Immunotherapy harnesses the natural power of the immune system and enhances its response to cancer. Immune checkpoint inhibitors are the most commonly used type of immunotherapy. There are several types, and they all work by interfering with mechanisms on a cancer cell or on a type of immune cell called T cells.
Recently, a new type of immune checkpoint inhibitor called a LAG-3 inhibitor was approved by the Food and Drug Administration (FDA). Hussein Tawbi, M.D., Ph.D., led the Phase II/III RELATIVITY-047 clinical trial, which led to the FDA’s approval of the LAG-3 antibody relatlimab for patients with advanced melanoma. We spoke with him about what makes LAG-3 inhibition different from other immunotherapies and what this new therapy means for patients.
What is LAG-3?
LAG-3 stands for lymphocyte-activation gene 3. It’s a signal on a T cell. To better understand LAG-3, it’s helpful to review how immune checkpoint inhibitors work.
Some checkpoint inhibitors are designed to focus on an immune process called priming. It’s the moment when T cells are alerted that there’s something wrong, which prompts their response to the potentially harmful cell or germ.
Dr. Jim Allison identified two signals involved in the priming of T cells. One signal activates the T cell and the other suppresses it. The signal that suppresses the T cell is called CTLA-4. It acts as a safety checkpoint and turns off the T cell after some time to prevent the attack of healthy tissue. Allison questioned if the checkpoint signal could be turned off to release the T cells and allow more to be primed. That idea was the birth of immune checkpoint inhibitors. In 2011, an anti-CTLA-4 antibody called ipilimumab became the first checkpoint inhibitor to be approved by the FDA.
We have since learned there are other checkpoints that prevent the immune system from doing its job successfully. These include PD-1 and PD-L1. T cells activated through priming express the protein PD-1 on their surface. Normal cells express a protein called PD-L1, which is a signal to a T cell to not attack. When the T cell shuts down after coming across PD-L1, this is called T cell exhaustion. However, tumor cells and the tumor microenvironment have taken on this mechanism, so they also can express PD-L1 and hide from the activated T cells. Anti-PD-1 inhibitors such as pembrolizumab and nivolumab block the binding of PD-1 and PD-L1 to reveal the tumor cells to the activated T cells.
That brings us to LAG-3, another checkpoint on the surface of T cells. T cells expressing LAG-3 show signs of activation and exhaustion so there’s evidence that they’ve started an attack against cancer but failed. Because of this, LAG-3 was an attractive target to explore to help unleash the immune system, much like we target PD-1.
Why should patients care about LAG-3?
Combining the CTLA-4 inhibitor ipilimumab and the anti-PD-1 inhibitor nivolumab improves their results. With ipilimumab, we can widen the scope of the T cells, meaning they can be primed for more antigens and take on more aspects of a tumor. And, with nivolumab, we can improve the success of the attack by removing the safety mechanism of the T cells.
But, with a broader scope, the T cells can take attack tissue they’re not supposed to recognize, like normal tissue. With that come side effects. So, we’ve been searching for other checkpoints to target that are just as or more effective with fewer side effects. LAG-3 looks to be just that.
We tested the LAG-3 inhibitor relatlimab in combination with nivolumab in a Phase I clinical trial in patients with metastatic melanoma who had already been treated unsuccessfully with other immune checkpoint inhibitors. Only about 10% to 15% of patients experienced side effects. The effectiveness was also about 15%. Although that may not sound impressive, it’s important to remember these patients had already had disease progression with other immunotherapies. And the patients who responded had strong, long-lasting results.
With the Phase I clinical trial, it became clear that the combination of the LAG-3 inhibitor relatlimab and nivolumab may be beneficial, so we decided to study it in patients with metastatic melanoma who hadn’t received previous treatment.
We found the combination improves progression-free survival by about 25%. That’s similar to what we see with ipilimumab and nivolumab, but without the severity of side effects. Our findings show patients who received ipilimumab and nivolumab have almost three times more side effects than what we saw patients experience with the new combination of relatlimab and nivolumab. It’s a comparison of about 59% to 21%.
It’s really exciting. We’ve found a new checkpoint that improves the effectiveness and precision of the immune attack on a tumor, but with less of an impact on normal tissue.
What is next for LAG-3 inhibitors?
Now, we’re looking at relatlimab and nivolumab in different clinical settings. In a study led by Rodabe Amaria, M.D., we investigated relatlimab and nivolumab in patients with stage III melanoma before surgery.
Again, we saw results comparable to ipilimumab and nivolumab, but with a drastic difference in side effects. 20% to 30% of patients experience severe side effects with low-dose ipilimumab and nivolumab before surgery. With relatlimab and nivolumab, no patients experienced severe side effects.
It’s amazing. Patients can get a similar benefit without a major increase in side effects.
This is a game-changer for patients with metastatic melanoma, but it’s just the start. More studies are underway to explore the LAG-3 pathway so more patients with more cancer types can hopefully have the same benefit.