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

13.5 Applications of CpG DNA in Immunotherapy of Cancer
fold increase in CTL responses and substantial therapeutic activity even when vaccination
was delayed until day 7 after injection of mice with a B16 melanoma that expressed
OVA [127].
CpG-B ODN have also been shown to enhance tumor immunotherapy with adoptive
transfer of T cells primed against the tumor cells. Donor mice are immunized
against a tumor such as the A20 lymphoma, and then stimulated in vitro with APCs
and irradiated tumor cells. The addition of a CpG-B ODN to the in vitro culture improved
CD4 T cell recovery by 12- to 70-fold and the recovered cells were effective at
eliminating an established A20 lymphoma in recipient mice without apparent induction
of autoimmune disease [128]. There has been much recent interest in the use of
DC vaccines for tumor immunotherapy. CpG is an effective adjuvant for DC co-cultured
with irradiated tumor cells, providing a substantial increase in both prophylactic
and therapeutic activity in a murine colon cancer model [129].
13.5.3
Application of CpG DNA to Enhance ADCC for Treating Cancer
Passive immunotherapy with monoclonal antibodies (mAbs) against tumor antigens
has not been as effective in humans as originally hoped. Nevertheless, three mAbs,
Rituximab, Herceptin and Alemtuzumab, have been approved by the US Food and
Drug Administration. Multiple mechanisms probably contribute to the antitumor
activity of mAbs, but one of their major mechanisms is probably antibody-dependent
cellular cytotoxicity (ADCC). mAbs specific for tumor cell surface antigens
bind to the tumor cell, which can then be recognized by lymphocytes such as NK
cells and neutrophils which express Fc receptors. To test the hypothesis that the efficacy
of antitumor mAbs could be improved by activation of ADCC with CpG-B
ODN, we used the 38C13 B cell lymphoma in syngeneic immunocompetent C3H
mice [130]. Several days after tumor implantation, the mice were injected with a
dose of CpG-B ODN sufficient to cause systemic immune activation and enhanced
Fc receptor function. They were then treated with a standard dose of the mAb.
Although treatment with mAb alone gave only a 10% long-term survival, mice pretreated
with CpG-B ODN had 70±80 % survival [130]. The CpG-B ODN was equally
effective at promoting survival when administered before the mAb, on the same
day, or up to 2 days after the mAb. However, delayed administration of CpG-B ODN
until 4 days after mAb resulted in survival that was indistinguishable from mAb
alone. Dose±response studies showed that high doses of CpG-B ODN (up to 200 mg)
enhanced the antitumor activity of mAb more effectively than lower doses, but
some activity was apparent even at doses of just 2 mg/mouse [131]. With repeated administration
of CpG and mAb, even large established tumors could be cured in this
model [131].
CpG-B ODN have pronounced phenotypic effects on normal and primary human
malignant B cells from patients with various histologies, inducing expression of
class I and II MHC, CD20, CD40, CD54, CD58, CD80 and CD86 and improved activation
of T cells in an allogeneic MLR [132±134]Ç Interestingly, the CpG-B ODN appeared
less effective at inducing normal B cells to express increased levels of CD20.
277