DNA fusion vaccine designed to induce cytotoxic T cell responses against defined peptide motifs: implications for cancer vaccines
DNA fusion vaccine designed to induce cytotoxic T cell responses against defined peptide motifs: implications for cancer vaccines
DNA vaccination offers a strategy to induce immune attack on cancer cells, but tumor Ags are often weak. Inclusion of a "foreign" protein increases immunogenicity, and we found previously that fusion of the fragment C (FrC) of tetanus toxin to the tumor Ag sequence promotes Ab and CD4+ responses against B cell tumors. For CTL responses, use of the full two-domain FrC may be less helpful, because known immunogenic MHC class I-binding peptides in the second domain could compete with attached tumor-derived epitopes.
Therefore, we removed the second domain, retaining the N-terminal domain, which contains a "universal" helper epitope. We investigated the ability to induce CTL responses of candidate peptides placed at the C terminus of this domain. As test peptides, we repositioned the two known CTL motifs from the second domain to this site. Strong CTL responses to each peptide were induced by the engineered construct, as compared with the native FrC construct. Induced CTLs were able to specifically kill tumor cells transfected with FrC as a surrogate tumor Ag both in vitro and in vivo.
Further reduction of the domain to a short helper epitope generated only weak CTL responses against fused peptides, and synthetic peptides mixed with the plasmid containing the first domain were ineffective. The single FrC domain-peptide vaccine design also was able to induce high levels of CTLs against a known epitope from carcinoembryonic Ag. Response to peptide was suppressed if two FrC domains were present, consistent with immunodominance. These principles and designs may have relevance for cancer vaccines delivered via DNA.
1558-1565
Rice, Jason
d58d4fcd-8dc0-4599-bf96-62323d579227
Elliott, Tim
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Buchan, Sarah
9ade187d-f127-45de-ad90-9d544d64718a
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
2001
Rice, Jason
d58d4fcd-8dc0-4599-bf96-62323d579227
Elliott, Tim
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Buchan, Sarah
9ade187d-f127-45de-ad90-9d544d64718a
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Rice, Jason, Elliott, Tim, Buchan, Sarah and Stevenson, Freda K.
(2001)
DNA fusion vaccine designed to induce cytotoxic T cell responses against defined peptide motifs: implications for cancer vaccines.
Journal of Immunology, 167 (3), .
(doi:10.4049/?jimmunol.167.3.1558).
(PMID:11466377)
Abstract
DNA vaccination offers a strategy to induce immune attack on cancer cells, but tumor Ags are often weak. Inclusion of a "foreign" protein increases immunogenicity, and we found previously that fusion of the fragment C (FrC) of tetanus toxin to the tumor Ag sequence promotes Ab and CD4+ responses against B cell tumors. For CTL responses, use of the full two-domain FrC may be less helpful, because known immunogenic MHC class I-binding peptides in the second domain could compete with attached tumor-derived epitopes.
Therefore, we removed the second domain, retaining the N-terminal domain, which contains a "universal" helper epitope. We investigated the ability to induce CTL responses of candidate peptides placed at the C terminus of this domain. As test peptides, we repositioned the two known CTL motifs from the second domain to this site. Strong CTL responses to each peptide were induced by the engineered construct, as compared with the native FrC construct. Induced CTLs were able to specifically kill tumor cells transfected with FrC as a surrogate tumor Ag both in vitro and in vivo.
Further reduction of the domain to a short helper epitope generated only weak CTL responses against fused peptides, and synthetic peptides mixed with the plasmid containing the first domain were ineffective. The single FrC domain-peptide vaccine design also was able to induce high levels of CTLs against a known epitope from carcinoembryonic Ag. Response to peptide was suppressed if two FrC domains were present, consistent with immunodominance. These principles and designs may have relevance for cancer vaccines delivered via DNA.
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Accepted/In Press date: 21 May 2001
Published date: 2001
Identifiers
Local EPrints ID: 26568
URI: http://eprints.soton.ac.uk/id/eprint/26568
ISSN: 0022-1767
PURE UUID: e72463fc-a696-47ad-92e6-90ef523a64c8
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Date deposited: 20 Apr 2006
Last modified: 16 Mar 2024 03:19
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Author:
Jason Rice
Author:
Sarah Buchan
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