The Role of the Intestinal Microbiome in Allogeneic Hematopoietic Cell Transplantation

March 03, 2021

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Yale Cancer Center Grand Rounds/Blanche Tullman Lecture | March 2, 2021

Marcel van den Brink, MD, PhD, MSK

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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.