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

13.5 Applications of CpG DNA in Immunotherapy of Cancer
In the less aggressive model, AC29, treatment with CpG-A resulted in a greater than
90 % long-term survival rate, while in the more aggressive AB 12 model, treatment
still gave greater than 40 % long-term survival [108]. In both models, CpG treatment
led to a protective memory response, since surviving mice resisted repeat tumor
challenge. CD8 + T cells and NK cells were absolutely required, and CD4 + T cells contributed
to the CpG-induced protective effect [108].
Using systemic or local therapy with an NK-optimized CpG-A ODN, we prevented
death in 80 % of syngeneic C57 BL/6 mice after an otherwise lethal challenge of
poorly immunogenic B16 melanoma [109]. Even when treatment was begun 3 days
after tumor challenge, 60 % of mice could still be cured of disease with CpG-A treatment.
Of interest, CpG-B ODN treatment was less effective in this tumor model
[109]. SCID mice were also protected against tumor challenge by CpG DNA, indicating
that neither B nor T cells are required. In contrast to the mesothelioma models
described in the preceding paragraph, specific immunity was not generated, since
CpG-treated mice that had survived a tumor challenge were not protected against
subsequent tumor challenges [109].
CpG-B ODN also have therapeutic activity in several mouse tumor models as monotherapy,
with either local or systemic administration. Injection of CpG DNA directly
into a tumor lesion may activate DCs in or around the tumor, inducing a Th1-like cytokine
environment which may overcome the normal immune suppressive effects of
the tumor and result in an effective antitumor immune response. In support of this
hypothesis, Carpentier et al. have demonstrated that daily injection of CpG-B ODN
for 15 days into syngeneic neuroblastoma tumor nodules results in complete tumor
regression in about 50 % of the mice [110]. Animals cured with CpG treatment were
protected against further tumor challenge, suggesting the development of an antigen-specific
T cell response, in contrast to the lack of a role for T cells in the case of
the B16 model described in the previous paragraph. These results demonstrating the
development of an active antitumor response following treatment with CpG-B ODN
have recently been extended to a glioblastoma model [111] and a T cell lymphoma
model [109].
In the C1498 mouse AML model, a CpG-A ODN was ineffective when used alone,
but a CpG-B ODN had both preventive and therapeutic activity [112]. NK cells were
required for the CpG-induced protective effect, but neither T nor B cells contributed
and no memory response appeared to be induced. In a post bone marrow transplantation
AML model CpG ODN alone had little effect, but either CpG-A or CpG-B
ODN substantially improved the efficacy of donor lymphocyte infusion (DLI) [112].
A combination of a CpG-A ODN together with a CpG-B ODN synergized strongly
with DLI in this model, giving 90 % long-term survival when DLI alone gave 0 %
[112]. In summary, monotherapy of tumors with either CpG-A or CpG-B ODN alone
or in combinations of the two or with other immunotherapies may be useful, depending
on the tumor type. It appears that CpG-A may be most effective against NKsensitive
tumors, and CpG-B may be most effective when broader immune activation
and an adaptive immune response can enhance the efficacy of therapy.
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