T-cell receptor

Then we have cell therapies Cell therapies can be autologous cell therapies or allogenic.

And for autologous, we have CAR-T cells or TCR-T cells.

CAR-T are T cells derived from patients and engineered to express surface proteins that target antigens on the surface of cancer cells.

TCR, T cells, again are patient-derived T cells engineered to recognize a tumor-specific protein fragment with the MHC combination within cancer cells.

David Hill at CHOP has shown that there are milk-specific T-cells.

They respond to milk in culture, and they have a certain TCR and a different profile than the other pathogenic effector T-cells.

So if that type of test actually is commercialized and validated and then the trial is done that, yes, you have these T cells and I take milk out of your diet and you get better, that's huge, right? Then you can have a really good conversation with your parents, your families, your patient and say, you look like this might actually work for you.

Let's try it.

But this idea that you need to have, you need to have it both ways.

You need to have a cell that survives really long because you need that TCR to survive for a long time so you can potentially detect all of these potential pathogenic proteins or like you are able to respond to all of these pathogens.

But on the other hand, you need to be ready to respond to it very quickly.

So it's very interesting.

So that's our value proposition.

Our value proposition is also to work on both surface and intracellular cancer biology with antibody-based T-cell engager or a TCR-based T-cell engager.

Got it.

And you mentioned earlier making sure that the T cell's health is good enough to actually kill the tumor.

Two things already have been now revealed.

So neutrophil myelinase isoform 2, which remember was involved in the whole Nrf2 keep activity, that's why I'm bringing it in now, its expression is is indeed essential for T-cell receptor signal amplification and the sustained level of the amplification, when specifically antigen presentation is relatively low.

And what it induces, the NSM-2, on the TCR with low antigen presentation, is a particular enzyme called PKC zeta.

That's a protein kinase C isoform zeta.

And what PKC zeta does is generate microtubule polarization.

Because now you've got diacylglycerol.

Diacylglycerol, remember, via allosteric activation, activates the protein kinase C-zeta.

And what does that PKC-zeta enzyme do? TCR-mediated T-cell activation.

What's DBTV and what is improving T-cell receptor stability matter for manufacturer and scale?

you know, this first T-cell engager that's been approved for solid tumors, it was actually a T-cell engager that was targeted against peptide MHC complexes.

And it uses what's called a T-cell receptor or a TCR.

T-cell receptors are the protein in your body that naturally recognizes peptide MHC complexes.

They're known to people like them because they have this great specificity.

They've been engineered to be specific to peptide MHC versus something like an antibody that other people are working on where the specificity is a little bit more unknown.

And so what this first molecule was that was developed and it was approved in 2022, it's a molecule called Kimtrek or Tabentafusp approved for uveal melanoma.

It has this great specificity, but there are challenges from a manufacturing standpoint when it comes with using something like a TCR or a T cell receptor.

And we really don't see much of a clonal overlap between those expanded Tregs versus the non-expanded Tregs.

So, yeah, to get to TCR signals, it's still tricky, right? I mean, even in mouse, it's not trivial.

What helps is that the activation time point is always really well defined, right? We know when the T cells get activated, so then we know what markers to look for.

And there are some reporter mice, too, with Nr77 is the one protein that really specifically indicates that a T cell got a T cell receptor signal and not a cytokine signal.

I mean, we're also thinking if there's acute inflammation, CD8 T cells can get activated by inflammatory cytokines if the right cytokines are around us.

It's termed either inflammation-driven activation or bystander activation.

And T cells can even... kill stress cells independently of the um of a strong tcr signal um if they express nkgd so basically almost start acting like in case cells so they get activated through these um pro-inflammatory cytokines they start to express granzyme to express nkgd and then stress cells will express the ligands for nkgd so then um these bistro activated t cells um uh could potentially kill stressed or infected cells in a TCR-independent manner.

So we were thinking maybe this is what will happen, and we're kind of hoping this will happen, because that's what my lab has also been interested for a long time, is sort of bystander activation in tissues.