The 2018 Nobel Prize in Physiology or Medicine was awarded to American immunologist Jim Allison and Japanese immunologist Tasuku Honjo “for their discovery of cancer therapy by inhibition of negative immune regulation.” The award honors researchers for outstanding discoveries that leave a lasting impact on efforts to improve human and animal health.

Nobel Medal

In an interview with PBS, Allison explains that his fight with cancer started at a young age, when his mother passed away from lymphoma. Two of his uncles also lost their fight with cancer, one with melanoma, one with lung cancer. More recently, Allison’s brother passed away after a battle with prostate cancer. When Allison entered the field of immunology, he could see the potential for immuno-oncology. His primary interest was in T-cells, cells programmed to find the “bad guys” and take them down. All he had to do was determine how to convince the T-cells that tumor cells were worth their efforts. However, for decades, researchers had been trying to do just that with no success. Allison’s and Honjo’s discoveries changed all of that. When they discovered how to take the brakes off the T-cells, the immune system did the rest of the work for them.

Traditionally, cancer therapies have fallen into one of four categories: surgery, radiation, chemotherapy, or hormone therapy. One of the difficulties in treating cancer in patients has been that the immune system recognizes tumor-cells as “non-self” (cells or proteins that are abnormal, foreign, or disease-causing), but do not attack the tumor-cells). T-cells, the soldiers of the immune system, recognize cells as self (normal, non-diseasing-causing) or non-self. Once a T-cell binds and recognizes a non-self cell, additional helper-proteins must react to initiate a full immune response. Similarly, there are proteins that act as brakes to the immune response. Even though T-cells seem to recognize that tumor-cells are abnormal or problematic, if additional proteins do not react to initiate response, or proteins are inhibiting the response, then the immune system does not react to the tumor. This is what usually happens and is why the body is unable to fight off cancer as readily as it can the common cold.

Allison and Honjo’s discoveries would have been impossible without the use of transgenic mice (genetically modified mice) which allowed them to isolate certain aspects of the immune system for study. Mice are often

used in immunological studies, as genetic control makes it much easier to isolate and target an individual part of the immune system. While studying T-cells, Allison realized that the protein CTLA-4, a protein on the surface of T-cells, serves as a brake to stop T-cells from creating a full blown immune response. This is beneficial in some circumstances. It stops us from unnecessarily getting sick. However, Allison hypothesized that CTLA-4 might contribute to the immune system’s lack of response to tumor cells. His team subsequently developed an antibody that would bind to CTLA-4 and block its response. As if miraculously, it would turn off the brakes on the immune system. In order to test this, Allison’s research group again looked to mice.  In one of Allison’s key studies, mice were injected with human colon cancer cells, which was then successfully treated with the CTLA-4 antigen, and the mice were deemed to be cancer-free. In another paper, Allison compared the immunotherapy treatment in wild-type mice and in transgenic athymic mice (mice bred to lack a thymus, the organ where T-cells mature). After the therapy was established in animal models, testing moved forward with human clinical trials. During clinical trials in patients with advanced melanoma, the CTLA-4 antibody allowed the patient’s immune system to aggressively fight the tumor cells.

Around the same time, Honjo was also studying T-cells in Japan. However, instead of focusing on CTLA-4, Honjo focused on PD-1, another protein expressed on the surface of T-cells. When an antibody designed to block PD-1 is administered, not only does it allow T-cells to initiate a full immune response, it amplifies that response. In patients with metastatic cancer, a condition previously considered untreatable, PD-1 pathway blockage has led to long-term remission. Like Allison, Honjo also used mice in his discovery of PD-1.

Cancer treatments including and inspired by Allison and Honjo’s CTLA-4 and PD-1 manipulations are now referred to as immunotherapy, a fifth category of cancer treatment that relies on the body’s own ability to fight off illnesses.

Allison and Honjo are not the first Nobel Laureates to utilize animal models in their research. In fact, of the 216 award recipients for Physiology or Medicine, 180 of them have used some sort of animal model. To name a few, fruit flies were used to uncover the molecular basis of the circadian rhythm, and dogs used to develop MRIs, while horses were used to develop the diphtheria vaccine.

Immunotherapy has come a long way in treating patients with difficult cancers. In fact, the drugs seem to work against many different types of cancers, including: melanoma, lung, kidney, and bladder cancer. When the treatment works, it can seem to work miracles by treating patients who have no other options and who have been previously deemed untreatable. In 2006, Allison met a patient who experienced the phenomenon of immunotherapy. Sharon Belvin was 22 years old and had just completed her undergraduate degree when she went to the doctor complaining about exhaustion. She was diagnosed with more than 30 metastatic melanomas littered throughout her body. In the past, metastatic melanoma was an automatic death sentence. However, after trying immunotherapy, her immune system destroyed all the tumors, and she is now nearly fourteen years in remission. However, this treatment does not always work, and it is currently unknown why some patients have virtually no response to immunotherapy drugs while presenting seemingly supernatural cures in others.  Allison says that the next step is to determine the reasons behind the randomness of the treatment’s efficacy on patients. There are research groups around the world who are looking into this very question. Their hypotheses range from blaming T-cell exhaustion to neoantigens, a new branch of antigens. Both Honjo and Allison continue their studies today, with goals to continue moving forward to finding answers. But one thing is for sure, animal models are likely to continue to be a part of their quest every step of the way.

 

By Alissa Hatfield

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