Lessons from Coley's Toxin
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
References (32)
- et al.
Coley's Toxins, tumor necrosis factor and cancer research: a historical perspective
Pharmacology & Therapeutics
(1994) - et al.
Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors
Immunity
(1994) - et al.
Interferon-gamma expression is an independent prognostic factor in ovarian cancer
American Journal of Obstetrics and Gynecology
(2004) Contribution to the knowledge of sarcoma
Annals of Surgery
(1891)Late results of the treatment of inoperable sarcoma by the mixed toxins of erysipelas and Bacillus prodigiosus
The American Journal of the Medical Sciences
(1906)Coley's Toxins in perspective
Nature
(1992)- et al.
Chemical treatment of tumors: V. Isolation of the hemorrhage-producing fraction from Serratia marcescens (Bacillus prodigiosus) culture filtrate
Journal of the National Cancer Institute
(1943) - et al.
An endotoxin-induced serum factor that causes necrosis of tumors
Proceedings of the National Academy of Sciences USA
(1975) Tumor necrosis factor (TNF)
Science
(1985)- et al.
The immunological basis of endotoxin-induced tumor regression. Requirement for T-cell-mediated immunity
Journal of Experimental Medicine
(1978)
The immunological basis of endotoxin-induced tumor regression. Requirement for a pre-existing state of concomitant anti-tumor immunity
Journal of Experimental Medicine
Requirement for Valpha14 NKT cells in IL-12-mediated rejection of tumors
Science
Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production
Journal of Immunology
Systemic administration of rIL-12 induces complete tumor regression and protective immunity: response is correlated with a striking reversal of suppressed IFN-gamma production by anti-tumor T cells
International Immunology
Immune response against large tumors eradicated by treatment with cyclophosphamide and IL-12
Journal of Immunology
Pre-existing tumor-sensitized T cells are essential for eradication of established tumors by IL-12 and cyclophosphamide plus IL-12
Journal of Immunology
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