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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 T-cells that are trying to destroy the melanoma cells, engaging the CTLA-4 checkpoint halts the immune response at an even earlier point. When patrolling T-cells first recognize the threat of cancer cells stimulation of CTLA-4 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.

Relatlimab targets a novel immune checkpoint called LAG-3

Ten of the currently approved ICIs target either CTLA-4 or PD-1/PD-L1. With the 2022 approval of relatlimab + nivolumab (together called Opdualag), the FDA has added a new target to the ICI arsenal. Relatlimab inhibits LAG-3, which is another immune checkpoint besides CTLA-4 and PD-1. Relatlimab was the first LAG-3-targeting ICI to be approved, but it is not the only one under development: others include Immutep, Fianlimab (which is currently in phase III clinical trials against melanoma), and MK-4280.

LAG-3, similar to CTLA-4 and PD-1, can be found on the surface of activated immune cells. It has multiple binding partners, one of the most important being the protein responsible for compatibility between different tissues in the case of organ or bone marrow transplantation.  Upon interaction with any of these ligands for LAG-3, inhibitory signals are sent into the immune cell. Again, this process is an important part of immune homeostasis, meaning the day-to-day balance of our immune system, highlighted by the fact that genetic loss of LAG-3 in newborn mice predisposes them to the development of autoimmune diseases (loss of CTLA-4 causes severe autoimmune diseases, while loss of PD-1 is associated with only mild disease).

LAG-3 has also moved into the limelight due to research that showed when tumors were treated with PD-1/PD-L1 inhibitors, other immune checkpoint molecules, including LAG-3, were upregulated as a compensatory response. These findings indicate that when we tackle one of the mechanisms cancer uses to suppress our immune system, cancer can utilize other mechanisms as back-up to escape from control by our immune systems. This information led researchers to further explore combination therapies and novel ICI targets.

In clinical trials, relatlimab was tested in combination with the anti-PD-1 inhibitor nivolumab. ICIs have already been proven to be more effective in combination than as single agents. For example, it has been shown that the combination of two different ICIs nivolumab and ipilimumab was more effective than either ICI alone at treating melanoma that has metastasized to the brain. However, this increased efficacy comes with more frequent and serious side effects. Side effects can be a huge burden to patients and can lead to discontinuation of treatment. When relatlimab was combined with nivolumab, adverse events occurred about twice as frequently as when patients received nivolumab alone. However, the relatlimab + nivolumab adverse event rate appears to be about three times lower than with other ICI combinations such as nivolumab and ipilimumab. Therefore, using combination therapies including relatlimab or potentially other LAG-3 targeting ICIs may offer a safer and better tolerated option for treatment of cancer.

Novel immune checkpoint inhibitors may have higher efficacy or better safety profile

The search for new ICIs has accelerated, in the hope that novel ICIs may have fewer side effects, in combinations or alone, or be more effective—or both. Immunotherapies come with many side effects that can limit treatment options for patients. Alternatives that are better tolerated could significantly enhance patient lives and lead to better treatment outcomes as well.

Additionally, 50% of patients with melanoma still do not respond to current immunotherapies. Novel therapeutic approaches are therefore needed to expand the success of immunotherapies. LAG-3 is just one of several promising targets for novel ICIs. Others include TIM-3, TIGIT, VISTA, B7-H3, and BTLA. Additional molecules that are immunomodulatory and may synergize with one or more ICIs include ICOS, CD40L, OX40, 4-1BB and CD47.  Many clinical trials are trying to determine whether blocking these other checkpoints, either alone or in combination with existing ICIs, could lead to better results than current treatment regimes. Similar to LAG-3, these novel ICI targets hold a lot of therapeutic promise. For example, there is currently a phase III trial evaluating the blockade of TIGIT in combination with the PD-1 inhibitor pembrolizumab in patients with resected high-risk melanoma. Another example is VISTA, which is still in early clinical trials. VISTA may be particularly interesting to patients with melanoma because about one third of melanomas show high levels of this immune checkpoint protein, which is associated with advanced disease and worse prognosis. Additionally, similar to what has been shown with LAG-3, treatment of melanomas with PD-1 blockade leads to increased levels of VISTA, indicating that tumors use immune suppression via VISTA as a back-up mechanism to escape the antitumor effects of blocking the PD-1/PD-L1 interaction.  The efficacy of these and other novel ICIs remains to be seen, but patients should look out for new developments in this field.

Overall, the discovery of immune checkpoints and their therapeutic blockade has had significant impact on many thousands of melanoma patients, extending survival by years and potentially curing as many as 35-40% of patients with metastatic melanoma. Nonetheless, a substantial proportion of patients still does not reap the benefits of immunotherapy, and too many recipients of immunotherapy struggle with debilitating side effects that require treatment discontinuation. Therefore, it is important that more research is done on novel immune checkpoint inhibitors and new combination treatments that show increased efficacy and tolerability.

 

Paul Bunk is a Ph.D. Candidate at Cold Spring Harbor Laboratory, a New York-based research institute world-renowned in the fields of cancer biology, neuroscience, and plant biology. Paul works in the group of Semir Beyaz and focuses his research on the impact of metabolism on immune cells and their ability to fight cancer. With this research, the Beyaz Lab sits at the cutting edge of cancer immunology and hopes to help make better immunotherapies for the future.