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

268 Cancer Immune Therapie: Current and Future Strategies
Edited by G. Stuhler and P. Walden
Copyright # 2002 Wiley-VCH Verlag GmbH & Co. KGaA
ISBNs: 3-527-30441-X (Hardback); 3-527-60079-5
(Electronic)
13
Applications of CpG Motifs from Bacterial DNA
in Cancer Immunotherapy
Arthur M. Krieg
13.1
History of Cancer Immunotherapy with Bacterial Extracts andNucleic Acids
For centuries there have been sporadic reports of patients with advanced malignancy
who underwent spontaneous regression following a bacterial infection (reviewed in
[1]). However, there was no systematic effort to investigate this phenomenon until
the 1890s, when a New York surgeon, William B. Coley, became aware of a patient
with a widely metastatic sarcoma who had experienced a remarkable and complete
tumor regression following a streptococcal infection in the region of the tumor. Suspecting
that the streptococcal infection may have triggered the regression, Coley
took the heroic step of injecting a live streptococcal culture into an unresectable sarcoma
in a patient with hopelessly advanced disease. Although the patient almost succumbed
to the infection, he too experienced a complete regression [2]. In order to reduce
the toxicity of this new form of treatment, William Coley then began treating
many sarcoma patients with a mixture of killed bacteria including Streptococcus and
Proteus, which became known as ªColey's toxinsº. Over the next decades, Coley treated
close to 1000 patients with his toxin and achieved an astonishing response rate
of more than 40% in these advanced malignancies, some of which persisted for decades
[2, 3]Ç Despite his impressive success rate and the success of some other investigators
using his toxins, this form of cancer immunotherapy was not widely pursued
in the years following Coley's death. Nevertheless, bacterial immunotherapy for cancer
lives on in the use of the attenuated mycobacteria Bacillus Calmette-Guerin
(BCG) as a therapy for human bladder cancer [4, 5]Ç
Perhaps the most important lesson to be gained from this brief history of immunotherapy
with bacteria is that by activating the immune system with bacterial components,
it is possible to induce sustained remissions in at least some humans with
advanced malignancies. It is now clear that the ªColey's toxinsº did not in fact contain
toxins as originally assumed, but rather that bacterial products activate innate
and acquired immune defense mechanisms that can kill tumor cells. In the century
that has passed since Coley's initial therapeutic successes, we have gained a much
better understanding of the immune system, which allows us to provide a better answer
to the question of what may be the microbial products that induce these antitu-