History credits Wan Quan (1499-1582), a pediatrician of the Ming Dynasty with the first effective ‘vaccination’ for smallpox (variola), which was then a major and often fatal infection. Properly known as variolation, the procedure consisted of rubbing powered scabs or pustule fluid from a person who’d had skin lesions of smallpox into superficial scratches on an immunologically naive person who had not previously had smallpox. Within 2 weeks, the inoculated/scratched person would develop a mild (usually, but not always) form of smallpox and thereafter remain permanently protected against smallpox. The inoculation procedure (variolation) trudged across the steppes and by 1718, some 200 years later, was used by Lady Mary Montegu, wife of the British ambassador to the Ottoman Empire, to protect her children from smallpox.
Edward Jenner (1749-1823), an English physician, has been called the father of immunology for creating the first proper vaccine*. It was common knowledge of the era that prior infection with cowpox, which occurred in milkmaids, rendered one immune to smallpox. Jenner postulated that the pus in the blisters that milkmaids received from cowpox, which is similar to smallpox, but less virulent, protected them from smallpox, a hypothesis held by other workers of the day. By the late 1700s, five different investigators had tested cowpox vaccines. What made Jenner’s contribution so important to medical science, was the final proof: when those who’d been inoculated with cowpox were later challenged with smallpox, they were immune to smallpox.
*The word vaccine originally derived from Variolae vaccinae (smallpox of the cow). Over time, vaccination replaced cowpox inoculation; its use was initially confined to smallpox until Louis Pasteur proposed broadening the word to cover all protective inoculations
With the benefit of time and hindsight, it seems overly generous to call Dr. Jenner the father of immunology, when the contributions of Paul Erhlich (1854-1915), a century on, to the nascent field were both broader and of greater depth. Ehrlich first postulated the existence of antibodies in 1891 and proposed the side-chain theory of lock and antigen-antibody interaction in response to pieces of the immune puzzle provided by Kitasato Shibasaburo’s work on diphtheria and tetanus toxin antibodies, for which Ehrlich was awarded the 1908 Nobel Prize in Physiology or Medicine. His later work led to the proposal that a ‘magic bullet’, which would home in on specific targets including cancer cells and pathogens without harming the body. Whilst Compound 606 (Salvarsan), the first effective treatment for syphilis fit some of the criteria for a magic bullet (and was hailed as such in its day), armed with the arrogance of 20:20 hindsight, we now recognize that as a bullet, it wasn’t magic enough.
The 20th century marked the beginning of an explosion of knowledge in immunology which shows no sign of abating in the 21st century. Landmark leaps include: Discovery of hapten (1917), reticuloendothelial system (1924), anaphylaxis (1942), antibody production in plasma B cells (1948), graft-versus-host disease (1953), interferon (1957), radioimmunoassay (1960), thymus involvement in cellular immunity (1961), Gell and Coombs classification of hypersensitivity (1963), ELISA (1971), immune network hypothesis (1974), monoclonal antibodies and NK cells (both 1975), somatic recombination of immunoglobulin genes (1976), IL-1, IL-2 (1980), and HIV-1 and T-cell receptor (1983).
The last thirty years have been especially gratifying as theory has led to therapy. In my professional life, I’ve read about the science behind recombinant hepatitis B vaccine (1986), danger model for immune tolerance (1994), regulatory T cells (1995), Toll receptors (1997), FOXP3-regulating T cell development (2001), HPV vaccine (2005), immune checkpoint inhibitors, ipilimumab approved for stage IV melanoma (2010); pembrolizumab and nivolumab for melanoma (2014); and atezolizumab for bladder cancer (2016); and the first autologous CAR T-cell therapy tisagenlecleucel, which was approved for pediatric B-ALL, at cost ($475,000 per patient) that tragically few can afford (2017).
Nearly a century passed before science caught up to theory and truly specific magic bullets overcame the immune system’s hurdles, succeeded in Phase 3 trials and went online therapeutically. The current generation of magic bullets, antibody-drug conjugates (ADCs), combine the exquisite
Four ADCs are FDA approved for managing cancer:
• Gemtuzumab ozogamicin (Mylotarg®), 2001, AML
• Brentuximab vedotin (Adcetris®), 2011, HL and relapsed sALCL (systemic anaplastic large cell lymphoma)
• Trastuzumab emtansine (Kadcyla®), 2013 for HER2-positive metastatic breast cancer who failed with trastuzumab (Herceptin®) and a taxane (in the bottom image, there are, on average, 3.5 molecules of the cytotoxic drug emtansine, DM1 per carrier antibody)
• Inotuzumab ozogamicin (Besponsa®), 2017 for relapsed or refractory CD22-positive B-cell acute lymphoblastic leukemia