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WSCS 2015: Stem Cell Transplant

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WSCS 2015: Stem Cell Transplant

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SPEAKERS

Lakshmanan Krishnamurti, Md, Children's Healthcare Of Atlanta



Edmund K. 'ned' Waller, Md, Phd, Emory University School Of Medicine




We've had some technical issues that we will resolve but I'm very pleased to reduce doctor Krishnamurti who's the director of the transplant program from memory and my colleague at Aflac Cancer Center chris has been a leader in developing allogeneic transplant for the treatment of sickle cell disease and he has led a multimeter international study that showed the feasibility of this approach and was recently awarded a very large are one grand from the federal government and in partnership with the BMT CTM will take this study's the next level.

So we're very pleased to hear about his very exciting results and using stem cell therapy to cure a really terrible disease crash good afternoon thank you for putting up with quote unquote technical difficultiesit's my job today as soon as this lights come on, ok to talk about sickle cell disease as an archetype of a disease that he can cure by stem cell transplantation and a lot of the things that apply for sickle cell disease for transplant also apply for stem cell gene therapies so I think this is really important beyond transplantation so it's customary to start with a conversation about about patho physiology so the time after lunch is not a good time to talk aboutpathophysiology but there is really no time to talk no good time to talk about it.

I'm only showing you this cartoon to point out that even though as you see if I have a point if you want to point out that we started off thinking about sickle cell disease has a point mutation in the glob in gene and that causes a single amigo acid substitution and polymerization as you see on the left side to really do so on the left side there's a summary of what we actually know that it's not just get there is a lot of downstream effects all few more losses and baseball exclusion and so really there are two elements of sickle cell disease one clusion and second is hemolysis and the downstream effects of Human's this picture is to show you that it's a disorder that affects multiple organs the commonest and most important manifestation is pain and pain as you know is a very ill understood and poorly managed condition especially anybody else's pain but stroke complications renal complications about 20hypertension bone can problems so in short sickle cell disease has decreased survival in their late thirties as the median survival and as a quality of life worse than cystic fibrosis and cancer.

So what can be done about disease so starting in the nineteen seventies and eighties became began a systematic approach to give comprehensive care so we would now diagnose all children on a newborn screening and the 50 states and re district of Columbia and then enrolled them in this really all-embracing care that in walls includes education pneumococcal prophylaxis because it's been stopped working and then early diagnosis of complications and treatment of pain and gave antibiotics so gradually there's been an improved quality of life and improve survival starting in the early nineties then we started with the next level of palliative care which is drugs to increased haemoglobin such ashydroxy urea for patients who had a stroke and are at high risk for recurrence of stroke to get chronic blood transfusions once a month and then treat the complications of chronic transfusion such as iron overload with iron, which was originally intravenous and subcutaneous in now is available early or should we try to cure this disorder instead of trying to live with it or trying to palliative.

I think that the curative approaches and there's a lot of overlap in the two curative therapies and are primarily talked about the stem cell transplantation because that's my test this afternoon but also gene therapy of Giselle briefly alluded to so there is it's a genetic disease and the one thing about genetic diseases same mutation many phenotypes so we're always faced with whom do you offer a serious and potentially difficult expensive and potentially lethal intervention with the aim of curing so the general feeling within the community is the three factors we would take into account when deciding who would get a transplantation would be age severity of disease and the type of donor that's available.

The original studies that were to power study started for children and adults children did great the Abelson badly and so for thirty years nobody did transplantation for adults with sickle cell disease which is a travesty because by then the disease was really bad and so we transplanted children who had a potential to do badly but if they didn't get transplanted then they went to adulthood they were doing badly and we said sorry so this is changing.

I'll briefly talk about that because this is a disease which is not an acute illness but a chronic illness we were hesitant to willingly offered the transplant everybody because especially the transplant is not a walk and the park and so we came up as a moral lesson consensus criteria for disease severity and these criteria have remained static over the years with very little change and then the type of donor available to mass majority of transplants have been done from Matt sibling donors that HLA identical donors but the story is now changing with the National Marrow Donor Program and having more than seven million registered donors available and also the wed transplants were getting a little bit smarter with that forward.

Dr Waller was going to give you the details on what you do in transplants I'm just going to stick with one slide so in summary this what you do in any haematopoietic stem cell transplantation did you collect the patient's bone marrow or you could be collecting peripheral blood cells or umbilical cord blood they you may process again the processing maybe red cell depletion that plasma depletion or not you may cryopreserved but if you didn't have to ship it somewhere else you don't have to cry preserve it and then the patient get's chemotherapy to empty they married to create space for the new cells to enter the stem cell Neish and then you basically give it back and then maintain them on a minister passion for a period so that they don't reject the donor cells and also the donor cells do not attack them so that's the graft and the host and so the graft versus host disease is one of the really bad complications so if you're in a rush to leave.

I'll tell you what my talk is in this light and so then you will all be fine if you want to catch the bus so what are the results for stem cell transplantation for sickle cell disease to this point so they're excellent results of BMT from Matt sibling donors so what's the problem with that availability of donor so by pure mathematics is only a one in four chance that you will be a donor but a fact with small families and melted families that chance is actually closer to 14 percent eighty-five percent of the patients are not going to have a donor available the other issue is really asocial issue that you can have the best transplant centre in the world down the road but you don't have access to it you don't have a wariness of it your care primary-care sucks so these are actually not trivial issues even though the curative treatment is available today bone marrow transplant from an unrelated donor is feasible.

We have the National MarrowDonor Program more than seven million people have registered to be donors but the challenge is again these are african-american patient's most of the patients come from donors are people who showed up to donate blood you know blood donors are 90% Caucasian and so here we have a disease that predominantly affects african-americans and you don't have enough donors only 19percent of african-americans will find an eight out of eight HLA matched donor the other issues graft-versus-host disease which has no advantage in this condition but the fear that you will lose one bad morbidity to get a second bad morbidity we now know that bone marrow transplant in adults is effective does all the work that's happened in the last three to four years again availability of donors if you think that children have a problem with access to care.

You have to see what happens to adults it's really hot trending then unfortunately they may be too sick to get a transplant and then bone marrow transplant from happening identical donors this is exciting so we always wanted to match a full match the only full relative is your full sibling and so therefore if you didn't get that you know it was too risky and now that we have new approaches where you can get a half match which means both your parents are half matched so potentially everybody could get a transplant and then finally gene therapy studies are open there are some preliminary data that are quite exciting but then these are all gene transfer lentiviral vector who knows what the future will bring.

So it's too early to talk about that so dead actually is the summary of my talk should I keep talking that ok earlier this week on Monday at the American Society of Haematology meeting this study was presented of all the results in everywhere in transplantation for sickle cell disease is one thousand patients in eighty-eight centers in 23countries so this is the most recent data as you can see there's only four hundred and thirty-nine patients transplanted in the United States and there are 100,000 patients with sickle cell disease in this country alone the majority of these patients were transplanted from matched sibling donors remember that 14% and one of the outcomes like fantastic.

The three-year overall survival is 94% so for a bone marrow transplant you know position that is just unthinkable unbelievably good and then this picture shows you that for the different types of stem cell donors so the top the blue arrow is bone marrow the blue line the red line is better for all blood stem cells and then the green line on top as umbilical cord blood stem cell again from sibling donor and looks like mad sibling bone marrow which is a common as has that the ninety-four percent outcome or denied much smaller number just 89 outcomes really good how what proportion of patients are cured 90% kidding bone marrow transplant are cured so this is in the region realm of dreams this is such good results.

We don't get in any other condition so naturally the community has SAT up and take notice of it so these are the trance plans reported to the CIB MTR until 2012 and as you can see there's a quantum leap in the number of transplants starting 2007 the important thing to notice is that this not only indicates people want a transplant people don't want people wanna cure so if if so those of you are thinking about doing so gene therapy research should take heart from this that there is a real demand for curative therapy for sickle cell disease so excellent outcomes with massively transplant conditioning regimens oh well tolerated they have good organ function results have been reproduced in 23 countries and low incidence of long-term sequels 90%cured and doing well so what is the problem well this is not a walk in the park.

It's it's probably about a severe a treatment as you can get this side of living a lot of the time that's what it is even though we're making it better graft versus host disease is real risk of exchanging one bad morbidity for a second the best morbidity we're giving chemotherapy there's a very significant risk of treatment-related malignancy it costs a lot of money several hundreds of thousands of dollars it's not available to most other people in the world who have sickle cell disease who half of them live in three countries Nigeria the Democratic Republic of Congo and India so you can imagine that we cure or 400patients are happy but it's not actually getting to people who need a habit and so the other issue is that until 2000 until now.

We were sent us on medic aid was not routinely covering transplantation and so we hope that as of January 2016 this coverage will happens OKs so let's talk about what we need to do unrelated donor transplantation because only the minority of people will have an unrelated will have a related don't know what are the results so these results again we're presented at the same time on Monday so this is a big empty Clinical Trials Network study so they used umbilical cord blood from an unrelated donor bone marrow transplant from an unrelated donor and the engraftment from the umbilical cord blood arm was poor and they had to close that arm off the patients who received a bone marrow transplant overall survival was 86% so fourteen percent of the patients die from the treatment overall survival and cure was 76% the study goal was a few better than 75% its success.

I think is a single stills I'm not happy saying I cured three-quarters of the patients that went through this horrible treatment for a projection 10% so there's something about sickle cell disease that makes engraftment sustained difficult than that may be related to their bone marrow being hyper active they're being chronic inflammation and so they may be roles for drugs to study why there is a barrier to engraftment and what interventions can change that this is the worst part that 62% graft-versus-host disease and 38% got chronic graft-versus-host disease that was expensive and that's the stuff of nightmares about morbidity chronic morbidity which is why this particular study did not hit one out of the park patients also had neurological complications.

Which are mostly reversible there's a unique complication related to transplanting sickle cell disease what is the status of adults remember the food studies were in children so 84 @ also been reported to see a BMT our outcomes are still pretty good ninety percent overall survival 82% in three years and then seventy-nine percent in five years so what's happening now is if you go toclinical trials.gov which I did and looked at all the clinical trials that are open what transplant for adults with sickle cell disease the age limit has now changed the median is 45 years and there in just 30 to seven years and no upper limit of age at all the important thing here is that the field is ready to offer and intensive treatment even for adults and that ithink is what I would take it in aa mixed group like this.

I'll talk to you about two studies briefly so this was study was done at the National HeartLung and Blood Institute Tidal's group and they actually tested this out in a mouse and they came up with in on Milo ablative regimen what is non Milo white bone marrow a blatant Marina very little chemotherapy so they gave conditioning regimen and I T cell antibody called alemtuzumab and that three hundred centigrade of TBI so conventional doses like twelve to thirteen hundred TVI and then they used a graft-versus-host disease prophylaxis with said almost since it almost the advantages it's not kidney taught so he doesn't cause neurological complication so several innovations so they did this in patients adult patients 16 to 65 years of age and from Matt sibling donors using powerful blood and they got 87.5% long-term engraftment and nobody died so it's an outstanding advance in transplanting adults from Matt sibling donors at least for those fourteen percent we have secure now.

We also presented this on Monday and this is the results of the study that we led and this was a pilot study of transplant in adults with sickle cell disease and this was a mix of this is not an on my little later because that doesn't work for unrelated donors so we were able to transplant patients who had related donors and unrelated donors and we had a ninety percent overall survival and event-free survival and so we believe now that even a dose can get a massively are unrelated donors what's interesting is that we did not observe high rates of graft-versus-host disease that was observed that other regimen in children so we think that whether you getgraft-versus-host disease how much again it depends on exactly how you do the transplant and the details of that so based on this we are now doing this for the first time was actually comparing transplant to know transplant.

I think the CMS went and looked at all the data they said that we've done people have done small studies but haven't shown that what happens to people who were who had who did not have eligible for transplant but didn't go to transplant because they did not have a donor so this study will actually amulti center 40 institutions study that's Donna start early in 2016 patients will see if my transplant physician and they will agree to have a transplant and then they'll get an HLA typing and they'll be biologically randomized to transplant or no transplant based on whether they do have a donor or not so there's an exciting thing that we're looking forward to talk briefly about happen identical transplantation so this is a cool party trick so typically they've done transplantation we get chemotherapy or radiation therapy and then we give the stem cells and then we don't give any chemo and stuff.

We don't want to word this time so that we just gave so it turns out that these stem cell this several of the hematopoietic cells have an enzyme called aldehydede hydrogenase and aldehyde dehydrogenate is what you need for inactivating a chemotherapy called psych cyclophosphamide so it turns out that aldehyde dehydrogenates there in high levels in the stem cells but not in all reactive lymphocytes so what you can actually then do is you can give to stem cells the immune system responses responds to the foreign antigen and there's a liberal proliferation and then you come and give cyclophosphamide killed a limitless lymphocytes while still protecting the hematopoietic stem cells and this way they're able to get old overcome the barrier off disparity and do happen identical transplant.

So this is a regimen out of Hopkins so they gave a small dose of cyclophosphamide it says hi a 14.5 they give a little bit of radiation Lodeiro bean give the donor cells and then on day three and forgives I talk and kill off the limb presides and keep the stem cells and keep them in grafted so it's really very exciting initial results they have fourteen patients are they published their twenty-six patients so far but engraftment is about 50 to 60% very welltoleratedwe still have some work to do but we're able to do help identical transplant this can be a game-changer so and then finally just want to let you know that gene therapy studies are open including this by Bluebird bio the HPV 569 that's their first concert this is their second constructs so they've made some improvements in their design and what is a prolific this is how they do this you collect the stem cells city 34 selection antiviral vector transaction and then mile ablation so even in this you do get my location and I'll give you some very preliminary results that were presented again this week.

There is a promise that gene therapy has a some preliminary results 1 patient with severe sickle cell disease his long enough out off the procedure is making half sickle haemoglobin and half this mutant and bicycling haemoglobin and the patients actually doing better in terms of clinical outcomes there are two other sickle cell patients that have had a gene therapy and are still undergoing follow-up so excellent results like we talked earlier but my transplant from unrelated donors as feasible from a transplant from adults is effective from a transplant perhaps identical family don't as possible and gene therapy studies are open thank you very much well that's great I Chris really did a phenomenal job both for filling in for some of our technical malfunctions and setting the stage to what I hope to do is address some problems of graft-versus-host disease and engraftment clearly stem cell transplant for all the different aspects of stem cell therapy and regenerative medicineis by far and away the largest clinical application of transplant technologies.

These are the numbers of tautologous transplants in the blue and allogeneic transplants in the green in the United States you can see it's continuously rising the indication for tautologous transplant is primarily those patients with chemo sense to be logical malignancies in germ cell cancer allogeneic transplant recipients are largely those patients with haematological malignancies particularly those malignancies where the stem cell itself in the bone marrow is affected acute leukaemia AML and a lol the auto transplant depends mainly on the intensity of the chemotherapy to eliminate those cells which are key most sensitive the auto transplant maneuver benefits from the health care P effect of donor immune cells particularly T cells and its Christian indicated the donor T cells are two edged sword much as they help facilitate engraftment and eliminate malignancies.

They can also cause debilitating graft-versus-host disease and that's this that's the area that we want to address transplant outcomes vary according to the type of graft unrelated donors as the source the ground after associated with more graft-versus-host disease cord blood is a very attractive graph source because it's available on demand in a freezer but those cord blood units are too small for ninety percent of adults and even when we do use them as Chris showed you there can be an unacceptably high rate of graft rejection hypothetical transplants are very interesting but those patients with you get pissed transplants.

I class men have a high rate of relapse after allogeneic transplant and are often are susceptible to infections from paragraph sup slower in Grafton and blood stem cell grafts related donor or matched unrelated donor graft faster but have more chronic graft-versus-host disease for those of you who are not in the stem cell field is just illustrates that techniques were used to collect these stem cells the bone marrow harvest procedure really hasn't changed in a hundred and fifty years it's kind of dark area most barbaric procedure where under general anaesthesia put a hollow needle into the hip bone and draw back about a quart of bone marrow cells patients tolerated honours tolerated reasonably well but it's it's fairly technically cumbersome type of maneuver on the right side as the stem cell harvest procedure technically that's much easier doesn't involve time in the ORR the patient's hooked up to Nate Freeze's machine.

This century centrifuges the blood separating the white blood cells the red blood cells puts the white blood cells in a bag which are highly enriched for stem cells after GCSE mobilization so how do we get these cells in the blood this issue is particularly relevant to this end up telling us transplants where we mainly one enough stem cells to reconstitute the bone marrow after giving these high doses of chemotherapy or high doses of chemotherapy and radiation which are designed to eliminate residual cancer most of the stem cells in the bone marrow tethered in the bone marrow micro environment to stomal cells only a few of them circulate into the blood however with G CSF administration as an example we can stimulate bone marrow macro phages and osteoblasts.

It can then lead to down regulation of one of those Terry molecules called CX yield such that the stem cells are released from the bone marrow into the circulation adding other drugs that are direct antagonism between CXL 12 on the stromal cells and CXC our foreign this stem cells can further augment stem cell mobilization and that result of this as we have more stem cells in the blood where we can collect them using the a pheresis procedure so by knowing the stem cell content to the blood it's very easy to predict how many stem cells will collect into the bag and this is data from memory looking at the delivered stem cell dose in the bag on the y axis compared to the stem cell content of the blood on the x-axis.

You can see in at least a log plot is a direct relationship between blood stem cell content and how many stem cells we clicked in the bag left-hand panels mobilization of two drugs right hand panel is mobilization just with one drug CCSF what's the optimal dose is obviously a relevant question from a stem cell therapeutic standpoint and will be very relevant when we move into stem cell technologies in the halogenated setting more is better this is all data from the Fred Hutchinson Cancer Research Center that looked at patients undergoing tautologous stem cell transplant and correlated the fraction of patients who are in grafted with platelets on the y axis with the stem cell dose days after transplant are shown on the x-axis.

You can see with a low stem cell dose less than two and a half million stem cells per kilogram engraftment is slow and not all patients fooling around with stem cell doses of greater than two and a half or greater than 5 million cells per kilogram stem cell engraftment is much more predictable this is similar data looking at probability of engraftment by stem cell does now looking at neutrophils in the top data and again showing that stem cell dose of more than two and a half million CD 34 positive cells 234 is the stem cell marker per kilogram was highly associated with faster neutrophil engraftment as well as faster platelet engraftment in the bottom data this matter.

We've done multivariable analysis looking at the kinetics of engraftment and those patients who never achieve a normal platelet count after an auto transplant or who split the count goes up and then dribbles down post-transplant have significantly higher risk of dying than those patients who have robust engraftment so in a multivariate analysis we found four factors associated with survival one is achieving a normal platelet count the second is having a durable platelet count the third is the number of prior chemotherapy regimens and the fourth is having active cancer the time transplant so getting the stem cells to graph quickly is just as important as the control of the cancer.

Cancer is the major problem in this setting three-quarters of the deaths after auto transplant come from relapse of the patient's disease so let's turn now to the allogeneic transplant problem we talked a little bit about how to mobilize stem cells with the alchemist stem cell doses but clearly the problem we're offering curative therapy for patients with sickle cell disease is in the allergenic setting outside of course of gene therapy so this is our Emery algorithm for how to pick donors we prefer if available HLA matched related donor's brother sister donors then we turned to HLA matched or nearly matched unrelated donors and finally as a fourth choice we have looked at cord blood and happily transplants because of the problems that Chris indicated of engraftment and graft rejection.

The potential forgraft-versus-host disease unfortunately as our families have got smaller and yet more complex in terms of people marry and divorce and remarry and having kids with multiple different partners it's hard to find in HLA match related donor particularly the sickle-cell setting less than a quarter of patients are going to have an availableHLA matched sibling donor because of that nature wide the use of unrelated donor transplants has increased you can see in the light blue line the unrelated donor transplant number has crossed and exceeded the number of sibling transplants about five years ago cord blood and read and happier transplants in green remained fairly minority source of halogen aircraft's these transplants are curative for patients with refractory leukaemia or poor risk leukaemia this against those registry data with survival outcomes for patients with leukaemia and for those patients who undergo a sibling transplant early long-term survival of five years is about 55 percent.

We use an unrelated donor graft survival is still very good about 50% but not quite as good as with the sibling donor and that hence the programmatic decision here and elsewhere to prefer sibling donors if they're available so what happens when the transplant doesn't work relapse of the disease accounts for about a third of deaths after allogeneictransplant but now in contrast to the otter transplants that he will be again to see a significant contribution of death from graft-versus-host disease shown in the green portion of the pie and deaths from infections shown and the darker orange portion of the pie so those are failures of immune reconstitution after transplant graft-versus-host disease is too many donors T cells being too active infections are too few donors T cells being active enough so somewhere between the two.

We want to find a sweet spot we get effective immune reconstitution without graft-versus-host disease so to address the question of where to get the graphs from unrelated donors we've seen that the number of match related donors is going down the number of unrelated donor grafts is coming up what's the best source of graphs from those volunteer unrelated donors we performed a randomized clinical trial through the BMTC TN where donors and the recipients were randomized to either donate and receive a bone marrow graft harvest procedure should you or to donate and receive free CSF mobilize blood stem cell graft this study was limited to patients with AML AOL or my elodys plastic syndrome and enrolled 550 patients over about a seven year period and the results were published a couple years ago.

The new England journal overall survival was essentially equivalent is indeed what was predicted from the study because there have been registry data to suggest survival by itself was going to be similar between whether people got a bone marrow graft or a blood stem cell graft but what was different is that were there was this significantly more chronic graft-versus-host disease among those patients randomized to receive the blood stem cell graft and that contributed to a substantial portions of the deaths from graft-versus-host disease in fact a fifth of the deaths from patients received the GSF mobilize blood stem cell grafts were due to chronic graft-versus-host disease in contrast on the rights on the left side eight percent of the patients who died after marrow graft died of graft failure graft rejection the same problem Chris indicated is relevant to cord blood transplants for sickle cell patients with these patients can get quite sick with graft-versus-host disease this is picture of somebody with acute graft-versus-host disease of the skin.

It's like a terrible sunburn it can get so bad the spin actually blisters and peels off chronic graft-versus-host disease can cause focal areas of sclerosis and scar formation the skin and can lead to really disability where people are can't move their arms or legs can even take a deep breath because there's so much scar tissue in the skin around the abdomen and around the waist so what can we do in the setting of graft engineering and stem cell therapies to make to improve transplant outcomes well.

We want to get more of the good cells the cells that facilitate survival among patients and remove those cells which are most associated with poor transplant outcomes we want to optimize the use of drug therapies for patients to control graft-versus-host disease but still permit sufficient immune reconstitution that patients don't dive infections was part of that published study in the randomized study of marrow grafts forces blood stem cell grafts we analysed the Emory a liquor of each Grafton counted the number of stem cells of T cells and immune regulatory cells called dendrites cells and we correlated the content of cells in the graph with survival of the recipients what we found is that inpatients who got a bone marrow graft on the left side of the slide that there was decreased hazard ratio of death so more survival for patients who received a number of naive T cells either cd4 or CD eight or a number of donor plasma side to a dendrites cell greater than the median.

We decrease the risk of dying if you got more of certain immune cell subsets particularly plasma side to a dendrites cells and you can see this figure summarizes some of the survival outcomes with improved disease-free survival in the upper left-hand panel of the slide being seen among patients who received greater than the median number of plasma cytogenetic cells compared to inferior disease-free survival compared to patients who got less that's a pretty significant difference in disease-free survival about 20 percent at three years the difference in disease-free survival was due to less treatment-related mortality and the deaths from those patients who received few of these donors plasma cited indirect sales were deaths from acute and chronic graft-versus-host disease and graft rejection.

So overall more deaths with fewer donor plasmid side to drink sales and a particular more deaths from failure of immune reconstitution of the graft if you got more both donor plasma side into cells and naive T cells you did better than any other group with better than 60% three-year survival seen among the patients who have received more of both donor cell populations so this is sweet spot if you like this is kind of a clumsy cartoon the sweet spot is that kind of large black bowling ball but it tries to identify that there's an optimal content of different immune cells in the Grafton the excess access being a donor plasma cytogenetic cells on the y axis be the contents naive T cells and in the z axis being there Activation status there's an optimal place to construct a graph associated with the best outcomes we have a number of hypotheses about how these cells work and extend to explain the differences between bone marrow grafts and UCSF mobilize stem cell grafts ho main of the immune cells in the recipient is one hypothesis and the way they present al antigen is a second hypothesis.

We've tried to test that test these hypotheses using some mouse models show you these data very quickly the first day of show you be that the donor immune cells the plasma cells survive after transplant for about three weeks in this published data we used donor mouse which is transgenic express's luciferase as the source of the plasma cited indirect sales or a mouse that has the same cells that expressed GFP and shown in the upper panels are detectable in the liver as fluorescently green cells in the lower panels they can actually glow-in-the-dark the point where we can see them home into lymphoid organs they have in humans the plasma cited rid dick cells from bone marrow grafts have less schema Cox left is certain Chemical receptors associate with more how activation in particular CCR nine and more chemokin ereceptor.

I'm sorry cr7 and more CCR 92 compared to the plasma site or dendritic cells from a GCSE mobilize crap so we think that the same cells from different graphs sources home differently we've looked at gene expression in these sells comparing the cells from the bone marrow graft from a GCSE mobilize graph trying to understand why the GCS have grabbed causes so much more versus host disease done principal component analysis looking at the same cells sorted from bone marrow shown in the great circles' orgy CSF mobilize bloodshed in the dark green circles or cord blood like green circles and we can see each the same cell population from different grounds sources has a unique type of gene signature this looks in the heat map analysis at some genes which are over expressed in a bone marrow graft plasmacytoma indirect cells from bone marrow grafts in the upper right panel.

Those over expressed genes are red and cheese which are over expressed in the GCS to mobilize graft in the lower left corner and in particular in a volcano plot we identify the boss be as a dream which is highly over expressed in plasmacytoid dendrite cells from a bummer about compared to those same cells from a GCS up a large graph we think we began to identify the pharmacological targets where we can improve transplant outcomes to get less chronic graft-versus-host disease less graft rejection better survival being able to extend our J transplant to a broader range of patients including sickle cell patients by understanding where these cells go and how they behave when they get there and then targeting them with small molecule drugs that can alter their behaviour so to summarize we looked at June expression identify patterns of gene expression pathways which regulate their behaviour these cells in Vito is our target Apple pharmacological is the studies were going on to do now to try to improve transplant outcomes.

We think that the distribution of genes suggesting each of these graphs sources has unique characteristics which are predictable and exploitable based upon the source of the cells so and with this final slides us and we're also exploring new ways of mobilizing graphs using flip 3 ligands is another way of getting the cells you want out of the bone marrow and flip through like and in particular is cytosine which highly and reaches for plasmacytoma dendrites cells into the blood we're looking at adding back expended cell populations and the pharmacological interventions that I discussed.

I'll end with that if there are any of her couple of questions asked Chris to come back up would be happy to answer them thank you for your attention in the context of stencil meeting and regenerative medicine meeting how you both fore seen Excel trust in the future like let's say twenty years from now a bunch of sales in which very small proportion Artist Series sales and the rest who knows immune cell Chris Gives ideas I think one is that we have we're beginning to understand how to expand this you 34 positive cells not just expand not just mobilize cells from the bone marrow get more of them I think sr1which is aryl hydrocarbon antagonist is only allowed expansion of 234 positive cells from cord blood units that will allow us to use not just a 10 percent of cord blood units which are big enough but potentially all the cord blood units for the purpose of transplant secondly.

I think stem cells still have the possibility of being a vector for gene therapy showed some very early exciting data from Bloom berg suggesting correction of sickle cell anaemia with a stem-cell modified to express a type of haemoglobin A bit you can imagine that stem cell therapy could be used for a variety of diseases not just correction of hemoglobino pathies but look at this trip freeze likely to treat storage diseases or all you need to do is to deliver a little bit of the enzyme in fact we're about to launch a study of haemophilia were using gene therapy and stem cells to correct an album of factory level so I don't think stem cell transplants are going to go away I do think they'll still be used to treat malignancies particularly keen IANS I think their application regime replacement therapy will actually be increased.

I agree with everything that now net said but I want to point out just add that people are actively thinking about new targets for we had a speaker John Wagner he spoke here yesterday and then john was talking to us and Emery you're talking about cardiac diabetes brain disorder stem cells in right after John give us a top we work with the genetics people in the whole departments of their bottles of red wine and white line and we generated a list you know diseases that are potentially you know targets for stem cell therapies.

The second thing I see is that the future is closer than you think in clinical trials well we would like part of the reason that we're looking at different mobilization strategies and drug therapies to redirect the behaviour the cells is try to find an alternative to boomer harvest because it's labour intensive and it's inefficient and I can collect five people with the staff with blood stem cells the same staff that I need to click one person from the or any last questions where I think we're just one more question than we're out oftime hello thank you for such a presentation.

I want to ask a question the chemotherapy so as we know secondary to chemotherapy there are so many diseases and bone marrow or hematopoietic stem cell transplantation so are there in the reserves to reduce or to completely make over these chemotherapies in this damn cell transplantation thank you so there are some approaches of because drugs that mobilize endogenous themselves out of the bone marrow into circulation that allowed donor stem cells turned around so potentially if the bone marrow contains most the stem cells you can think about it like a parking lot all the parking slots are full of cars.

The cars on the road or circling around waiting for someone to leave their spot if you get all the cells to leave the bone marrow you create lots of new parking spots and allowing new donor stem cells to a graph so potentially why is that important if Chris has similar sickle cell disease and we want them to a graft with normal stem cells we could potentially avoid having to give them chemotherapy because a fraction of donor engraftment is enough to cure the disease that's trooper sickle cell disease that's trooper you'll hop at these into it briefly after that we're using less chemotherapy than we used to two appellate the marrow and secondly there are non chemotherapy base conditioning regimens like antibodies that are being considered in this is particularly exciting not only put on a transplant but also for gene therapy because you have to meet a standard of disease severity before you can do gene therapy because you have to give all this came up there and see if we can down antibody-based conditioning regimen than a lot of other conditions open themselves up to great and there and thank you for your attention.

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