Coley's Toxins

Immunotherapy

Coley's toxins were first used by surgeon and cancer researcher William B. Coley at Memorial Hospital (now Memorial Sloan-Kettering Cancer Center) in New York. While reviewing over 100 cases of sarcoma, he became aware that patients who developed bacterial infections after surgery did better than those without postoperative infections. He began research on use of toxins in cancer patients and, in 1896, presented a paper to the Johns Hopkins Medical Society reporting regressions of sarcoma among 93 patients whom he had treated with the toxins. Dr. Coley chose bacteria that would cause a high fever and mobilize the patient's immune system to fight the cancer cells. Knowing that using live bacteria was dangerous, and because he determined that the immune reactions depended upon the toxins of the bacteria rather than the actual bacteria, he experimented with the toxins alone. He settled on a combination of heat-killed gram positive Streptococcus pyogenes and nonpathogenic gram-negative Serratia marcescens. One of the biologically active ingredients in Coley's toxins is lipopoly saccharide (LPS), which causes hyperthermia. It causes a fever of 104° F to 105° F (40° C to 40.5° C) for 3 to 4 hours to enhance lymphocyte activity and boost the tumor necrosis factor (TNF).

The cell types most responsive to LPS are natural killer (NK) lymphocytes and macrophages. On detecting LPS, these cells release large amounts of inflammatory cytokines, one of which, TNF, is especially toxic to bacteria. Coley's toxins presumably involve activation of NK cells, and the products of these cells may combat the tumors.

Until 1930, Dr. Coley used these toxins to treat patients with a variety of cancers. Other physicians continued to use Coley's toxins through World War II. Many regressions of cancer were reported among patients treated, but the treatment fell into disuse with the advent of chemotherapy. The American Cancer Society for many years considered Coley's erysipelas toxins to be ineffective remedies. More recently, Coley's toxins have been cited as a promising treatment that may have been prematurely abandoned with the advent of modern radiotherapy and chemotherapy. Once considered unorthodox, such treatments for cancer might now be an adjunct to conventional surgery, chemotherapy, and radiation.

Reported uses

Coley's toxins are used outside the United States, in Mexico, Central America, Guatemala, Germany, and China. They've been used to treat renal, ovarian, breast, and testicular cancers; soft-tissue sarcomas; Hodgkin's disease; malignant melanoma; and cancers of the bone and connective tissue. Theoretically, joint treatment of bacterial toxins with radiation therapy might be beneficial for lesions that haven't metastasized or for controlling a symptomatic primary or secondary lesion in a patient with incurable metastases. Coley's toxins are used at some cancer clinics to "jump start" immune responses.

An adaptation of Coley's toxins, known as mixed bacterial vaccines, is administered to patients along with other immune-affecting agents at the Waisbren Clinic in Milwaukee, Wisconsin.

How the treatment is performed

The patient receives injections, either subcutaneous or I.V., every other week for 4 weeks and once a week thereafter. The dose schedule varies with the individual.

Coley's toxins are usually administered in a stepwise increasing dose, with the aim of maintaining a body temperature of 102.2° F (39° C) or higher. Patients must be monitored closely, and those who don't achieve this temperature receive higher doses.

Hazards

The most common side effects of the therapy include fever and nausea. Other less common side effects include headache, back pain, chills, angina, and occasionally herpes labialis. Over whelming the immune system with Coley's toxins could result in serious infections in immune compromised patients.

Available evidence suggests that Coley's toxins aren't harmful or dangerous to humans suffering from various types of neoplasms, provided the toxins are administered properly as to dosage, site, and the usual aseptic precautions.

Clinical considerations

• Coley's combined toxins are legal in the United States only if prepared and given within a physician's office. They may not be shipped.
• One study cautioned that patients with severe hepatic insufficiency due to metastatic disease or other pathology, and patients who have had severe heart conditions, should not receive the toxins. It also indicated the need for prolonged toxin therapy, but found that toxins were not helpful if begun after massive radiation and chemotherapy had destroyed a patient's immune responsiveness.

Research summary

During the 1980s, Coley's toxins were tested in mice at Temple University, Philadelphia, and they compared favorably with other biological response modifiers because of their enhancing effects on the immune response and oncolytic properties at nontoxic levels.

A 1999 study (Richardson, et al.), funded by the National Institutes of Health, completed a cohort analysis of treatment with Coley's toxins. Using a retrospective cohort design with external controls, 128 patients treated with Coley's toxins in New York from 1890 to 1960 were compared with 1,675 control patients from the Surveillance Epidemiology End Result population-based cancer registry of patients who received the diagnosis in 1983. The study suggested that treatment with Coley's toxins is not associated with an increased risk of mortality. Given the tremendous advances in surgical techniques and medicine in general, any cohort of modern patients should have been expected to do better than patients treated 50 or more years ago, but no such statistical advantage for the modern group was observed in the study. In the absence of demonstrated harmful effects and some indication of positive effects, the study findings called for a reevaluation of this therapy.