Immunotherapy Through History

Illustration by Caroline Cao

Illustration by Caroline Cao

Immunotherapy is a type of cancer treatment that harnesses the power of the human immune system to fight cancer. In the last decade, immunotherapies have revolutionized the field of oncology and personalized medicine. Chemotherapy and radiation therapy target cancer cells but often times, as collateral damage, destroy healthy tissue as well. As a result, physicians increasingly recommend immunotherapy when standard therapies fail, or even as a first course of action. Notebly, in October of 2018, Drs. James Allison and Tasuku Honjo won the Nobel prize of medicine for their work on immunotherapy(1). How did immunotherapy become the most promising form of cancer care and a medical hot topic of the 21st century?

The first concepts of immunotherapy arose in the late 19th century when Dr. William B. Coley, now known as the father of immunotherapy, noticed that cancer patients with the bacterial skin infection Erysipelas, went into spontaneous remission(1). In 1891, at the Bone Tumor Service at Memorial Hospital in New York, Coley began his research by injecting Streptococcus pyogenes and Serratia marcescens into patient tumors. Coley achieved remission in patients with sarcomas, lymphomas, and testicular cancers. These bacteria became known as “Coley’s toxins.” Coley believed that the body’s natural response to fighting the bacterial infection also prompted the response toward the human tumor, which is the exact principle that drives immunotherapies today(1). However, Coley’s toxins gradually disappeared from use because of his inability to follow sufficient scientific protocols and because of the rapid development of other cancer treatment technologies such as radiation and chemotherapies(1).

Immunotherapy gained scientific popularity again almost a hundred years later, in 1976 when Alvaro Morales et. al. established the effectiveness of the bacterium Bacillus Calmette-Guérin (BCG) in the treatment of superficial bladder cancer. This was a continuation of the study by Lloyd Old et. al in 1959 which showed the anti-cancer ability of BCG in the mouse model. Old’s contribution to the field of immunotherapy was extensive. In fact, In Drs. Stanley J. Oiseth and Mohamed S. Aziz’s paper titled “Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead”, it is argued that both Coley and Old should share the title for Father of immunology(1). Coley, Old, and Morales together laid the groundwork for how the role of the immune system in controlling malignant cells was conceived by many generations of future oncologists. Specifically, the idea that the immune system is made up of an adaptive and innate parts can be traced back to their studies. However, still “the immunologic component of these regimens [BCGs] was not [exactly] understood.”(1)

In the last two decades of the 20th century, immunotherapy was left out of mainstream oncology. This was largely due to the incredible advances in molecular biology that had quintessential applications in cancer treatments. For example, the discovery of Natural Killer cells, which are lymphocytes that are able to bind and consequently destroy tumor cells without the aid of an antigen, proved monumental in cancer treatment as a whole but put research of immunotherapeutic techniques on the back burner.

It was not until the turn of the century that many long standing questions about immunotherapy began to be answered. In 1998 and 2001, Dr. T.H Schreiber and his colleagues “provided key evidence of T cell-mediated tumor-specific immune surveillance.”(1)Essentially, their research showed  the mechanism by which lymphocytes protect against carcinogen-induced cancers. They also showed that the immune pressure on tumors selects for tumor cells that have low ability to provoke an immune response (i.e. low immunogenicity)(1). This discovery explained many previously unknown details of the immune response pathway like why some cancer and tumor types were seemingly unaffected by immunotherapies.

About a decade later, in 2010, immunotherapy finally became a physician-prioritized treatment of cancer. This was due to many developments in the decades prior such as the important discovery of the immune checkpoint, cytotoxic T-lymphocyte antigen 4 (CTLA-4). This discovery was made by James Allison in 1996 when he also showed that malignant tumors in animals could be successfully treated by blocking immune checkpoints. Not only did Allison find the checkpoint CTLA-4, but he also shed light on its significance in its broader immunological pathway. Furthermore, this lead to the “FDA approval of the revolutionary checkpoint inhibitor ipilimumab for the treatment of stage IV melanoma”  in April of 2018. These advancements in cancer care particularly drove the build-up of excitement in immuno-oncology that we have seen in the last 7-8 years.

Immunotherapy research has more momentum now than ever before. One of the most prominent concerns currently is that immunotherapies prove useful in the specific cancers they are designed to treat but only in a minority group of patients who have that type of cancer. In other words, there is a large variability in the successes of immunotherapy. Moving forward, the main challenge for researchers is to assess the potential reasons for this variability. Some reasons include: tumor heterogeneity, variability in cancer type and stage, treatment history, and the underlying immunosuppressive biology of the cancer(1).

In October of 2018, the Nobel Prize for Physiology and Medicine was awarded to James P. Allison and Tasuku Honjo for their long lasting and continuing work on immunotherapy(1). Allison’s groundbreaking discovery of the checkpoint CTLA-4 and Honjo’s discovery of another checkpoint (PD-1) made it possible for checkpoint inhibitors to be created and start the arduous process of obtaining FDA approval. Overall, Dr. Allison’s and Dr. Honjo’s discoveries are based on the same idea of braking mechanisms in the immune system. However, the pathways of each checkpoint is different and the nature of the cancer that follows is different for each(1). Drs. Allison and Honjo are credited with bringing immunotherapy out of skepticism to the forefront of cancer treatment. Tracing the principles of immunotherapy through the 19th, 20th, and 21th centuries show how it has become one of the most truly intensive and exciting areas of cancer care.

Edited by: Amaan Qazi

Illustrated by: Caroline Cao

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