Tri-specific Antibody SAR442257 in RRMM and Non-Hodgkin Lymphoma | Fredrik Schjesvold, MD, PhD | #ASH24

Hey, my name is Fredrik Schjesvold, I’m the head of the Oslo Myeloma Center in Oslo, Norway. We’re presenting a poster on a very novel drug. It's the first time it's been presented. It's not only novel in that way. It's also a very novel principle.

So this is a trispecific, probably all in myeloma and, have heard about, what the bispecifics have done, and they are approved now, both in the US and Europe, many other countries, where you have one protein antibody base that is targeting both the myeloma cell or the lymphoma cell.

And I see the three T-cell immune cell. So what happens when you bind these together is that the T-cell is activated, the immune cell is activated and it kills the myeloma cell or the lymphoma cell.

This trial was an attempt to increase even that efficacy. We know that there are very efficacious drugs, but they don't cure patients in late-line still. So, here they try to build even more potent T-cell stimulator.

So instead of having just one target protein on the T-cells, they had two. So the three that is commonly used. And CD28, which gives another signal from the T-cell to be stimulated. And on the other side, they're stimulating on the target in the myeloma and lymphoma cells.

So the intention here was to have an even stronger T-cell stimulation activation. So it kills more myeloma cells. For myeloma cells, they were targeted by, and lymphoma cells were targeted by CD38, which is the same target we use for daratumumab and isatuximab, and these are antibodies.

So, and it's also present on lymphoma cells. So, there was a valid sort of possibility that this increased T-cell activation would kill more of the cells.

So, the study is complete. It's a phase 1 study, dose escalation study. There were most myeloma patients, 40 myeloma patients and seven lymphoma patients. Non-Hodgkin's lymphoma. So there are so few. So it's difficult to discuss them. So I'll stay with the myeloma patients.

But the surprise, the results were not as we expected, actually. So what happened was that the T-cells were sold. They were very heavily stimulated with so much that they got exhausted quite early. So what happened was that, we do see a bispecific treatment on the T-cell treatments. We do see some CMV reactivation, and it's difficult to clear. Right in the virus or a COVID virus, but still, it's sort of manageable. And it's mostly blood samples and light symptoms. Here. We saw real escalations of even CMV, but also EBV, Epstein-Barr Virus, which you don't see so much for the other bispecifics.

So it seems that this double targeting of the T-cells is just too much. The T-cell just activates very and then they just exhaust, and I think that also is probably the explanation that the response rates were quite low.

I have to say that all patients were CD38 treated before without tumor isatuximab. And to see if that was the target here. So that's also a possibility.

So the efficacy and toxicity are two different questions sort of. But the toxicity with this, exhaustion and virus problems turned out to be so huge that the drug is not developing further. This presentation here and the following publication will be the end of this story, but I think it's learned a lot about how also not to stimulate T-cells because stimulating T-cells has been what we've been discussing for many years. So how to increase that?

And this was not the way important to understand because there was a belief in this before we tried in the lab. It works. So that's sort of nowadays, But here we at ASH, we will see a different concept using a trispecific.

This was a trispecific with two had some T-cell stimulating extra much and one on myeloma cell. Here we will see the opposite, where you have one on the T-cell, the two on the myeloma cell.

And that seems to be a better way of doing that. So that's trispecific coming towards CD38 and BCMA on the same cells, in addition to stimulating T-cells as usual.

So we have learned now this is more probably the way to go to move forward with that.

If you have a B cell, not a good B cell function, you get bacterial infections, you get pneumonia, some streptococcal diseases. So very common in myeloma. So we substitute the bispecific patients because they're so efficient against plasma cells that they kill all of the antibody production.

So we use immunoglobulins for that. But for the T-cell specificity that doesn't help, the antibodies don't help against intracellular agents like viruses. Then you need T-cells to work. And if you have a treatment that blocks both T-cells and B-cells, then it becomes difficult for the patients.

I think there's several things to understand about the study. One thing is that. When you run out of options, phase 1 trials, that is left when we don't have any more standard treatments. Phase 1 studies have the great advantage of offering you benefits, when there's no other possibility.

So I think patients should know that and also know that most phase 1 trials fail. But in my opinion, it's always better to try this because you can also be the patients that get the first possibility to use the drugs that we now use in the clinic before they get there.

So, to participate in phase 1 studies is a really good thing. But it's okay to also know that they are the least secure thing in treatment. We don't know before we start. I mean, everybody has to just accept that, but also phase 1 study patients are being even more taken care of than the other patients because we know so little and very few centers do phase 1 studies, selected centers.