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doi:10.1182/blood-2008-06-1631052008 112: 2602

Haruo SugiyamaExpectation for DNA leukemia vaccines

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NEOPLASIA

Comment on Chaise et al, page 2956

Expectation for DNA leukemia vaccines----------------------------------------------------------------------------------------------------------------

Haruo Sugiyama O S A K A U N I V E R S I TY G R A D U A TE S C H O O L O F M E D I C I N E

In this issue ofBlood, Chaise and colleagues report that rationally designed DNAvaccines encoding Wilms tumor gene WT1-derived epitopes and a part of tetanustoxin, which is a potent, universal inducer of helper CD4T cells, effectively in-duce WT1-specific CTLs in mice and confirm that WT1-derived epitopes caninduce epitope-specific human CTLs in vitro.

The majority of patients with leukemia can

achieveclinicalcomplete remissionfollow-

ing high-dose chemotherapy, butfrequently

relapse.To cureleukemia, eradicationof mini-

malresidualdiseaseis essential, andthegraft-

versus-leukemia(GVL) effectinducedby allo-

geneic stemcell transplantation(SCT) and/or

donor lymphocyte infusionis a potent weapon.

TheWilmstumorgene WT1protein is

overexpressed in leukemia and various types

of solid tumors andthus is a potential

pantumorassociated antigen and target for

GVL.1 WT1 protein is highly immunogenic

and thus WT1 antibodies and WT1-specific

cytotoxic T lymphocytes (CTLs) are sponta-

neously induced in leukemia patients, and

WT1-specific CTLs take part in GVL reac-tions following SCT. Therefore, various mo-

dalities of cancer immunotherapy targeting

WT1protein epitopes arebeing developedor

arealready in use.2

In this issue ofBlood, Chaise et al report

the development of a DNA vaccine targ eting

WT1 and clearly demonstrate the potential

of this approach to induce and expand func-

tional tumor-specific cytotoxic responses.

One remarkable aspect of this particular

WT1 DNA vaccine is that it also contains a

portion of the tetanus toxin, which is a po-tent inducer of helper CD4 T cells.3-5

Helper CD4 T cells are needed for expan-

sion of CD8 CTLs, and expansion of

CD8 CTLs is dependent on the presence

of helper CD4 T cells.6,7 Indeed, helper

CD4 T cells expanded from a nontolerized

tetanus-specific repertoire were critical for

effective priming of CD8 T cells following

immunization with a DNA vaccine contain-

ing tetanus toxin sequences. Furthermore,

this DNA vaccine was designed to contain

only the first domain of the C fragment of

tetanus toxin, without the second domain of

the C fragment, which contains known im-

munogenic MHC class I binding peptides

that can compete with tumor-antigenderived peptides for MHC class I. Because

tetanus toxin binds promiscuously with

MHC class II molecules, it is a universal

helper epitope without restriction to specific

MHC class II proteins. Therefore, this

DNA vaccine particularly well-designed to

induce universal helper T cells, followed by

the induction of WT1-specific CTLs.

Another advance described by this study

is the effective use of electroporation to de-

liver the DNA vaccine.8 Induction of antitu-

mor CTLs by DNA fusion vaccines is de-

pendent on the dose of plasmid and the

volume of injection. Cellular uptake of DNA

appears to be a significant limiting factor for

transfection and vaccine efficacy in vivo.

Low DNA vaccine dose and low injection

volume resulted in poor antigen expression

and reduced immunogenicity in vivo. Dose

and volume are limiting factors when scaling

up to humans. In vivo application of electro-

poration to an injection site can increase

DNA uptake by muscle cells and mono-nuclear cells, leading to increased antigen

expression and enhanced immunogenicity.

Electroporation may also give rise to an un-

defined adjuvant effect, probably mediated

by local tissue damage and the resultant re-

lease of inflammatory factors. For antibody

induction, DNA vaccination is generally less

effective than protein vaccination. However,

priming and boosting with naked DNA by

using electoporation dramatically increases

antibody levels.

This well-designed DNA vaccine encod-

ing the first domain of frag ment C of tetanus

toxin fused to 1 of 3 minimal WT1-related,

HLA-A*0201restricted epitopes (WT1.

37, WT1. 126, or WT1. 235) was shown by

Chaise and colleagues to result in induction

of WT1-peptidespecific CTLs in human-

ized transgenic mice expressing chimeric

HLA-A*0201, without affecting hematopoi-

etic stem cells. The induced WT1-peptide

specificCTLs killed target cells in a peptide-

specific manner. Furthermore, these

3 WT1-epitope peptides induced peptide-

specific CTLs from human peripheral blood

mononuclear cells, andthe induced CTLs

could kill target cells in both peptide-specific

and HLA-A*0201restrictive fashion.Taken together, these results stronglyindi-

cate thatrationally-designed DNAvaccines en-

codingWT1-derived epitopes,particularly

WT137-45, have the potential to induce andex-

pand functional tumor-specific cytotoxicre-

sponses in cancer patients, andthat these DNA

vaccinesshouldalsobe useful in clinicalsettings.

Weawait clinicaltrial resultswith enthusiasm.

Conflict-of-interest disclosure: The author

declares no competing financial interests.

REFERENCES

1. SugiyamaH. Cancer immunotherapy targetingWilms

tumor geneWT1 product. Expert Rev Vaccines.2005;4:

503-512.

2. Oka Y, Tsuboi A, Taguchi T, et al. Induction of

WT1 (Wilms tumor gene)-specific cytotoxic T lympho-

cytes by WT1 peptide vaccine and the resultant cancer

regression. Proc Natl Acad Sci U S A. 2004;101:13885-

13890.

3. Rice J,ElliottT, BuchanS, StevensonFK.DNA fusion

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5. StevensonFK,OttensmeierCH, Johnson P,et al.DNA

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852-856.

8. BuchanS, GrnevikE, Mathiesen I,KingCA,

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