Recent Advances in the Evolving Treatment Landscape of Melanoma

Key Takeaways

• It's really interesting that it has a lot of homology to CD-4. And if you look at the all the extracellular domains, there are four domains that are almost identical ... they're almost identical to CD-4 and we know that its primary ligand is MHC class 2.
• So, the original thought was that this is the mechanism of action of LAG-3, but that's not necessarily true. First of the intercellular domain, we have a different domain than most checkpoints that doesn't actually have an item, a domain and again, it has this ipi sequence and a skill motif. And once it's activated, it does inhibit T-cell activity.
• It's co-expressed in cells that are kind of more deeply exhausted than in T-cells that are more deeply exhausted than cells that express PD-1 alone.
• What we also learned is there are many other ligands that actually can attach to LAG-3 and inhibit its function, including FGL-1, L-selectin, galectin. And more recently, one of the intersecting results has shown that really most of its activity is related to its association with the TCR complex.
• And in fact what we see happen on the intracellular is actually we see sequestering of the Zinc ion, which is actually a really important co-factor in the phosphorylation of ZAP 70 that truly determines the activation of a T-cell and the intracellular signaling of the TCR CD-3 or TCR rCD-3 complex.
• It turns out that LAG-3 truly modulates the kind of amplitude of what comes through the TCR pathway or the activation of the TCR on T-cells. So the more activation you have, the more relevant CD LAG-3 is. And that probably explains some of the clinical results, why we see an improvement in the PD-1 refractory disease. It's only about 12% activity. You go to the first line, it's 45%. You go to the neoadjuvant and it's 57% responses. So really interesting to see that.
• The last thing I would say is if you see this particular situation here, you have a cleavage of LAG-3 at the cell surface and we have actually soluble LAG-3 that's present. And we don't fully understand what that does. In our trials we actually saw that when you treat with an anti, like three antibody serum like soluble LAG-3 levels decrease, but we think it's more of a pharmaceutic marker. We're not sure that it's a pharmacodynamic one. So if you look at where LAG-3 is expressed, it's expressed on multiple immune cells from CD-4 positives to CD-8 positives T-cells. It's expressed on Tregs and importantly on antigen presenting cells as well. And each of them, there are different ways that it inhibits an immune response but technically in every single one of them, it does lead to immune suppression. And ultimately when you block LAG-3, you kind of reactivate exhausted T-cells