Novel personalized cancer vaccine platform based on Bacillus Calmette-Guèrin.
active
adaptive immunity
cellular
immunity
immunogenicity
immunotherapy
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:
07 2021
07 2021
Historique:
accepted:
15
06
2021
entrez:
16
7
2021
pubmed:
17
7
2021
medline:
12
1
2022
Statut:
ppublish
Résumé
Intratumoral BCG therapy, one of the earliest immunotherapies, can lead to infiltration of immune cells into a treated tumor. However, an increase in the number of BCG-induced tumor-specific T cells in the tumor microenvironment could lead to enhanced therapeutic effects. Here, we have developed a novel cancer vaccine platform based on BCG that can broaden BCG-induced immune responses to include tumor antigens. By physically attaching tumor-specific peptides onto the mycobacterial outer membrane, we were able to induce strong systemic and intratumoral T cell-specific immune responses toward the attached tumor antigens. These therapeutic peptides can be efficiently attached to the mycobacterial outer membrane using a poly-lysine sequence N-terminally fused to the tumor-specific peptides. Using two mouse models of melanoma and a mouse model of colorectal cancer, we observed that the antitumor immune responses of BCG could be improved by coating the BCG with tumor-specific peptides. In addition, by combining this novel cancer vaccine platform with anti-programmed death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy, the number of responders to anti-PD-1 immunotherapy was markedly increased. This study shows that intratumoral BCG immunotherapy can be improved by coating the bacteria with modified tumor-specific peptides. In addition, this improved BCG immunotherapy can be combined with ICI therapy to obtain enhanced tumor growth control. These results warrant clinical testing of this novel cancer vaccine platform.
Sections du résumé
BACKGROUND
Intratumoral BCG therapy, one of the earliest immunotherapies, can lead to infiltration of immune cells into a treated tumor. However, an increase in the number of BCG-induced tumor-specific T cells in the tumor microenvironment could lead to enhanced therapeutic effects.
METHODS
Here, we have developed a novel cancer vaccine platform based on BCG that can broaden BCG-induced immune responses to include tumor antigens. By physically attaching tumor-specific peptides onto the mycobacterial outer membrane, we were able to induce strong systemic and intratumoral T cell-specific immune responses toward the attached tumor antigens. These therapeutic peptides can be efficiently attached to the mycobacterial outer membrane using a poly-lysine sequence N-terminally fused to the tumor-specific peptides.
RESULTS
Using two mouse models of melanoma and a mouse model of colorectal cancer, we observed that the antitumor immune responses of BCG could be improved by coating the BCG with tumor-specific peptides. In addition, by combining this novel cancer vaccine platform with anti-programmed death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy, the number of responders to anti-PD-1 immunotherapy was markedly increased.
CONCLUSIONS
This study shows that intratumoral BCG immunotherapy can be improved by coating the bacteria with modified tumor-specific peptides. In addition, this improved BCG immunotherapy can be combined with ICI therapy to obtain enhanced tumor growth control. These results warrant clinical testing of this novel cancer vaccine platform.
Identifiants
pubmed: 34266884
pii: jitc-2021-002707
doi: 10.1136/jitc-2021-002707
pmc: PMC8286790
pii:
doi:
Substances chimiques
BCG Vaccine
0
Cancer Vaccines
0
Types de publication
Journal Article
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. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: VC is co-founder and shareholder at VALO therapeutics. Not related with this project. EY, BM and VC are co-inventors in a patent application based on the present work.
Références
J Immunother. 2012 Nov-Dec;35(9):716-20
pubmed: 23090081
Nat Rev Urol. 2014 Mar;11(3):153-62
pubmed: 24492433
Cell Host Microbe. 2018 Jan 10;23(1):89-100.e5
pubmed: 29324233
J Natl Cancer Inst. 1976 Apr;56(4):803-10
pubmed: 1255799
Immunology. 2004 Jul;112(3):461-70
pubmed: 15196215
Lancet Oncol. 2021 Jan;22(1):107-117
pubmed: 33253641
Cancer. 2010 Apr 1;116(7):1767-75
pubmed: 20143434
J Pharm Sci. 2004 Oct;93(10):2458-75
pubmed: 15349956
Mol Ther. 2018 Sep 5;26(9):2315-2325
pubmed: 30005865
J Virol. 1982 Jul;43(1):26-36
pubmed: 6287001
Cell. 1988 Sep 9;54(6):777-85
pubmed: 3261634
Microbios. 1992;70(284-285):185-98
pubmed: 1406339
Ann Surg. 1974 Oct;180(4):635-43
pubmed: 4412271
JAMA. 2020 Nov 17;324(19):1980-1991
pubmed: 33201207
J Immunother. 2015 Nov-Dec;38(9):371-5
pubmed: 26448581
Expert Opin Investig Drugs. 2019 Sep;28(9):757-770
pubmed: 31412742
JAMA Oncol. 2021 Apr 1;7(4):501-502
pubmed: 33377964
Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4652-7
pubmed: 20133772
Science. 1992 Jan 24;255(5043):456-9
pubmed: 1531159
Cancer Cell. 2020 Apr 13;37(4):443-455
pubmed: 32289269
Mol Med Rep. 2015 Aug;12(2):3073-80
pubmed: 25962477
Nature. 1970 Dec 19;228(5277):1210-1
pubmed: 4922500
J Innate Immun. 2014;6(2):152-8
pubmed: 24192057
J Immunother. 2018 Apr;41(3):125-129
pubmed: 29293165
Immunology. 2014 Oct;143(2):277-86
pubmed: 24773322
J Immunogenet. 1989 Aug-Oct;16(4-5):291-303
pubmed: 2639904
Allergy. 2020 Jul;75(7):1815-1819
pubmed: 32339299
PLoS One. 2008;3(11):e3790
pubmed: 19023426
Mol Ther. 2009 Oct;17(10):1814-21
pubmed: 19603003
J Natl Compr Canc Netw. 2016 Apr;14(4):450-73
pubmed: 27059193
Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):4958-63
pubmed: 24639491
AIDS Res Hum Retroviruses. 1991 Jul;7(7):615-20
pubmed: 1768463
Surgery. 1970 Jul;68(1):158-63; discussion 163-4
pubmed: 10483463
Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16723-8
pubmed: 21933959
Front Oncol. 2017 Apr 05;7:61
pubmed: 28424760
Proc Natl Acad Sci U S A. 2020 Aug 4;117(31):18627-18637
pubmed: 32680964
Oncoimmunology. 2015 Oct 29;5(4):e1105429
pubmed: 27141389
Nat Rev Urol. 2017 Apr;14(4):244-255
pubmed: 28248951
Microbiol Spectr. 2014 Feb;2(1):MGM2-0028-2013
pubmed: 26082111
Oncoimmunology. 2018 Sep 19;8(1):e1512329
pubmed: 30546947
Microbios. 1988;53(216-217):191-5
pubmed: 3292875
Mol Ther Oncolytics. 2021 Feb 10;20:459-469
pubmed: 33718594