Paul Lammers, MD, MSc, breaks down T-cell antigen coupler technology and its use in various solid tumors.
In the first of 3 videos, Paul Lammers, MD, MSc, chief executive officer of Triumvira, discusses the company’s unique T antigen coupler (TAC) T-cell technology. Daniel Olson, MD, Assistant Professor of Medicine, the University of Chicago Medicine, presented an abstract about the ongoing phase 1/2 study evaluating the safety and efficacy of TAC01 in HER2-expressing relapsed or refractory tumors (NCT04727151) at the Society for Immunotherapy of Cancer 38th Annual Meeting November 1-5, 2023
Here, Lammers describes the TAC mechanisms and what sets it apart from chimeric antigen receptor (CAR) T-cell therapy.
0:09 | This all goes back to McMaster University in Hamilton, Ontario, Canada, where Johnathan Bramson, professor of immune biology, started to work on CAR Ts about 15 years ago, together with his postdoc, Christopher Helson, who now is our director of platform development in the company. And he said, look, the CAR Ts were very effective, but we killed so many mice in the lab it was ridiculous. Because they're so toxic, and they're known to be extremely toxic. And so he said, look, we started to come up with looking at different structures, means to activate T cells that are more safe and more natural. So they looked at a lot of different vectors instead of CAR Ts and found out a structure known as TAC or T-cell antigen coupler, and it has 3 separate components.
1:00 | On the outside of the cell it has a binding domain that binds to an antigen presented on the tumor cell. It could be HER2, it could be claudin 18.2, it could be GUCY2C, it could be GPG3, doesn't matter. And you can take anything. Yeah, you can take a peptide, single-chain antibody, you can take a DARP in—designed ankyrin repeat protein—it all works. And it's very similar to what you put on top of CARs, right. And it needs to recognize an antigen. That binding domain is linked to a proprietary single-chain antibody that binds to the epsilon domain of the normal T-cell receptor, the outside of the T-cell receptor. So the T-cell receptor has 8 extracellular proteins: alpha, beta, gamma, delta, and epsilon; 2 epsilon domains and 2 delta domains. So, it binds to, to the to the epsilon domain. This means that all the activity of the TAC goes through the normal T-cell receptor, which we think is extremely important. CAR T works outside of the TCR. Because it has an own activation domain and co-stimulatory domain. The TAC doesn't have that.
1:46 | So, all the activity goes through the normal TCR. And the third component of the TAC. So, we have the binding domain, we have an epsilon binding domain, then we have 2 parts of the CD4 co-receptor, also part of the vector: a transmembrane domain that helps anchor the TAC into the surface of the T cell. But very importantly, it has an intracellular regulatory domain known as LCK, a kinase that phosphorylates the 10 different activation motifs on the inside with the TCR. So, what that means is that is responsible for activating the T cell that needs to be activated. But more importantly, to silence the T cell when it does not need to be activated. The problem with CAR T cells is they're always activated. They're built to produce cytokines. When you manufacture CAR T cells, they start producing cytokines in the process because that's how they're built. They have their own activation and co-stimulatory domains. The TAC doesn't have it. So that means is that the TAC T cells have a number of ideal characteristics for adoptive cell therapy. So we don't see that that what you call tonic signaling. CAR T cells are always activated, also always producing cytokines. So we see a very low-profile cytokine release, effective enough to kill tumor cells, but it doesn't lead to toxicity. So we have never seen any of the toxicities in animals. And we see that now reflected in our clinical trial also where we have a really, really good safety profile.
3:24 | And also, the T cells are not premature exhausting, because the majority remains as memory phenotype cells, which is ideal. They penetrate deeply into solid tumors, they get activated only when you meet up with the tumor cell presenting that antigen. And we've done this, we've shown this through basically persistence models. So where we rechallenge the mice that have been cured with fresh tumor, the tumor doesn't take. So really that shows that they are very persistent.