NOTES FROM THE LAB

Novel Targets for Immune Checkpoint Inhibitors

By Paul Bunk, Ph.D. candidate, Cold Springs Harbor Laboratory

Survival rates of patients with melanoma have drastically improved in the last two decades. In the early 2000s, patients with Stage IV melanoma had a median life expectancy of about seven months. This number has now risen to just over six years, according to long-term follow up from the CheckMate 067 study. What is behind this significant progress for patients and families? The answer is immunotherapy—and more precisely immune checkpoint inhibitors (ICIs). The first two drugs of this class, ipilimumab (Yervoy) and nivolumab (Opdivo), were approved for the treatment of melanoma in 2011 and 2014, respectively, and overall, eight more ICIs were approved in the ten-year span between 2011 and 2021 In March 2022, the FDA approved a completely novel type of ICI, relatlimab, in combination with nivolumab—which together are known as Opdualag--for a total of 11 ICIs approved since 2011

What makes this drug novel? Why is it exciting? And why do researchers keep looking for new ICIs if our existing drugs have had so much success already?

Immune Checkpoints And Cancer

To answer these questions, we should first review the immune system in general Our immune system consists of a group of cells that are tasked with defending the body against all kinds of threats. These threats include viruses and other pathogens, as well as mutated cells that could become cancer Our immune cells are very effective at getting rid of dangers; however, their activity needs to be tightly regulated so that they do not overreact and hurt our own bodies. If the immune system goes awry, the effects can range from uncomfortable, as in the case of allergies, to debilitating and even life-threatening, as in the case of autoimmune conditions

This balance between reacting but not overreacting is where immune checkpoints come into play. As the name suggests, immune checkpoints keep immune responses in check—or, regulate them In general, they work like this: When an immune cell gets activated (when it reacts to a threat), it will start expressing immune checkpoint proteins

These proteins are basically emergency “off buttons ” If these proteins find their counterparts (called ligands) nearby, the checkpoint gets activated and starts shutting the immune response off—the presence of the ligands sends a message to the immune system that there is not actually a threat after all. But if these proteins do not find ligands nearby, the checkpoint is not activated, and the immune system launches an immune response designed to destroy the threat

These regulatory mechanisms are important for us to stay healthy because they allow the body to keep immune cells “ on ” when needed and to turn immune cells “off” if they are activated inappropriately. Unfortunately, these same mechanisms are exploited by cancer cells. Cancer cells often express the ligands of immune checkpoints, allowing them to turn off immune cells that should be attacking the growing tumor. This so-called “immune evasion” can be seen with melanoma

You might be familiar with the immune checkpoint protein called PD-1, which can be expressed when immune cells encounter melanoma cells and sense the threat. Inside of the melanoma tumor, the tumor cells will express the ligand of PD-1— called PD-L1, and the immune checkpoint PD-1 will be tricked into stopping the immune response This means the body’s own immune system is not able to fight the cancer, and tumors are allowed to grow uncontrolled Another immune checkpoint protein called CTLA-4 may also be familiar to patients with melanoma. Like PD-1, CTLA-4 can be expressed when immune cells encounter melanoma cells In this case, the cancer cells trick the immune system in a slightly different way

While expressing PD-L1 allows cancer cells to inhibit activated Tcells that are trying to destroy the melanoma cells, engaging the CTLA-4 checkpoint halts the immune response at an even earlier point. When patrolling Tcells first recognize the threat of cancer cells stimulation of CTLA4 leads to the immune response being stopped in its track before immune cells can even be fully activated.

Immune checkpoint inhibitors (ICIs) can tackle this issue. ICIs are antibodies that can bind to either the immune checkpoint molecule or its ligand, and by doing so will disrupt the activation of immune checkpoints and reinvigorate immune cells. The first ICI to be approved was ipilimumab (Yervoy), which blocks CTLA-4, in 2011 for melanoma.

In 2014, nivolumab (Opdivo) and pembrolizumab (Keytruda), which both block PD-1 on immune cells binding to PD-L1 on cancer cells and other nearby cells that suppress immune responses in cancer, were approved in melanoma Besides the subsequent FDA approval of eleven single ICIs, there have been a number of approvals for combinations of ICI with other immunotherapy or other ICI, and ICI plus traditional cell-killing chemotherapy or so-called molecularly-targeted therapy, which blocks very specific chemical pathways in cancer cells with unique genetic mutations