Development of DNA vaccines to induce immunity against intracellular tumour antigens
Development of DNA vaccines to induce immunity against intracellular tumour antigens
We previously reported that the non-toxic Fragment C (FrC) region of tetanus toxin is a potent immunoenhancer. A DNA vaccine encoding a tumour protein linked to FrC induced protective immunity in vaccinated mice, in contrast to a similar vaccine lacking the FrC sequence.
For intracellular tumour antigens, induction of CD8+ T cells is particular desirable. To activate CD8+ cell responses two changes were made to our vaccine design; first the N-terminal domain of FrC was removed to delete potentially competitive epitopes. Second, epitope presentation was enhanced by re-positioning minimal tumour peptides to the C-terminus of the remaining FrC sequence. This novel vaccine (p.DOM-peptide) proved an effective means to prime peptide-specific CTLs. To determine whether this design was applicable to a tumour antigen and to delineate the reasons for its success, we used a minimal H-2Ld-binding peptide, AH1, derived from the endogenous retroviral gene product, gp70, and expressed by the murine colon carcinoma, CT26. Vaccination with this second-generation design (p.DOM-AH1) activated functional AH1-specific CTLs capable of specifically lysing a panel of cells lines expressing the AH1 epitope. Importantly this vaccine also afforded protective immunity against CT26 tumour challenge in mice. Comparison with other AH10-containing DNA vaccines confirmed that both epitope competition and efficient tumour-peptide processing contribute to the efficacy of the p.DOM-AH1 vaccine.
Finally, we have focused on the tumour-associated transcription factor, WT1, to investigate whether DNA vaccination can induce immunity against this clinically relevant auto-antigen. Encouragingly, administration of a p.DOM-peptide vaccine encoding a minimal WT1-derived HLA-A2-binding epitope induced strong responses in humanised transgenic mice following injection by the DNA/EP prime/boost vaccination schedule.
University of Southampton
Buchan, Sarah
87e38403-54ed-4d88-802c-9a1107b7d304
2005
Buchan, Sarah
87e38403-54ed-4d88-802c-9a1107b7d304
Buchan, Sarah
(2005)
Development of DNA vaccines to induce immunity against intracellular tumour antigens.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
We previously reported that the non-toxic Fragment C (FrC) region of tetanus toxin is a potent immunoenhancer. A DNA vaccine encoding a tumour protein linked to FrC induced protective immunity in vaccinated mice, in contrast to a similar vaccine lacking the FrC sequence.
For intracellular tumour antigens, induction of CD8+ T cells is particular desirable. To activate CD8+ cell responses two changes were made to our vaccine design; first the N-terminal domain of FrC was removed to delete potentially competitive epitopes. Second, epitope presentation was enhanced by re-positioning minimal tumour peptides to the C-terminus of the remaining FrC sequence. This novel vaccine (p.DOM-peptide) proved an effective means to prime peptide-specific CTLs. To determine whether this design was applicable to a tumour antigen and to delineate the reasons for its success, we used a minimal H-2Ld-binding peptide, AH1, derived from the endogenous retroviral gene product, gp70, and expressed by the murine colon carcinoma, CT26. Vaccination with this second-generation design (p.DOM-AH1) activated functional AH1-specific CTLs capable of specifically lysing a panel of cells lines expressing the AH1 epitope. Importantly this vaccine also afforded protective immunity against CT26 tumour challenge in mice. Comparison with other AH10-containing DNA vaccines confirmed that both epitope competition and efficient tumour-peptide processing contribute to the efficacy of the p.DOM-AH1 vaccine.
Finally, we have focused on the tumour-associated transcription factor, WT1, to investigate whether DNA vaccination can induce immunity against this clinically relevant auto-antigen. Encouragingly, administration of a p.DOM-peptide vaccine encoding a minimal WT1-derived HLA-A2-binding epitope induced strong responses in humanised transgenic mice following injection by the DNA/EP prime/boost vaccination schedule.
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Published date: 2005
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Local EPrints ID: 465621
URI: http://eprints.soton.ac.uk/id/eprint/465621
PURE UUID: 47ea8376-cc30-463a-99e2-08a26861d9a0
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Date deposited: 05 Jul 2022 02:06
Last modified: 23 Jul 2022 02:16
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Author:
Sarah Buchan
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