What is an allogeneic CAR-T cell?

What is an allogeneic CAR T cell? What are some of the advantages to using allocard T cells? That's an important question. So first, the CAR T treatment, right? The CAR T is when we take the T cells from a patient, we train those T cells to recognize multiple myeloma and fight multiple myeloma. So one of the reasons patients develop multiple myeloma is because our immune system cannot see plasma cells, plasma cells that form multiple myeloma. They cannot see the plasma cells as a malignancy. So the T cell's job is to kill those plasma cells. With the CAR T therapy, we take those T cells out, we train them, put them back to the patient, and that's where they go after the plasma cells and control the multiple myeloma. Allogeneic T cell is when you take somebody else's T cells and those T cells are already trained to fight multiple myeloma or to fight plasma cells and give them to the patient. You could imagine the differences here is when we take it from a patient, we have to aphorize the T cells, we have to train those T cells, make them angry, and then give them a virus or even a gene, add a gene to this T cells to make them recognize plasma cells as they are, malignant cells, and go after those plasma cells. This process takes few weeks to be done. So that's a time wasted and sometimes it's a precious time for myeloma patients. If their myeloma is growing fast, you need to act on it fast. So the concept of an allogeneic CAR is that that could potentially be used for everybody and there what is happening is that in addition to putting in the CAR like is done for autologous T cells, they're also down regulating certain molecules on the surface of these T cells that are normally responsible for generating an immune response and so they're generating an even more artificial, more genetically modified T cell that allows it to escape immune recognition by the host. So we can get a third party T cell and put it into me and to you and it would not be rejected by either one of us. How many CAR T products can be made from one donor's T cells? The thing that I think people need to recognize is that this is however a product that cannot be given indefinitely and so can one product be given to 10 patients, 20 patients? I think it's not clear how many products can actually be made from it but certainly from a patient perspective what that improves is the downtime of having to manufacture products for a patient at any given time which currently ranges somewhere between seven to 20 days from what they call needle in to needle out from when you take the T cells out to when the patient gets the cells back. With the universal CAR T that time frame is significantly more reduced because the product theoretically is already made. What is an autologous versus an allogeneic CAR T cell? What are the benefits of allogeneic CAR T cells? The first experience with allocars were sort of just it happened that way in that the first ALL patients about 60 percent of them had already had an allogeneic transplant, a transplant from another person for their ALL and then it came back. So their T cells were harvested and some of them were from the donor and then were manufactured and given back. Now that potentially would raise concern because with those donor cells attacked the recipient and caused something called graft versus host disease. Well as it turns out they're probably tolerant because they were in the patient for a while. So that's one example of how an allogeneic was CAR T was used but it was from the patient's own bloodstream. There are a couple of other strategies. One is to develop what is called a universal CAR where you take that T cell and you engineer it so it won't react against the human being. The one problem with an allogeneic CAR T cell is that it potentially could target the patient's tissue system and start to attack it and cause something like what we call graft versus host disease. So there are a few ways that you could get around this. One is you figure out how to disable this recognition system and it's called the T cell receptor. Well there is this gene modification thing which people may have heard about this CRISPR and TALEN where you can actually specifically edit out a particular molecule in a cell and then grow it up. So for example if you took out the T cell receptor you now have created a T cell that no longer is what we call alloreactive and that would allow you to begin to use it as a universal CAR T cell. And then what you could do is manufacture your CAR T cell, put it in your anti-BCMA for example, put that in the cell, grow up a huge batch of them, put them in the freezer and now you have something you can just pull out of the freezer and give to the patient say after their lympho depletion because the one problem right now with the current way of doing it autologous you have to take them out of this patient. You have to send them off to the laboratory. They have to be grown up and there can be a 10 to 14 to 21 day delay while you're waiting and during that time period the patient's disease might get out of control. If that were to happen that would be bad. So if you can just pull it right out of the freezer and use it that would be very interesting. There is a company called Selectis which is doing this where they're not only knocking out the T cell receptor, they're putting in the CAR, in this case CD19, say for ALL, they are then also knocking in, putting in a molecule called CD34 because that's not normally seen on T cells so you can track it, keep track of it and see what it's doing. You can also put in a CD20 molecule and that can be recognized by a drug called rituximab which binds CD20 and potentially would kill yourself if it was misbehaving. They also knocked out CD52. CD52 is a molecule on T cells and if you give an anti-CD52 antibody you can wipe out the T cells in the patient. In other words use this for lymphodepletion and now you put in your T cell that is lacking CD52 in this molecule, this antibody CD52, allimtuzumab won't have any activity against it. So you can create this sort of this Franken cell where you've done all these different things to it and yet it's active against the tumor so it's very exciting. There are a variety of other strategies like this that are being incorporated so it's just sort of the, this is sort of cell engineering 101 and we're just beginning to understand how this is going to work so that we can really develop targeted therapies and yet it'd be great to just pull something out of the freezer and use it. Allogeneic T cells, one of the benefits is it's off the shelf means we literally get it off the shelf, it's ready, it's already trained, we can deplete, kill the original T cells of the patient by giving chemotherapy and then give the new T cells and hope that those T cells will do their job. The other benefits is sometimes you know with all the chemotherapy that myeloma patients go through, you know there's this speculation that T cells might not be as fit for you know fighting, building up a fight against multiple myeloma, getting new fresh allogeneic T cells might be very helpful there. We're still early in allogeneic T cells treatment so the downside is we're still learning about this. Early results are very promising, we saw some results in the last ASH meeting, it's promising results. Those T cells as if they are getting designed right now, they have a suicide gene so if we get in trouble with with those T cells we could simply switch on and off, we can just switch them off and kill them with simple treatment. I see for the new future, for the future this is the new strategy that is going to be, we're going to go through it but once we build more knowledge base about it. When you start thinking about what's the best cell product to go with, you think initially that using the patient's own immune cells but we know that myeloma poisons the immune cells, it poisons a lot of the body and so maybe the cells of their immune system are not the optimal starting point to make a designer immune therapy. So if you had a normal cell that you could put into any patient that was well and all of its kind of functions were maintained that would be better and so it's possible to do that now and what's making that possible is CRISPR technology. So we can use the CRISPR technology to knock out some of the important genes that would be recognized by somebody else's immune system so that when you put them into that patient they're not recognized and rejected. So we're starting to be in a position where we have cells that come off the shelf like using a drug that you can put into any patient, they're active, they're functional and not prone to the problems of manufacturing and a significant delay between when you collect them and when you give them back to the patient. So allocartes will be a good thing if they were to work. Allogenic cartes cells are universal because you could have one donor and then those T cells can be used to all patients and they can be expanded and grown in the lab where you can just use them to all patients. Theoretically yes, yes there is a risk of graft versus host even though with the early trials I did not see much of this happening for myeloma patients. Still that you can tell from the design of those T cells they have a suicide gene, a suicide receptor. For example you could have CD20 as added to this T cells so when you give Ritoximab the T cells will die if in case you need to switch off graft versus host disease or disorder but from the early results I, to my knowledge, patients did not require Ritoximab at all you know and they never needed to turn this suicide gene on. So it's still within the built-in design of these T cells. It's very promising and it's they have the suicide gene to assure us if we need it we can always turn them off. Do you think the allocynate CAR T cells will replace autologous CAR T cells? It depends on on the safety profile from a logistic perspective I think it does make life much easier because you can have a single allodonor and create a hundred products and if a patient is coming to see me today for a CAR T cell therapy I don't have to wait for you know four or five or six weeks to give them that therapy I can schedule the lympho-depleting chemotherapy two days from now and give them that product next week you know obviously insurance approval wise you know above you know barring all those issues but logistically I think it would be better. The only caveat is it has to be have have a similar safety profile. Right now it's very early to say whether that that will come to fruition.