Long-term survival of patients with stage III colon cancer treated with VRP-CEA(6D), an alphavirus vector that increases the CD8+ effector memory T cell to Treg ratio.
CD4-CD8 Ratio
adaptive immunity
clinical trials as topic
immunotherapy
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:
11 2020
11 2020
Historique:
accepted:
20
10
2020
entrez:
12
11
2020
pubmed:
13
11
2020
medline:
18
9
2021
Statut:
ppublish
Résumé
There remains a significant need to eliminate the risk of recurrence of resected cancers. Cancer vaccines are well tolerated and activate tumor-specific immune effectors and lead to long-term survival in some patients. We hypothesized that vaccination with alphaviral replicon particles encoding tumor associated antigens would generate clinically significant antitumor immunity to enable prolonged overall survival (OS) in patients with both metastatic and resected cancer. OS was monitored for patients with stage IV cancer treated in a phase I study of virus-like replicon particle (VRP)-carcinoembryonic antigen (CEA), an alphaviral replicon particle encoding a modified CEA. An expansion cohort of patients (n=12) with resected stage III colorectal cancer who had completed their standard postoperative adjuvant chemotherapy was administered VRP-CEA every 3 weeks for a total of 4 immunizations. OS and relapse-free survival (RFS) were determined, as well as preimmunization and postimmunization cellular and humoral immunity. Among the patients with stage IV cancer, median follow-up was 10.9 years and 5-year survival was 17%, (95% CI 6% to 33%). Among the patients with stage III cancer, the 5-year RFS was 75%, (95%CI 40% to 91%); no deaths were observed. At a median follow-up of 5.8 years (range: 3.9-7.0 years) all patients were still alive. All patients demonstrated CEA-specific humoral immunity. Patients with stage III cancer had an increase in CD8 +T VRP-CEA induces antigen-specific effector T cells while decreasing Tregs, suggesting favorable immune modulation. Long-term survivors were identified in both cohorts, suggesting the OS may be prolonged.
Sections du résumé
BACKGROUND
There remains a significant need to eliminate the risk of recurrence of resected cancers. Cancer vaccines are well tolerated and activate tumor-specific immune effectors and lead to long-term survival in some patients. We hypothesized that vaccination with alphaviral replicon particles encoding tumor associated antigens would generate clinically significant antitumor immunity to enable prolonged overall survival (OS) in patients with both metastatic and resected cancer.
METHODS
OS was monitored for patients with stage IV cancer treated in a phase I study of virus-like replicon particle (VRP)-carcinoembryonic antigen (CEA), an alphaviral replicon particle encoding a modified CEA. An expansion cohort of patients (n=12) with resected stage III colorectal cancer who had completed their standard postoperative adjuvant chemotherapy was administered VRP-CEA every 3 weeks for a total of 4 immunizations. OS and relapse-free survival (RFS) were determined, as well as preimmunization and postimmunization cellular and humoral immunity.
RESULTS
Among the patients with stage IV cancer, median follow-up was 10.9 years and 5-year survival was 17%, (95% CI 6% to 33%). Among the patients with stage III cancer, the 5-year RFS was 75%, (95%CI 40% to 91%); no deaths were observed. At a median follow-up of 5.8 years (range: 3.9-7.0 years) all patients were still alive. All patients demonstrated CEA-specific humoral immunity. Patients with stage III cancer had an increase in CD8 +T
CONCLUSIONS
VRP-CEA induces antigen-specific effector T cells while decreasing Tregs, suggesting favorable immune modulation. Long-term survivors were identified in both cohorts, suggesting the OS may be prolonged.
Identifiants
pubmed: 33177177
pii: jitc-2020-001662
doi: 10.1136/jitc-2020-001662
pmc: PMC7661359
pii:
doi:
Types de publication
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 : P01 CA078673
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014236
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016086
Pays : United States
Informations de copyright
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: PB and JS were employed by AlphaVax Inc. HKL was on the Scientific Advisory Board of AlphaVax Inc and has equity in AlphaVax.
Références
Nucleic Acids Res. 2012 May;40(10):4288-97
pubmed: 22287627
In Vivo. 2010 Sep-Oct;24(5):607-28
pubmed: 20952724
J Clin Oncol. 2015 Dec 10;33(35):4176-87
pubmed: 26527776
N Engl J Med. 2018 Mar 29;378(13):1177-1188
pubmed: 29590544
Clin Adv Hematol Oncol. 2018 Nov;16(11):735-745
pubmed: 30543589
Vaccine. 2009 Dec 11;28(2):484-93
pubmed: 19857446
Commun Biol. 2019 May 14;2:183
pubmed: 31098416
Clin Cancer Res. 2019 May 1;25(9):2725-2736
pubmed: 30635338
N Engl J Med. 2005 Dec 22;353(25):2654-66
pubmed: 16371631
Cytometry A. 2015 Jul;87(7):636-45
pubmed: 25573116
Nat Rev Immunol. 2012 Feb 17;12(3):191-200
pubmed: 22343568
Nat Med. 2018 Nov;24(11):1655-1661
pubmed: 30297911
JAMA. 2017 Jun 20;317(23):2392-2401
pubmed: 28632865
Immunotherapy. 2019 Aug;11(11):953-966
pubmed: 31192764
Front Immunol. 2019 Jun 11;10:1315
pubmed: 31244854
Sci Rep. 2016 Feb 10;6:20686
pubmed: 26861911
Cancer Res. 1997 Oct 15;57(20):4570-7
pubmed: 9377571
Curr Opin Mol Ther. 2001 Aug;3(4):407-12
pubmed: 11525565
N Engl J Med. 2020 Jun 18;382(25):2469-2471
pubmed: 32558474
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Hum Vaccin Immunother. 2018 Feb 1;14(2):250-254
pubmed: 29083978
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Ann Surg. 2013 Dec;258(6):879-86
pubmed: 23657083
Oncoimmunology. 2018 Sep 21;7(12):e1500671
pubmed: 30524892
Expert Rev Clin Immunol. 2017 Mar;13(3):235-245
pubmed: 27552944
Oncologist. 2020 Jan;25(1):33-45
pubmed: 31383813
Nat Methods. 2017 Jul;14(7):707-709
pubmed: 28504682
J Clin Invest. 2010 Sep;120(9):3234-41
pubmed: 20679728