The Power of Synergy: Moving LAG-3 from Bench to Bedside
Hope came on March 18, 2022.
It was the day the U.S. Food & Drug Administration (FDA) approved Opdualag, which brings together PD-1 and LAG-3 checkpoint blockade to energize the immune system against melanoma. Once energized, the immune system is better positioned to attack and destroy melanoma cells.
Opdualag combines nivolumab with relatlimab and are given together as one medicine. Both drugs — called immune checkpoint inhibitors — work by releasing the brakes of the immune system, allowing it to attack cancer cells. Nivolumab (brand name Opdivo), first approved by the FDA in 2014 to treat patients with advanced melanoma, targets the immune checkpoint PD-1 and has since been approved to treat patients with a wide variety of other cancers. Relatlimab is a new drug targeting a different immune checkpoint, LAG-3, and is the first anti-LAG-3 therapy to earn FDA approval.
Opdualag proved to be a tour de force. In clinical trials:
The benefits also extend to the field at large, where research into Opdualag significantly advanced researcher’s understanding of two different checkpoint pathways and the ways in which they intersect. Not only this, Opdualag opens the door for significantly more patients to benefit from combination immunotherapy.
The journey to FDA approval was a culmination of efforts and discoveries over several decades. In the 1990s, lymphocyte-activation gene 3 (known as LAG-3) was discovered. However, it wasn’t until 2004 that Dr. Drew Pardoll and colleagues at Johns Hopkins University and St. Jude Hospital discovered that it was a new immune checkpoint. But it was not until 2009 that LAG-3’s relevance to cancer immunotherapy began to be elucidated with the support of an MRA Team Science Award.
“Findings from research supported by the MRA grant demonstrated that, while blocking LAG-3 by itself had very little anti-cancer activity, when you combined it with anti-PD-1 [checkpoint immunotherapy], that duo was significantly more effective than either alone,” says Pardoll. “It’s a situation where 1 plus 1 equals 5—where you get something more than just adding the effect of the two drugs together.”
Findings from this research were published in 2012. “It was a very successful outcome,” says Pardoll. “It’s a perfect example of the outsized impact of MRA funding, which is strategically targeted to push the field further. The full impact of advancements are often not fully understood until an FDA approval years — or even decades — later.”
Like other lab-based discoveries, research into the therapy that would later be named Opdualag was advanced into clinical trials. This is a critical step in the research process as many therapies show success in model systems only to fail when administered to patients. That’s where Dr. Evan J. Lipson, a medical oncologist also at Johns Hopkins, picked up the mantle. “The basic science researchers passed the baton to me and my team of translational researchers. We began testing LAG-3 checkpoint blockade by itself and in combination with PD-1 blockade to understand whether the benefits seen in the laboratory could be translated safely and effectively into patients with cancer,” says Lipson.
The answer was a resounding yes.
The benefits also extend to the field at large, where research into Opdualag significantly advanced researcher’s understanding of two different checkpoint pathways and the ways in which they intersect. Not only this, Opdualag opens the door for significantly more patients to benefit from combination immunotherapy.
The journey to FDA approval was a culmination of efforts and discoveries over several decades. In the 1990s, lymphocyte-activation gene 3 (known as LAG-3) was discovered. However, it wasn’t until 2004 that Dr. Drew Pardoll and colleagues at Johns Hopkins University and St. Jude Hospital discovered that it was a new immune checkpoint. But it was not until 2009 that LAG-3’s relevance to cancer immunotherapy began to be elucidated with the support of an MRA Team Science Award.
“Findings from research supported by the MRA grant demonstrated that, while blocking LAG-3 by itself had very little anti-cancer activity, when you combined it with anti-PD-1 [checkpoint immunotherapy], that duo was significantly more effective than either alone,” says Pardoll. “It’s a situation where 1 plus 1 equals 5—where you get something more than just adding the effect of the two drugs together.”
Findings from this research were published in 2012. “It was a very successful outcome,” says Pardoll. “It’s a perfect example of the outsized impact of MRA funding, which is strategically targeted to push the field further. The full impact of advancements are often not fully understood until an FDA approval years — or even decades — later.”
Like other lab-based discoveries, research into the therapy that would later be named Opdualag was advanced into clinical trials. This is a critical step in the research process as many therapies show success in model systems only to fail when administered to patients. That’s where Dr. Evan J. Lipson, a medical oncologist also at Johns Hopkins, picked up the mantle. “The basic science researchers passed the baton to me and my team of translational researchers. We began testing LAG-3 checkpoint blockade by itself and in combination with PD-1 blockade to understand whether the benefits seen in the laboratory could be translated safely and effectively into patients with cancer,” says Lipson.
The answer was a resounding yes.
Lipson recalls seeing a patient with melanoma who, despite having received nivolumab (Opdivo), had several tumors, each about the size of a quarter. Within just weeks of starting Opdualag therapy, the tumors had shrunk substantially. “It was remarkable,” Lipson says. “The LAG-3 lightbulb came on. The dramatic improvements we were seeing in patients mirrored what Dr. Pardoll had demonstrated in the lab: we can activate T cells against cancer by targeting LAG-3 in ways we can’t by targeting PD-1 on its own.” Almost 3 years later, this patient is off therapy with no evidence of melanoma. Indeed, in many patients, Opdualag’s impact appears to be durable, meaning that after the drugs activate the immune system against cancer, a patient’s immune cells can keep cancer in remission for years.
Although the scientific breakthroughs are remarkable, the real heroes of clinical trials are the patients. “Without patients, there could be no clinical trials,” says Lipson. “I’m grateful to them for saying, ‘I want to partner with you in pushing the cutting edge forward.’ They’re putting their faith in us that we’re going to provide them with excellent care and learn something along the way.”
Both Pardoll and Lipson agree that these breakthroughs wouldn’t have been possible without MRA—an organization they credit for always prioritizing science, for being real partners in this process, for connecting collaborators, and who they praise for the scientific rigor of its grant proposal evaluation process. Said Pardoll: “The MRA grant was our very first funding to use mouse models to determine how LAG-3 blocking antibodies might be used most effectively in cancer therapy. That helped guide the decade-long translational work by our clinical research colleagues and the rest is history.”
Opdualag is now a standard-of-care therapy for patients with advanced melanoma. It, and other drugs like it, are being studied–and showing promise–in patients with a wide variety of other tumor types, including cancers of the head and neck, colon, stomach, liver, and lung. The successful development of Opdualag from the basic science lab to the clinic is yet another example of how MRA is leading the way in advancing treatment for patients with melanoma and leaving a lasting impact on cancer research at large.