Over the next several months, we will highlight innovations from the past decade at The Johns Hopkins University to illustrate the depth, breadth and impact of research from the university’s many divisions and disciplines.
The story of the U.S. Food and Drug Administration’s approval of a new immunotherapy treatment for certain types of skin cancer in 2022 began almost two decades earlier in a Johns Hopkins University laboratory.
The new treatment combines two types of therapies to treat metastatic or inoperable melanoma: relatlimab and nivolumab. Relatlimab is the game-changer that originated from the Johns Hopkins Sidney Kimmel Cancer Center.
In 2004, Drew Pardoll, MD, PhD, and colleagues discovered that the lymphocyte-activation gene 3, or LAG-3, was a new immune checkpoint. Checkpoints are proteins that stop the immune system from responding to cancer cells. Checkpoint inhibitor drugs block these proteins, unleashing the immune system to battle the cancer.
Pardoll is the Abeloff Professor of Oncology, Medicine, Pathology and Molecular Biology and Genetics at the Johns Hopkins University School of Medicine. He is the Director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy and Co-Director of the Cancer Immunology Program at Kimmel.
In 2010, Pardoll began to study the effects of antibodies that blocked LAG-3 on cancer treatment in mice. He and his colleagues found that blocking LAG-3 by itself had little effect on cancer but, when combined with another drug targeting checkpoint PD-1, it was highly effective. Anti-PD-1 antibodies had just been demonstrated by Suzanne Topalian, Bloomberg-Kimmel Professor of surgery and oncology at Hopkins, to be clinically effective in many cancers. “It’s a situation where 1 plus 1 equal 5—where you get something more than just adding the effect of the two drugs together,” Pardoll told the Melanoma Research Alliance (MRA), which provided a grant for the study. The findings from this study were published in 2012.
The next challenge of translating the lab results into success with human cancer patients fell to Evan J. Lipson, MD, associate professor of Oncology at Johns Hopkins. Lipson co-led the RELATIVITY-047 trial, which was the first phase III randomized clinical trial to show a clinical benefit from the combination of nivolumab, the original anti-PD-1 antibody developed by Topalian, with relatlimab, the first human anti-LAG-3 blocking antibody that Pardoll developed originally with the biotech company, Medarex. The study findings were published in The New England Journal of Medicine in January 2022.
“Our findings establish the LAG-3 pathway as the third immune checkpoint pathway in history for which blockade has clinical benefit,” Lipson said.
The RELATIVITY-047 trial was a global study that enrolled 714 patients with previously untreated, inoperable melanoma, an aggressive type of skin cancer. Patients received either nivolumab alone or a combination treatment of nivolumab and relatlimab. The median time before the cancer worsened was 10.2 months in patients receiving the combination treatment, versus 4.6 months in those that received only nivolumab. At one year, the cancer did not worsen for 48% of patients receiving the combination, compared to 36% for the others. “It was remarkable. The LAG-3 lightbulb came on. The dramatic improvements we were seeing in patients mirrored what Dr. Pardoll had demonstrated in the lab,” Dr. Lipson told the MRA.
Based on the outcome of this study the FDA approved the combination treatment in March 2022. Opdualag combines the PD-1 blocker nivolumab with relatlimab, which is the first FDA-approved drug to block the activity of LAG-3. It is manufactured and sold by Bristol-Myers Squibb, which sponsored the RELATIVITY-047 trial.
Johns Hopkins Technology Ventures (JHTV) brokered a license agreement between the university and Bristol-Myers Squibb that provides the pharmaceutical company the rights to use the Johns Hopkins technology to develop the drug and bring it to market. The agreement provides royalties to the university and Pardoll, who is also credited as the inventor of a patent for the blockade of LAG-3 for cancer treatment.
The use of Opduolag in melanoma is expanding, with sales revenues expected to surpass $1 billion in 2025. Combinations of anti-PD-1 and anti-LAG-3 are being tested in 10 additional cancer types, showing promising early clinical results that support the broader use of this combination.
Relatlimab Milestones:
- 2004: Drew Pardoll discovers that LAG-3 is a new immune checkpoint.
- 2010: Pardoll and his research team begin a study to see how relatlimab, a LAG-3 blocking drug, treats cancer in mice.
- 2012: Findings from the study are published showing that a combination of a LAG-3 blocker and PD-1 blocker is an effective cancer treatment.
- 2018: The RELATIVITY-047 trial begins enrolling patients and randomly assigning them to receive relatlimab with nivolumab or nivolumab alone.
- January 2022: Results from the RELATIVITY-047 trial published in The New England Journal of Medicine show the combination treatment with relatlimab to be a more effective treatment than nivolumab alone.
- March 2022: The FDA gives approval for the combination treatment (relatlimab and nivolumab, marketed as Opdualag) as a new therapy for patients with metastatic or inoperable melanoma.