Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

274 13 Applications of CpG Motifs from Bacterial DNA in Cancer Immunotherapy
also have enhanced ability to activate NK cells since the CpG motif is PO [90, 86]Ç
The addition of poly(G) motifs to the 5' and 3' ends of the ODN enhance the cellular
uptake, and substantially improve its ability to activate NK cells [90, 104] and to induce
IFN-a production from human plasmacytoid DC precursors [102]. The uptake
and activity of bDNA or PO ODN without poly(G) motifs can be similarly enhanced
using cationic lipids [47] or antibodies [100], in which case the cytokine induction
can be increased to a level comparable to that seen with a poly(G) CpG-A ODN.
In contrast to CpG-A ODN, CpG motifs in nuclease-resistant phosphorothioate backbones
have dramatically enhanced B cell stimulatory properties but reduced NK stimulation,
despite being much more stable than phosphodiester ODN [53, 90, 92,
93]. ODN in which the CpG motif has a PS backbone are therefore termed CpG-B
ODN [101], to reflect this enhanced B cell activation. Even though CpG-B ODN as a
family have similar properties, there can still be qualitative differences in their effects,
and some are substantially more effective at inducing the expression of TNF-a
than others [105].
13.5
Applications of CpG DNA in Immunotherapy of Cancer
13.5.1
CpG-A or CpG-B DNA as a Monotherapy
As reviewed in the Introduction, the antitumor effects of infections have been recognized
for hundreds of years, effectively demonstrating that immune activation can
result in tumor eradication. This point is consistent with the recently rediscovered
role of ªcancer immunosurveillanceº, mediated by IFN-g and lymphocytes, in suppressing
tumor growth [106]. By inducing IFN-g production and activating lymphocytes
CpG-induced innate immune activation might enhance cancer immunosurveillance,
and prevent tumor development.
The efficacy of CpG-A DNA in treating tumor-bearing mice has been examined in
several experimental models. In some models, plasmids containing CpG motifs
were stabilized by the formation of complexes with cationic lipids, which enables
them to induce systemic NK cell activation and Th1 cytokine production [107].
Methylation of the plasmids reduced their immune stimulatory effects, demonstrating
the CpG-specificity. Such cationic lipid±DNA complexes are taken up in the pulmonary
vascular bed and trigger the local accumulation of activated NK cells that
produce IFN-g. Mice were given tumors by i.v. injection with experimental fibrosarcoma,
melanoma or colon carcinoma cell lines, and then treated with i.v. cationic lipid±DNA
complexes 3 and 10 days later [107]. Mice with intact immune systems had
a marked decrease in the number of pulmonary metastases, compared to mice given
lipid or DNA alone [107]. However, these CpG-A molecules had no protective effects
in mice depleted of NK cells with anti-asialo-GM1 antiserum or in mice genetically
deficient in IFN-g [107]. Similar cationic lipid±plasmid DNA complexes have been
demonstrated effective in two murine mesothelioma models, AC29and AB12 [108].