DNA vaccines to target the cancer testis antigen PASD1 in human multiple myeloma
DNA vaccines to target the cancer testis antigen PASD1 in human multiple myeloma
We previously described PASD1 as a new cancer testis antigen in multiple myeloma (MM) that is retained post-therapy, suggesting the use of vaccination strategies to induce anti-PASD1 immunity in a setting of minimal residual disease. We have focused on DNA fusion gene vaccines, coupling fragment C domain (DOM) of tetanus toxin with PASD1 sequence, and examined efficacy in Human Leukocyte Antigen (HLA)-A2 (HHD) transgenic mice using a human MM cell line expressing PASD1 protein and chimeric HLA-A2 class I molecules as target. DNA vaccines encoded two HLA-A2-restricted epitopes (p.DOM-PASD1(1), p.DOM-PASD1(2)) and full-length PASD1 (p.DOM-PASD1FL). p.DOM-PASD1(1) proved superior to p.DOM-PASD1(2) in generating T-cell responses in HHD mice, able to lyse the chimeric murine RMA-HHD cells. Boosting by electroporation significantly enhanced p.DOM-PASD1(1). Only p.DOM-PASD1(1) induced cytotoxic T-lymphocytes (CTLs) were able to lyse human MM target cells expressing endogenous antigen. The p.DOM-PASD1FL vaccine predominantly induced strong PASD1(1) over PASD1(2) T-cell immune responses, indicative of immunodominance. Importantly, p.DOM-PASD1FL generated immune-mediating killing of native chimeric MM cells, in the absence of exogenous added peptide, implicating PASD1(1) specific CTLs. These data demonstrate that PASD1-derived epitopes are both efficiently and selectively processed and presented by native human MM cells. Notably, they permit the use of PASD1-encoding DNA vaccine therapy in a clinical setting.
1951-1959
Joseph-Pietras, D.
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Gao, Y.
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Zojer, N.
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Ait-Tahar, K.
53866c38-5455-459f-8a94-31184afdc5b0
Banham, A.H.
6186fe6c-06b6-48ca-9c39-1759f3188834
Pulford, K.
9200dcb8-c60c-42ce-a23d-5caec04b704c
Rice, J.
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Savelyeva, N.
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Sahota, S.S.
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November 2010
Joseph-Pietras, D.
3002f7ea-3689-40c3-8949-9da8f0753c91
Gao, Y.
3f048356-567d-4308-853f-d98fabfcb6fb
Zojer, N.
5dec9dcd-c973-44e7-80c5-28b6f62713f9
Ait-Tahar, K.
53866c38-5455-459f-8a94-31184afdc5b0
Banham, A.H.
6186fe6c-06b6-48ca-9c39-1759f3188834
Pulford, K.
9200dcb8-c60c-42ce-a23d-5caec04b704c
Rice, J.
d58d4fcd-8dc0-4599-bf96-62323d579227
Savelyeva, N.
804c3e15-d260-4717-9b7c-15c16ba87fc7
Sahota, S.S.
66c1457f-cba2-4c49-9c8c-fcee0748b6b8
Joseph-Pietras, D., Gao, Y., Zojer, N., Ait-Tahar, K., Banham, A.H., Pulford, K., Rice, J., Savelyeva, N. and Sahota, S.S.
(2010)
DNA vaccines to target the cancer testis antigen PASD1 in human multiple myeloma.
Leukemia, 24 (11), .
(doi:10.1038/leu.2010.196).
(PMID:20861911)
Abstract
We previously described PASD1 as a new cancer testis antigen in multiple myeloma (MM) that is retained post-therapy, suggesting the use of vaccination strategies to induce anti-PASD1 immunity in a setting of minimal residual disease. We have focused on DNA fusion gene vaccines, coupling fragment C domain (DOM) of tetanus toxin with PASD1 sequence, and examined efficacy in Human Leukocyte Antigen (HLA)-A2 (HHD) transgenic mice using a human MM cell line expressing PASD1 protein and chimeric HLA-A2 class I molecules as target. DNA vaccines encoded two HLA-A2-restricted epitopes (p.DOM-PASD1(1), p.DOM-PASD1(2)) and full-length PASD1 (p.DOM-PASD1FL). p.DOM-PASD1(1) proved superior to p.DOM-PASD1(2) in generating T-cell responses in HHD mice, able to lyse the chimeric murine RMA-HHD cells. Boosting by electroporation significantly enhanced p.DOM-PASD1(1). Only p.DOM-PASD1(1) induced cytotoxic T-lymphocytes (CTLs) were able to lyse human MM target cells expressing endogenous antigen. The p.DOM-PASD1FL vaccine predominantly induced strong PASD1(1) over PASD1(2) T-cell immune responses, indicative of immunodominance. Importantly, p.DOM-PASD1FL generated immune-mediating killing of native chimeric MM cells, in the absence of exogenous added peptide, implicating PASD1(1) specific CTLs. These data demonstrate that PASD1-derived epitopes are both efficiently and selectively processed and presented by native human MM cells. Notably, they permit the use of PASD1-encoding DNA vaccine therapy in a clinical setting.
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Published date: November 2010
Organisations:
Cancer Sciences
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Local EPrints ID: 179151
URI: http://eprints.soton.ac.uk/id/eprint/179151
ISSN: 0887-6924
PURE UUID: 2d32d1ff-d623-4049-a3ee-315d27892de6
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Date deposited: 31 Mar 2011 15:12
Last modified: 14 Mar 2024 02:48
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Author:
D. Joseph-Pietras
Author:
Y. Gao
Author:
N. Zojer
Author:
K. Ait-Tahar
Author:
A.H. Banham
Author:
K. Pulford
Author:
J. Rice
Author:
S.S. Sahota
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