Nobel Prize in Medicine Honors Immunotherapy Researchers

For many years cancer treatment involved chemotherapy, surgery and radiation to stop the growth of cancer cells. But in the past few decades, researchers began studying how the human body’s immune system could be bolstered to fight the disease itself.

After losing friends and family to cancer, James Allison and Tasuku Honjo each became interested in studying cancer and understanding the way it changes the body, particularly immune cells. Their groundbreaking research opened the door for immunotherapy.

Allison’s research focused on the CTLA-4 protein, which regulates T-cells, the workhorses of the immune system. Oftentimes the protein blocks the immune system from attacking cancerous cells. However, Allison developed an antibody to inhibit the CTLA-4 protein and in 2011, the FDA approved ipilmumab, or Yervoy, to treat advanced melanoma.

Yervoy led to the creation of a new drug class called checkpoint inhibitors. Checkpoint inhibitors stop proteins from blocking an immune response and free T-cells to attack malignant tumors. Studies have shown that these inhibitors work in patients with melanoma, as well many other solid tumors.

In 1992, Tasuku Honjo, a professor of immunology at Kyoto University, discovered a protein called Programmed Cell Death Protein 1 (PD1), which is on the surface of immune cells and determines if cells grow normally or turn cancerous. His research showed that the protein inhibits the function of the body’s natural immune defenses.

Working from this discovery, a 2012 study showed that blocking the protein could help the body fight cancer. This led to the development of pembrolizumab, or Keytruda, and nivolumab, or Opdivo, both approved in 2014 to treat melanoma. Subsequent clinical trials have demonstrated the safety and efficacy of these and other checkpoint inhibitors in many different forms of solid tumors, including lung cancer, head and neck cancer, and others.

The groundbreaking research by both Allison and Honjo has opened new doors for cancer research and led to the creation many checkpoint inhibitors, leading to the extensive study of these new medicines. Their discoveries have given many cancer patients a chance at living more normal lives and living longer.  

The Mystery of TP53 Unraveled

Mutations within a person’s DNA is one of the most common causes of cancer. p53 is one of the most commonly mutated genes among cancer patients and is a tumor-suppressor that works to regulate cell division and prevent cells from reproducing too quickly. However, when the DNA is mutated, the gene can lose this function and allow cells to grow out of control. Mutations in p53 are found in almost every kind of cancer, including lung, ovarian and laryngeal, among others.

For years, this mutation has intrigued scientists, as the DNA changes can occur at over 1,100 sites within the gene, though there are places, called “hot spots,” where mutations most frequently occur.

A recent study published in Nature Genetics by researchers from the Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and others, found that hotspot mutations are not more likely to produce cancer than mutations at other points within the genetic code.

The study used the newest technology available to create a library of all possible variants of the p53 gene — 8,258 in total. After sequencing the genes, researchers compared hot spot mutations to others and found that they were no more likely to promote cancer than mutations in other locations. They concluded that the tendency of mutations to occur in those locations is due to the way mutations occur and which parts of the body are exposed to carcinogens.

“This indicates we’re correct that mutations in p53 are focused on certain hot spots because those spots are targeted by the specific carcinogens to which cells are exposed,” said William Hahn of Dana-Farber in an interview. Hahn was the senior author of the study and serves as the deputy scientific officer at Dana-Farber.

Understanding the role gene mutation plays in causing cancer is imperative as gene sequencing becomes more common in cancer treatment.