What are dual CAR-T cells?

What are dual CAR T cells? What happens with dual CAR T is that the T cell is engineered to recognize two different proteins on the surface of the myeloma cell and by doing that it reduces the risk of developing resistance. There are no commercially available products that will do that, but the ability to engineer two recognition sites increases the likelihood that the re-engineered white blood cell will effectively kill the myeloma cell. So right now the CAR T are single antigen targets, that means they are targeting one particular antigen. And dual target means you are targeting the two different antigens. So for example, the most common antigen that we target right now is BCMA, but we know that that is not enough. That means patients relapse even after getting the best response and continue to maintain the response for a long time, they still relapse after. That means there is no cure yet. And not everybody also responds to BCMA targeted antigen. So there is an interest and there is a rationale for targeting other antigens in addition to the BCMA. So for example, you are targeting the BCMA plus other antigen, let's say CD38 or CD19 or SLAMF7. So if you are targeting the two different antigens, that is called dual targeted CAR T. Right now we have very early clinical data on the dual targeted CAR T. For example, two years ago there was an ass abstract coming from China that targeted BCMA and CD19. Similarly there was data from the University of Pennsylvania that showed some activity of the dual target. There they targeted BCMA and CD19. And there is a clinical trial I think undergoing right now targeting BCMA and SLAMF7. We need to see how those compare with the single target CAR T in the current setting. Right now most of our studies have looked at CAR T's where we take your T cells, we engineer again basically a receptor on them that goes after one target, so BCMA. Well we can put multiple different targets in one cell. So a dual CAR T or a dual target CAR T is going after two different proteins. So express on the cancer cell. So there is some published data for example looking at CD19 and BCMA as a dual target that haven't looked super promising. Then there are again a number of additional targets that are earlier in development but we're looking at like something called SLAMF7, CD38. There's a number of these in addition to those. So dual CAR T refers to CAR T cells that have not only one but two CAR receptors and target two epitopes on the myeloma cells or any tumor cells. And there are currently no approved CARs that are doing that but this is something that is being investigated preclinically and I think there may also be some early clinical trials that are not reported yet. And the advantage is that you not only target one surface antigen on the cell but target two and this may be more potent than just targeting one and the other is immune escape. So we know from BCMA CAR T cells and CD19 CAR T cells that they sometimes lose their CD19 target on the cell or the BCMA and this would result in resistance because the CAR T cannot identify it anymore. But the chances are less likely if you have two epitopes that you are targeting because then the cell would need to lose both of them. So there may be an advantage but I think that has to be shown in clinical trials and I think the current ideas is having two CARs in one T cell but the other approach having two different CAR T cells could also do, right? It can even combine CAR T cells with bytes or any other drugs. So there's also not a restriction why it should only be two. You could think about three, four, five, six but however the production and generation of these products may be even far more complex than the current ones. But clinical trials have to show whether this is really beneficial and whether it's feasible to produce these in high amounts. Are there trials using dual target? Yes, there are trials that are available that are looking at targets including BCMA plus CD38, BCMA plus CD138 designed to destroy the myeloma cells at two different approach points. What are the advantages or disadvantages of dual target? So as I already mentioned, the theoretical advantage is that if you are targeting two different antigens, which then you probably would provide more effective killing than the single target. That is number one. Number two, if you are using one target and then that target gets lost, that is called antigen loss or antigen down regulation, tumor try to escape out of that, then you can capture or you can kill that tumor by targeting the other antigen at the same time. So that is one advantage, theoretical advantage. Again, as I said, we have to see how that is going to compare with the single target. But that is one of the reasons that we are targeting the two different antigens is because you want to prevent the antigen loss mechanism by the tumor relapses. Number one. Number two, you want to provide a more effective killing or even more efficient killing of the tumor cells by targeting two antigens at the same time. Now the disadvantage, I would say there is no additional disadvantage beyond what is already there in the engineering of the construct. If something is in the complexity of the engineering is needed to construct a dual target that might put into higher cost or higher complexity of manufacturing. But beyond that, there is no additional disadvantage. But if you are targeting some other targets, which could be expressed by some other cells as well, normal cells as well. For example, CD38 is a target that is expressed by a lot of hematopoietic cells, like red blood cells and other cells as well. So if you are targeting that in addition to the other antigen, which is more specific to the cancer cells, in this case the myeloma cells, then you could be seeing a lot of other overlapping toxidies that you don't want to see in that patient. So that could be one potential disadvantage. It really depends on what the second target is in terms of the disadvantages. So CD19, for example, is more ubiquitously or evenly expressed in a lot of different B cells. So what that can do then, if you are knocking down CD19, is you can really suppress the immune system. So that additional target depends on where else it is expressed. The advantage is, if you are targeting just BCMA and the cancer kind of outsmarts that, you have another target that the treatment is still going after. So you would expect less relapses or more efficiency in terms of treating the cancer. But again, you have to weigh that with the side effects of an additional target and how that might affect the immune system, other organs, so on and so forth. The advantage would be if resistance is from the loss of one of those targets. Therefore, even if you lose one of the targets, there's another target that's still present that can still leave the myeloma cell susceptible to killing from the CAR T cell. Does dual target use one CAR T with two receptors, or is it two different CAR T cells infused at the same time? When one says dual target, it is classically one type of T cell that binds onto more than one target. There has already been clinical trials to try to generate different groups of T cells that recognize different antigen and then mix them together. I think both are really legitimate choices. What is going to be easier down the road, particularly in thinking about how difficult it is to engineer all of the CAR T products, perhaps with the need for one lintiviral vector only to generate ability of the T cells to bind both targets concurrently, that's probably going to be a little bit more efficient. The way you can target the two different antigens is there are different ways you can target. One is you can infuse a co-infusion of those two different CAR T. Each construct is targeting a single antigen, but you are giving the infusion one after the other one. That has been shown, that has been done already in myeloma. Again, the data from China, they did BCMA targeted CAR T followed by the CD19. That is called co-infusion of the CAR T. In other cases, the engineering is done such that the CAR T receptors are expressed, or the antigen are expressed on the same receptor, or the same CAR receptor. They could be tandem CAR, means like one after the other one, or there is a bisestronic in the two different branches of the receptor can act as an antibody for that tumor antigen. Both strategies of one CAR T cell with two receptors versus two different types of CAR T cell are both being explored right now.