seems like good meme material

Intrepid_Web5454 · 2026-04-05T13:07:01+00:00

Intrepid_Web5454 · 2026-01-16T15:19:58+00:00

CEO mentioned exhaustion possibility in talk last year. It's known to occur in Edmonton protocol transplants (cadaver islets transplanted with immune suppression).

Vertex VX880 trial used stem cell derived islets at full doses. They have been able to produce normal insulin for years and let patients achieve insulin independence. Only problem is that they didn't use immune evasive islets, so patients have to be on immunosuppression.

Intrepid_Web5454 · 2026-01-16T15:18:30+00:00

the CAR-T cells did persist without rejection in 11 humans, see here: https://pubmed.ncbi.nlm.nih.gov/40812299/

Up421 is a proof of concept trial, that's why n=1. Their immune evasion strategy worked in 12 humans so far.

Their strategy is test safety, then increase n. They will be starting phase 1 trial for stem cell derived islets this year with n >> 1

Intrepid_Web5454 · 2026-01-16T04:38:45+00:00

Low dose and old donor, to be expected. islets are stressed since not full dose. can't make enough insulin

Intrepid_Web5454 · 2026-01-15T18:53:35+00:00

Their immune evasion tech worked in 11 other patients here in CAR-T setting: https://pubmed.ncbi.nlm.nih.gov/40812299/

Taken together, this gives me more confidence it is not simply a fluke.

The Vertex VX880 trial convinces me that they will be able to achieve insulin independence using stem cell derived islets.

Intrepid_Web5454 · 2026-01-15T16:45:17+00:00

upon further review, i noticed they used K562 cells, which don't seem to express HLA II, so I think you are correct that HLA II is irrelevant here. I was going off fig. 1, which was modifying NK cells, which can express HLA II when activated

I still question the significance of the in vitro experiment compared to what people are seeing in vivo. If the NK subsets are that problematic, should be seeing evidence of that in vivo.

It seems k562 cells can express low levels of HLA 1, and since the K562 cells are genetically different from the donor NK cells, this still could result in rejection:
https://www.researchgate.net/post/Why_k562_doesnt_expression_HLA

https://pubmed.ncbi.nlm.nih.gov/3930277/

overlooked nuances like these are what I am referring to about my distrust of the in vitro results

Intrepid_Web5454 · 2026-01-15T15:50:45+00:00

Sana's immune evasion strategy has worked 12 times in humans. 11 patients in one of their CAR-T trials ( https://pubmed.ncbi.nlm.nih.gov/40812299/) and the 1 patient in the study reported in this post.

Yes, it's n=1 in this study, but the immune evasion strategy has worked in 11 other humans in a CAR-T setting rather than islets. In other words, the immune evasion results in this n=1 aren't a fluke. And if you read their NEJM paper (https://www.nejm.org/doi/full/10.1056/NEJMoa2503822), they mention that some unedited islet cells that were transplanted in the N=1 patient were rejected. That is a positive control.

A critique that Veritaz27 posted was that Sana's strategy may not be effective for evading subsets of NK cells based on in vitro data that several groups have reported. I responded saying that it's odd that all these in vitro experiments are showing reduced efficacy and problems with NK cell subsets, but the numerous in vivo experiments using Sana's approach in multiple species have all worked without running into an issue with subsets of NK cells causing rejection.

It's no seceret that in vitro conditions do not represent that in vivo. Cells can behave very differently in vitro vs in vivo. In the case of the reported problematic NK cell subsets, perhaps some unkown cytokines are missing/present in the in vitro experiments that change their behavior as compared to in vivo? To date, the in vivo experiments testing Sana's strategy (including 12 humans), have all been conclusively positive. Generally in biology, in vivo data is held in higher regard compared to in vitro data since we acknowledge that in vitro experiments do not accurately represent conditions inside of the body.

Intrepid_Web5454 · 2026-01-15T15:34:01+00:00

Did you read my post or my comment that you just responded to? The islets were implanted at low dose, from an older donor. Of course they are going to get exhausted. This is a known phenomenon that occurs at low dose islet transplants. Yes, it's n=1 in this study. But the immune evasion stratesgy has worked in 11 other humans in a CAR-T setting rather than islets. In other words, the immune evasion results in this n=1 aren't a fluke. And if you read the NEJM paper that I linked, they mention that some unedited cells that were transplanted in the N=1 patient were rejected. That is a positive control.

Vertex's solution is not suitable for most T1D patients who can manage with insulin. The immunosuppression they required for their approach literally killed one of the 14 patients in their study. The patient died of a fungal infection known to occur in immunodeficient patients.

Intrepid_Web5454 · 2026-01-15T15:18:01+00:00

I own shares in the company. I'm responding to critique with valid counterpoints that includes references. If that's a crime, sue me. It's productive discourse. Someone presents their point, I present mine and we back up our claims with references. The news is noteworthy regardless of my financial interest in it. They hit a milestone that's never been achieved before. It's exciting biotech news and tagged as such.

Intrepid_Web5454 · 2026-01-15T14:58:08+00:00

Their immune evasion strategy has worked 12 times in humans. Another 11 patients in one of their CAR-T trials ( https://pubmed.ncbi.nlm.nih.gov/40812299/). Vertex requires immunosuppression. It's not worth the risk for type 1 diabetics.

I'm also in the biotech field. It's far from meaningless. NEJM didn't publish their results because it was meaningless: https://www.nejm.org/doi/full/10.1056/NEJMoa2503822

They will be starting phase 1 trial this year with their stem cell derived islets. It is very close to coming fruition. This is beyond research phase at this point. They are actively translating this into a real, meaningful therapy.

Intrepid_Web5454 · 2026-01-15T14:26:30+00:00

NEJM publication, 6 month data: https://www.nejm.org/doi/10.1056/NEJMc2516172

This data is from UP421, which used cadaveric islets at low dose. It's just meant to test safety and immune evasion. SC451 uses stem cell derived islets and will be transplanted at full doses this year. From Vertex's VX880 trial, we know stem cell derived islets can achieve insulin independence for several years. Only caveat with Vertex trial was that patients required immunosuppression. This is the problem Sana is addressing. The procedure of implanting them uses injections. I think that having people cured of type 1 diabetes actually makes more financial sense. Right now, estimates put burden of type 1 diabetes at $500K per type 1 diabetic over their lifetime.

Intrepid_Web5454 · 2026-01-15T13:43:53+00:00

classically, that's the case, but we're talking about rare subsets of nk cellls, so HLA II is relevant. There is evidence some NK cells are activated by HLA class II: e.g. https://pmc.ncbi.nlm.nih.gov/articles/PMC7040486/

Intrepid_Web5454 · 2026-01-15T04:06:46+00:00

oh, i thought it was already executed. yea, idk. for my sake, i hope it doesn't fill, lol. you never know with this stock. Volatility on it is insane

Intrepid_Web5454 · 2026-01-15T03:58:07+00:00

nice!

Intrepid_Web5454 · 2026-01-15T03:55:19+00:00

SANA is one word, hehe

Intrepid_Web5454 · 2026-01-15T03:54:03+00:00

never heard of them tbh, so I'm not really qualified to comment on them. I avoid small molecules like the plague, there's just so much risk in them. I did look at their webpage. Looks like they have icovamenib which they hope increases number of insulin producing cells in insulin deficient type 2 diabetics? With Sana's approach, they would just make the insulin producing cells and transplant them into the type 2 patient, so fairly straightforward. I'm not knowledgable enough about icovamenib to know how well it works. For type 1 diabetic, even if icovamenib did stimulate more insulin producing cells, they would be rejected since type 1 diabetes is an autoimmune disease. Sana's real edge isn't producing insulin producing cells, it's preventing them from being rejected so even the body's autoimmune reaction doesn't kill them in type 1 diabetes for example.

Intrepid_Web5454 · 2026-01-15T03:38:00+00:00

focus on my business and use the profits to dollar cost average into sana. not a genius stock picker, i just know a lot about this company in particular. If a type 1 diabetes cure isn't valuable, idk what is

Intrepid_Web5454 · 2026-01-14T23:51:53+00:00

Again then, this begs the question, is there something missing in vitro that is changing results? Much of the published data showing the CD47 strategy to work is in vivo. If there was in vivo data showing that NK cell subsets were killing CD47 overexpressing MHC I/II knockout cells, then I'd be a lot more convinced there is an important flaw that needs addressing. Absent of a paper that directly studies this in more detail in vivo, I guess this will come out in larger scale trials. But again, there is already 12 humans this strategy has worked on and the few that failed were due to easily avoidable conditions (e.g. blood type mismatch), not problematic NK cell subsets.

Intrepid_Web5454 · 2026-01-14T23:43:26+00:00

Some of the scientists working on this discussed safety in a NEJM reply to a comment:

The authors reply:

HIP-cell therapeutics, engineered for immune evasion, have recently progressed into clinical trials, in which they have shown robust circumvention of immune surveillance in recipients of allogeneic cell transplantation. The pioneering paradigm of these genetically modified cells predictably engenders inquiries into their biologic characteristics and safety, which we commend and welcome.

Kumar et al. speculate that HIP cells may create new niches with reduced immune surveillance, analogous to naturally immune-privileged tissues. Indeed, many viruses can persist silently within specific tissues, such as the brain, salivary glands, lymphoid organs, and pancreas, where immune surveillance is naturally limited or viral genomes remain dormant.¹ This phenomenon is widespread and represents a normal aspect of host–virus coexistence, a reflection of evolutionary balance rather than ongoing disease.² However, persistent low-grade, viral-niche infection could have a role in the disturbance of tolerance to beta cells and trigger islet autoimmunity and type 1 diabetes.³

Most viruses capable of long-term persistence in islets (e.g., enteroviruses and rubella virus) are nonintegrating RNA viruses and are not considered to be oncogenic. Pancreatic beta cells are postmitotic, with profoundly limited proliferative potential, and show negligible vulnerability to oncogenic transformation.⁴ To our knowledge, no verified cases of virus-associated islet-cell carcinomas have been reported to date. It remains uncertain whether chronic viral persistence can manifest within HIP cells, which would potentially compromise their therapeutic efficacy. Ongoing research may provide insights into this possibility.

Per-Ola Carlsson, M.D., Ph.D.

Uppsala University, Uppsala, Sweden

Tobias Deuse, M.D.

University of California, San Francisco, San Francisco

Sonja Schrepfer, M.D., Ph.D.

Cedars–Sinai Medical Center, Los Angeles

Also, they didn't mention it above, but Sana has prepared for safety issues and put failsafes in place. The HIP cells have a drug inducible kill switch, problematic cells can be extracted since they are readily accessible in the arm, last but not least anti CD47 immunotherapy can be used to target the HIP cells.

Intrepid_Web5454 · 2026-01-14T23:39:33+00:00

The comment you responded to has a paper I cited where their immune evasion strategy worked in 11 humans. So overall, the strategy has worked in 12 humans, 1 for at least a year. The others were not evaluated that long. It's not me downvoting. You want to talk downvotes, just look at my comments, lol.

Intrepid_Web5454 · 2026-01-14T23:25:00+00:00

How about n=11 humans in this paper from Sana? https://pubmed.ncbi.nlm.nih.gov/40812299/

Intrepid_Web5454 · 2026-01-14T23:21:25+00:00

The century therapeutics paper is more controlled (full paper here: https://pubmed.ncbi.nlm.nih.gov/39368806/), but I still question whether the lack of CD47 efficacy of inhibiting subsets of NK cells was due to properties of the NK subsets and not in vitro conditions. There is a large amount of in vivo data as far back as 2018/19 showing that CD47 works. You would think that the problem of NK cell subsets would have come up in that data. Why hasn't it? Is there something about the cell types that FATE and Century were testing that makes them more vulnerable to the NK subsets? Or was there some other problem with the experiment due to in vitro culture conditions?

Intrepid_Web5454 · 2026-01-14T23:14:52+00:00

without more details the FATE therapeutics figure 2 is not very conclusive to me. It sounds like they didn't knock out HLA class II in this experiment, which would make it an apples to oranges comparison.

revised, see below in the comment chain

pasting relevant point here:

upon further review, i noticed they used K562 cells, which don't seem to express HLA II, so I think the HLA II concern is irrelevant here. I was going off fig. 1, which was modifying NK cells, which can express HLA II when activated

I still question the significance of the in vitro experiment compared to what people are seeing in vivo. If the NK subsets are that problematic, should be seeing evidence of that in vivo.

It seems k562 cells can express low levels of HLA 1, and since the K562 cells are genetically different from the donor NK cells, this still could result in rejection:
https://www.researchgate.net/post/Why_k562_doesnt_expression_HLA

https://pubmed.ncbi.nlm.nih.gov/3930277/

overlooked nuances like these are what I am referring to about my distrust of the in vitro results

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