What are T cells? So T cells are a very important part of the immune system. They belong to a family of cells called lymphocytes. The white cell family has five big families and one of them is lymphocytes. And even with T cells there are different type of T cells. You have the helper T cells, you have the cytotoxic T cells. Each of them do a certain function. The cytotoxic T cells are charged with getting activated and taking out the enemy. So cells that don't belong to the body or bacteria or viruses, etc. And helper T cells kind of help them along the way by producing cytokines to prime them. So the memory T cells have developed memory against a specific antigen that they can react against. So the lymphocytes that we have circulating in our blood on a normal basis are both T cells, B cells, natural killer cells. There are several other types of lymphocytes. The ones we use to make CAR T cells are the T cells, which are a type of lymphocyte. We have several types of T cells. We have T cells that are cytotoxic, meaning that they are capable of killing tumor cells. We have T cells that we call helper cells that are capable of helping the other guys to kill tumor cells by making cytokines, by activating the immune system and by activating additional cells in the immune system. We actually collect all the T cells to make CAR T cells. We don't really discriminate between these types. Although in the future, we might be able to do a better job at this by selecting specific types of T cells. But those types of strategies are still in development and there's extensive research undergoing. The CD4 positive T cells are what we call helper T cells. And the CD8 positive T cells are the cytotoxic T cells. And there are some additional subtypes that are more smaller populations that we have in the blood that are maybe less important for this process. Both of these cell types help in the case of CAR T cells because they both work together to kill tumor cells. Should there be a certain ratio of CD4 plus to CD8 plus T cell in the CAR T cell product? There is a lot of research ongoing to determine whether there needs to be a certain ratio between the CD4 cells and the CD8 cells. And some CAR T products are being developed with a set ratio of, let's say, one to one between the CD4s and the CD8s. We're still lacking head to head studies to see whether this approach is, in fact, better than just taking the patient's T cells with whichever ratio they have. But these are ongoing studies and there is a lot of interesting research in not just using differentially CD4s and CD8s, but even building on some of the other lymphocytes that we have in our blood. A very important emerging area of research is the use of natural killer cells, which are another type of lymphocytes that is not a T cell. But they also have very, very good capacity to kill tumor cells. There are a lot of clinical trials ongoing, including here at Columbia, using natural killer cells for the same purpose that we've been using T cells, with one of the potential advantages that they seem to have fewer side effects. But these are very, very early steps in development. We don't know that they're as effective as the CAR T cells. So we usually recommend for patients to go for these type of clinical trials if they've exhausted other options. These are fairly early phase trials. There are additional subgroups of T cells in our blood and in our organs in addition to just CD4s and CD8s. There are various phases of differentiation of T cells from naive T cells to memory T cells to effector T cells until they actually become exhausted and senescent. So there is also a lot of ongoing research to try and understand, is there one better cell type to generate the CAR T cells? The confusing thing is that once you infuse these cells into the body, no matter what their specific type was, they would interact with the tumor and they may they may undergo additional differentiation. But it still does seem that the more naive and memory cell, early memory cells that you have in the CAR T product that we infuse might be a little bit better. But we haven't yet achieved the goal of defining on purpose what's going to be in the bag. Currently, we just use whichever T cells are in the patient's blood, which could very well be one of the reasons that some patients fail these therapies, that on occasion the T cells coming from the patient are simply not potent enough or potentially too differentiated or exhausted. Because T cells do get exhausted like we do after a hard day's work. So when the T cells encounter, let's say, large amounts of tumor that they need to kill, then they may get exhausted or we use another term senescence to describe this aging phenomenon of CAR T cells. This is one of the reasons why some patients fail to respond well to CAR T cells, amongst some other reasons, some of them known, some of them unknown. And there is a lot of ongoing research in trying to overcome these limitations by either creating combination therapies. One of the interesting approaches that is worth mentioning in terms of maybe having more potent T cells is what happens if we take them from a donor rather than from the patient. Obviously, patients with lymphoma or myeloma would have had prior therapies. Usually, these are not particularly young individuals, although we do have young individuals with these diseases. So one of the thoughts is, why don't we take a healthy donor who's never seen chemotherapy or any cancer therapy and is maybe on the younger side, are these going to be more potent T cells that would make better CAR T cells? So these are some of the more interesting ongoing clinical trials. And we have a whole series of them here at Columbia using what we call allogeneic CAR T cells, CAR T cells that come from a donor. For a whole spectrum of diseases, and that includes both several types of lymphoma, chronic lymphocytic leukemia, and of course, multiple myeloma. I think this is a very promising strategy. It makes it a little bit easier for the patient because we don't need to undergo the phase of collecting the cells. So you already skip a step. And it also makes the process faster because the CAR T cells made from the donor are made similar to any other drug, and they're simply placed in a liquid nitrogen freezer, just ready to go. So our ability to administer to patients is, in fact, faster. We are still working on overcoming one major limitation, which is how to make them persist in the body for longer, because being cells that come from a donor, our body would tend to reject them. And in that case, their effect would be limited. But these are some of the more interesting studies that are ongoing right now.