Over a century ago, a New York physician, William B. Coley, noted that some cancer patients experienced tumor regression following episodes of acute bacterial illness. Dr. Coley hypothesized that the two events were linked and treated an inoperable cancer patient with a viable bacterial culture to induce a "commotion in the blood." Remarkably, the patient recovered from both the bacterial infection and the tumor. From 1900 to 1936,
Coley went on to successfully treat many tumor-bearing patients with heat-killed bacterial cultures known as Coley's Toxins (8,9). We now realize that Coley's Toxins contained at least two bacterial-derived molecules with potent immunostimulatory activity; lipid A and bacterial DNA (see "MPL Adjuvant and CpG").
During the period that Coley was treating cancer patients with his bacterial toxins, other scientists were documenting that antibody responses to experimental antigens were enhanced in animals infected with Mycobacterium tuberculosis. Several investigators went on to show that killed whole mycobacteria, as well as other Gram-positive and Gram-negative bacteria, enhanced the antibody response to exogenous antigens (reviewed in ref. 10). In the meantime, Arthur Johnson identified lipopolysaccharide (LPS) as the component of Gram-negative bacteria that had potent adjuvant properties (11).
This early work has led to the development of many of the modern immune adjuvants currently in clinical trials with cancer vaccines. Furthermore, the nonspecific approach used by Coley and others is still being investigated. For example, the therapeutic efficacy of bacille Calmette-Guerin (BCG) against superficial bladder cancer has been correlated with the secretion of Th1 cytokines and chemokines (reviewed in ref. 12). Additionally, an immunostimulant prepared from heat-killed Mycobacterium vaccae, SRL 172, has shown some benefit in human malignancies (13-16).
It is now known that host recognition of microbial components occurs through the recently described TLRs. This family of receptors and their associated intracellular messengers evolved to recognize and respond to conserved microbial components. The response manifests in an immediate activation of cells of the innate immune system resulting in the secretion of inflammatory cytokines, reactive oxygen intermediates, and defensins. In addition to providing immediate nonspecific protection, this inflammatory response induces and regulates the initiation of the antigen-specific adaptive immune responses, controlling dendritic cell (DC) maturation and differentiation of T helper (Th) cells (reviewed in ref. 17).
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