Immune Checkpoint Inhibition and Novel Therapies for Myelodysplastic Syndromes/Neoplasms

October 13, 2023

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Yale Cancer Center Grand Rounds | October 13, 2023

Presented by: Dr. Amer Zeidan

ID10859

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00:00Thank you so much for coming.
00:02You know, we are getting back to
00:04full in person and I know there are
00:06a lot of people on Zoom as well.
00:07So thank you so much for coming today.
00:09And I will be talking about immune
00:12checkpoint inhibition and Novant
00:13therapies for myelodysplastic syndromes.
00:16These are my disclosures
00:17and this is the outline.
00:18I'm going to cover 4 areas that have seen a
00:21lot of developments in the last few years.
00:23The first one is updates and classification
00:26as well as risk stratification
00:28and response assessment MD's,
00:31the evolving therapies for lower risk MD's,
00:33high risk MD's and then specifically
00:36about the immune checkpoint inhibition
00:37efforts that I have been trying to
00:40kind of doing in these disease areas.
00:43So what are myelodysplastic syndromes,
00:44neoplasm.
00:45You can see that we actually have
00:47formally added the name neoplasms finally
00:49because for a long time myelosplastic
00:52syndromes were thought of as syndrome
00:54or pre leukemia or a disorder,
00:57but they are actually cancers and this
00:59has been formally diagnosed by The Who.
01:01They are basically uncommon
01:03only four in 100,000 a year,
01:0620,000 cases of MD's in the US.
01:09However,
01:09the median ages in the early 70s
01:11and the number of patients with MD's
01:13has been increasing because we have
01:15more and more cancer survivors.
01:17I share many patients with many of you
01:19on the solid pumor side because those
01:22patients have secondary myelodysplastic
01:24syndromes and those can be among the
01:27most challenging patients to treat.
01:29And you can see here another fact that
01:31emphasizes the malignant nature of MD's.
01:33So this is the five year survival
01:35of patients with MD's in Violet
01:37and you can see it's 31%,
01:39very close to what you get with
01:41AML which is 25% but much worse
01:43than some of the more common solid
01:45tumors such as breast and lung when
01:47you take all the patients together.
01:49Again further emphasizing the
01:51malignant nature of these conditions.
01:54And more recently,
01:55we also understood that there is a
01:59large number of people who go through
02:01a process called clonal hematopoiesis
02:03of indeterminate potential or CHIP.
02:05And this is a condition that happens
02:08in up to 10% of people older than 70.
02:11And some of those progress to MD's
02:13and some don't,
02:14but they are also associated with
02:17inflammation and cardiovascular
02:18risk and many other syndromic
02:21dysfunction across the body.
02:23This is why multiple disciplines including
02:25cardiology have been interested in this.
02:27And for that more and more cancer
02:29centers have been interested in
02:30establishing clinics for chip and seekers.
02:33And here our newest recruit, Dr.
02:35Lourdes Mendez has taken over this
02:37aspect and I think this is going to
02:40become very important in the coming years.
02:43The management of MD's,
02:44as I'm going to show you in a little bit,
02:45has been difficult to get new therapies.
02:47And part of this is because of the
02:50large heterogeneity of the disease.
02:52This is a schema showing the
02:54genetic landscape of MD's.
02:55And you can see here that there are more
02:57than 40 recurrently abnormal somatic
02:59mutations that can happen in patients.
03:01However, less than six of those
03:03happen in more than 10% of patients.
03:06Therefore, there are many different driver
03:08genes and developing therapies that
03:10work across the spectrum for patients
03:13with MD's has been quite challenging.
03:15Another I think challenging feature
03:17has been the classification of MD's.
03:19And over the years,
03:20how do you separate MD's from
03:22AML has been a moving target.
03:24Historically A+ count of 30% was used
03:28and then this was changed to 20% most
03:31recently last year and this created a
03:34huge difficulty in the field is the
03:38target blast count has been moved to 10%.
03:40So now there is this new entity
03:43called MD's slash AML which is 10 to
03:4519% blast and this is causing a lot
03:47of confusion for patients especially
03:49that the PATH reports get released
03:51immediately to patient nowadays or
03:53they are being told that you have
03:55MD's by 1 classification and AML
03:59by another classification.
04:00And to address this issue,
04:02we actually have worked with a large
04:05number of international colleagues to
04:07establish international consortium of MD's.
04:10This is an effort that involves
04:12many experts across the world to
04:14try to come up with a unified way
04:17of classifying the disease.
04:19And indeed we have put together
04:21more than 70 more than 7000 cases,
04:23which by the numbers of MD's is
04:26quite actually quite large of highly
04:28annotated cases to try to come up
04:30with one unified classification.
04:32There's another update of this effort
04:34that will be presented in ASH in an
04:36oral fashion this year and hopefully
04:38the paper will be published soon so
04:39that we can have one common way in
04:42which we can talk to patients with MD's.
04:46After that.
04:47What is I think important is the risk
04:49stratification. Why is that important?
04:51Because patients with MD's
04:52have variable prognosis.
04:53Some patients can live for multiple
04:55years while other patients have
04:57prognosis that's almost akin to
04:58that of acute leukemia patients,
05:00meaning that the prognosis can
05:01be less than six to nine months
05:04and therefore having good risk
05:05stratification systems is very important.
05:08Historically,
05:08you can see in this table four of the
05:10most commonly used stratification systems.
05:13All of them rely on the number of
05:15the plast in the bone marrow as
05:16well as the karyotypic abnormalities
05:18and the blood counts.
05:20However,
05:20none of those were very good because
05:23for a long time we and others have
05:25shown that some of the patients that
05:28are called lower risk MD's die quickly
05:30die within two years of diagnosis.
05:32More than 1/4 of those lower risk
05:34MD's patients and it was clear that
05:37these prognostic risk scores are
05:38not capturing the whole spectrum
05:40of the disease severity.
05:42And we also have shown that among
05:44patients with therapy related MD's,
05:46which historically have been
05:48considered very high risk disease,
05:50some of them do OK,
05:52do better than some of the other patients.
05:54And that's again reflective of the
05:56variability on prognosis of those patients.
05:59And This is why it's important to
06:01apply good risk stratification
06:03process for every patient.
06:06After all of this basically the IPSSM,
06:08the molecular IPSS was finally published
06:10after a large international effort in
06:12the New England Journal of Evidence.
06:14You can see the Bernard ET al Citation.
06:17But the short of this is that it
06:20incorporated the molecular alterations
06:21in the calculation and that led to a more
06:25accurate risk stratification picture.
06:27And we have shown in a large
06:30analysis of two phase,
06:31phase two and phase three trials that
06:34were presented last year in ASH that this
06:36system does lead to upstaging of patients.
06:39You can see in red the high risk
06:41patients by the old scoring system,
06:43the Ipss, then the revised Ipss,
06:45then most recently the molecular IPSS.
06:47And you can see that the number of
06:49patients who are being diagnosed
06:51now as high risk disease because
06:52their prognosis is indeed poor,
06:54is becoming higher and therefore
06:56more of those patients are being
06:58directed for aggressive treatments.
07:02The last area I want to cover before we go
07:04to therapeutics is the response criteria.
07:06This is actually a very important
07:08area because response criteria have
07:11been quite problematic in MD's.
07:12And I can tell you that it's my
07:16belief and several of my colleagues
07:18at the same believe that it has
07:20impeded drug development in MD's.
07:22Why is that?
07:23Because some of the issues with
07:24the response criteria have led
07:26to certain medications moving
07:27from phase one to phase three.
07:29That probably should not have been the case.
07:31And This is why we have many
07:33Phase 3 failures in MD's.
07:35So again using a large international
07:38effort over the last two years
07:41that was coordinated through the
07:43international working group,
07:45we have revised these response
07:47criteria and this consensus proposal
07:50for revised international working
07:52group criteria has been now published
07:55and it started to be implemented
07:57in some clinical trials protocols.
07:58We have been in discussions with the
08:01FDA as well about implementing this in,
08:04in their assessment and I'm hopeful
08:07that this will become a more uniform
08:10way of looking at clinical trial
08:13to further like establish their
08:15the efficacy of therapeutics in a
08:18more consistent fashion.
08:19And we are validating this using
08:22WD database which will look both
08:24at the international working group
08:26criteria as well as the IPSSM.
08:28We actually have this database
08:30again with 15 different centers.
08:33Six of those presentations are
08:35going to be upcoming in in ASH,
08:37two of them are oral presentations
08:39by Doctor Tarek Iwan and by
08:41our newer newest recruit Dr.
08:43Ian Beversdorf.
08:44So I think this is going to
08:46further validate these response
08:49criteria as the way to establish,
08:53establish them as a way to
08:55approve medications in the future.
08:57So now moving from classification
08:59and response assessment to other
09:02therapies and you are looking here
09:04at the approved therapies in in the
09:06top line by the FDA and in the lower
09:08line by the EMA.
09:09And what you can quickly see compared
09:11to many solid tumours is that we
09:13don't have many approved therapies.
09:14This has been a very frustrating Rd.
09:16for drug development in MD's and
09:19in high risk MD's. For example,
09:21we did not have a drug approved in
09:24the last 20 years until the year 2020.
09:27So I'm going to show you the main
09:29therapies that we currently have
09:31available and how we are finally breaking
09:33through that deadlock of therapeutic
09:35evolution and we are starting I think
09:37to have better therapies come along.
09:40So the traditional approach of
09:42treating patients with lower risk MD's
09:44depends on symptom control because we
09:46cannot currently cure these patients.
09:48The only way to cure a patient with
09:50MD's with bone marrow transplant,
09:52but bone marrow transplants are
09:53usually reserved for patients
09:55who have higher risk disease,
09:56not lower risk disease.
09:58For patients with anaemia,
09:59the standard treatment would be ESA's
10:02erythropoiesis stimulating agents.
10:04However, those drugs are not active
10:06except in less than 1/2 of patients,
10:0940% and the response last less
10:11than 12 months.
10:12And I'm going to show you how this landscape
10:15has changed in the last couple of years.
10:17So the first I think major improvement
10:20was the introduction and final approval
10:22of this drug called luspetercept,
10:24what is luspetercept,
10:25the silicon trap.
10:26It works on a pathway called
10:28transforming growth factor pathway.
10:30These ligands suppress erythropoiesis,
10:32especially late erythropoiesis
10:34and using this ligand trap has
10:36led to restoration of effective
10:38erythropoiesis and ultimately
10:41improved transition independence.
10:43This led to transition independence in
10:45around 40% of patients in the in the
10:48phase three Middle East trial which
10:50was the landmark paper published in
10:51the New England Journal of Medicine.
10:54And based on this this drug was approved.
10:56And we have subsequently published
10:58additional follow up from this trial
11:00that showed that this drug not only
11:02lead to high rates of transfusion
11:05independence but it actually also
11:06leads to significant reduction in
11:08transfusions for patients who do not
11:11become transfusion dependent and
11:12lead to hematologic improvements.
11:14And this year the major development
11:16in lower risk MD's has been the final
11:19publication of the commands trial
11:20which looked at the activity of the
11:23specter sit in the frontline setting.
11:25So this is comparing it against
11:28erythropoiesis stimulating agents
11:29in patients with ringsidroplasts
11:32and without ringsidroplasts.
11:33So this was a primary analysis.
11:35This paper is now out in The Lancet
11:38journal showing that patients who
11:40received Los Pertoset achieved
11:4260% transition independence,
11:43almost double that what you expect
11:46with patients who receive ESA.
11:48So clearly a very active drug and it's
11:50moving to the frontline treatment of
11:52MD's which is a fundamental change in
11:54how we treat patients with lower risk MD's.
11:57We are trying to move this
11:59further through two other trials.
12:02One is the element trial,
12:03which is a large phase three trial
12:05that will be looking at patients
12:07who are not transfusion dependent.
12:09Here we are trying to move the
12:11bar higher and
12:11we are trying to prevent patients
12:13from even becoming transfusion
12:15dependent by treating them at a
12:16earlier stage of their anaemia.
12:18So this trial which will open at
12:20TLI think will be very important as
12:23a landmark trial in the management
12:25of MD's if it's positive because it
12:27would be the first time we get a drug
12:29potentially approved for patients who
12:31are not yet transfusion dependent.
12:33And another phase three trial that
12:35we are working on with the sponsor
12:37basically is looking at the use of
12:39the drug at maximal doses because we
12:41currently many of the patients are
12:43not being escalated to the right dose
12:45that leads to highest response rate.
12:48So I think starting with the higher
12:50response with the higher dose is going
12:52to increase the response rate and
12:53potentially open the door for more and
12:55more patients responding to this drug.
12:58And this trial is also up going to open ATL,
13:01another drug that I think generated
13:03a lot of interest is Amitelestad.
13:05This is a first in class telomerase
13:08inhibitor.
13:08So telomerase activity in patients
13:10with MD's has been associated with
13:13high risk disease and inhibition
13:15of the telomerase it has led to
13:17restoration of effective erythropoiesis
13:19in a large phase two trial.
13:21This is a drug that's given intravenously
13:24every four weeks and in a phase two trial
13:27lead to 40% transfusion independence.
13:29So this was taken to a phase three trial.
13:32We have presented the data of this
13:35paper in in Asch or sorry in ASCO
13:392023 and the paper is now in Lancet in
13:42press where patients were randomized to
13:45receive hematillostat versus placebo.
13:47Again those are patients who are
13:49heavily transfusion dependent with
13:51lower risk MD's and you can see here
13:53again that the rate of transfusion
13:55dependence was similar to phase two
13:57trial with 40% compared to 15%.
14:00And importantly,
14:02the degree of hemoglobin elevation
14:04is actually quite prominence.
14:05So the hemoglobin increase was almost
14:073 grams on average from a hemoglobin
14:10of eight to hemoglobin of 11.
14:12So quite active and the durability
14:13is very good, It's around 51 weeks,
14:16which fought by MD's criteria is
14:18actually pretty good.
14:20So this drug is currently in front
14:22of the FDA for consideration of
14:23approval and if it gets approved it
14:25will offer another I think very good
14:28opportunity for our patients with
14:29lower risk MD's to become transition free,
14:31which is very important moving
14:33to high risk MD's.
14:35This is where we have more of our
14:38recent failures I would say in
14:40in development of new therapies.
14:42This figure I'm showing you has not
14:44really changed in the last almost 20 years.
14:46So patients who are candidates
14:48for transplant go for transplant
14:50and those who are not the receive
14:53hypomythylating agents.
14:53However,
14:54we know that hypomuthilating agent
14:57treatment by itself is not great.
14:59The long term survival only if you
15:01use HMA without going to transplant
15:03is less than 4% and for that reason
15:06we strongly encourage patients
15:08to consider
15:09transplant whenever possible,
15:10but also try to build up on HMA
15:13therapy to improve outcomes.
15:15And this is kind of a summary of
15:17three different real life studies
15:19that we have done that show that the
15:21real life outcomes with Hmas are
15:23actually much worse than what you
15:25see in clinical trials with immediate
15:27survival of only one year on average
15:29for patients with high risk MD's.
15:30Again further emphasizing the point
15:33for new therapies for patients with
15:36high risk MD's and we have tried,
15:38we have tried for a very long
15:40time over the last 20 years.
15:42Unfortunately this graveyard of
15:43combinations of drugs that were added
15:46to hypomthilating agents keep expanding.
15:48The latest addition was this drug
15:51magrolimab which works on the CD 47 pathway.
15:53This is a very,
15:55this drug has generated a lot of
15:58excitement early on but unfortunately
16:00a recent press release couple of
16:02months ago showed that phase three
16:05trial of this drug was negative.
16:07We can talk I guess in a in another
16:09time once the data is publicly released
16:12about the reasons for for failure and
16:14how we can try to come up out of this system.
16:17The good news is that we have other
16:20drugs that are more exciting and
16:22potentially could lead to approval.
16:24One of them is venetoclax.
16:25So venetoclax is an oral PCL 2 inhibitor.
16:28This is already approved for patients with
16:31acute myeloid leukemia who are older.
16:33The frontline phase two trial should
16:36CR responses of around 35% and across
16:40the genetic spectrum of MD's we have
16:43published a phase 1P study that shows
16:45that adding venetoclax to HMA is
16:47actually active in the HMA failure setting,
16:50which is a very difficult
16:52setting to treat patients in.
16:53It leads to responses as well
16:56as transition independence.
16:57But the pivotal phase three trial is is
17:00fully accrued now it's called Verona.
17:02This trial might change the
17:04landscape of how high risk MD's is,
17:07is going to be treated.
17:09This is the scheme of the trial that
17:11we presented a couple of years ago.
17:12This trial is now fully accrued.
17:13It's the results are actually expected by
17:16early 2024 and if this trial is possible,
17:20it would lead to a new standard of care.
17:22Now moving to immune dysregulation
17:25myeloid malignancies and this is
17:28an area where I have personally
17:29invested quite a bit of time trying
17:32to develop new therapies for both
17:34MD's and acute myeloid leukemia.
17:37So we know that the most effective
17:39treatment for patients with MD's
17:40and AML is bone marrow transplant,
17:42which is effectively is an
17:44immune intervention.
17:45We know there is significant
17:47dysfunction in the immune system
17:49happens in patients with MD's and AML
17:51both at diagnosis but also during
17:53the progression of the disease.
17:55There is both quantitative and
17:57qualitative abnormalities that happen in
17:59the T cells including the regulatory T cells,
18:02but also in the macrophages
18:04and the ANKAE cells.
18:05And study after study have shown
18:08that these increase in frequency
18:10as the disease progresses.
18:12The question has been
18:14always are these pathogenic,
18:15are they basically mediating the
18:17progression and the resistance of AML and
18:20MD's or are they basically are adhering,
18:22they are just a phenomena that comes
18:25with the progression of the disease.
18:27And the first trial I think that generated
18:29a lot of interest of immune checkpoint
18:31inhibition which clearly in solid
18:33tumors have led to a major revolution,
18:34but in in in blood tumors has not
18:37led to the same impact so far.
18:40However, the Dana Farber group
18:43published this trial using Epilumab
18:45which is a CTL A4 inhibitor
18:47approved for multiple solar tumors.
18:49Now it was a small phase one study,
18:52but it was done in the post
18:54transplant setting where the drug
18:56was given for patients who relapse
18:58after transplant and what they have
19:00shown that the drug was tolerated.
19:01There were some GVHD but generally it
19:04was well tolerated for the most part and
19:07they were able to achieve 5 responses,
19:105 complete remissions out of 13 patients,
19:13which again was a proof of principle
19:15that immune checkpoint inhibition
19:17post transplant does actually work.
19:19And this generated a a number of trials
19:22looking at the drug in MD's and AML.
19:24This is one of the trials,
19:26one of the early trials that I have
19:28worked on actually when I was at
19:30Hopkins and later moved it to Yale.
19:32It was multicentre,
19:33it was in the post relapse setting
19:36for patients with MD's.
19:38So this was not after transplant,
19:40this was after HMA failure in
19:42patients with MD's.
19:44And while we have shown that
19:45the drug was well tolerated,
19:46we could manage the immune related
19:48adverse events effectively similar
19:50to what they do in solid tumors.
19:52The clinical responses were generally very
19:54low and the drug was not clinically active.
19:57We did achieve some disease stabilisation
20:00but stable disease always very tricky
20:02in MD's to figure out is it related
20:05to the biology of the disease being
20:07indolent in some patients or is it
20:09related to the activity of the drug.
20:11However,
20:12among those patients who had stable disease,
20:15we have conducted extensive correlative
20:17testing with Leo Loznick at Hopkins.
20:20And we have shown that there was an
20:22increase in the frequency of Icos
20:24which is costimulatory molecule,
20:26but this this was not basically
20:30associated with increase in the
20:32peripheral T cell receptor diversity in
20:35terms of association with the response.
20:37And I think trying to find biomarkers
20:40for patients has been one of the
20:43also challenging areas in immune
20:45checkpoint inhibition in MD's.
20:47Of course single arm trials
20:49as I mentioned are not very,
20:51are not very definitive in any
20:53kind of activity.
20:54Some of those phase one trials
20:56have shown positive signals,
20:58but the definitive way to achieve
20:59that would be with a randomized
21:01trial and we worked with the with
21:03the Celgene slash BMS to develop
21:06this trial of randomized trial.
21:09This was the only randomized published
21:11trial to date of immune checkpoint
21:13inhibition both in MD's and AML.
21:15So patients with MD's or AML
21:18in two separate cohorts,
21:19more than 210 patients were
21:21randomized to receive azacitidine
21:23or azacitidine with dorvalumab.
21:25Many of you are probably familiar
21:27with this PDL 1 inhibitor which is
21:29approved to multiple solid tumors
21:31and has shown overall survival
21:33prolongation in in several settings.
21:35However, again this was a negative trial.
21:38You can see here complete overlap in
21:40the overall survival and progression
21:41free survival cares and no difference
21:43in the primary endpoint which
21:45was the overall response rate.
21:47So this was disappointing.
21:48We try to understand better
21:50why is that the case,
21:52why did the drug not lead to improvement?
21:54So the first theory is that one common
21:57thing we see with MD's trials is that
21:59when you add a drug in top of MD's,
22:01you lead to less exposure of
22:03azacitidine which is the only
22:05drug shown to improve survival.
22:07And therefore maybe adding the volumab
22:09has led to reduced exposure of Aza and
22:12that's why we did not see benefit.
22:14But you can see in this analysis
22:16in the green bars that the number
22:18of cycles between the two arms was
22:21actually similar and most patients
22:22have received more than four cycles.
22:24So it doesn't seem like this
22:27underlines the lack of therapeutic
22:29efficacy to the right.
22:31You can see also that there was similar
22:33hypomethylation which how we think how
22:35those drugs hypomethylating agents work
22:37and no difference between the two arms.
22:40So doesn't seem like there
22:42was antagonism there.
22:43We also tried to see if there was
22:45an increased expression in PDL 2
22:47as a mechanism to bypass the PDL 1
22:49inhibition and that also was not the case.
22:52So none of those mechanisms seem to
22:55suggest why the drug did not work.
22:58What was actually quite surprising
23:00is that when we conducted serial
23:02flow cytometric analysis,
23:04we did not see T cell expansion in
23:08diversity or in quantity by flow cytometry,
23:12neither in the bone marrow or in the
23:14peripheral blood between the two arms.
23:16And this was particularly surprising
23:19because there has been a prevailing
23:21theory that the reason why immune
23:23checkpoint inhibition does not
23:24work in AML is that once you give
23:27it subsequent lines, third,
23:28fourth line,
23:29that the immune system has been beat
23:31up a lot by the chemotherapy.
23:33So here we were giving it in the
23:35frontline sitting and still it did
23:37not lead to immune stimulation.
23:38And the last thing we tried to
23:40do with this trial is to look at
23:42substance of patients because here
23:44you are putting all newcomers
23:46together and maybe certain subsets
23:48of patients benefit better.
23:50So we tried to look at 2 specific subsets,
23:52patients who have TP 53 mutations,
23:55which have been shown to have a micro
23:57environment in the bone marrow that
23:59is more immunosuppressive and might
24:00be more amenable to immune checkpoint
24:03inhibition based on multiple sources
24:04of data as well as patients who
24:07have splicing factor mutations,
24:08which Omar Abdullah have from
24:10Sloan Kettering and others have
24:11shown could be more susceptible
24:13to immune checkpoint inhibition.
24:15However, we also did not see any any
24:19activity in those patients who have TB 53.
24:23This analysis was presented by Yan in a
24:26couple of years at ASH and is currently
24:29under consideration for publication.
24:31So we tried to think further about how
24:34can we overcome this immune checkpoint
24:37resistance for patients and one theory was,
24:41is that myeloid derived suppressor
24:43cells could be a mediating resistance.
24:46This was based on solid tumours
24:48and we replicated the data.
24:50Doctor Tikkun Kim who's currently at
24:52Vanderbilt was here at TL did very nice
24:56preclinical trials that suggested that
24:58there could be the benefit of combining
25:00a drug that targets myeloid derived
25:02suppressor cells such as entenostat
25:04which is a Estonia acetylase inhibitor
25:07with with Pimpro or PD1 inhibitor.
25:10And based on these preclinical data,
25:12this was translated to a clinical trial,
25:15multi centre phase one trial that was
25:18conducted in collaboration with the UM
25:21one group under Pat Larosso with the
25:24theory again that adding Antinostat
25:26would suppress myeloid giraffe,
25:27suppress our cells and therefore
25:29allow pimprolismab to exert its
25:31immune chip point inhibition.
25:32So that the trial has been presented by Anne,
25:35I'm not going to go through the
25:37results because again unfortunately
25:38it was clinically negative.
25:39We are currently going through the
25:42correlative data to understand what led
25:44to the failure of the clinical data.
25:47However,
25:47I think there are more exciting agents.
25:50One of them is sabatolimab.
25:53So sabatolimab is a novel
25:55immune checkpoint inhibitor.
25:56Sabatolimab targets term 3.
25:57So term 3 is not only expressed on T cells
26:01and medias immune checkpoint inhibition,
26:03but it's also expressed in leukemia stem
26:06cells and leukemia plast and targeting.
26:08Term 3IN.
26:09Preclinical data has suggested a
26:11potential not only efficacy but a
26:13potential π functional mechanism
26:15in which it can lead to immune
26:18checkpoint inhibition but also direct
26:20targeting of the leukemia stem cells.
26:23So the stimulus MD's one trial was the
26:25first randomized trial with this drug.
26:27This trial randomized patients to
26:30receive HMA versus HMA with sabatolimab
26:32and the primary endpoint was complete
26:36response and progression free survival.
26:38We presented this data in ASH last year.
26:41Currently the manuscript is under
26:43review and while the the trial
26:45did not meet its end point,
26:47there was no significant statistically
26:49improvement in complete remission
26:51or progression free survival.
26:53You can see that there was a late
26:55separation in the curve of the
26:57progression free survival and some
26:59trend toward improvement with the PFS.
27:02So we also sub analyse these data
27:04and what we have found is that
27:06patients who have lower disease
27:08burden seem to benefit more.
27:10However, of course this is ad hoc analysis,
27:13exploratory analysis.
27:14But what was also exciting is
27:16among the patients who achieved
27:18response as you can see in the red,
27:21patients who achieved The Who
27:22got the combination seems to have
27:24doubled the duration of response
27:26compared to those who have HMA alone,
27:28which again suggests that the
27:30combination might deepen the response
27:33leading to longer duration of activity.
27:37So the stimulus MD's two is a large
27:40randomized phase three trial of Sabatolimab
27:43plus Aza versus Sabatolimab alone and
27:45this trial again is fully accrued more
27:48than 530 patients enrolled on this trial.
27:51This trial is also expected
27:53to report by early 2024.
27:55So between venetoclax and sabatolimab,
27:58hopefully one of those two at least will
28:00will be positive and change the landscape
28:02of how we treat patients with high risk MD's.
28:05So moving to the AML front where
28:08we have also tried to move
28:10some of those concepts forward.
28:12So the plus AML one is a randomized
28:14phase two trial an IAT that is also
28:18running through the UM 1 mechanism
28:21with Pat Larosso Rory has been doctor
28:24Shalis has been working on this with me
28:27and this trial is actively enrolling.
28:29We have more than 40 patients right
28:31now where patients are getting 7 +
28:343 versus 7 + 3 with pemprolizumab.
28:36The primary endpoint is MRD negative CR,
28:41another randomized phase two trial
28:43that we are working through the same
28:45mechanism as last ML2 and this trial
28:47looks at older patients where the
28:49combination is is a citedine with
28:51venetoclax plus minus Pemprolizumab.
28:54This trial is also through the UM 1
28:58mechanism and through both of those
29:00trials and in collaboration with CMAC,
29:02which is a cancer immunotherapy
29:05monitoring group.
29:05Within C Tib,
29:07we are conducting an extensive set
29:09of correlative studies who are also
29:11collaborating with Doctor Jerry
29:13Radic from the Hajj to look at MRD
29:16negativity through different more
29:19sensitive techniques including
29:21circulating tumor DNA and at the
29:23level of the stem cells and looking
29:26at as I mentioned that other leukaemia
29:29specific T cell activation and a
29:32number of other I think important studies.
29:36Finally on the same front we have
29:38the plasty ML3 trial which is a
29:40phase two trial looking at combining
29:43IDH inhibitors with pimprolism AB.
29:45This is based on preclinical data
29:47suggesting that patients who have IDH
29:50mutations also have immunosuppressed
29:52micro environment.
29:53So Doctor Lourdes Mendez and Dr.
29:56Max Stoll at Hutch who I forgot to
29:58put his picture sorry are working on
30:01this trial and hopefully this trial
30:04is approved by Merck and hopefully
30:06it's going to open next year.
30:07And lastly on that front,
30:09we also have another trial with
30:11the triplet is Evan Sabatolimab.
30:12This is a phase two trial which
30:15enrolled more than 80 patients.
30:17We presented the data lost ash and
30:20for the only for the safety cohort,
30:23the full set of data has not been
30:25presented and I think we have shown
30:28extensively that immune checkpoint
30:30inhibition while can be difficult in
30:33patients with leukaemia is difficult
30:36to administer for multiple reasons.
30:38For example,
30:39our patients are often have
30:41deep thrombocytopenia,
30:42so we cannot biopsy them.
30:43If the patient has
30:44inflammation in their lung,
30:46sometimes it's difficult to know
30:47is this a fungal infection or is
30:50this pneumonitis And in solid
30:51tumours it's easy or not
30:53at least easier to go and get a
30:55biopsy out of the of the lung.
30:57But in our patients it's very
30:58difficult to get biopsies.
31:00We're also hesitant to give steroids
31:01many times because of fungal infections
31:03that are common in our patients.
31:05So conducting immune checkpoint
31:08inhibition trials in patients
31:10with MD's is a bit challenging.
31:12However it is it can be done and this
31:15is retrospective analysis that was done
31:17by Doctor Shalas in you're looking at
31:20our own data showing that the number
31:22of immune related adverse events was
31:25somewhat similar to what is seen in
31:27patients with solid tumors when they
31:29get immune checkpoint inhibition.
31:31But also importantly that we are not seeing
31:34excess mortality when we use these agents.
31:37So I think it's certainly feasible.
31:39I think it's certainly has a
31:41way to kind of move forward and
31:44one of those agents I have deep
31:46confidence is going to be positive.
31:48But I think another important
31:50concept that we need to apply is
31:53biomarker selection of patients,
31:55because currently we are unrolling all
31:59newcomers regardless of their susceptibility
32:02to immune checkpoint inhibition.
32:05And I keep making the analogy of
32:07like trying to treat patients with
32:09IDH or all patients with an IDH
32:12inhibitor when you only should treat
32:13the ones with the IDH 1 mutation
32:15or the same thing with the EGFR.
32:17So we really should select patients
32:19who are more likely to respond
32:21to the specific pathway.
32:22This is an example of I think a
32:25nice effort looking at an immune
32:27effector signature to try to
32:29define subset of patients.
32:31This is clearly retrospective,
32:32but I think this is what should
32:34be applied in clinical trials
32:35in a prospective fashion,
32:37so we can select patients who
32:38are more likely to respond.
32:40So and I'd like to thank the
32:43our colleagues in the leukemia
32:45and myeloid malignancy program,
32:47including our wonderful MPs and the
32:52fellows and mentors and collaborators.
32:55All of them have been working with us,
32:56but also importantly our clinical
32:58research team who has been fundamental
33:00to all those clinical trials that
33:03I've just shown you and have been
33:06extremely productive even during
33:07COVID and all the staffing shortages
33:10that we had over the years.
33:12And at the end I'd like to thank all
33:14the organizations that helped fund my
33:16research and all the collaborators
33:18and happy to take any questions.
33:27Have a great time and let me apologize
33:30for not being here yesterday.
33:32I realized I was supposed to notice
33:35I heard you again well on your
33:38own It's it's a pretty impressive
33:41body of work that that that we've
33:45seen over these past few years.
33:49What do we know about and I thought this
33:52team eventually was when I was here,
33:54but is there any fundamental
33:57difference in MD's in younger
34:00individuals than those who are,
34:02you know, more typically,
34:03yes, age, you know,
34:06so the occasional 40 or 50 year old person,
34:09you see it because this heavy year,
34:1080 year old. Yeah,
34:12this is actually a very important question.
34:14So the majority of MD's
34:16patients are older than 65,
34:17around 85% of patients are older than 65.
34:21We do see MD's in younger patients,
34:23but generally tend to be two big areas.
34:26One of them is previous exposure
34:28to chemotherapy or radiation in
34:30the context of solid tumours,
34:32usually breast cancer actually
34:34is 1 common setting where we see
34:37patients who have received radiation
34:38or chemo and have secondary cancer.
34:40But the second big area is
34:43genomic predisposition.
34:43So there are a number of patients who
34:46have for example underlying Franconia's
34:48anemia or plastic anemia or some
34:50kind of hereditary predisposition.
34:52The number of those predisposition
34:56genes actually has been increasing
34:58or we are discovering more and more
35:01of them and it's quite fascinating.
35:03For example, there is one called DDX 4,
35:05one that we did not for know about
35:07until you know a few years ago and
35:09it turned out that 10% of patients
35:11with AML and MD's have that.
35:14And those are I think important
35:16because they underlie different,
35:18different clinical behaviour.
35:20Those patients for example tend
35:22to be more indolent.
35:24I have a 96 year old patient with
35:26AML who has DDX 41 germline and
35:29it's just just mind boggling to
35:31me that you think that someone
35:33carried this mutation until she was
35:3595 to develop finally AML.
35:37So those tend to happen in older patients.
35:39There are other ones that tend
35:41to happen at a younger age.
35:42But I think the biggest message usually,
35:44I,
35:45I usually say regarding younger
35:46patients the MD's is you have to
35:48look for other things because there
35:50are many things that mimic MD's
35:51and you want to make sure what
35:53you are dealing with is indeed
35:55MD's because the treatment is,
35:56is is different.
36:00Yes.
36:13Yeah, this is a very good question.
36:14And actually this has always come up
36:16in our discussions with you know,
36:18with IR, BS and regulators.
36:19And there's actually a large chunk
36:22of evidence based on as I mentioned,
36:24the problems that most of the
36:26trials that we have done in the
36:29field have been single arm trials.
36:30So most of what we have right
36:33now is anecdotal experience.
36:35We are not seeing overall,
36:36if you look at the entirety of data,
36:39we're not seeing an increased incidence
36:41of GVHD that is that is of high severity.
36:45However, we have never had a randomized
36:48trial that would look at this in both
36:51in both arms and This is why I think
36:53our tube last trials are going to be
36:55very important because we have two
36:57arms and patients from both arms are
36:59going to transplant and I think this
37:01is going to give us a good sense of of that.
37:04The, the other argument I always
37:06say is that while there could be a
37:09potential that you could increase GVHD,
37:11there's also a potential that
37:12you could actually increase GVL,
37:14right,
37:14because the way GVL is a graft
37:16versus leukemia effect and this is
37:18how we think transplant can work.
37:20So I think it's always a risk benefit
37:22and I don't think you can answer
37:25that without a randomized data.
37:27This is something we are certainly
37:29keeping a very close eye on in our
37:31different trials and the regulators
37:33have been also kind of keeping
37:34a close eye on this.
37:36And I have to say in in our practice
37:39we usually try to say stop the
37:43immune checkpoint inhibitor like you
37:44know in the last six weeks before
37:47transplant 6 to 8 weeks ideally just
37:49because of that theoretical concern.
37:51I would say at the end is that in
37:53immune checkpoint inhibitors are
37:55approved in in in some in substance
37:59of lymphoma and in in that setting
38:01like Hodgkin's disease and generally
38:03there has not they have not seen
38:05that that issue as much.
38:07So I guess we'll,
38:08you know,
38:08we'll have to wait and see for AML and MD's.
38:11Yes.
38:29Yeah, this is a great question And
38:31part of why I did not divulge and
38:33like go too much into this is that
38:35this methylation business has been
38:37I think one of the most challenging
38:39aspect of you know Steve Gorwin,
38:41he used to be like he used to hate
38:43calling these hypomethylating agents
38:45because we we are not even 100% sure
38:47that this is how they actually work.
38:49You know, we always like to
38:50call them DN MT3 inhibitors.
38:53I guess the big answer is that in those
38:56trials that I presented they did not
38:59do like site specific methylation.
39:01But we still don't fully understand
39:03what because you are seeing
39:05a mix of hyper methylation,
39:07hyper methylation depending on where
39:08you are looking within the genome and
39:10until now we don't fully understand the
39:12mechanism of action of these drugs.
39:14I did not go into this because of,
39:17of, you know,
39:18the nature of of the audience here.
39:19But I think one of the biggest
39:22challenges in my own view about why
39:24we could not go beyond HMAS is that
39:26we are stuck with this schedule
39:27that is at the approved seven days
39:29of azacitidine in every single
39:31trial that we have.
39:32And this is a myelosuppressive
39:34combination and trying to add things
39:36to it has been quite challenging.
39:38But currently it's not
39:40considered ethical to randomize,
39:42you know,
39:43without including the seven days of HMA
39:45because it's the only drug that has
39:47been want to improve our all survival.
39:50But you're right,
39:50I mean there could be trials,
39:51there could be agents that could
39:54antagonize that methylation or it could
39:56be the other way around where this
39:58methylation is negatively impacting it.
40:00So that has been a big,
40:03I think, problem, Nathaniel.
40:18Like those seven the therapy,
40:21we know that those therapies
40:24result in quite profound immune
40:27suppression and not only they,
40:29they're also quite lymphopenic when you have
40:330.1. So does it make sense to
40:37give them concurrently? I mean,
40:39you're trying to mount some different
40:44response at the same time,
40:45completely suppressing their chemo,
40:47so it doesn't make sense
40:49to get them concurrently.
40:50Or would you have a more clever way
40:53where you perhaps cumulate the marrow,
40:55allow them to recover,
40:56have some given or reconstitution and
41:01then, you know, yeah.
41:02So there are people working on
41:03concepts like this where they are
41:05giving it around the time of immune
41:06reconstitution as you mentioned.
41:08I think 2 points on this front is that they
41:10actually have combined and solid tumours.
41:12They have multiple and you know,
41:14Barbara and others know more about
41:15this like solid tumours where you
41:17are giving chemo with immune therapy
41:18and it seems like it has worked,
41:20but they're, yeah,
41:21their drugs are not as lymph,
41:22you know, lymphodepleting as ours.
41:25But the other thing we actually
41:26have tried to do on these trials,
41:27I did not go into this into detail is that
41:29we moved the initiation of the immune
41:31checkpoint inhibition to day eight.
41:33So rather than waiting until day 21 when
41:35you know all the cells have have died.
41:37So around the aid,
41:38the idea of doing it early is
41:40similar to that you have.
41:42This is when you have all the antigens being,
41:44you know,
41:45from the dying cells coming out
41:47and trying to activate lymphocytes
41:49at that at that point.
41:50But you're right,
41:51I mean this is another I think big
41:53challenge of when what is the exact
41:55time to to use these these drugs has
41:58been somewhat kind of frustrating
42:00I have to say with with both PD1,
42:03PDL 1 so far and because multiple
42:05trials have been negative.
42:07So it might be that none of those
42:09pathways are you know what really
42:11is important in the MLN MD's and
42:14maybe the Sabatoli map that I
42:15just showed or some other.
42:17You know there are other,
42:19I did not go on to this as well in detail,
42:21but they are lag three, they are Lil RP4.
42:23There are a number of other immune
42:25checkpoint pathways that are also
42:28being tested in MD's and AML.
42:30Yes,
42:30with
42:51the the actually TM3 without the PD one.
42:53Yeah, so I did not go through that the
42:55solid tumor literature with TM3 but
42:58they actually had a big trial combined
43:00TM3 and PD1 and that has not led to
43:04clinical improvement in solid tumours.
43:06So the development has been
43:08largely focused on the MD's space.
43:10They have a, the company has sponsored
43:13trials where they are combining different
43:16immune checkpoint inhibitors and
43:18actually sabatorimab with other drugs.
43:20So those I think could give you know an idea,
43:25but from a regulatory path,
43:27you know you're as I was saying a little
43:29bit earlier is you have to combine with
43:31HMA to kind of get your first approval
43:34and then I think you know contagion, hago.
43:37Contagion also said like the real
43:39research starts once a drug is approved
43:41like you really need to get like
43:43something like once it's approved,
43:44I think you can do all kinds of concepts
43:46but the initial focus is always on
43:48trying to kind of get the trial that
43:51leads to approval and then you can
43:52do all these kind of bigger concepts.
43:55You can do them now in a small phase
43:56one study, but not in a large setting.
43:59Yes, Sir.
44:17I
44:51Again, I think this is a very good question.
44:53Clearly the post transplant setting is a
44:56very important development area because
44:58most of our patients unfortunately
45:00despite transplant they they relapse.
45:02So I think with the epilogue map, the trial,
45:05the New England Journal paper I showed you,
45:08people have had a very tough
45:10time replicating these,
45:11I would say outside of, you know,
45:15occasional responses.
45:16So most people are not using Epilomab
45:19of kind of label to to give it.
45:21And most of those responses by the
45:23way happened in the extramedullary
45:25relapses like skin disease and
45:27probably that speaks to different
45:29microenvironment between the bone marrow,
45:30between the extramedullary
45:32versus the bone marrow relapse.
45:34In terms of your other questions
45:36specific about the TM3,
45:38there's actually a trial giving
45:40TM3 inhibitor post transplant.
45:41I didn't go into this one,
45:43but this one is ongoing and I
45:45believe there could be presentations
45:47in the near future about this.
45:49I'm. I'm not involved in it.
46:07Yeah. No. I I think again, like,
46:09you know, I think it's like
46:10we're getting out like that.
46:11Sit right. Sitting.
46:23Yes,
46:42sorry, Could you phrase your hand?
46:51Is there any evidence that that
46:55prevents basically the development
46:57of an MPs or weighted MPs or AFL?
47:02Just thinking of like ways to
47:04sort of look at that rather
47:06than a code reading with like
47:11yeah, I think inhibiting development of
47:14MD's. This is actually an area
47:18that is getting more attention now
47:19because of what I showed at the
47:22beginning like this chip slash seeker
47:23spectrum where clonal hematopoiesis.
47:25We are seeing some of this
47:27actually in solid tumors.
47:27For example a breast cancer patient
47:30under you know underlying more and
47:34more people are doing these next Gen.
47:36sequencing and then the patient turned
47:38out to have TP 53 mutation chip like
47:40the blood counts are completely
47:42normal but she has TP53 mutation.
47:43And one of the increasing questions
47:45that are being asked like you know
47:47the oncologists are afraid to give
47:49chemotherapy because that TP53 clone
47:51could expand and lead to MD's or or AML.
47:55So I would say this is an evolving area.
47:57Currently we don't think immune
47:58checkpoint inhibition would work.
48:00Most of the trials that are looking
48:02at agents are looking at things
48:03that are very
48:06non-toxic. Let me put it this way
48:08because those are patients with good
48:10counts generally and normal bone marrow.
48:12So they are like they are trials of
48:14vitamin C and you know inflammation,
48:16anti-inflammatory agents etcetera.
48:18However those drugs can be given together.
48:21One of the things actually we benefited
48:23from doing these trials is that I have
48:25a number of patients I share with
48:27our colleagues here that need some,
48:29you know that that need immune
48:30checkpoint inhibition.
48:31I have multiple patients including
48:33with Barbara where they are on some
48:35kind of immune checkpoint inhibitor
48:37and they have MD's now and I need to
48:39give them azacitidine because they
48:41have MD's and we have been doing
48:43this in a number of patients and
48:45for the most part is pretty safe.
48:47So this in the past used to
48:49be a horrendous situation.
48:50It's still a horrendous situation.
48:51You have two active tumours,
48:53MD's and solid tumour,
48:54but many of those patients used to get
48:57only supportive care and nothing else.
48:59But now we for the most part because
49:01immune checkpoint inhibitors generally
49:02will not lower your blood count.
49:04So they are able to give them even
49:07with patients with MD's and I'm
49:08able to treat the patient with
49:10azacitidine because it does not
49:12worsen their immunosuppression.
49:13You can give it safely.
49:14But again,
49:15this I think how to prevent
49:17clonal evolution is I think is
49:20an important area as well.
49:25OK. Thank you so much my e-mail
49:28if anybody has any questions then.