What if the key to curing cancer wasn’t to destroy cancer cells with chemotherapy, but to coax the immune system to do it instead? 

Many immunologists spend their careers dreaming of making discoveries that lead to a new treatment or cure a disease. But for immunologist James Allison, his dreams became reality when he got the opportunity to meet a woman who was alive because of his discoveries that led to checkpoint blockade inhibitors.  

A New Approach to Cancer Treatment

In 2004, a 22 year old woman named Sharon Belvin heard the words no one ever wants to hear: stage 4 melanoma. The cancer had spread throughout her body, and the prognosis was grim. She had been looking forward to planning her wedding, but instead, she faced round after round of chemotherapy. When the cancer continued to grow and her options were exhausted, her doctor offered her a last-ditch chance– a spot in a clinical trial for a radically different approach to cancer treatment.  

Instead of relying on toxic drugs to attack her cancer directly, this new therapy aimed to activate Sharon’s immune system to fight the cancer itself. The experimental drug being tested in the trial was ipilimumab, what we now know by the brand name Yervoy. 

Yervoy is a monoclonal antibody immunotherapy– a drug that alters how the immune system functions. It exists today thanks to Allison’s groundbreaking research, which built on multiple fundamental discoveries in immunology that paved the way for its development.  

To develop Yervoy, researchers first needed to understand how T cells–an army of immune cells that can search out and destroy infected or cancerous cells–were switched on.  

Stop and Go Signals

Allison, who became fascinated by T cells as an undergraduate, devoted his career to figuring out how they work. His research revealed that T cells are tightly controlled by a system of checks and balances to prevent them from causing unnecessary damage to the body.   

Each T cell carries a “fingerprint” of a specific target–usually from an infectious agent such as a virus or bacteria–and it spends its life roaming the body searching for its target. But finding a match isn’t enough to switch on the T cell. They also need a special ‘go’ signal from the immune system that tells the T cell to get to work eradicating the target. . When infection or tissue damage is detected elsewhere by the immune system, an alert is sent. This is the required ‘go’ signal (called costimulation) that works together with the fingerprint to switch on T cells. Researchers discovered the molecule responsible for this critical ‘go’ signal was CD28.   

The key discovery that eventually led to Yervoy came when Allison and colleagues studied another molecule that looked like CD28’s twin. They assumed this new molecule, CTLA4, worked like CD28 to switch on T cells. To their surprise, experiments showed the opposite effect–CTLA4 didn’t turn on T cells, it turned them off. They had found a T cell brake!  

Allison wondered what would happen if they released the brakes–if they blocked CTLA4 with a monoclonal antibody–in a model of cancer. The results were astonishing: tumors disappeared! The antibody treatment called ipilimumab was advanced to several clinical trials for melanoma, like the one Sharon enrolled in, where some patients showed complete responses with no detectable cancer!  

Alison’s discovery marked the birth of checkpoint blockade therapy, and paved the way for the groundbreaking cancer treatment Yervoy that received FDA approval in 2011. 

But could lightning strike twice? Could there be another way to unleash the immune system to eliminate cancer?   

Removing the Brakes

On the other side of the world–and around the same time– Tasuko Honjo and his team shed light on a different mystery: why cancer seemed invisible to the immune system. Honjo’s group had identified a new molecule they called PD-1 and discovered that like CTLA4, it acted like a brake on T cells. Some cancers display PD-1’s partner called PD-L1, which communicates to the PD-1 on T cells to tell them to “Stand down. Don’t respond”, helping the cancer to evade immune attack. Honjo’s team discovered that monoclonal antibodies that block PD-1, or PD-L1, remove the stop signal and free the immune system to attack the cancer.  

These discoveries gave rise to a new class of cancer immunotherapies: checkpoint blockade. These now include pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentriq), among others. Even more exciting, dozens of additional immune checkpoints have since been identified, offering promising new targets for future cancer immunotherapy treatments. 

The success of therapies targeting CTLA4, PD-1 and PD-L1 were only possible due to the basic immunology research of Allison and Honjo who shared the 2018 Nobel Prize in Physiology or Medicine for their groundbreaking work.  

When Sharon received Yervoy, her own immune system was unleashed to attack her melanoma–and it won. She went into remission and has stayed there ever since.