Can BCMA disappear as a target?

So the first human being to ever have a response to an anti-BCMA therapy was a patient number seven on the first NCI CAR T cell trial for myeloma. And she in fact did not have a clinical response to her treatment, but when you look at the BCMA expression, it used to be high, and then it became low after she got CAR T cells targeting BCMA. So this was the first inclination that we had that something, the CAR T cells were exerting some sort of effect. So true BCMA loss, which is true by allelic BCMA loss is not all that common, but it is reported. BCMA expression can reduce and perhaps that does have a component that contributes to the resistance. There are several factors that go into it. T cell health is one, T cell engineering is another. How effective is your binding antibody? If the CAR that you're putting on there, it doesn't bind to your target very well, then it doesn't matter how healthy your T cells are, you will not get the sort of response that you want. You may not get the sort of durability that you want. There are other things being looked at such as T cell health, the kind of T cells that you're looking at, T cells that might have more memory and perhaps persist for longer. All of these things go into making a decision, seeing whether there is resistance to BCMA for instance, and whether people can have long term duration responses to CAR T cells. But I think we will find that as we tinker with the engineering, improve the manufacturing, improve the T cells, and improve the CARs themselves, then we will see longer and longer durations of remissions and responses. So we now have a number of BCMA targeted therapies that are very, very effective. We have the CAR T cells, we have bispecific antibodies, and we have antibody drug conjugates. And unfortunately, multiple myeloma cells, they tend to, after a while, become resistant to the drugs that we have. And in terms of the BCMA targeted therapies, one possible mechanism of resistance is that BCMA, which normally sits on the cell surface, can be shed from the cell surface. So the number of receptors on the cell surface is then decreased, so there are fewer receptors for the drugs to bind to. That was shown in a presentation today with treatment with, in patients treated with BALENTIMED MAFEDOTIN, where we saw during treatment that the number of receptors went down, and then after stopping treatment, BCMA receptors came back. Another possible mechanism is that on the genomic level, so on the chromosome level, the chromosome, the part of the chromosome where BCMA is located can be deleted. This also was shown for GPRC5D. So if there is no gene, if that has been lost coding for BCMA or GPRC5D, there will be no receptor on the cell surface and the drugs will not be able to bind. So that's another possible mechanism of resistance. So for the first possible mechanism that I mentioned, that we have fewer BCMA receptors on the cell surface, when we stop treatment, we see that these receptors tend to come back. So therefore we can treat with several different BCMA targeted therapies, maybe not one after another, although we have seen that that still can work, but it might be good to sequence them and have another drug target in between and then re-treat with BCMA targeted therapy again. Can BCMA disappear from the surface of the myeloma cell? There are a variety of reasons why a therapy against BCMA might stop working. And a lot of these are theoretical, but some of the reasons are that perhaps the multiple myeloma stops expressing BCMA on the surface. And this is a marker that is on most myeloma cells, but one of the ways that cancer figures out how to grow is that it decides to lose whatever it is that's being targeted and it figures out a different way to grow. And so that's one kind of easy way to explain it, but I think that it's a lot more complicated than that. There are a lot of patients who are receiving BCMA directed therapies who don't lose BCMA expression and the treatments still stop working. And so I think that it goes back to what is the type of therapy, how long has it been given? Most of these treatments that are being given today are using the body's T cells or manufactured T cells in order to target the BCMA. And sometimes the T cells stop working, whether those are CAR T cells or whether those are the body's T cells. And then it doesn't really matter what the BCMA is doing. It may just have something to do with that. And so I think that it does matter which type of treatment somebody might be on. If it's a CAR T cell, perhaps if it stops working right away, that might just be that either the T cells weren't very good or it might be that it wasn't the right target for that patient. But if it worked and it's been a long time, then it could just be that the T cells just had reached the end of their lifespan and the cancer started growing again and then retargeting BCMA might very much work. And a variety of different reasons might exist for different types of therapies. By specifics, overcoming resistance to that might be a little bit more tricky. But there's a lot of research going on into this. And so we're going to figure it out. Finding the right antigen on the surface of the malignant plasma cell is a crucial step if you want to design an effective agent, an effective drug, whether an antibody, whether a cellular therapy like CAR T cells. But we have to acknowledge that the malignant cells and the plasma cell in multiple myeloma is a very clever cell, unfortunately, can try at some point to avoid being killed by these agents. And one way to do this is to down regulate or even the antigen would disappear completely. So if your target is BCMA, the cell through different complex mechanisms, this is why I said it is a clever malignant cell, can manage to make BCMA disappear from the surface. And then obviously your drug cannot see its target anymore. So this is a common immune escape mechanism among many others, of course, because these nasty cancer cells, like in myeloma, always will find or try to find a trick to escape the agent. And that is exactly the idea in general where we try to find a way to do this. We try to combine different agents together to avoid an escape for one agent, then you have the other agent which will take control and so on. It can and that is one of the reasons why patients may relapse. So BCMA can disappear, it can get secreted. So some of the studies that we're looking at right now is preventing the immune system from releasing BCMA from the plasma cell. So there are drugs we can give to help prevent that. So a kind of BCMA escape is another way, so even though the BCMA is still expressed, the treatments stop working. But one way that it fails to work is it just disappears. So the myeloma cells that are left behind don't have BCMA, so drugs going after BCMA will become way less effective in those situations. We know that BCMA can disappear as a target after T-cell directing therapies, that includes CAR T-cells or bispecifics, but actually that doesn't seem to be a very common mechanism of resistance in myeloma. In other hematologic tumors it does seem to be more common, but in myeloma it looks like there's probably other mechanisms of resistance.