Elsevier

Surgical Oncology

Volume 15, Issue 1, July 2006, Pages 25-28
Surgical Oncology

Lessons from Coley's Toxin

https://doi.org/10.1016/j.suronc.2006.05.002Get rights and content

Abstract

The active molecule in Coley's Toxin is not tumor necrosis factor (TNF) or endotoxin (LPS), but interleukin-12 (IL-12). IL-12 holds the key to improved anti-tumor immuns response.

Section snippets

Coley's Toxin

Despite the fact that surgeon William B. Coley's pioneering work in cancer immunotherapy with bacterial toxins was carried out over a century ago [1], the significant clinical observations [2] and the mechanism behind it remain unexplained until now. A compiling of Dr. Coley's clinical observations indicated that in certain tumor types such as soft tissue sarcoma and lymphoma, the response is remarkable even by today's standards. For example, out of 104 inoperable sarcoma patients who were

Tumor necrosis factor (TNF)

Knowing that the major effect of Coley's Toxin comes primarily from endotoxin (LPS) of Gram-negative bacteria [4], [5], the discovery of TNF in the 1970s [6] was thought to have provided a satisfactory answer [3], [7]. However, subsequent testing using recombinant TNF showed many of the toxicities of Coley's Toxin/endotoxin without equaling the significant anti-tumor efficacy in both clinical trials and laboratory studies. It is worth noting that even amid the enthusiastic belief that TNF had

IL-12

IL-12 was first described as a NK cell activating cytokine, and subsequent studies showed IL-12 also target T cells. It is now well recognized that IL-12 plays a central role in the connection between innate and adaptive immunity by promoting the development of cell-mediated Th1 type of immunity. Corresponding to the ability of IL-12 to target both T and NK cells, the anti-tumor activities of IL-12 from various studies can also be divided into two types: the one that depends on NK/NKT and the

Pre-existing immunity

Now that we know that IL-12 is responsible for the effect of Coley's Toxin against established large tumors, new knowledge obtained from the study of IL-12-induced tumor rejection may shed light on the question why Coley's Toxin worked well in some cases, but not others. In the case of IL-12- (and endotoxin)-induced tumor rejection, an anti-tumor immune recognition in the form of a Th1 response must be present prior to the start of therapy in order for the host to respond to the therapy [14],

Reasons for prior failures

Previous clinical trials with IL-12 have not yielded success and the reasons for failure may be multiple. First of all, melanoma and renal cell carcinoma patients were selected in these trials. Coley had indicated that melanoma (“melanotic sarcoma” in his writing), is the type of cancer “with which I have had no permanent success”. Secondly, the early trials have used intensive dosing of IL-12 favoring the generation of NK/NKT, but not T cells with high toxicity. Thirdly, IL-12 was used alone

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