Throughout the history of science, there have been many firsts. Anaximander, a Greek scholar,  was the first person to suggest the idea of evolution. Contrary to popular belief, the Montgolfier brothers were the pioneers of human flight by their invention of the hot air balloon, as opposed to another pair of brothers, the Wright brothers. In 1976, the first ever vaccine was created by an English doctor, who tested his theory in a rather peculiar manner that would not be approved by today’s ethics guidelines (Rocheleau, 2020).

While there have been many extraordinary discoveries, there continue to be many firsts and many breakthroughs that have pathed the way for the next steps in research. In particular is research into ground-breaking treatments for cancer patients. 

1890s: Radiotherapy (Gianfaldoni, S., Gianfaldoni, R., Wollina, U., Lotti, J., Tchernev, G., & Lotti, T. 2017)

In the last decade of the 19th century, Wilhelm Conrad Rцntgen made the discovery of X-rays, drastically changing the medical scene for treating many diseases. From this discovery, Emil Herman Grubbe commenced the first X-ray treatment for breast cancer, while Antoine Henri Becquerel began to delve deeper into researching radioactivity and its natural sources. In the same year that Rцntgen discovered X-rays, Maria Sklodowska-Curie and Pierre Curie shared theirs vows together, and only three years later, discovered radium as a source for radiation. 

By then, during a time where skin cancers were frequently treated, this discovery had kick-started the research field into X-rays as well as the use of X-rays in the medical field. Scientists and clinicians have gained a greater understanding of radiation as treatment for diseases, but the research does not stop there and the advancement of radiotherapy only continues to thrive. 

1940s: First Bone Marrow Transplant (Morena & Gatti, 2011)

Following World War II, the physical consequences of war accelerated research into tissue transplantation. Skin grafts were needed for burn victims, blood transfusions needed ABO blood typing, and the high doses of radiation led to marrow failure and death. During this time, Peter Medawar started his research into rejection of skin grafts as requested by the Medical Research Council during World War II. It was a priority for the treatment of burn victims. Medawar had concluded that graft rejection was a result of an immunological phenomenon related to histocompatibility antigens. Histocompatibility antigens are cell surface glycoproteins that play critical roles in interactions with immune cells. They are unique to every individual and essentially flags one’s cell as their own, therefore making every individual physically unique. 

1953: First Human Tumour Cured

In 1953, Roy Hertz and Min Chiu Li used a drug, methotrexate, to treat the first human tumour — a patient with choriocarcinoma. Choriocarcinoma is an aggressive neoplastic trophoblastic disease, and can be categorised into two types — gestational and non-gestational (Bishop & Edemekong, 2023). The cancer primarily affects women, as it grows aggressively in a woman’s uterus (MedlinePlus., 2024). However, it can also occur in men as part of a mixed germ cell tumour  (Bishop & Edemekong, 2023). 

Methotrexate is commonly used in chemotherapy as it acts as an antifolate antimetabolite that induces a cytotoxic effect on cells. Once methotrexate is taken up by cells, it forms methotrexate-polyglutamate, which in turn inhibits dihydrofolate reductase, an enzyme important for DNA and RNA synthesis (Hanood & Mittal, 2023). Therefore, by inhibiting DNA synthesis, the drug induces a cytotoxic effect on the cancerous cells. Since the first cure of choriocarcinoma using methotrexate, the drug has both been commonly used for chemotherapy and other applications, including as an immunosuppressant for autoimmune diseases (Hanoodi & Mittal, 2023). 

1997: First ever targeted drug: rituximab (Pierpont, Limper, & Richards, 2018)

Jumping ahead a few decades and 1997 was the year that JK Rowling published Harry Potter and the Philosopher’s Stone. It was also the year that the first targeted anti-cancer drug was approved by the U.S Food and Drug Administration (FDA), rituximab. Ronald Levy created rituximab with the purpose of targeting malignant B cells. B cells express an antigen – CD20 – which allows B cells to develop and differentiate. Rituximab is an anti-CD20 monoclonal antibody, meaning that it targets the CD20 antigens expressed on malignant B cells. It had improved the progression-free survival and overall survival rates of many patients who had been diagnosed with B cell leukemias and lymphomas (Pavlasova & Mraz, 2020). Much like the Philosopher’s Stone, you may consider rituximab to increase longevity of patients diagnosed with B cell cancers. 

Although Levy created this drug, his predecessors should not be ignored. Prior to his research and development of rituximab, research and development of monoclonal antibodies can be dated all the way back to the late 1970s (Pavlasova & Mraz, 2020). César Milstein and Georges J. F. Köhler developed the first monoclonal antibody in the mid-1970s, and first described the method for generating large amounts of monoclonal antibodies (Leavy, 2016). Milstein and Köhler were able to achieve this by producing a hybridoma – “ a cell that can be grown in culture and that produces immunoglobulins that all have the same sequence of amino acids and consequently the same affinity for only one epitope on an antigen that has been chosen by the investigator” (Crowley & Kyte, 2014). They had produced a cell with origins from a myeloma cell line and spleen cells from mice immunised against sheep red blood cells (Leavy, 2016). 

Going forward: CAR T Cells

The most recent and exciting development in cancer research has been the development and usage of chimeric antigen receptor (CAR) T cells. CAR T cell therapy is a unique therapy customised to each individual patient, as the CAR T cells used are derived from the patient’s own T cells. The process involves leukapheresis, where the patient’s T cells are collected, and these collected T cells are then re-engineered to include the CAR gene. The patient’s own CAR T cells are produced, expanded and subsequently infused back into the patient. 

The first concept of CAR T cells to be described was in 1987 by Yoshihisa Kuwana and others in Japan. Following this, different generations of CAR T cells have now been developed and trialled, leading to the FDA’s first two approvals for CAR T cells (Wikipedia Contributors, 2024). This research avenue has only scratched the surface, with many individuals now exploring the best collection methods and how best to stimulate the “fittest” T cells - the apex predator of immune cells. 

A recent paper was published where CAR T cells were trialled as a second line therapy to follow ibrutinib-treated blood cancers. The phase 2 TARMAC study involved using anti-CD19 CAR T cells to treat patients with relapsed mantle cell lymphoma (MCL) who had been exposed to ibrutinib, a drug used to treat B cell cancers by targeting Bruton Kinase Tyrosine (BTK) found in B cells. The study showed that 80% of patients who had previous exposure to ibrutinib and were treated with CAR T cells as a second-line therapy achieved a complete response. Furthermore, at the 13-month follow-up, the 12-month progression free survival rate was estimated to be 75% and the overall survival rate to be 100% (Minson et al., 2024)! 

It is without a doubt that as humans, we are naturally curious creatures. It is with this curiosity that we have journeyed through the many scientific breakthroughs and innovations. And within each special nook and cranny of countless fields of science, from flight to evolution, from vaccines to cancer treatments, there have been multitudes of discoveries. There is no doubt that the number of innovations will only continue to grow.

References 

Bishop, B., & Edemekong, P. (2023). Choriocarcinoma. StatPearls.

Crowley, T., & Kyte, J. (2014). Section 1 - Purification and characterization of ferredoxin-NADP+ reductase from chloroplasts of S. oleracea. In Experiments in the Purification and Characterization of Enzymes (pp. 25–102).

Gianfaldoni, S., Gianfaldoni, R., Wollina, U., Lotti, J., Tchernev, G., & Lotti, T. (2017). An overview on radiotherapy: From its history to its current applications in dermatology. Open Access Macedonian Journal of Medical Sciences, 5(4), 521–525. https://doi.org/10.3889/oamjms.2017.122

Hanoodi, M., & Mittal, M. (2023). Methotrexate. StatPearls.

Leavy, O. (2016). The birth of monoclonal antibodies. Nature Immunology, 17(Suppl 1), S13. https://doi.org/10.1038/ni.3608

MedlinePlus. (2024). Choriocarcinoma. MedlinePlus. https://medlineplus.gov/ency/article/001496.htm#:~:text=Choriocarcinoma%20is%20a%20fast%2Dgrowing,pregnancy%20to%20feed%20the%20fetus

Minson, A., Hamad, N., Cheah, C. Y., Tam, C., Blombery, P., Westerman, D., Ritchie, D., Morgan, H., Holzwart, N., Lade, S., Anderson, M. A., Khot, A., Seymour, J. F., Robertson, M., Caldwell, I., Ryland, G., Saghebi, J., Sabahi, Z., Xie, J., Koldej, R., & Dickinson, M. (2024). CAR T cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: The phase 2 TARMAC study. Blood, 143(8), 673–684. https://doi.org/10.1182/blood.2023021306

Morena, M., & Gatti, R. (2011). A history of bone marrow transplantation. Haematology/Oncology Clinics, 21(1), 1–15.

Pavlasova, G., & Mraz, M. (2020). The regulation and function of CD20: An "enigma" of B-cell biology and targeted therapy. Haematologica, 105(6), 1494–1506. https://doi.org/10.3324/haematol.2019.243543

Pierpont, T. M., Limper, C. B., & Richards, K. L. (2018). Past, present, and future of rituximab: The world’s first oncology monoclonal antibody therapy. Frontiers in Oncology, 8, 163. https://doi.org/10.3389/fonc.2018.00163

Rocheleau, J. (2020). 50 famous firsts from science history. Stacker. https://stacker.com/environment/50-famous-firsts-science-history

Wikipedia contributors. (2024, October 6). CAR T cell. In Wikipedia, The Free Encyclopedia. Retrieved October 17, 2024, from https://en.wikipedia.org/w/index.php?title=CAR_T_cell&oldid=1249695600