Being in the melanoma space has given me a really incredible opportunity to watch the evolution of how we think um about modulating the immune system for the treatment of of cancer. Um, and if we look at the history of treatment of cutaneous melanoma in particular, uh, we can track kind of the various, um, modalities of the immunotherapy we've, we've developed, right? With early on the approvals of interferon, which was approved for the adjuvant therapy of high-risk cutaneous melanoma, um, and, and IL2. Um, with that ultimately moving on to the approvals of ipilimumab in 2011, the anti-PD1 antibodies and ultimately combination therapy, uh, with PD1 CTA4 and then LAG 3 PD1, um, and now more recently with the approvals of things like lifeluil, right, so cell therapy now being approved. Um, I, I think it's, um, I think it's informative to go back and and look to see why uh the field, particularly melanoma, was so interested in this sort of strategy, right? Um, and I think that the story of IL2 is, is really illustrative, right? IL2, um, if you go back, when was this this was discovered in 1976, right? Um, as a key cytokine that uh would drive T cell proliferation. Um, NK cell development, um, terminal differentiation of your, your factor T cells and so forth, um. And although it was also found to activate some of the um suppressor methods like deregulatory cells, um I think You know, the early, um, Findings, uh, were sufficient to, to ask Steve Rosenberg, right, at the MCI to say, well, what happens if we actually use this for cancer therapy? And so it was in 1984, I believe, uh, that the first patient with melanoma, a lot of extra, um, soft tissue disease, metastatic disease, um, a large burden of disease. Um, he treated this patient with high dose IL2. And uh as uh those of you who may have used yoy to your careers, um, you know, it was a tough treatment regimen, a lot of toxicities that patient ultimately ended up being intubated uh for the uh cytokine li syndrome and capillary leak and so forth. Um, but ultimately she, she achieved a complete response to therapy. And and so that was really remarkable. So I think over the course of the next decade at the NAH under the leadership of Steve Steve Rosenberg, hundreds of patients with melanoma and renal cell cancer were treated with high dose CL2. And uh that experience, of course, has been summarized, uh, response rates on the order of 15% or so, with about 8% of patients achieving complete responses to therapy, with most of those being durable. And I think that gave um You know, the, the first. Major um piece of evidence that this sort of immunotherapy can lead to not just disease control but but even cures in these really refractory cancers at the time. Moving on through the course of development of immunotherapy for for melanoma, you know, that led to ultimately looking at other ways to activate the immune systems, the finding of CLA4 um understanding that biology. Ultimately leading to the approval of the map in 2011, um, and then anti-PD1 and Eyevo. And, and so where are we with Checkpoint blockade just kind of as a summary. Um, Percutaneous melanoma, obviously this is, this is the standard first line therapy, um, better than targeted therapy in our Brap melanoma patient population, and what do we expect? Um, with these therapies, we're now able to tell our patients in clinic with metastatic disease, liver metastasis, brain metastasis, visceral disease, um, that with these therapies, the goal is actually cure and we're able to get a complete responses, um, long term durable responses which median survival is now about 50%, um, at 6 years, 7 years. And so we're, we believe we're curing 40 to maybe as high as 50% of our patients with metastatic disease with combination checkpoint blockade, which is pretty remarkable because that's, that's not where we were, uh, even 15 years ago. Still a major gap, right? Even for curing 40 to 50% of patients, that leaves a lot of patients behind. And so there's been continued development looking at other immunological checkpoints. Can we target other things like lag 3 and certainly the combination of PD1 plus lag 3 leads to improved outcomes when compared to single agent PD1. Um, Not compared head to head versus it beingivvo, but certainly toxicity profile is a little bit better with PD one lag-based therapy. Again, uh, another step forward, another tool, uh, in what we can provide our patients, but, but not curing everybody. Um, and so the, the most recent approval for cutaneous melanoma is Lifausil, uh, which in the PD1 refractory patient population, you know, we can use lipoucil, um, pills-based therapy again also coming from Steve Rosenberg. Um, where, uh, with administration of this population, we're seeing response rates on the order of 30%, again, many of these very, very durable. So again in melanoma, we've moved from cytokine-based therapy to checkpoint blockade, um, to tills, um. Uh, and that's, I think the major advances for for cutaneous melanoma. In the melanoma space that leaves some of our less common subtypes behind. And so when we think of melanoma, we have our executaneous melanomas which are um you know, characterized by high mutation burden, um, high expression of PDL one, and high responsiveness to these immunotherapies, but there are rarer subsets of melanoma, these extracutaneous melanomas, like ocular melanomas arising from the eye, mucosal melanomas arising from the mucosal surface of the body, um, um. The syno nasal tract oral cavity of the vaginal area in a rectal region. Um And these extracutaneous melanomas are far less responsive to those um those immunotherapies that have shown so much promise and effectiveness in cutaneous disease. Um, I would say as an aside for for uveal melanoma, there's another immunotherapy that was just approved a couple of years ago called tebeius, which is actually the first by specific agent. Um, targeting CD3, uh, and GP 100, uh, tumor associated antigen on melanoma, and that's the first drug to ever show an improvement in terms of survival in, uh, in uvel melanoma, that drug was approved as well, again, and that's that's the first by specific to be approved for a solid tumor. Now if you go to mucosa melanoma, um, there we don't have any agents approved, nothing with proven efficacy, and it is pretty remarkable in this day and age. It's 2024 and still we have diseases like mucosa melanoma for which there is no real standard of care. Right, there's no therapy that we've proven um to be effective. Uh, we've tried checkpoint blockade. Some activity, but dramatically inferior to what we see with cutaneous melanoma. Um, we've tried cytokine, so we've tried um IL2 based therapies, uh, and then the Anderson. Did a series of small clinical trials of um what's called bio chemotherapy, so the combination of inter interferon IL-2 and chemotherapy and various subsets of mucosa melanoma, and those trials showed some modest response rates but no real durability and no real evidence of improvements for survival. And so this is A rare disease, uh, for which, uh, we need effective therapies.
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