The Role of the Intestinal Microbiome in Allogeneic Hematopoietic Cell Transplantation

Transcript

• 00:00Today too, are y'all catch Santa grand
• 00:03rounds? Today is a special day. It's one of
• 00:06our endowed lectureships.
• 00:07This is the blanched Omen lecture series
• 00:09was established in 2012 by Marvin Sears,
• 00:12who many of you might remember was a
• 00:15longtime chairman of our Department
• 00:16of Optomology and Visual Sciences.
• 00:18He established his series in honor
• 00:21of his mother Blanched Holman,
• 00:23who eventually succumbed to
• 00:24acute myelogenous leukemia,
• 00:25and this is the first and
• 00:28I'll lecture series at Yale.
• 00:30Devoted to hematology, malignancy's.
• 00:31It's intended to bring
• 00:33into Yale pioneers
• 00:34that have made major contributions
• 00:36to our understanding of the current
• 00:38trends in hematologic oncology
• 00:40to a very exciting today to have
• 00:42Marcel Vandenbrink as our speaker
• 00:44and to introduce myself today.
• 00:46I'm going to turn the podium
• 00:48over to Stephanie Helene,
• 00:49the director of our Division of
• 00:51Hematology. So Stephanie, the floor
• 00:53is yours. Thank you, Dan.
• 00:55So it's my absolute pleasure
• 00:57to introduce Doctor myself,
• 00:58wondering who is the head of division
• 01:00of hematologic malignancy Malignancy's
• 01:02at Memorial Sloan Kettering.
• 01:04Cancer Center so Doctor Funding Bank
• 01:05is an expert in hematopoietic stem cell
• 01:08transplantation and he obtained his MD
• 01:11and PhD from the University of Leiden,
• 01:13completed a postdoctoral fellowship at
• 01:15the Pittsburgh Cancer Institute and his
• 01:17residency at Duke University Medical Center.
• 01:20He has been the head of the Division
• 01:22of Hematology Malignancies since 2008
• 01:24is also a professor of medicine and
• 01:27immunology at Weill Cornell Medical
• 01:29College as a physician, scientist,
• 01:31Doctor, Vandenbrink studies,
• 01:32allogeneic stem cell transplantation.
• 01:34Both in the clinic and the laboratory,
• 01:36and his research is currently
• 01:38focused on two areas.
• 01:39One is to study the role that
• 01:41microorganisms living in the testing
• 01:43playing in patients undergoing stem
• 01:45cell transplantation and in those
• 01:47receiving cancer immunotherapy.
• 01:48He's developing strategies to help
• 01:50the body rebuild the immune system
• 01:52after bone marrow transplantation.
• 01:53His research in both of these areas
• 01:56is being translated into clinical
• 01:58trials that are currently ongoing
• 02:00at Sloan Kettering and beyond.
• 02:02In 2010,
• 02:02Doctor Finder bring started the Susan and
• 02:04Peter Solomon Divisional Genomics program,
• 02:07which focuses on targeted therapeutic
• 02:09therapy approaches for patients
• 02:10with less with blood cancers such as
• 02:13leukemia and this program was actually
• 02:15instrumental in the development of
• 02:17the first genomic profiling test.
• 02:18Pro Haematological malignancy is
• 02:20called Foundation One Heme which
• 02:22we are happy to use,
• 02:23so I'm turning over the podium to
• 02:26Doctor Vandenbrink who will tell
• 02:28us incredibly exciting stories on
• 02:30the intestinal microbiome in stem
• 02:32cell transplantation. So welcome.
• 02:33And we look forward to your presentation.
• 02:37Thank you so much.
• 02:39Thank you so much for these kind kind words.
• 02:41Of course this is again going to be a
• 02:44lecture by zoom and we were just saying how?
• 02:48Slowly but steadily we're getting a little
• 02:50bit tired of that and would like to have
• 02:52some real physical lectures again and see
• 02:54your audience and work with your audience.
• 02:56But no matter what, it is a fantastic honor
• 02:59to be your guest and to speak for you.
• 03:02So the first thing that I have to tell
• 03:04you honestly is that I do have a conflict
• 03:07of interest because some of the data,
• 03:09some of the studies that I
• 03:11will be showing were actually
• 03:12sponsored by the company serious.
• 03:15I'm not sure if I still need
• 03:17to show these kind of slides.
• 03:20I think that most of us will have
• 03:23a concept now that the microbiome
• 03:26that lives inside of us and on us is
• 03:29definitely relevant for a lot of the
• 03:32Physiology and one way of looking
• 03:34at that is what is summarized here.
• 03:37That one should start thinking about
• 03:39a human multi species symbiotic
• 03:41supra Organism with a constant
• 03:44interaction between microbes.
• 03:45And human human cells.
• 03:49So we've been doing that basically since
• 03:512009 and our focus was very much when we
• 03:54started on allogeneic transplant patients,
• 03:57but since then we have broadened
• 03:59our whole scope.
• 04:00These are the current leaders of our
• 04:02group and the original gangster,
• 04:05Eric Pamer.
• 04:05As since then left us and has bolted
• 04:08for the University of Chicago,
• 04:10so these are the folks within my
• 04:13lap that are working on this,
• 04:15and I will mention some of their names.
• 04:18When we get to their studies.
• 04:22So an easy way to summarize about 10
• 04:25years of work by our group and by others
• 04:28within the context of allogeneic bone
• 04:30marrow transplantation and trying to
• 04:32see if there's a clinical relevance to it.
• 04:34Changes within the gut flora is
• 04:36to take as a starting point the
• 04:38causes of death within the first
• 04:40year after allogeneic transplants.
• 04:42And if you do that,
• 04:44then you can paint a cladogram an
• 04:46indicate with a blue color text said
• 04:49that are linked to good outcomes,
• 04:51and with red color text editor
• 04:53linked with bad outcomes.
• 04:54And you can differentiate the
• 04:56various clinically relevant outcomes
• 04:581st and most of all,
• 04:59of course,
• 05:00the overall the overall survival rate,
• 05:02where you can see that certain texts are
• 05:05linked in a positive or a negative way.
• 05:08Then of course the second one that we
• 05:11have focused on very much is if certain
• 05:14texts are linked to a graft versus host,
• 05:17and I'm giving you one study here from
• 05:202015 where we demonstrated in a patients
• 05:22that during the time the time period.
• 05:25Of neutrophil engraftment which is
• 05:27about 14 days out from allogeneic
• 05:29transplant that the abundance of
• 05:32a commensal enercell called sub
• 05:34laudia was clinically relevant.
• 05:36It seemed because patients who at
• 05:38that point had low levels of that of
• 05:42that texture had a greater incidence
• 05:45of little a graph versus host which
• 05:47is marked here with these red bars and
• 05:51that leads to overall worse outcomes.
• 05:54Many other clinically relevant
• 05:56outcomes can also be linked to changes
• 05:58within the flora, such as infections,
• 06:01organ toxicity, and even relapse.
• 06:03So now you can start to paint a
• 06:06picture really of what the different
• 06:08taxa could be linked to an.
• 06:10In some cases we have some mechanism also,
• 06:13and I will show you some of that.
• 06:18Now, many of these studies that
• 06:19we did and that others who did
• 06:22were limited by small group sizes.
• 06:24For instance,
• 06:25here I am showing a study early on
• 06:27where we demonstrated that if you
• 06:29look again at the time of neutrophil
• 06:32engraftment after an allogeneic
• 06:33transplant at the diversity within
• 06:35the gut flora that patients who
• 06:37had that point had higher diversity
• 06:39had a better overall outcome,
• 06:41and that seemed to be linked
• 06:43to the incidence of lethal.
• 06:45A graft versus host.
• 06:46But again,
• 06:47this was a single center small study.
• 06:50So we felt very fortunate when
• 06:52some of our dear friends and
• 06:54colleagues from all over the world
• 06:57were willing to work with us,
• 06:59so that now we could do a much larger
• 07:02study looking at 1300 plus patients.
• 07:04These patients were getting allogeneic
• 07:07transplants for AML and DS NHL.
• 07:10And the first thing that really
• 07:12struck us that if we looked at
• 07:14the at the at the baseline sample,
• 07:17so the samples when patients come
• 07:19in for their allogeneic transplant,
• 07:21that the composition of the flora was
• 07:24not that different between those centers.
• 07:26And I'll give you some reasons
• 07:28for that later,
• 07:29an SEC that in all four in all four centers.
• 07:33What we notice is that the moment that
• 07:36they come in for allogeneic transplant,
• 07:38there is a.
• 07:40A dramatic drop within the
• 07:43diversity of the gut flora.
• 07:45And thus that matter a clinically yes
• 07:48it does, as I'm showing here again,
• 07:50taking as a time point around
• 07:52neutrophil engraftment,
• 07:53which,
• 07:54as I said already,
• 07:55is about 14 days out from allergen
• 07:58echo transplant patients who at
• 07:59that point had higher diversity,
• 08:01that better overall outcomes.
• 08:03And this was holding up for
• 08:05the New York and patients,
• 08:07but also for the combined cohort
• 08:10of the other three centers.
• 08:12When we took a deeper dive,
• 08:14So what makes or what leads
• 08:17to that a difference?
• 08:18Then it seemed to be mostly linked
• 08:20to transplant related mortality,
• 08:22not so much relapse and within
• 08:25that category it actually seems
• 08:27to be mostly a difference in
• 08:29lethal graft versus host again.
• 08:32You can go one step further and
• 08:33you can start to think about
• 08:35certain attacks are that are
• 08:37linked to more favorable or worse
• 08:39outcomes and that you can validate.
• 08:42Then again by taking all of the
• 08:44patients of the other three cohorts,
• 08:46and indeed see that certain a
• 08:48consortia would be linked to
• 08:49better or worse outcomes.
• 08:51As you can tell we're not so
• 08:53focused on really zooming in
• 08:55too much on certain attacks,
• 08:57a except for one and I'll
• 08:59get back to that one later.
• 09:02I told you already that these patients
• 09:04came in with fairly similar diversity
• 09:07and the composition of their flora,
• 09:09and when we analyze that actually
• 09:12against normal healthy folks,
• 09:14what we saw is that all at all of
• 09:16these centers patients come into
• 09:19a transplant with lower diversity,
• 09:21and we speculate that that is
• 09:24because most of them will have gone
• 09:27through a year or so of chemotherapy.
• 09:29Neutropenic fevers treated
• 09:31with all kinds of antibiotics.
• 09:33And so on.
• 09:34But what was interesting is that
• 09:36coming in with an even lower
• 09:39diversity coming into a transplant
• 09:41was again linked to worse outcomes.
• 09:44Similar findings we have now also
• 09:47for Ottawa transplant where we see
• 09:49a similar drop within the diversity
• 09:51which starts at the moment that these
• 09:54patients come in for a transplant.
• 09:56And again if we take asmark
• 09:58the time point of neutrophil.
• 10:00So engraftment,
• 10:01which is about 9 days out from Ottawa
• 10:04transplants we see again that having
• 10:06at that time point higher diversity
• 10:09is linked to better overall outcomes.
• 10:14Now, Meanwhile, a number of studies,
• 10:16specifically within checkpoints and blockades
• 10:19have also demonstrated that diversity
• 10:21seems to matter for certain outcomes.
• 10:23In this case, responses to checkpoint
• 10:26blockade and we have some early data
• 10:30also that this might matter for
• 10:33the efficacy of car cell therapy.
• 10:36Some studies that were still finishing
• 10:38at the moment seem to indicate also
• 10:40that changes within the gut flora
• 10:42specific texture could be linked with
• 10:44the pace of the CD four and regeneration
• 10:47after an allogeneic transplants.
• 10:48I don't want to make too much of a
• 10:50deal here of these various attacks
• 10:53are because we still want to take
• 10:55that into a germ free mouse.
• 10:57Models and study data further,
• 10:59but this gives us hints of which
• 11:01assault apps might be or which
• 11:04text that might be relevant.
• 11:05Another critical feature is
• 11:07that with the loss of diversity,
• 11:09what happens also is that in some
• 11:11of these patients specifically
• 11:13within the post transplant period,
• 11:15there is a moment that their whole flora
• 11:18is being dominated by a single taxer.
• 11:21If you use as a definition that domination
• 11:24is when more than 1/3 of your flora
• 11:27is dominated by a certain attacks,
• 11:30and then we actually notice that in all
• 11:33patients at all centres they will have.
• 11:35At a certain at time points,
• 11:38a dominance or almost all,
• 11:40and what was very striking is that all
• 11:43four centers had all former centers
• 11:45that the most prominent bacteria that
• 11:48would do that is Enterococcus an.
• 11:50We knew already from studies at
• 11:53our center that having a state of
• 11:56dominance with Enterococcus within
• 11:58the post transplant period was linked
• 12:00to a 9 faults of risk for bacteremia,
• 12:03with VRE for instance.
• 12:06Bob was very striking.
• 12:07Is that at all four centers?
• 12:09It was one specific species that
• 12:11would do that that would lead
• 12:13to a state of a dominance and
• 12:15that was Enterococcus aficion.
• 12:16As I'm showing you here.
• 12:20And that seemed to matter clinically.
• 12:22Also because what we know Tist
• 12:24is having during the period or
• 12:26the post transplant period at one
• 12:28point a state of dominance with
• 12:30Enterococcus aficion was linked to
• 12:33greater risk of graft versus host,
• 12:35worse overall outcomes,
• 12:36and specifically an increased
• 12:38incidence of lethal a graft versus
• 12:40host that was true for all of the
• 12:43New York of patients and also held
• 12:45up when we took the three cohorts
• 12:48from the other centers together.
• 12:51So we took that into mouse models
• 12:53and what I'm showing you here is
• 12:55every box is 1 mouse where we did
• 12:58sequential a sequencing an in this
• 13:00case here if we add some of T cells
• 13:03to the allograft with which these
• 13:05mice were being a transplanted which
• 13:07will lead to a graft versus host.
• 13:09As you can see here,
• 13:11lethal a graft versus host.
• 13:13Then you must notice that there are these.
• 13:15These these red diamonds here,
• 13:17which means that there's a blooming
• 13:19of Enterococcus happening during the
• 13:21development of a graft versus host.
• 13:23In these mice,
• 13:24these mice are not getting any type
• 13:26of antibiotic or anything else.
• 13:28We thought first.
• 13:29Well,
• 13:29maybe that is just for one strain
• 13:32or for one setting,
• 13:33so we did different strains
• 13:35in three different settings.
• 13:37For for monitoring a graft versus
• 13:39host causing a graft versus
• 13:41host in all of these cases,
• 13:42we kept on finding about seven days out
• 13:45from Allergan Aker transplant during
• 13:47the development of a graft versus host.
• 13:49There's a blooming of Enterococcus.
• 13:53Those that matter in these mouse models.
• 13:56Well,
• 13:56we test the debt by taking a germ free mice,
• 14:00giving them a minimal flora
• 14:02plus or minus Enterococcus.
• 14:03In these mouse models.
• 14:04By the way we saw blooming with different
• 14:07with a different species was not physiome,
• 14:10but Enterococcus faecalis an.
• 14:12If we did that.
• 14:13If these mice had
• 14:15Enterococcus in their flora,
• 14:16then indeed they had worse
• 14:18a graft versus host,
• 14:20and again had a blooming of Enterococcus.
• 14:24So we took that further into these
• 14:26mouse models and analyzed mechanisms,
• 14:28and since this is published,
• 14:30I'm only going to summarize
• 14:32it here with Soma schematics.
• 14:34So what we think is happening and
• 14:36what kind of data we have so far
• 14:39is that the damage caused by chemo
• 14:42and by the conditioning regiments
• 14:44plus the Elo activated T cells
• 14:46which specifically targets the
• 14:48crypt stem cells and causing a
• 14:51graft versus host within the gut.
• 14:53That will lead to enterocyte damage.
• 14:56The enter sites therefore start
• 14:58to make less of an anti microbial
• 15:01approaching called REC 3 which
• 15:03is known as we and others have
• 15:06actually demonstrated to be a an
• 15:09anti and anti microbial approaching
• 15:11that can contain Enterococcus.
• 15:13Another thing that also happens is
• 15:16that he enterocytes specifically
• 15:18within the ilium or less,
• 15:19are capable of making electees
• 15:21that will lead them to increase
• 15:24levels within the lumen.
• 15:26Of lactose and that plus the fact that
• 15:30there's less of rec rec three will
• 15:33then lead to an Enterococcus blue.
• 15:35The Enterococcus Bloom
• 15:36pushes away some of the year.
• 15:38Commensal flora well.
• 15:39One of the beneficial things that the
• 15:42commensal flora does is we and others have.
• 15:44A demonstrated is that it makes a
• 15:47butyrate and butyrate is an intraluminal
• 15:49nutrient for these intro sites.
• 15:51So if there's less a butyrates
• 15:53then that will lead to even more
• 15:55damage to the enterocytes and
• 15:57now you're in a downward spiral.
• 15:59And things get worse and worse.
• 16:02So we're trying to figure out are
• 16:04there ways that we can maybe blocked
• 16:07AT and we thought initially about
• 16:09some bacteriophages and other things.
• 16:12But then the post Doc who was
• 16:14working on this Christof Stein
• 16:16touring are did a very simple thing.
• 16:19He analyzed simply what are the
• 16:21pathways with already nutrients.
• 16:23As I mentioned already,
• 16:24that Enterococcus favors well.
• 16:26As I said already, it likes Electo,
• 16:29so in his culture system for intro
• 16:31Enterococcus he simply poured some lactaid.
• 16:34From the local pharmacy and
• 16:36demonstrated that with that.
• 16:37Of course he could block the
• 16:40growth of these bacteria.
• 16:42He then went back to these mouse
• 16:44models and what he did there,
• 16:46he's bought Chow without electrons,
• 16:48which is actually difficult because lactose
• 16:50is everywhere in many different nutrients.
• 16:52But he was able to get that mate
• 16:55and when he put these mice in two
• 16:57different models on the child,
• 16:59it was lactose free.
• 17:01Who could get somewhat less a
• 17:03graft versus host me.
• 17:04You're not curing a graft
• 17:06versus host with this,
• 17:07and he could block the
• 17:10blooming of Enterococcus.
• 17:11So then he took that finding back to humans.
• 17:15And we looked in our patients.
• 17:17A cohort.
• 17:18Are there maybe patients who
• 17:20have lactose intolerance?
• 17:21When we looked at that we hoped,
• 17:24of course,
• 17:24is that that would be linked to
• 17:27increased levels of graft versus host.
• 17:29We didn't really find that there was a trend,
• 17:32but what we did notice is the
• 17:35moment that patients come off
• 17:37antibiotics and that is the 0 here.
• 17:39Then those patients who are
• 17:41lactose intolerant will have
• 17:43higher levels of Enterococcus.
• 17:47So as I've been trying to show you here
• 17:49in this part so the Enterococcus can
• 17:51dominate in the post transplant period,
• 17:54it is linked to a graft versus host,
• 17:57and lactose is one of the basic nutrients
• 18:00for Enterococcus and using lactate or or.
• 18:02Basically strategies like that could
• 18:04potentially block the bloom of Enterococcus
• 18:06an in that way limit the graft versus host.
• 18:09This of course begs for a clinical
• 18:11study which we haven't done yet,
• 18:13so I can't tell you anything about that.
• 18:17Meanwhile, other centers have also
• 18:19demonstrated that the levels of
• 18:21Enterococcus within the post transplant
• 18:23periods are linked to a graft versus host.
• 18:26I'm just showing you one out of several here.
• 18:31Another disease that we were interested
• 18:33in is the a complication of chronic graft
• 18:36versus host after allogeneic transplant,
• 18:38so we try to figure out if changes within
• 18:41the four I could be relevant for that also.
• 18:44Now, the onset of chronic graft
• 18:46versus host is of course much,
• 18:48much later is about 200 days out,
• 18:50and what we did in this case is we
• 18:53looked at the samples about 100 days out
• 18:56and try to see if there were certain
• 18:59texts on maybe that could be linked.
• 19:01In a favorable or an unfavorable
• 19:04way with the onset of chronic graft
• 19:06versus host much, much later,
• 19:08and indeed we have some hints now such
• 19:11as Streptococcus in Accra Mencia.
• 19:13That seems to favor the onset
• 19:15of chronic graft versus host.
• 19:17So of course that this needs much
• 19:20much more work.
• 19:21Another feature in this article that
• 19:23I'm not summarizing is that there might
• 19:26be also a role for certain short chain
• 19:28fatty fatty acids that might limit the
• 19:31incidence of chronic graft versus host.
• 19:35Now I mentioned already a few times
• 19:37that this drop in the diversity within
• 19:40the gut flora is pretty dramatic in
• 19:43all patients who have an allogeneic
• 19:45bone marrow transplantation.
• 19:47So we went back and we try to
• 19:49analyze what are possible factors
• 19:51that might cause that dramatic loss,
• 19:54and the first one of course,
• 19:57that we looked at was antibiotics.
• 20:01And indeed,
• 20:01if you look at the use of
• 20:03broad spectrum antibiotics,
• 20:05so those type of antibiotics that
• 20:07we typically give when a patient
• 20:10has fever and neutropenia,
• 20:11and specifically will do damage to
• 20:13their commensal enter up flora,
• 20:15then indeed the exposure to those
• 20:18types of antibiotics will lead to
• 20:21a greater drop in the diversity.
• 20:24We analyzed over a period about 10
• 20:26years the use of antibiotics in
• 20:29our allogeneic transplants patients
• 20:31and try to see if certain types of
• 20:34antibiotics were linked to greater
• 20:36incidence of lethal graft versus host
• 20:38an we came up with two piperacillin
• 20:41tazobactam and imipenem also
• 20:43mirror mirror Panama's.
• 20:44We're using it now,
• 20:46but for this study we could only look at
• 20:49me Pennant and those are indeed two types
• 20:52of antibiotics that do more damage to the.
• 20:56Commensal anaerobic flora,
• 20:57then many other types of
• 20:59broad spectrum antibiotics,
• 21:00such as it's ever been.
• 21:02As I'm showing you here that was LinkedIn D2,
• 21:06higher incidence of lethal graft versus host.
• 21:08We took that again into a mouse
• 21:10model and we could see indeed that
• 21:13these two broad spectrum antibiotics
• 21:16that damage the analog flora would
• 21:18lead to worse graft versus host.
• 21:21And to make a Long story short,
• 21:24because this is all published when
• 21:26we studied this further in this
• 21:29mouse model we saw a few things.
• 21:31First of all,
• 21:32we saw a change within the gut flora
• 21:34that there was a blooming of a bacteria.
• 21:37Ecker, Ecker,
• 21:38Mencia and Accra.
• 21:39Mencia lives very close to the mucus
• 21:41layer and has mucolytic enzymes and
• 21:44therefore will lead to a greater breakdown.
• 21:46We actually speculate of the mucus
• 21:48layer and we could to demonstrate
• 21:51that the gut barrier function.
• 21:53More impaired in these mice treated with
• 21:56this broad spectrum antibiotic than not,
• 21:58and that again, might set up a
• 22:01cascade of a number of things,
• 22:03more stimulation of potentially of certain
• 22:06dendritic cells that I won't get into now.
• 22:09They will make higher levels of
• 22:11aside account that we know is
• 22:14linked to gut a graft versus host,
• 22:16which is all 2020 three that
• 22:19will lead to greater activation
• 22:21of Elo activated CD 4T cells.
• 22:23In this model that we are using,
• 22:25those are the driving donor T cells
• 22:28that will give you a graph versus host,
• 22:30leading to worse overall graph versus host.
• 22:33Specifically within the column.
• 22:36So a number of studies have looked
• 22:39now over the last decades or so.
• 22:42If the use of broad spectrum
• 22:44antibiotics has any impact on
• 22:46outcomes after allogeneic transplant,
• 22:48and as we were chatting earlier
• 22:51the the the first studies looking
• 22:53at the use of antibiotics,
• 22:55broad spectrum antibiotics in humans
• 22:57in the 1970s and 80s actually seemed
• 23:00to indicate that wiping out the whole
• 23:03flora would lead to better outcomes.
• 23:06Specifically, less graft versus host,
• 23:08and there are some pediatric studies
• 23:10that still seem to indicate that,
• 23:13but the bulk of the stories,
• 23:15the bulk of the studies over
• 23:17the last two years,
• 23:19do seem to indicate that the use
• 23:21of broad spectrum antibiotics
• 23:23is linked to worse outcomes,
• 23:25specifically,
• 23:26increased levels of lethal graft versus
• 23:28host or graft versus host overall.
• 23:33So what can we do about that?
• 23:35Well, one of the things that we have
• 23:38been looking at is a beta lactamase
• 23:41that you would give orally so that
• 23:43within the lumen you can block
• 23:45any kind of effects of whatever
• 23:48type of antibiotic you are using.
• 23:50So these are some early studies
• 23:52with such a compound,
• 23:53so if we get gift that then indeed
• 23:56we can block in a normal mouse
• 23:58the change within the diversity.
• 24:00The blooming of Enterococcus.
• 24:02When you treat a mouse with both an
• 24:05antibiotic and this beta beta lactamase,
• 24:07and if you take it to a mouse
• 24:10model for graft versus host,
• 24:12similarly you can somewhat block the
• 24:14worsening of graft versus host that you
• 24:17would get with the with the antibiotics.
• 24:19Of course, we're looking forward
• 24:22to taking this into trials now.
• 24:25A second major factor,
• 24:26we think that can impact on the dramatic
• 24:29loss of diversity are are the different
• 24:32types of a conditioning regiments.
• 24:35So we took a deep dive here.
• 24:37As all of the different types of
• 24:40air conditioning regiments that
• 24:41we have been using at our center,
• 24:43and as you can see,
• 24:45there are many.
• 24:45You can put them into three
• 24:47categories based upon their strength.
• 24:49Going from my lower blade of two reduced
• 24:53intensity tune on my lower blade.
• 24:55And if you do that as you would expect,
• 24:59the ones with lower strength indeed
• 25:01curfew less of a drop in the diversity.
• 25:05And even if you were control
• 25:06for the use of antibiotics,
• 25:08you still keep on finding that same thing.
• 25:13Another thing that was very interesting
• 25:15when we looked at it in some more detail
• 25:18is that certain regiments and we don't
• 25:20know why we need to study that further,
• 25:22such as this one with fludarabine,
• 25:24cyclophosphamide and low dose at TV.
• 25:26I seem to be linked to the
• 25:28blooming of certain bacteria,
• 25:30and here I'm pointing out again
• 25:31the one that I mentioned earlier,
• 25:33Accra Mencia.
• 25:37Another factor that hasn't been
• 25:39studied with that much detail yet,
• 25:41but we know is a major factor for
• 25:45changes within the flora is diet.
• 25:47So to be able to get accurate dietze data,
• 25:52we hired a nutritionist who very carefully
• 25:55day by day and almost 100 patients
• 25:59monitored exactly what these patients 8.
• 26:02The first thing that he notices
• 26:04if he looked at the onset when
• 26:07patients come into transplant that
• 26:10calculating the Nutrition risk index.
• 26:12Patients coming in with lower levels
• 26:15for that index have already a lower
• 26:19diversity within their flora.
• 26:21Another thing that he notices that
• 26:23the calorie intake the moment that
• 26:26these patients are comin goes down
• 26:28dramatically and follow sort of the same
• 26:31pattern as that drop within diversity.
• 26:34And he first would have analyzed
• 26:36the usual aspects that people look
• 26:39at when they're studying a diet.
• 26:41So calories, protein, fats, fiber and swim.
• 26:44And he found indeed that calorie
• 26:47intake was positively correlated
• 26:49with the diversity fiber also
• 26:51and also positively with blodia.
• 26:53And that is a true for both calories and
• 26:56fiber and negatively for Enterococcus so.
• 27:00That was interesting,
• 27:01but what I actually found even
• 27:04more interesting is a different
• 27:05way to look at a diet,
• 27:08and that is to look at it as a taxonomy.
• 27:11So now you look at all of the
• 27:14fruits of products more than these
• 27:16categories like protein, fat and so on.
• 27:19And when we analyzed our data like that,
• 27:22what we saw was that the footer
• 27:25diversity immediately dropped when
• 27:27patients come into a hospital,
• 27:29and that that diversity.
• 27:30Again,
• 27:31drops more for those patients who get a
• 27:34stronger type of a conditioning regiment.
• 27:40You can then start to look at
• 27:42certain food groups and how
• 27:44they are linked to a diversity,
• 27:47and that was very interesting because
• 27:49then you find something that we didn't
• 27:52really thought of and that is that the
• 27:55intake of fruits and sugars and sweets
• 27:57and beverages that that is actually
• 27:59linked negatively to the diversity.
• 28:01So we're still trying to figure out why
• 28:04that is and one of the theories that
• 28:07we have is that these these sugars.
• 28:10These very simple sugars.
• 28:12That they actually might feed some of
• 28:15the pathogens or the bacteria that are
• 28:18taking over in times of low diversity.
• 28:20And in that case might make matters worse,
• 28:24as has been shown.
• 28:25For instance, for an enteritis,
• 28:27ferrea colitis model.
• 28:28And again you see there if you feed
• 28:31these mice while they're getting DSS.
• 28:34Also, simple sugars and you
• 28:36see him blossoming of again and
• 28:39bug like Accra Mencia.
• 28:43So now we can start to make these kind
• 28:46of tables where we can see what food
• 28:49groups might have impact on certain tax.
• 28:52And of course this can.
• 28:54This can help us to start to a compose,
• 28:58maybe a diet that would be a beneficial
• 29:01for specific patients in specific
• 29:03settings and that is of course our
• 29:06ultimate goal with all of this.
• 29:10Another category is drugs and.
• 29:14Patients who are getting an allogeneic
• 29:17bone marrow transplantation at
• 29:19any given moment are probably on
• 29:21seven or eight different drugs.
• 29:23And it was a very nice study a couple
• 29:25of years back where it was demonstrated
• 29:28that many drugs that weren't antibiotics
• 29:31that they actually could also impact
• 29:34on many of the bacteria that are
• 29:37part of the commensal flora and just
• 29:40to highlight some of these drugs.
• 29:42These are all drugs that we
• 29:44frequently give to our patients,
• 29:46including things like slight cyclosporin.
• 29:50So a very talented,
• 29:52say, graduate student.
• 29:53It's the following thing.
• 29:54She took all of the data that we have
• 29:57from all of the samples on 1100 patients.
• 30:00And she put them in a you map and
• 30:03therefore could see all these clusters.
• 30:06Then she analyzed these clusters
• 30:08a little bit better.
• 30:09She came up with 10 different clusters
• 30:12and labeled them and then analyze.
• 30:14Since we had to kinetic data if
• 30:16the starting or stopping of a
• 30:19certain drug would have impact
• 30:20on the flora in these patients,
• 30:23moving from one cluster to another cluster
• 30:26or staying put in that same a cluster.
• 30:29And when she did that kind of an analysis,
• 30:32what was very striking is that,
• 30:34of course the antibiotics will have
• 30:36impact if you a transition to another
• 30:39cluster or if you stay where you are
• 30:42so you can see here from this data.
• 30:44But all of these other drugs and
• 30:46she looked at a grand total of 6063
• 30:49different drugs can have impact also.
• 30:51So it's a little bit early to
• 30:53show you data yet,
• 30:55but we have we have some data now
• 30:57that seem to indicate a certain.
• 31:00Pain medicines might have impact
• 31:01on changes within the gut flora,
• 31:03so there's a lot of work still
• 31:06there that we can expand on.
• 31:09Now of course,
• 31:10the ultimate goal for many people is
• 31:13to take this back into the clinic,
• 31:15and we've been thinking, of course,
• 31:17about that.
• 31:17Also,
• 31:18I'm still very cautious because I
• 31:20feel that we're in the early going,
• 31:22so we still need to know much, much more.
• 31:25But if you categorize the difference
• 31:27in therapies in four,
• 31:28then you can think about the
• 31:30use of antibiotics,
• 31:31and that is probably the lowest hanging
• 31:34fruit because those are drugs that
• 31:36we given that we can easily monitor.
• 31:38The second category would be.
• 31:40Pre biotics were thinking of there
• 31:41is to maybe give specific nutrients
• 31:44that would help that would feed
• 31:46that would favor texture that
• 31:48we think could be of benefit.
• 31:50The one that most people are
• 31:51focused on is Pro Biotic.
• 31:53So now we're talking bout fecal
• 31:56transplant engineered microbes and
• 31:57so on and so on and there certainly
• 32:00with an allergen Aker transplant
• 32:01there's a lot of work going on
• 32:04within that field and then a fourth
• 32:06category would be post biotics so
• 32:08those could be certain products made.
• 32:10By bacteria I mentioned already short
• 32:13chain fatty acids such as a butyrate,
• 32:15and there are trials going on with that.
• 32:18What are we doing at the moment?
• 32:21Well, as I said already,
• 32:23for us the lowest hanging fruit is
• 32:25antibiotic stewardship avoids the use
• 32:27as much as possible of these broad
• 32:29spectrum antibiotics that do damage
• 32:31to the commensal enrolled flora.
• 32:34So we have a a trial open at
• 32:36the moment where patients who
• 32:38get fever neutropenia will be.
• 32:40A randomized to either getting our
• 32:43standard of care which is piperacillin
• 32:46tazobactam versus cefepime and try
• 32:49to win these patients as quickly
• 32:52as possible off antibiotics.
• 32:55A second study that we have finished
• 32:57already as an auto fecal transplant.
• 33:00So the thinking there was when patients
• 33:03come off antibiotics which is about 14
• 33:05days out from the allergen acre transplants,
• 33:08why don't we give them back their
• 33:11original flora from pre transplant?
• 33:13And since this was led by Eric
• 33:16Pamer Ann Young Tower our primary
• 33:18focus was the prevention of C diff.
• 33:22So we looked at that mostly,
• 33:24and as these things go in this series,
• 33:27the incidence of a C diff
• 33:29was actually relatively low,
• 33:31so we didn't see much there.
• 33:33But what we did notice is first
• 33:36of all that's the concept worked.
• 33:39You could indeed this is the pre transplant
• 33:42and diversity pattern of a patient,
• 33:44who then was transplant again
• 33:46with an auto fecal transplant,
• 33:48and indeed would get pretty
• 33:50much their own flora.
• 33:52Back so the concept seemed to be working,
• 33:55but in terms of clinically relevant outcomes,
• 33:57the only thing that we saw in this
• 34:00very small series was actually
• 34:02something that we weren't counting on,
• 34:05and that is that the activation of
• 34:07certain viruses which commonly happens
• 34:09within the context of allogeneic transplant,
• 34:11such as CMV and EBV was somewhat
• 34:14lower in those patients who have been
• 34:17treated with an auto fecal transplant.
• 34:20Another thing that we notice is that
• 34:23auto fecal transplant seemed to favor
• 34:27the engraftment reconstitution of
• 34:29neutrophils, lymphocytes and monocytes.
• 34:34A study that we're working on
• 34:36that is not open yet is to really
• 34:39rationally design A consortia of these
• 34:41bacteria pretty much based upon that,
• 34:44we'll that I started out with that
• 34:46whole a cladograms where I indicated
• 34:49how certain flora elements were
• 34:51linked to good or bad outcomes and
• 34:53based upon that we have created a
• 34:56consortium and we want to give these
• 34:58bacteria back again at that time
• 35:01point of neutrophil engraftment,
• 35:02which is about 14 days out
• 35:04from allogeneic transplant.
• 35:06As I've said many times by now.
• 35:10So with that I would like to stop.
• 35:13I would like to summarize basically
• 35:16that what I've been trying to show
• 35:18you is that changes within the gut
• 35:21flora are linked to overall survival.
• 35:23Lethal graft versus host bacteremia,
• 35:25sepsis, engraftment and even a relapse.
• 35:28I gave you a specific story about
• 35:30how the dominance with Enterococcus
• 35:32within the post transplant period
• 35:35is linked both in mouse and men
• 35:37to lethal graft versus host.
• 35:39And I told you about the various
• 35:42factors that we think can have
• 35:44impact on the gut flora,
• 35:46such as the use of antibiotics,
• 35:48but also other types of drugs,
• 35:50diet and conditioning regiments.
• 35:52So with that I would like to of course
• 35:56thank all of my funding agencies in my
• 35:58fantastic lap and the many folks who
• 36:01we have worked with at other centers.
• 36:03So with that I would like to stop and
• 36:06I should probably stop sharing also.
• 36:09If I can do that? It seems to be.
• 36:14But
• 36:15thank you myself for this really,
• 36:17really fascinating talk.
• 36:18I have to say I coming up with
• 36:21questions and was every next step
• 36:24you answered my first question,
• 36:26so maybe I can start with one so.
• 36:31Right, so you are receiving these patients
• 36:34for transplant after they have gone
• 36:37through months and months of treatment.
• 36:39And have you looked at how you know?
• 36:42For example,
• 36:43you know whether patients receive, you know,
• 36:46is decided in or targeted therapy or
• 36:49chemotherapy before coming to transplant,
• 36:51does that effect?
• 36:53What you see, then,
• 36:55in terms of transplant outcomes,
• 36:57yes. So this is
• 36:59of course, where we still
• 37:01don't have very good data.
• 37:03We do have some collection also of
• 37:05samples from patients before transplant,
• 37:08specifically with AML.
• 37:09We see a bit of the same patterns,
• 37:12but it hasn't been analyzed that well
• 37:14yet that we see with allogeneic bone
• 37:17marrow transplantation that an AML
• 37:19patient getting in induction regiment
• 37:21will have the same pattern of the loss
• 37:24of a diversity dominance with certain
• 37:26tax are specifically with with again,
• 37:29Enterococcus,
• 37:29but we need much more work to analyze that,
• 37:32and as I hinted at,
• 37:34almost every drug that they might have
• 37:37seen in the year prior to a transplant,
• 37:40potentially.
• 37:40Could have impacted on their floor,
• 37:42so it's very worthwhile to look at that.
• 37:46OK, awesome. So we have questions
• 37:49from the audience from Lucas Cauda,
• 37:51who says great talk in his first
• 37:54question is how well does this correlate
• 37:57with amino acid magic biomarkers?
• 37:59Rank 3 S, T2, etc.
• 38:05So as you know, since you
• 38:07know about these markets,
• 38:09then you know of course those are
• 38:11the markets that have been developed
• 38:14by Jamie by Jamie Ferrara an he
• 38:17is doing these kind of studies
• 38:19with Ernst Holler at the moment,
• 38:21within the context of the Magic Consortium,
• 38:24and I haven't seen direct connections
• 38:27yet between, for instance,
• 38:28which would be really interested rectally,
• 38:31gamma and form.
• 38:32So those are the studies that.
• 38:34They are doing,
• 38:35but I haven't seen any data from them yet.
• 38:38We have only very limited data
• 38:40because we haven't used that
• 38:42panel that they are using so much.
• 38:45OK, awesome and I'm gonna read you.
• 38:47The second question from Lewis
• 38:49is one of our transplanters.
• 38:50Is the New York poupan commercialized
• 38:52for other sites to study?
• 38:56The New York School bank. Well,
• 38:59we we don't have a New York school bank.
• 39:02I wish actually that we have one
• 39:05and the one that most people have
• 39:07used is open open Biome and I was
• 39:09just reading that they might have
• 39:12some trouble and that they are
• 39:14closing and that is a company and
• 39:16not for profit company in Boston.
• 39:18So that's where a lot of people
• 39:20have been getting flora from.
• 39:22We at the moment are working with
• 39:25some companies also and I put
• 39:27didn't put that into my slide 2.
• 39:29Potentially do a sequel transplant
• 39:31for Graft versus host and you might
• 39:34have seen very small as series from
• 39:37all over the world where people
• 39:39have tried that for steroids or
• 39:42refractory graft versus host.
• 39:43They would do a fecal transplant.
• 39:46Different concepts sometimes that
• 39:47you just do a normal donor or even
• 39:51one company is sponsoring a trial
• 39:53where they take a whole bunch of
• 39:56healthy healthy folks and literally
• 39:58mix all of the feces.
• 40:00And give One Giants and
• 40:02transplants with that,
• 40:03and they seem to have some benefit,
• 40:06so there is a lot of focus at the moment
• 40:09on doing fecal transplant for steroids.
• 40:12Refractory graft versus host and with
• 40:15small series showing showing benefits,
• 40:17but we need much more work and I want
• 40:20to emphasize that there are also
• 40:22risks because we all realize you're
• 40:25dealing with patients where the
• 40:28gut barrier is negatively impacted
• 40:30by the conditioning regiment.
• 40:32I'm so any kind of bacteria that you
• 40:35give there have a higher likelihood
• 40:37to pass the gut Scott Barrier and
• 40:40you might know of the negative
• 40:43outcomes that we're seeing with
• 40:45some of these fecal transplants
• 40:47where the product wasn't carefully
• 40:49screened enough for certain bacteria,
• 40:51which led to two patients getting
• 40:54seriously ill and one of them dying.
• 40:57So there there are a lot of
• 40:58a lot of risks there, so.
• 41:02Then you have a question.
• 41:03Do you want to ask it directly?
• 41:07Hi, fantastic talk thank you.
• 41:11Do you see similar effects of the
• 41:13microbiome in auto transplants?
• 41:16Yeah, so I showed some of the data.
• 41:19So for autotransplant we see
• 41:20the same drop in the diversity,
• 41:23again starting immediately and
• 41:24we see also links to outcomes.
• 41:26So for instance,
• 41:28for myeloma we could very nicely
• 41:30see that patients with a with
• 41:32less of a loss in their diversity
• 41:34would have better PFS and OS,
• 41:37so that that seems to be a real benefit.
• 41:40All of this needs to be studied
• 41:43in much more detail because now of
• 41:45course you're talking about it.
• 41:47Order whatever transplants are not talking
• 41:50about a graft versus host or something.
• 41:52Things like that,
• 41:53but there are signals there that are
• 41:56absolutely worthwhile studying for.
• 42:00Now, so I think it's it's
• 42:03fascinating where that in this
• 42:04population you are studying the
• 42:07immune system so intricately and.
• 42:09And can some of this work
• 42:11trying to be transplanted?
• 42:12You know their translator to
• 42:14patients who are not in the.
• 42:16Transplant setting in terms of
• 42:18you know immune interaction.
• 42:19I think you were mentioning the
• 42:22the effects on immunotherapy.
• 42:25So I think that is of course
• 42:27where a number of companies and
• 42:30number of centers and number of
• 42:33scientists are going with this.
• 42:35The general concept being that the
• 42:37gut flora can modulate immunity,
• 42:39which it almost has to write
• 42:41because you're in a constant
• 42:43interaction there with God for us.
• 42:46So it's very clear that T cell repertoire
• 42:49and activation of innate cells is very
• 42:52much modulated by changes within the floor.
• 42:54That is obvious.
• 42:56So people have taken this,
• 42:58of course within the field of a
• 43:00checkpoint blockade much much further.
• 43:02You might know there was a back
• 43:04to back to back science articles
• 43:06demonstrating that certain compositions
• 43:08of the flora were linked to better
• 43:11outcomes with checkpoint blockade,
• 43:12foreign Melanoma and so on,
• 43:14and that has led to a series of trials
• 43:17that are going on at the moment.
• 43:20It has also and I always tell that
• 43:23story because I want to warn people.
• 43:26It has led to negative outcomes and
• 43:28what I mean by that is that because so
• 43:32many patients heard about these stories?
• 43:34Oh, you can do something with microbiome,
• 43:37and my checkpoint therapy is
• 43:39going to go better.
• 43:40They went to their own pharmacy.
• 43:43They started to buy local Pro,
• 43:46Pro,
• 43:46Biotic and Drugs etc and A and
• 43:49a scientist at Anderson had
• 43:51actually carefully analyzed it.
• 43:54And found that those people
• 43:56who did do it do it yourself.
• 44:00Probiotics had worse outcomes
• 44:02from their check.
• 44:03One blockades then patients
• 44:04who didn't do that.
• 44:05So there are certain dangers and I think
• 44:08we have to warn people also about this.
• 44:11This is not sort of a free for all and
• 44:14and we still need to understand much more.
• 44:17What are the dietary elements?
• 44:19What are the bacteria that really
• 44:21matter for certain outcomes?
• 44:22As I illustrated also simply
• 44:24telling people to eat a lot of
• 44:26fruit well in certain context it
• 44:28might be a bad thing actually.
• 44:31Who would have thought that?
• 44:33Dance, it's understand the questions.
• 44:36I think it's fascinating that cross
• 44:38centers you know in in the world,
• 44:42whereas diet is probably quite
• 44:44different that you have such homogeneous
• 44:46or similar starting populations.
• 44:48Yeah, yeah, that we found very fascinating,
• 44:52right? I mean, you're talking with
• 44:54patients from by iron versus the North
• 44:58of and of Japan, and you would
• 45:01really think the diets
• 45:03are completely different.
• 45:04And they will go into these transplant
• 45:07with completely different flora.
• 45:08But as I mentioned during my talk,
• 45:11also, we really think that that is
• 45:13because most of these people have
• 45:15injured microbiomes to start with.
• 45:17They come, they come into transplant
• 45:19already having steam for a year or so.
• 45:22So many drugs and antibiotics.
• 45:24That is probably why it's so simple.
• 45:28Something something so.
• 45:30Do you have a? Do you have a
• 45:33suggestion of a simple measure?
• 45:35So we ask our hospital to change the diet.
• 45:40What food is served in the cafeteria?
• 45:42Well, I think
• 45:44first of all, when we
• 45:45started to look at the diet,
• 45:48I don't know how it is at your center.
• 45:51But on our transplants floor we it's
• 45:54almost like an like an ICU, right?
• 45:57We have such detailed data about
• 45:59everything finals every eight
• 46:00hours and and daily chemistries
• 46:02and blood counts and everything.
• 46:04But when it comes to what
• 46:07do patients actually eat?
• 46:08Most of what we saw is?
• 46:11Eight half sandwich or something like that,
• 46:13so we have no detail about
• 46:15what we're actually eating,
• 46:16so I think that is a moment
• 46:18where we need to operate.
• 46:20We need to take that a little bit
• 46:22more serious now that we know that
• 46:24it's a major factor that can have
• 46:26impacts on microbiome microbiome.
• 46:28I hope that you got that out of this lecture.
• 46:31Really seems to impact on
• 46:32clinically relevant outcomes,
• 46:33so that's one of the things that
• 46:35I'm trying to fight for within
• 46:37our hospital so that we take
• 46:39that a little bit more serious.
• 46:41We really need to know what our patients eat,
• 46:44not just nurses scribbling down like well,
• 46:47ate something,
• 46:48and then we can learn a lot from it.
• 46:51And then we need to understand
• 46:52in much more detail which
• 46:54of dietary elements do what.
• 46:58OK, that's that's fascinating,
• 46:59so I'm not going to get more questions,
• 47:01so I get to have all the questions in the
• 47:03entire conversation here for everybody.
• 47:06But you know that that seems like
• 47:08a fantastic project where you could
• 47:10potentially engage the patient right
• 47:12in documenting using Epic using. Well,
• 47:14I maybe maybe we close on the House and.
• 47:19Maybe a fantastic collaboration
• 47:20that we would could then do with.
• 47:22You have to do that.
• 47:24Take that epic interface and
• 47:25put it to use for patient care.
• 47:27That'd be wonderful.
• 47:28Thank you awesome.
• 47:30So we're not getting more questions
• 47:32you have answered.
• 47:33Everybody's questions so thank you
• 47:35so much again for giving a fantastic
• 47:37talk and you certainly have my
• 47:39mind spinning and I don't know if I
• 47:42should drink on my ginger tea now.
• 47:44Let's see how that goes.
• 47:47OK, thank you very much.
• 47:49Much is great.
• 47:50Thank you.