so um we have you know I mean we’ve looked at uh CSF and and also in plasma for a variety of different biomarker types cell-free DNA being one of them um the cell-free DNA field is really I think where a majority of the work has been done right now in terms of um potential candidate biomarkers in patients with brain tumors. There’s a number of groups that have looked at the utility of cell-free DNA, largely for diagnostic purposes...
so um we have you know I mean we’ve looked at uh CSF and and also in plasma for a variety of different biomarker types cell-free DNA being one of them um the cell-free DNA field is really I think where a majority of the work has been done right now in terms of um potential candidate biomarkers in patients with brain tumors. There’s a number of groups that have looked at the utility of cell-free DNA, largely for diagnostic purposes. And so, you know, that in and of itself is a class of molecular classification. There’s some really nice work that’s been done there out of MSK and then other institutions. On our end, you know, we’re really interested in identifying monitoring biomarkers. So things that we can use to be able to track disease response, especially for patients that are undergoing chemoradiation or immunotherapy, where there is that question of progression versus not. And especially as we start to think about new types of clinical trials that are more response-adaptive based and using that feedback. So the study that we looked at with cell-free DNA was longitudinally over time. We have patients who are having Ommaya reservoirs implanted at the time of surgery, whether that’s resection or biopsy. And the Ommaya reservoir is really just kind of a, it’s a CSF access device that allows us to sample that CSF over time whenever there’s an, whenever the patient undergoes imaging. And we’ve seen with that cell-free DNA that there’s a really nice ability actually to see decreasing tumor burdens, whether that’s a first resection or chemoradiation in patient-specific mutations, so the variant allele frequencies, as well as even overall the copy number burden, which is the chromosomal complexity of that patient’s CSF cell-free DNA. Moreover, we can really see, you know, if we have the tissue to compare to, we see similarities in the tissue and the CSF variants. And importantly, you know, it’s easy for us on an MRI to see decreasing tumor burden for a resection. I mean, that’s kind of a yes or no question. Like I was mentioning, the question of progression versus pseudoprogression or radiation necrosis is really challenging. And one of the things that we’ve seen with that longitudinal sampling in that paper is that we had a patient who we were unsure if it was very early disease progression or pseudoprogression from recent radiation. And we could see that there was a, you know, over time, a decreasing copy number burden, decreasing IDH1 variant allele frequency in their known IDH mutated tumor. And so that gave us a lot more confidence that what we were seeing was actually pseudoprogression and not disease progression. So, you know, and similarly, we’ve been able to see progression in other patients with their cell-free DNA and CSF. So, you know, I think it’s a really promising source for liquid biopsies and a really promising biomarker type. There’s still some unknowns about it, like what is the impact of inflammation on the stromal cell-free DNA release, and could that adversely impact our ability to detect changes over time? Tumor to CSF contact is also, again, kind of a rate-limiting step there. We’ve had some patients who’ve had disease progression further away that’s not in contact with a CSF space. And so there’s a more limited ability to detect progression there. But nevertheless, I think a really exciting candidate biomarker type and the ability, I think, even just to prove that there’s feasibility and promise to it is exciting. And I think especially for, you know, partners in industry who maybe have a targeted agent, like against an EGFR, an IDH or something like that, there’s opportunities there.
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