RE:Science discussion - for TLT geeks only
DJDawg wrote:
I was reading up on the whole issue of partial response (PR) and had a few thoughts.
The company and a few posters are hopeful that patients who have positive cytology but normal appearing cystoscopy may in fact get to be labelled as CR if they find that the cancer is in fact upper tract (ureter and higher). The way do do that is a CT scan.
It is confusing to me but from what I can see, most bladder cancer doesn't have upper tract cancer at the same time. Depends on smoker status but range is something like 2-20%. That means that for all the PR's in the TLT research, not that many are likely to switch to CR due to upper tract foci.
The thing I have found interesting is that CT scans are cheap and easy to order. Doesn't take long to get one at all. I can say that as I i have worked in parts of healthcare where CT requisitions were placed. MRI's were a totally different thing. It seems odd to me that there are patients that have been PR for so long as if it was in fact an upper source for the cytology, the CT would have been done by now.
My hunch is that many have had CT and no upper source was found. BUT, that they have been kept rolling in the study and are still PR because if you find the positive cell cytology in the urine that means that, at best, they are PR. If you cannot see the cancer on the scope and you cannot see any recurrence on the ureteric CT imaging, then you can't quite say that they are full NR either as a full Non-response would be cells found and some kind of visualization of cancer recurrence together.
So what does that mean? My hunch is that they are dealing with a new issue of sorts which is due to how TLD-1433 works. If cancer growths are a collection of cells that are not entirely uniform then I think that the rapid growing ones are the ones that are likely most drug avid. The treatment protocol would lead to the fast multiplying and expanding cells being ablated. Leaving the slow growing and slow multiplying residual cells still present for some patients. Those cells may still shed a few here and there so that they are on the cytology but if they are not rapid growing and dividing, they may stay at low size so that you don't get the ability to see the leftover cancer focus. Means in a way that you are in PR limbo for a while.
But I think that this is still a good thing. Research into a variety of cancers have shown that transferrin receptors are more highly expressed in the rapid growing and dviding cancer cells. Which makes sense as they may need iron to grow and spread. So the TLT drug approach is most effective at attacking rapid, aggressive cell lines with high transferrin receptor expression. If cancer clumps or collections have a mix of cells, then the ones that are not rapid expanders are perhaps not going to to killed off as well by the drug. Which is not the worst thing as those slow growing and slow multiplying cell lines are not as likely to invade, spread, metastasize.
All in all, I wonder if it is going to play out that TLD-1433 works to kills of all cancer in some patients but in others, only kills off the aggressive cell lines, leaving some cancer still present. That would count as a non-progression in my view. Non progression still means no need to remove bladder. Non-progression for brain and lung cancer could still mean that the patient does well, with the cancer being restrained into being a slow, stable cell line leftover. Not ideal but still a good thing. The area that I used to work in dealt with thyroid cancer. Many patients had surgery and a type of ablation. Then still had some cancer cells left. However, they would just have imaging for years and year and nothing would change. The few small clumps of definite leftover cancer would stay the same. Which is funny if the initial cancer had growth and spread all over the neck. With thyroid cancer, when you ablate the left over cancer cells, the treatment also is selected more towards fast growning and fast mutiplying cells. So even if you are not cured in the end, you can live decades plus with a residual clump of cells.
When I've read up on immunotherapy with BCG or the like, it strikes me that the methodology works against NMBIC cells without any distinction for aggressive cells or slower cells. As such, it seems like it is whack a mole therapy. Cells grow and divide, BCG tries to attach and trigger immune response to the cancer cells. If cells divide faster, cancer spreads and wins. If BCG/immune response is faster, cancer is treated.
So in summary
- I'm bored (obviously)
- CT's are easy and quick to get, even if you factor in pandemic.
- upper tract cancers is not too too common (at same time as bladder cancer)
- Suspect many PR's have had CT scans and that they are still labelled PR because CT didn't find anything, but neither did the cystoscope - I call this limbo PR
- suspect many PR's are in limbo because the left over (after TLD-1433) cancer cells have been selected to be slow going.
- TLD-1433 working against agressive (high transferrin receptor expressing) cancer cells is a good thing and may make some patient's long lived but not necessarily cured. That is still a valuable drug.
Comment away. I'm no expert :)
Boy, back from the Holiday vacation & it seems I missed a lot. Good points DJDawg.
It is my understanding that a PR can also represent a positive cytoscopy with a negative urine cytology. In such an instance, a patient would require a bladder biopsy which could delay the reporting of response results. Such a patient would be considered a "CR" if he were to have biopsy-proven benign or low-grade NMIBC.
Regarding "slow-growing" cells, I'm not sure what you're referring to. There are cancer stem-like cells (CSCs) found in many cancers, including bladder cancer. Although these cells generally make up a very small fraction of any particular cancer, they are very resistant to chemotherapeutics & essentially act as a reservoir of malignancy, relapse & metastasis.
Fortunately, cancer's thirst for iron may turn out to be its Achilles heel. It has been shown that CSCs also have a similar thirst for iron & hence increase their expression of transferrin receptors = more sites for Rutherrin/TLD-1433 to dock at & be the perfect Trojan horse...then throw in a healthy dose of an immune response. Happy New Year may have a new meaning : )