What other targets are being explored in CAR-T cell therapy?

In multiple myeloma, we're fortunate in that there's a number of CAR T cell targets which are being explored. The most common one is BCMA, also known as B cell maturation antigen, which is very specific for myeloma cells and late B cells. However, there are a number of different targets being looked at. The key ones are called GPRC5D, which is expressed on myeloma cells, but is also expressed on skin and testes. And also something called CS1, also known as SLAMF7, which is specifically expressed on B cells and plasma cells. There's a little bit of work looking at CD38, and we get to see some results on that. Yeah, so right now the most common target is BCMA. So BCMA is a lead target antigen for CAR T and actually for all immunotherapeutic targets, even for bi-specific antibodies and antibody drug conjugate, because that is very specific and present in the long-leaved plasma cells and plays a significant role in the growth of myeloma cells. Because when you want to choose a target for the CAR T, you want to be specific, as much specific as possible to prevent what we call as on-target off-tumor toxidase. Because if they are targeting other cells, which are not related to the tumor, but that is still expressed, then you could have a lot of other toxidase which you don't want. In addition to that, BCMA, there are a number of antigens that are being explored. Again, it's pretty early right now. As I said, CD19 as a part of the dual target, not as a single target. CD38, there is again data from China that are targeting BCMA and CD38 together. SLAMF7, CD138, and then the other receptors like TASC and then APRIL, which is one of the ligands for the BCMA. So those are the targets being explored at the current setting. There are GPRC5D-targeted CAR T therapies also in development as well, and those trials ongoing and that's another exciting way to target GPRC5D on the myeloma cell. What things should be considered when using CD38 as a CAR T target? So CD38 is a target of monoclonal antibodies, namely daratumab and isotuximab, and these drugs are routinely used in myeloma practice. So once you know that those are effective, the question has always been, can you use that as a target for other therapies such as CAR T cell therapy? So these are under investigation, but we have to be a little bit careful with CD38. CD38 is also expressed on the respiratory tract. So it's on the lining of your windpipe going down into the lungs. And that's one of the reasons why we have to give a lot of steroids when we first deliver CD38 antibodies because of the risk of reactions. So clearly if you're going to give a CAR T cell therapy against that, you do have to be very careful about causing any respiratory or lung problems. So yes, it's being evaluated, but I haven't seen any data yet. What is CD229 and can it be a myeloma CAR T target? It is expressed on all myeloma cells. It's strongly expressed on all myeloma cells. It's expressed on the tumor cells of almost 100% of your patients. And that's a very rare thing for any target, I think. But it is also expressed on normal cells. And we're talking about normal white blood cells, normal immune cells. So in the beginning, we found out that the target CD229 is expressed on normal T cells even. So we said that's something that's a no-go, right? If your treatment is a T cell treatment, you don't want the target to be expressed on T cells, right? Because that would undermine your whole approach, right? But then we found out, and that's what research is all about. At that time, that was just an idea, a hypothesis. But then we found out if you activate a T cell, and that's what you always do when you produce CAR T cells, you activate them, right? Cell activation leads to loss of CD229. And that's why CAR T cells do not express CD229. It's gone from these cells. And that's the case for all the activated T cells in your body as well. So then we said, so these things look much better now for CD229 CAR T cells because we know that the target is not uniformly expressed on all normal lymphocytes, such as T cells, and so forth. But that wasn't enough. So we said, is there anything we can do to help the CAR T cell differentiate between a normal lymphocyte and a myeloma cell? And I can't give you any details right now, but I can tell you that we found an excellent way of doing exactly that. So we think that we've been able to develop an optimized CD229 CAR T cell approach that's able to differentiate between malignant and normal white blood cells. And that's an enormous advantage, in my opinion, for this whole field. And this just shows what research is about. Our goal has never been to develop a product, but our goal has been to develop a treatment that works for our patients.