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-3targeting 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 PD1 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 LAG3, 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