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DNA vaccination induces WT1-specific T-cell responses with potential clinical relevance

DNA vaccination induces WT1-specific T-cell responses with potential clinical relevance
DNA vaccination induces WT1-specific T-cell responses with potential clinical relevance
The Wilms tumor antigen, WT1, is associated with several human cancers, including leukemia. We evaluated WT1 as an immunotherapeutic target using our proven DNA fusion vaccine design, p.DOM-peptide, encoding a minimal tumor-derived major histocompatibility complex (MHC) class I–binding epitope downstream of a foreign sequence of tetanus toxin. Three p.DOM-peptide vaccines, each encoding a different WT1-derived, HLA-A2–restricted epitope, induced cytotoxic T lymphocytes (CTLs) in humanized transgenic mice expressing chimeric HLA-A2, without affecting hematopoietic stem cells. Mouse CTLs killed human leukemia cells in vitro, indicating peptide processing/presentation. Low numbers of T cells specific for these epitopes have been described in cancer patients. Expanded human T cells specific for each epitope were lytic in vitro. Focusing on human WT137–45–specific cells, the most avid of the murine responses, we demonstrated lysis of primary leukemias, underscoring their clinical relevance. Finally, we showed that these human CTL kill target cells transfected with the relevant p.DOM-peptide DNA vaccine, confirming that WT1-derived epitopes are presented to T cells similarly by tumors and following DNA vaccination. Together, these data link mouse and human studies to suggest that rationally designed DNA vaccines encoding WT1-derived epitopes, particularly WT137–45, have the potential to induce/expand functional tumor-specific cytotoxic responses in cancer patients.



0006-4971
2956-2964
Chaise, Coralie
1c0ee786-5e8e-402d-aa36-d44f8c80c7da
Buchan, Sarah L.
9ade187d-f127-45de-ad90-9d544d64718a
Rice, Jason
d58d4fcd-8dc0-4599-bf96-62323d579227
Marquet, Jeanine
fdd23488-0d73-46e2-a2c1-581f24172c5f
Rouard, Hélène
72101550-3280-4ddc-bdb7-bdc36e6480ef
Kuentz, Mathieu
cae6812b-465d-4c7f-a579-7025450340d7
Vittes, Gisella E.
0421ca22-87a5-4995-a18a-c4da932838b5
Molinier-Frenkel, Valérie
8f6e5eb4-4e18-42ac-a2ca-2c866f0affb1
Farcet, Jean-Pierre
b8793506-ff1c-436b-8ac6-a24e8344ab54
Stauss, Hans J.
0b2c23a9-dd72-4b95-9654-e8a41d807691
Delfau-Larue, Marie-Hélène
cd7439f6-f3fb-4801-9774-10b50eb6b032
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Chaise, Coralie
1c0ee786-5e8e-402d-aa36-d44f8c80c7da
Buchan, Sarah L.
9ade187d-f127-45de-ad90-9d544d64718a
Rice, Jason
d58d4fcd-8dc0-4599-bf96-62323d579227
Marquet, Jeanine
fdd23488-0d73-46e2-a2c1-581f24172c5f
Rouard, Hélène
72101550-3280-4ddc-bdb7-bdc36e6480ef
Kuentz, Mathieu
cae6812b-465d-4c7f-a579-7025450340d7
Vittes, Gisella E.
0421ca22-87a5-4995-a18a-c4da932838b5
Molinier-Frenkel, Valérie
8f6e5eb4-4e18-42ac-a2ca-2c866f0affb1
Farcet, Jean-Pierre
b8793506-ff1c-436b-8ac6-a24e8344ab54
Stauss, Hans J.
0b2c23a9-dd72-4b95-9654-e8a41d807691
Delfau-Larue, Marie-Hélène
cd7439f6-f3fb-4801-9774-10b50eb6b032
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c

Chaise, Coralie, Buchan, Sarah L., Rice, Jason, Marquet, Jeanine, Rouard, Hélène, Kuentz, Mathieu, Vittes, Gisella E., Molinier-Frenkel, Valérie, Farcet, Jean-Pierre, Stauss, Hans J., Delfau-Larue, Marie-Hélène and Stevenson, Freda K. (2008) DNA vaccination induces WT1-specific T-cell responses with potential clinical relevance. Blood, 112 (7), 2956-2964. (doi:10.1182/blood-2008-02-137695). (PMID:18502835)

Record type: Article

Abstract

The Wilms tumor antigen, WT1, is associated with several human cancers, including leukemia. We evaluated WT1 as an immunotherapeutic target using our proven DNA fusion vaccine design, p.DOM-peptide, encoding a minimal tumor-derived major histocompatibility complex (MHC) class I–binding epitope downstream of a foreign sequence of tetanus toxin. Three p.DOM-peptide vaccines, each encoding a different WT1-derived, HLA-A2–restricted epitope, induced cytotoxic T lymphocytes (CTLs) in humanized transgenic mice expressing chimeric HLA-A2, without affecting hematopoietic stem cells. Mouse CTLs killed human leukemia cells in vitro, indicating peptide processing/presentation. Low numbers of T cells specific for these epitopes have been described in cancer patients. Expanded human T cells specific for each epitope were lytic in vitro. Focusing on human WT137–45–specific cells, the most avid of the murine responses, we demonstrated lysis of primary leukemias, underscoring their clinical relevance. Finally, we showed that these human CTL kill target cells transfected with the relevant p.DOM-peptide DNA vaccine, confirming that WT1-derived epitopes are presented to T cells similarly by tumors and following DNA vaccination. Together, these data link mouse and human studies to suggest that rationally designed DNA vaccines encoding WT1-derived epitopes, particularly WT137–45, have the potential to induce/expand functional tumor-specific cytotoxic responses in cancer patients.



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Published date: 3 October 2008
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 73218
URI: https://eprints.soton.ac.uk/id/eprint/73218
ISSN: 0006-4971
PURE UUID: ed63e5fc-5d41-4aa8-ae16-c2d44385f45a
ORCID for Freda K. Stevenson: ORCID iD orcid.org/0000-0002-0933-5021

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Date deposited: 03 Mar 2010
Last modified: 06 Jun 2018 13:01

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Contributors

Author: Coralie Chaise
Author: Sarah L. Buchan
Author: Jason Rice
Author: Jeanine Marquet
Author: Hélène Rouard
Author: Mathieu Kuentz
Author: Gisella E. Vittes
Author: Valérie Molinier-Frenkel
Author: Jean-Pierre Farcet
Author: Hans J. Stauss
Author: Marie-Hélène Delfau-Larue

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