Coley’s Toxin to First Approved Therapeutic Vaccine—A Brief Historical Account in the Progression of Immunobiology-Based Cancer Treatment


Robert Koch, a German physician who is credited with discovering bacteria causing tuberculosis and cholera, and his proteges, Emil von Behring, Paul Ehrlich, and Friedrich Loeffler, all Germans, and Shibasaburo Kitasato, a microbiologist from Japan, were the prominent personalities belonging to “the golden age of bacteriology” [24]. Their work in the last quarter of nineteenth century not only enabled the identification of causative agents of several bacteria, but also led to discovery of the “magic bullet”, which could impart protection against toxins of specific bacterial infections. In 1884, Friedrich Loeffler acknowledged the etiologic agent of diphtheria as bacteria, as described by Edwin Klebs [25,26]. Klebs had already realized the role of “a circulating toxin in blood stream” as the reason for manifestations of the disease, and Loeffler suggested that neutralizing this toxin could be effective in curing the disease. In 1888, Emile Roux and Alexandre Yersin from the Pasteur Institute, Paris, France, isolated this “circulating toxin” [26]. The same year, Behring also published his report on anthrax and noted that the serum of the rats that were able to kill anthrax bacteria was responsible for the immunity exhibited by rats against anthrax [26,27]. Subsequently, in another experiment, he injected untreated guinea pigs with diphtheria toxin and treated them afterward with sera of animals that had survived the disease, thereby leading to the discovery of the antibodies and the principle of ‘the antitoxin effect of serum therapy’ [26]. Kitasato, in a separate report, also noted similar findings with mice and rabbits immunized with cell-free fluid against tetanus [26]. In 1890, Behring and Kitasato published together on their success in being able to cure animals infected with both diphtheria and tetanus and on how they could protect uninfected animals through passive immunization with antibodies against these bacterial toxins [26,28]. Further, Behring teamed up with Ehrlich, and produced a high-quality, standardized anti-diphtheria serum from dairy cattle, which they distributed to pediatric clinics across Berlin [29]. This serum therapy was hugely successful and reduced the mortality rate of diphtheria drastically between 1892 and 1894 and was hailed unanimously as the best method of cure ever devised till then in pre-antibiotic era [26]. Interestingly, Ehrlich had already noted that exposure to a toxin in small incremental quantities could render the animals immune to subsequent lethal doses, which forms the basis for modern vaccination [29,30]. Behring was awarded a Nobel prize in 1901, the first for medicine and physiology, for his work on serum therapy [26]. Later, Ehrlich also received the Nobel prize in 1908, together with Elie Metchnikoff, for his work in immunology [29]. Nevertheless, the discovery of antibodies, which Ehrlich referred to as the “magic bullet”, has also been a historical milestone in tumor immunobiology, as this understanding laid the foundation for several concepts of immune-mediated tumor cytolysis.



Source link

K. Devaraja www.mdpi.com