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

278 13 Applications of CpG Motifs from Bacterial DNA in Cancer Immunotherapy
Such changes would be expected to make the malignant cells better targets for Rituximab,
as well as for immunotherapy in general. Human clinical trials of this form of
combination immunotherapy have recently been initiated.
13.6
Conclusion
The early days of cancer immunotherapy were marked by the use of crude bacterial
extracts such as ªColey's toxinsª, which were remarkably effective despite their eventual
fall from favor. Even though BCG continues to be used in the treatment of
superficial bladder cancer, in today's regulatory climate it would be effectively impossible
to resurrect immune therapy with bacterial extracts on a widespread basis.
With the advent of recombinant cytokines, there was much hope that these would offer
a less toxic and more effective form of immunotherapy. Unfortunately, despite
some successes, immunotherapy using recombinant cytokines has not lived up to its
initial promise. Perhaps the use of a pharmacologic dose of a recombinant cytokine
can never reproduce the complexity of a multifaceted therapeutic antitumor immune
response in more than occasional cases. However, the field of immunology has advanced
to the point that we may now reasonably hope to achieve the same sustained
remissions in established advanced malignancy as were seen with the use of ªColey's
toxinsº by using molecular mimics of microbial molecules, instead of the bacterial
extracts themselves. CpG DNA, provides a way to induce the immune system to produce
a whole panoply of cytokines and chemokines in a coordinated manner, which
may be more effective and less toxic than the administration of individual recombinant
cytokines or chemokines in pharmacologic quantities. Synthetic CpG ODN are
essentially mimics of bDNA that ªtrickº the immune system into thinking that an infection
has occurred, leading to the initiation of remarkably effective immune defense
mechanisms. The orchestrated stimulation of the immune system with resulting
therapeutic power unleashed by CpG DNA has already been demonstrated in a
variety of mouse models, with encouraging results as reviewed above. Results from
initial human clinical trials with a CpG-B ODN suggest this approach may be reasonably
well tolerated in humans, but the full therapeutic benefit of these approaches
remains to be determined.
Acknowledgments
We thank Denise Arsenault for excellent secretarial assistance. Financial support
was provided through DARPA and the Coley Pharmaceutical Group.