Monoclonal Antibodies as Immunotherapy "Magic Bullets"
Diagrams illustrating Paul Ehrlich's Croonian Lecture "On Immunity with Special Reference to Cell Life," read 22 March 1900. Credit: Wellcome Library, London.
Immunotherapy — a pillar of cancer treatment — is also used to mitigate the effects of autoimmune diseases, where it is more "politely" called biological therapy. In the case of cancer, the greatest advances occurred because we have exploited the extraordinary specificity of monoclonal antibodies directed against cancer antigens, their microenvironment and vasculature, and T cell antigens, which allows the immune system to become activated (or re-activated) through mechanisms that are only partially understood.
Under ideal conditions, the immune system is able to recognize tumors and destroy them — or at least inhibit their growth — while sparing normal cells and tissue. If we were to imagine the perfect target for immunotherapy, it would be a molecular structure present only on the cancer. A structure of this kind has, however, proved elusive. The identification of cancer antigens that are specific or sometimes unique to that tumor is a source of tremendous scientific effort, and was called by Lloyd J. Old, MD, the founder of this medical discipline, "the philosopher's stone of cancer immunology."
More than a century ago, Dr Paul Ehrlich and other scientists introduced the idea that the immune system produced substances called “amboceptors, opsonins, antitoxins, and antibodies.” Ehrlich postulated that these substances bound to various structures on alien cells, allowing them to be utilized by the body or neutralized and eliminated.
Drs Emil von Behring and Kitasato Shibasaburo studied diphtheria and produced antitoxins (antibodies prepared from horses immunized against these bacteria) and injected children with diphtheria, saving the lives of thousands. For this breakthrough Dr von Behring received the first Nobel Prize in 1901. Ehrlich would go on to win the Nobel Prize in 1908 for his work on a treatment for syphilis by discovering an arsenic compound, Salvarsan, which is considered the first antibiotic and for which he coined the term "chemotherapy" or "chemio-therapy." Chemotherapy was a term used for the sulfa drugs developed in the 1930s, but eventually its use fell out of favor for the more descriptive term "antibiotic."
Curing people with life-threatening infections by administering immune sera containing antibodies directed against bacteria and viruses led to studies to see whether cancer would respond similarly. Yet outside of experimental animal models, results were not reproducible in humans, which led many to believe that cancer in man was fundamentally different from that in animals.
Even when animal experiments suggested that the immune system could recognize cancer and destroy it, in the early 1900s there was no clear understanding of the presence of species-related histocompatibility antigens, which were the real target.
Other problems encountered in human subjects were, in part, due to ethical considerations, as immunizing healthy people with cancer cells from others to generate antisera was too dangerous to consider. When antisera from vaccinated animals were administered, the differences in antibody structure led to clearing of these foreign antibodies by the recipient.