I think one of the many significant challenges we have in the field is is how are we going to develop. All of the drugs um that we have in the pipeline, uh, with a limited number of patients that we have, um, in, in a way I think we're in a very fortunate position where um we have a huge number of assets, um, new mechanisms. Uh, new avenues Um, in terms of biology to target, Um, and the question is how do we do this in the most rational fashion? So how do we do this, for instance, for immunotherapy? Um, we're still struggling with that for, for instance, even PD one based therapies, how can we best select, um, patients and certainly PDL one is, is a piece of that, but that's, uh, that's certainly not the answer. Um, but how do we do that with therapies like Nabaleukin neural tube-based therapies, um, and, and that's a, that's a complicated question. It's, it's almost like, um, You know, it really is akin, I think, to Uh, where we were with the idea of precision oncology even 20 years ago. We we're just trying to dissect um all the new genomic data that we could get with next gen sequencing. What does that mean? How do we use it? How do we understand that, um. And, and those were early days. I still feel like in terms of targeted therapy, we're still in in in early days, um, but that's particularly true for immunotherapy. Uh, so for these therapies, how do we best predict what the right disease is to treat? Who's gonna benefit, um, which patient, um, and, and. You know, they're gonna be tumor intrinsic factors obviously that that we have to look at um extrinsic factors, um, organ sites that involve the tumor micro environment. Um, You know, simplistically, I, I like the idea of effective versus immunosuppressive mechanisms, um, and, and are there tumors where, where that You know, that finely tuned balance, um, that allows continued tumor growth, um, maybe can be disrupted, um, and gain benefit, um. Um, you know, Um, So, you know, so, so, you know, what are the things that we can do, um, investigating tumor marker environment, what are the cells that we have there? What are the inhibitory factors that are that are really at play, um. You know, when, when we look at, for instance, another disease that I, I treat is, is uveal melanoma. Uh, which is, uh, again different from cutaneous, different from, from mucosal, uh, and this is one that frequently involves the liver, um, and, and more and more for the liver we're seeing, and, and this is actually not new, but um. Any cancer that goes to the liver, colon cancer, pancreatic cancer, uvular melanoma. Uh, they tend to do poorly. They're more aggressive, they respond less well to any therapy. They certainly respond less well to to immunotherapy, uh, and part of that is the tumor, but part of that is that microenvironment as well. And some in the liver, for instance, can we target things like MDSCs, right, which may be a primary factor there. Uh, and so back to the Nebalekin story, um, you know, are there tumors that are primarily Treg driven, um, that might be, um, Um, more susceptible to this therapy. Um, You know, there are a number of therapies that are being developed now that function primarily to suppress Tregs, uh, and even by doing that alone, we're seeing activities in some cancers. And so. Short answer, um, I think we still have a lot of work to do in terms of predictive biomarkers for the development of these sorts of therapies. Uh, I think this is a struggle not just for the cytokine-based or IL2 based therapies, but for all of our immunotherapies, um, and You know, we have to solve this. This is not not just an issue with patients, patient selection, but also how do we um think about rationally combining IL2 based therapies with PD1 with other immunotherapies with with other modalities of treatment. Um, so I'm afraid right now there are, there are more questions than answers, um, but thankfully, uh, we do have a number of, um, agents to test. Um, I think tools available to us to, um, um. Um, assess the tumor microenvironment, um, assess immune fitness, um, and I think we just have to look, we still have a lot of learning to do.
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