Phase I study of a multitargeted recombinant Ad5 PSA/MUC-1/brachyury-based immunotherapy vaccine in patients with metastatic castration-resistant prostate cancer (mCRPC).
Adenoviridae
/ genetics
Aged
Aged, 80 and over
Cancer Vaccines
/ adverse effects
Fetal Proteins
/ genetics
Genetic Vectors
Humans
Kallikreins
/ genetics
Male
Middle Aged
Mucin-1
/ genetics
Progression-Free Survival
Prostate-Specific Antigen
/ genetics
Prostatic Neoplasms, Castration-Resistant
/ genetics
T-Box Domain Proteins
/ genetics
Time Factors
Vaccination
Vaccine Efficacy
Vaccines, Combined
/ adverse effects
Viral Vaccines
immunogenicity
prostatic neoplasms
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:
03 2021
03 2021
Historique:
accepted:
21
02
2021
entrez:
25
3
2021
pubmed:
26
3
2021
medline:
18
12
2021
Statut:
ppublish
Résumé
Antitumor vaccines targeting tumor-associated antigens (TAAs) can generate antitumor immune response. A novel vaccine platform using adenovirus 5 (Ad5) vectors [E1-, E2b-] targeting three TAAs-prostate-specific antigen (PSA), brachyury, and MUC-1-has been developed. Both brachyury and the C-terminus of MUC-1 are overexpressed in metastatic castration-resistant prostate cancer (mCRPC) and have been shown to play an important role in resistance to chemotherapy, epithelial-mesenchymal transition, and metastasis. The transgenes for PSA, brachyury, and MUC-1 all contain epitope modifications for the expression of CD8+ T-cell enhancer agonist epitopes. We report here the first-in-human trial of this vaccine platform. Patients with mCRPC were given concurrently three vaccines targeting PSA, brachyury, and MUC-1 at 5×10 Eighteen patients with mCRPC were enrolled between July 2018 and September 2019 and received at least one vaccination. Median PSA was 25.58 ng/mL (range, 0.65-1006 ng/mL). The vaccine was tolerable and safe, and no grade >3 treatment-related adverse events or dose-limiting toxicities (DLTs) were observed. One patient had a partial response, while five patients had confirmed PSA decline and five had stable disease for >6 months. Median progression-free survival was 22 weeks (95% CI: 19.1 to 34). Seventeen (100%) of 17 patients mounted T-cell responses to at least one TAA, whereras 8 (47%) of 17 patients mounted immune responses to all three TAAs. Multifunctional T-cell responses to PSA, MUC-1, and brachyury were also detected after vaccination in the majority of the patients. Ad5 PSA/MUC-1/brachyury vaccine is well tolerated. The primary end points were met and there were no DLTs. The recommended phase II dose is 5×10 NCT03481816.
Sections du résumé
BACKGROUND
Antitumor vaccines targeting tumor-associated antigens (TAAs) can generate antitumor immune response. A novel vaccine platform using adenovirus 5 (Ad5) vectors [E1-, E2b-] targeting three TAAs-prostate-specific antigen (PSA), brachyury, and MUC-1-has been developed. Both brachyury and the C-terminus of MUC-1 are overexpressed in metastatic castration-resistant prostate cancer (mCRPC) and have been shown to play an important role in resistance to chemotherapy, epithelial-mesenchymal transition, and metastasis. The transgenes for PSA, brachyury, and MUC-1 all contain epitope modifications for the expression of CD8+ T-cell enhancer agonist epitopes. We report here the first-in-human trial of this vaccine platform.
METHODS
Patients with mCRPC were given concurrently three vaccines targeting PSA, brachyury, and MUC-1 at 5×10
RESULTS
Eighteen patients with mCRPC were enrolled between July 2018 and September 2019 and received at least one vaccination. Median PSA was 25.58 ng/mL (range, 0.65-1006 ng/mL). The vaccine was tolerable and safe, and no grade >3 treatment-related adverse events or dose-limiting toxicities (DLTs) were observed. One patient had a partial response, while five patients had confirmed PSA decline and five had stable disease for >6 months. Median progression-free survival was 22 weeks (95% CI: 19.1 to 34). Seventeen (100%) of 17 patients mounted T-cell responses to at least one TAA, whereras 8 (47%) of 17 patients mounted immune responses to all three TAAs. Multifunctional T-cell responses to PSA, MUC-1, and brachyury were also detected after vaccination in the majority of the patients.
CONCLUSIONS
Ad5 PSA/MUC-1/brachyury vaccine is well tolerated. The primary end points were met and there were no DLTs. The recommended phase II dose is 5×10
TRIAL REGISTRATION NUMBER
NCT03481816.
Identifiants
pubmed: 33762322
pii: jitc-2021-002374
doi: 10.1136/jitc-2021-002374
pmc: PMC7993215
pii:
doi:
Substances chimiques
Cancer Vaccines
0
Fetal Proteins
0
MUC1 protein, human
0
Mucin-1
0
T-Box Domain Proteins
0
Vaccines, Combined
0
Viral Vaccines
0
KLK3 protein, human
EC 3.4.21.-
Kallikreins
EC 3.4.21.-
Prostate-Specific Antigen
EC 3.4.21.77
Brachyury protein
EQ43SC3GDB
Banques de données
ClinicalTrials.gov
['NCT03481816']
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
Informations de copyright
© Author(s) (or their employer(s)) 2021. 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: ImmunityBio authors are employees of ImmunityBio, Inc.
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