Immune checkpoint inhibitors work by releasing the “brakes” on immune T cells, unleashing them upon cancer cells. After the discovery of two of these brakes, PD-1 and CTLA-4, and the subsequent cascade of drugs targeting them, the search for new checkpoints to target stalled. But this spring, the FDA approved a new melanoma drug called relatlimab, which targets LAG-3—the first new checkpoint in almost a decade.

Like many drug discoveries, this one comes after decades of incremental progress, beginning with French immunologist Frédéric Triebel’s discovery of the LAG-3 protein in 1990. Fourteen years later, then-Damon Runyon Clinical Investigator Charles G. Drake, PhD, conducted a study at Johns Hopkins in which he disabled LAG-3 in mice, inducing an autoimmune attack by T cells. Though the word “checkpoint” was not yet in use, scientists would later strive to translate this discovery into an effective checkpoint inhibitor.

This involved some amount of trial and error. Studies have shown that LAG-3 inhibitors alone are not very effective (Drake’s collaborator, Dario Vignali, PhD, has suggested that LAG-3 may be the “handbrake” to PD-1 and CTLA-4’s “footbrakes.”) At the same time, patients whose T cells express high levels of LAG-3 fare worse with existing immunotherapies, as former Clinical Investigator Jedd D. Wolchok, PhD, and his colleagues have shown. Crucially, Dr. Wolchok’s lab also demonstrated the advantage of combining checkpoint inhibitors. Their clinical trials showed that the PD-1 inhibitor nivolumab plus the CTLA-4 inhibitor ipilimumab substantially boosts survival for melanoma patients, albeit with serious side effects.  

At last, by pairing nivolumab with relatlimab, researchers (including Damon Runyon mentor F. Stephen Hodi, MD) have found a combination that provides similar benefit against melanoma with much less toxicity. If the trajectory of PD-1 and CTLA-4 inhibitors is any indication, the LAG-3 inhibitor will likely get approved for the treatment of other cancers in coming years.

“I was funded by Damon Runyon in the early 2000s, when immunotherapy was not at all a safe bet,” Dr. Wolchok recalls. Thanks to the high-risk research he and others have pursued, immunotherapy has come a long way, and more patients than ever face winning odds.