combination led to greater virulence. Coley published the results of his work as a case series, making it difficult to interpret them with confidence. According to the American Cancer Society, "more research would be needed to determine what benefit, if any, this therapy might have for people with cancer". The so-called Coley's toxins were used against different types of cancer from the year 1893 through the year 1963. Within the preparation's first decade, it was changed from an unfiltered mixture of killed bacteria to a porcelain-filtered mixture, which reduced the adverse effect profile. From 1923 on, Parke-Davis was the only commercial source of Coley's toxins in the United States. Hall (1997) explains that the versions used by Coley himself were custom-compounded, although the formula for the preparation was never standardized. In the wake of the thalidomide controversy and the Kefauver Harris Amendment of 1962, Coley's toxins were assigned "new drug" status by the Food and Drug Administration (FDA), making it illegal to prescribe them outside of clinical trials. Since then, several small clinical trials have been conducted with mixed results. Coley's toxins were also produced by the small German pharmaceutical company Südmedica and sold under the trade name Vaccineurin. However, production ceased by 1990 because of a lack of re-approval by German Federal Institute for Drugs and Medical Devices. Rationale There are multiple rationales proposed for how Coley's toxins affect the patient. Macrophages One rationale argues that macrophages are either in "repair mode", furthering the growing of cancer, or in "defense mode", destroying cancer. However, macrophages are in "defense mode" only if there is some recognized enemy. As cancer tissue is not recognized as enemy (but as normal body tissue), there is a need to bring more macrophages into "defense mode" by simulating an infection. The simulated infection results in a real fever. Unlike hyperthermia, real fever not only means heating of the body but also higher activity of the immune system. Thus, fever is seen as a precondition for a therapy using Coley's Toxins to succeed. Tumor necrosis factor and interleukin One of the agents in Coley's Toxin that is thought to be biologically active is a lipopolysaccharide which causes fever. The resulting fever from the lipopolysaccharide is thought to increase lymphocyte activity and boosts tumor necrosis factor (TNF). Tsung and Norton in Surgical Oncology reported that the active agent was thought to be interleukin-12, rather than TNF. Streptokinase