Immunotherapy has been making waves in the cancer field for the last decade, often perceived as a recent breakthrough. In reality, the roots of this concept extend back to ancient times. What exactly is immunotherapy, where did it originate, and why did it remain relatively unknown for an extended period? Let's dissect the details and explore how much progress has been made.
Immunotherapy is a specialized form of treatment designed to enhance the body’s immune response against diseases like cancer. While the immune system naturally identifies and eliminates abnormal cells to prevent the development of cancer, cancer cells employ various mechanisms to evade immune destruction. Therefore, recent advances in immunotherapies have removed the “breaks” exerted by the cancer cells on the immune system and activated the immune system to effectively fight the cancer. Despite its recent surge in popularity, the roots of this therapeutic approach can be traced back centuries. So, where did it all begin?
Let’s go diving into the very beginnings, from ancient Egypt around 3000 years ago to the early nineteenth century. Anecdotal reports suggested tumors spontaneously disappeared after high fever induced by infection. However, the first reported scientific attempt to modulate the immune system for cancer cure is credited to German surgeons Friedrich Fehleisen and Wilhelm Busch, who independently reported tumour regression following skin infection (erysipelas). Nevertheless, replicating these results posed a significant scientific challenge.
In the late 1800s, American surgeon and oncologist William Coley sought to systematically treat bone cancer using a similar approach. He injected bacterial organisms responsible for causing skin infection, leading to the stimulation of the immune system. As expected, the patient’s tumor disappeared, presumably because it was attacked by their own immune system. This experiment began Coley’s life-long study on immunotherapy, earning him the title of the Father of Immunotherapy. Although this was very exciting, two of the three patients died due to the infection. Coley then turned to heat-killed bacteria, creating what became known as Coley’s Toxin. For the next 40 years, he treated hundreds of patients with inoperable bone and soft-tissue cancer (sarcoma) using his toxins. Despite the success, Coley’s work was under criticism by the medical community for inconsistencies and difficulties in repeating the results. Thus, his work gradually fell out of favor and by 1952, Coley’s Toxins were no longer produced.
Despite the downward spiral of Coley’s treatment ideas, they never faded entirely. In the 1930s, the American Medical Association acknowledged the potential value of Coley’s Toxins. It wasn't until the 1950s that American physician Lewis Thomas first introduced the idea that the immune system could recognize cancer through proteins (antigens) found on cancer cells or released into the environment. After that, scientists delved into exploring and uncovering different molecules, pathways, and cells. This groundwork led to the discovery of antibodies, cytokines (signalling proteins), and critical types of immune cells, all of which became the basis for developing the cancer immunotherapies currently in use in clinics today.
However, the concept of using bacteria to activate the immune system persisted on the fringes of oncology. In the late 1970s, Canadian physicians Alvaro Morales, David Eidinger, and Andrew Bruce successfully used Bacillus Calmette-Guérin (BCG) — a strain of bacteria better known as the tuberculosis vaccine — to treat superficial bladder cancer. BCG became the first established cancer therapy employing bacteria and remains the treatment of choice for high-risk superficial bladder cancer.
So where is the field now?
From an idea once frowned upon by the medical community, immunotherapy has evolved into a cornerstone of cancer therapy. Virtually every cancer type has been influenced by immunotherapies or ongoing immunotherapy research. The field of cancer immunology is expansive, covering bacteria, viruses, antibodies, cell transfer therapy, immune system modulators, and much more. With daily breakthroughs, this field is set to continually grow and develop. After all, we now understand that William Coley's instincts were correct: Stimulating the immune system can indeed be an effective cancer therapy.
References:
1.DeLucia, D. C., & Lee, J. K. (2022). Development of cancer immunotherapies. Cancer Immunotherapies, 1–48. https://doi.org/10.1007/978-3-030-96376-7_1
2. Loughlin, K. R. (2020). William B. Coley. Urologic Clinics of North America, 47(4), 413–417. https://doi.org/10.1016/j.ucl.2020.07.001
3. Nathenson, M. J., Conley, A. P., & Sausville, E. (2017a). Immunotherapy: A New (and Old) Approach to Treatment of Soft Tissue and Bone Sarcomas. The Oncologist, 23(1), 71–83. https://doi.org/10.1634/theoncologist.2016-0025
4. Oelschlaeger, T. A. (2010a). Bacteria as tumor therapeutics? Bioengineered Bugs, 1(2), 146–147. https://doi.org/10.4161/bbug.1.2.11248