Phase I Trial of a Modified Vaccinia Ankara Priming Vaccine Followed by a Fowlpox Virus Boosting Vaccine Modified to Express Brachyury and Costimulatory Molecules in Advanced Solid Tumors.
Journal
The oncologist
ISSN: 1549-490X
Titre abrégé: Oncologist
Pays: England
ID NLM: 9607837
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
05
11
2019
accepted:
02
12
2019
pubmed:
27
12
2019
medline:
22
6
2021
entrez:
27
12
2019
Statut:
ppublish
Résumé
Modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury followed by fowlpox virus-BN-Brachyury was well tolerated upon administration to patients with advanced cancer. Sixty-three percent of patients developed CD4+ and/or CD8+ T-cell responses to brachyury after vaccination. BN-Brachyury vaccine also induced T-cell responses against CEA and MUC1, which are cascade antigens, that is, antigens not encoded in the vaccines. Brachyury, a transcription factor, plays an integral role in the epithelial-mesenchymal transition, metastasis, and tumor resistance to chemotherapy. It is expressed in many tumor types, and rarely in normal tissues, making it an ideal immunologic target. Bavarian Nordic (BN)-Brachyury consists of vaccination with modified vaccinia Ankara (MVA) priming followed by fowlpox virus (FPV) boosting, each encoding transgenes for brachyury and costimulatory molecules. Patients with metastatic solid tumors were treated with two monthly doses of MVA-brachyury s.c., 8 × 10 Eleven patients were enrolled from March 2018 to July 2018 (one patient was nonevaluable). No dose-limiting toxicities were observed. The most common treatment-related adverse event was grade 1/2 injection-site reaction observed in all patients. Best overall response was stable disease in six patients, and the 6-month progression-free survival rate was 50%. T cells against brachyury and cascade antigens CEA and MUC1 were detected in the majority of patients. BN-Brachyury vaccine is well tolerated and induces immune responses to brachyury and cascade antigens and demonstrates some evidence of clinical benefit.
Sections du résumé
LESSONS LEARNED
Modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury followed by fowlpox virus-BN-Brachyury was well tolerated upon administration to patients with advanced cancer. Sixty-three percent of patients developed CD4+ and/or CD8+ T-cell responses to brachyury after vaccination. BN-Brachyury vaccine also induced T-cell responses against CEA and MUC1, which are cascade antigens, that is, antigens not encoded in the vaccines.
BACKGROUND
Brachyury, a transcription factor, plays an integral role in the epithelial-mesenchymal transition, metastasis, and tumor resistance to chemotherapy. It is expressed in many tumor types, and rarely in normal tissues, making it an ideal immunologic target. Bavarian Nordic (BN)-Brachyury consists of vaccination with modified vaccinia Ankara (MVA) priming followed by fowlpox virus (FPV) boosting, each encoding transgenes for brachyury and costimulatory molecules.
METHODS
Patients with metastatic solid tumors were treated with two monthly doses of MVA-brachyury s.c., 8 × 10
RESULTS
Eleven patients were enrolled from March 2018 to July 2018 (one patient was nonevaluable). No dose-limiting toxicities were observed. The most common treatment-related adverse event was grade 1/2 injection-site reaction observed in all patients. Best overall response was stable disease in six patients, and the 6-month progression-free survival rate was 50%. T cells against brachyury and cascade antigens CEA and MUC1 were detected in the majority of patients.
CONCLUSION
BN-Brachyury vaccine is well tolerated and induces immune responses to brachyury and cascade antigens and demonstrates some evidence of clinical benefit.
Identifiants
pubmed: 31876334
doi: 10.1634/theoncologist.2019-0932
pmc: PMC7356719
doi:
Substances chimiques
Fetal Proteins
0
T-Box Domain Proteins
0
Brachyury protein
EQ43SC3GDB
Types de publication
Clinical Trial, Phase I
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
560-e1006Informations de copyright
© AlphaMed Press; the data published online to support this summary are the property of the authors.
Références
BMC Cancer. 2016 Aug 23;16(1):672
pubmed: 27553491
Eur J Cancer. 2011 May;47(7):1080-5
pubmed: 21220197
Cancer Res. 2003 Nov 15;63(22):7942-9
pubmed: 14633725
Oncoimmunology. 2015 Aug 12;5(1):e1067745
pubmed: 26942087
Nat Med. 1999 May;5(5):526-34
pubmed: 10229229
J Neuropathol Exp Neurol. 2013 Sep;72(9):816-23
pubmed: 23965741
J Immunol. 2005 Dec 15;175(12):8431-7
pubmed: 16339586
Am J Surg Pathol. 2015 Oct;39(10):1305-12
pubmed: 26099010
Front Oncol. 2018 May 03;8:143
pubmed: 29774202
J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
pubmed: 10655437
Cell Death Dis. 2013 Jun 20;4:e682
pubmed: 23788039
Ann Surg Oncol. 2013 Dec;20 Suppl 3:S509-16
pubmed: 23456319
Clin Cancer Res. 2017 Nov 15;23(22):6833-6845
pubmed: 28855356
Semin Oncol. 2012 Jun;39(3):358-66
pubmed: 22595058
Cancer Res. 2014 May 1;74(9):2510-9
pubmed: 24626094
Vaccine. 2009 Jul 16;27(33):4475-82
pubmed: 19450631
Oncotarget. 2015 Mar 10;6(7):4853-62
pubmed: 25605015
Semin Oncol. 2012 Jun;39(3):296-304
pubmed: 22595052
J Natl Cancer Inst. 2014 May 09;106(5):
pubmed: 24815864
J Clin Invest. 2010 Feb;120(2):533-44
pubmed: 20071775
J Pathol. 2006 Jun;209(2):157-65
pubmed: 16538613