humans
Immunogenicity, Vaccine
Immunotherapy
/ adverse effects
Insulin Receptor Substrate Proteins
/ genetics
Male
Melanoma
/ immunology
Mice
Mice, Transgenic
Middle Aged
Phosphopeptides
/ genetics
Pilot Projects
Proof of Concept Study
Skin Neoplasms
/ immunology
Vaccines, Subunit
/ administration & dosage
Xenograft Model Antitumor Assays
antigens
immunogenicity
immunotherapy
melanoma
neoplasm
vaccination
vaccine
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 2020
05 2020
Historique:
accepted:
07
04
2020
entrez:
10
5
2020
pubmed:
10
5
2020
medline:
8
6
2021
Statut:
ppublish
Résumé
Phosphorylated peptides presented by MHC molecules represent a new class of neoantigens expressed on cancer cells and recognized by CD8 T-cells. These peptides are promising targets for cancer immunotherapy. Previous work identified an HLA-A*0201-restricted phosphopeptide from insulin receptor substrate 2 (pIRS2) as one such target. The purpose of this study was to characterize a second phosphopeptide, from breast cancer antiestrogen resistance 3 (BCAR3), and to evaluate safety and immunogenicity of a novel immunotherapic vaccine comprising either or both of these phosphorylated peptides. Phosphorylated BCAR3 protein was evaluated in melanoma and breast cancer cell lines by Western blot, and recognition by T-cells specific for HLA-A*0201-restricted phosphorylated BCAR3 peptide (pBCAR3 pBCAR3 peptides were immunogenic in vivo in mice, and in vitro in normal human donors, and T-cells specific for pBCAR3 This study supports the safety and immunogenicity of vaccines containing the cancer-associated phosphopeptides pBCAR3 NCT01846143.
Sections du résumé
BACKGROUND
Phosphorylated peptides presented by MHC molecules represent a new class of neoantigens expressed on cancer cells and recognized by CD8 T-cells. These peptides are promising targets for cancer immunotherapy. Previous work identified an HLA-A*0201-restricted phosphopeptide from insulin receptor substrate 2 (pIRS2) as one such target. The purpose of this study was to characterize a second phosphopeptide, from breast cancer antiestrogen resistance 3 (BCAR3), and to evaluate safety and immunogenicity of a novel immunotherapic vaccine comprising either or both of these phosphorylated peptides.
METHODS
Phosphorylated BCAR3 protein was evaluated in melanoma and breast cancer cell lines by Western blot, and recognition by T-cells specific for HLA-A*0201-restricted phosphorylated BCAR3 peptide (pBCAR3
RESULTS
pBCAR3 peptides were immunogenic in vivo in mice, and in vitro in normal human donors, and T-cells specific for pBCAR3
CONCLUSION
This study supports the safety and immunogenicity of vaccines containing the cancer-associated phosphopeptides pBCAR3
TRIAL REGISTRATION NUMBER
NCT01846143.
Identifiants
pubmed: 32385144
pii: jitc-2019-000262
doi: 10.1136/jitc-2019-000262
pmc: PMC7228659
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Antigens, Neoplasm
0
BCAR3 protein, human
0
Cancer Vaccines
0
Guanine Nucleotide Exchange Factors
0
HLA-A*02:01 antigen
0
HLA-A2 Antigen
0
IRS2 protein, human
0
Insulin Receptor Substrate Proteins
0
Phosphopeptides
0
Vaccines, Subunit
0
Banques de données
ClinicalTrials.gov
['NCT01846143']
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : R01 CA190665
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA119954
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI033993
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI020963
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009109
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA044579
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA134060
Pays : United States
Informations de copyright
© Author(s) (or their employer(s)) 2020. 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: VE, RCO, KLC, AL, PM, JS and DFH have ownership interest in Agenus, which has licensed phosphopeptide technology and associated patent applications from the University of Virginia Licensing and Ventures Group. PM is now an employee of Agenus. VE is a consultant and the recipient of a Sponsored Research Agreement from Agenus. CLS is the recipient of research grants from GlaxoSmithKline, Merck, and Celldex, and is an inventor for patents for other peptides used in cancer vaccines, which are held by the UVA Licencing and Ventures Group; and is (or has been) a consultant/advisory board member for Immatics. Curevac, and Polynoma. MC is now an employee of AstraZeneca.
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