 Once a patient has been identified as a potential candidate for caramba, I mean obviously they need to get all the information that is out there from us as well as what they can find on the internet because you went well informed patient. They receive a treatment that's called leukophoresis and it's kind of like dialysis and so it's an extra corporeal circulation where we're collecting white cells from the blood, white cells that are part of the immune system and that's actually pretty, it's pretty unremarkable. So that's the first part and then we will manufacture the caramba product from that and approximately a halfway point we estimate whether we will be able to have enough cells to offer the patient a meaningful dose. At that time patients receive, patients are admitted to the hospital at that point and they receive a chemotherapy that serves the purpose of eradicating the same cells that we collected a week earlier so that the cells that we give back, the caramba T cells, that they can expand nicely in vivo and this chemotherapy isn't super toxic, it is less toxic than the chemotherapies that they have previously had for tumor control but it does knock down the white blood cell count and then actually the treatment with the caramba cells is pretty anticlimactic. It's a tiny little bag of cells that drips in and you feel nothing, it just drips in and that's it you know. Over the course of the next couple of days and weeks we are expecting for the caramba T cells to expand because they will recognize the antigen, the antigen SLAMF7 is what the antigen is called, they will recognize that, they will kill all the cells that express the antigen and hopefully they will kill all the tumor cells and if that happens, when that happens sometimes the patients can run a fever, can get signs of a systemic inflammation type disease, sometimes they will need medications. We have not experienced that from caramba in the caramba trial, I mean extrapolating from car treatments for other illnesses. So the very worst thing that could happen and even that is already not a drama, the very worst thing that could happen is that the clinicians have decided to give the patient a chemotherapy on day nine and then on day 14 we do not have a product to give or not a large enough product to give. The chemotherapy even though it is toxic, isn't super toxic and it doesn't get the patient into trouble, it's probably not high enough in those and not the right medication that the patient derives a benefit from the chemo in terms of tumor control but it doesn't really harm him either. What we have seen happening is that the cells die, a lot of cells die during the processing particularly when you give the cells the electric shock to to shuttle the gene into the cell. We lose 50-60% of the cells due to that and we need the cells to expand in vitro and they do not always do that particularly the CD8 positive cells do not always do that. So we have on two occasions not managed to manufacture enough cells not the dose of cells that we would have liked to administer. So we gave what we had which was the dose that we had you know we're in a dose escalation and we gave the dose not at the level that the patient should have been treated but at the next lower. So that's what happens. Why do the T-cells not expand as well as we would like not as well as they do when we take T-cells from healthy donors? These are not healthy donors these are patients who have had a lot of chemotherapy that continuously when knocking down knocking down knocking down their immune system and eventually it is just a little tired. It is not because cell therapy products are considered medicines we are very very rigid and what we are allowed to do and that applies to pretty much anything I cannot even simply increase the number of starting cells at the beginning. There's a maximum we have defined and we're always using the maximum provided the patient has given us enough cells they sometimes don't. We're going to start with the maximum cells and we're going to go to exactly we're going to manufacture it exactly as we have described it in the process that our regulators have allowed us to use and we cannot deviate from that and that includes the expansion time. However if the cells don't like to proliferate for 14 days they don't proliferate I mean it's sort of it's an intrinsic property of the cells that doesn't allow them to proliferate as well as we would like. So it's not just a numbers game it's not like to having too few cells causes less than optimal response but that which causes the T cells to not expand ideally in vitro also causes them to not expand ideally in vivo and that's why we don't see the best possible clinical results and what I mean by that if we gave them another two days we might make dose but we're not going to solve the problem. So no we cannot expand them any longer but even if we could it wouldn't do us any good. We have a very very carefully designed process and it is when we use healthy donor cells it is a very very robust process. So there are we do have some ideas how we can possibly make the process better we are thinking about caramba 2.0 but as I said this is a medicine we cannot just play around with it in in a running trial. So the one thing that we can obviously not control is T cell quality and that's what's haunting us that's what's haunting everybody it's not us it's not our process it's the disease and I think I think what would definitely help is to go into an early line of treatment and I think it would make sense because we know that whatever is out there is is effective but it doesn't afford cures. So I think you could definitely try the car in a relatively early phase of the disease and if it doesn't do its thing you can still do all the other therapies but that's something that's a beef that we'd have to to have with with our regulators again it's not something that we can just decide to do there are of course inclusion criteria. For the patient's safety we do this interim clearance before the decision is made to to to start the chemotherapy or not which is based on the number of car expressing T cells on day six. So we are that that is that is for added safety of the patient we can reassess on day nine depending on what the kinetics are whether whether to move forward with the chemotherapy or not. Well right now we have been asked to space the patients by at least four weeks that is due to let us because they extrapolated from how quickly adverse events were seen after CAR-T with other indications and other targets and so that sort of limits us obviously theoretically to 12 but really to seven or eight patients a year. If we if we did not have that the current process doesn't lend itself to start starting on any other day than Monday so the atheresis collection on Monday so that gives us roughly 45 slots or so per year we could we could probably satisfy those and of course it's a it's a process that because it is very robustly described could easily be transferred to other manufacturing sites they would need to practice it a little but it's it's quite feasible to to increase access by multiplying the manufacturing sites. The one impediment to scaling I just mentioned is is the the minimum time lag between between two manufacturing that is something that I think will remain until we have treated a sufficient number with an effective dose and not seen limiting toxicity. We are we have a couple of thoughts about the manufacturing process you know that the target SLEM-F7 is not exclusively expressed on the cancer cells on the myeloma cells but it is also expressed on some normal cells very importantly it is also expressed on some normal blood cells specifically the CD8 T cells and so what happens is that as we put the car into the cells they start killing other T cells that express the antigen and specifically those that do not express the car so at the end of the day we have a very nice and relatively pure population of CD8 cells with 80 plus percent car marking but it's a small number because a lot of them have killed each other and the T cell even though it has multiple killing capacity it's limited it cannot kill forever so we think that could be benefit in stopping the killing in vitro by giving inhibitors of the car signaling and that is something that Michael Hudecek has actually reported previously that he can stop the car from killing both in vitro and in vivo even he can even give it a break in vivo it's a small molecule it's called dazatinib and it inhibits one of the kinase is downstream the car intercellular signaling domain so that's something you can add dazatinib you can certainly shield the antigen if you are so inclined they're antibodies that that can compete with the car and they can you could make an FAB fragment from the antibody and just you know base the cells in it and they would be covered in the antibodies so they couldn't couldn't get killed that is is something we're looking at we are reconsidering the cytokines that we're adding we're using IL-2 right now and of course there are reports that the quality of the T cells can be maintained a little bit better in other cytokine cocktails specifically IL-7 IL-15 I don't have two great hopes for that but there's certainly a variable that we're also going to test dazatinib I think is the most most likely to make meaningful different make a meaningful difference