Targeting Apoptosis in Leukemia:lessons and challenges

February 27, 2024

Information

Yale Cancer Center Grand Rounds | February 23, 2024

Presented by: Dr. Marina Konopleva

ID11370

To CiteDCA Citation Guide

00:00Good morning, everyone.
00:01Thank you so much for coming.
00:04It's really a true pleasure today
00:06to have with us one of the gents
00:08of acute myeloid leukemia and
00:11myeloid neoplasms in general.
00:12So Doctor Marina Konopoliva is
00:15a professor in the Department of
00:17Oncology and Molecular Pharmacology
00:19and the Merriam Faculty Scholar
00:22in Cancer Research at the Albert
00:24Einstein College of Medicine.
00:26After spending many,
00:27many years in the Andy Anderson,
00:29where she has really made
00:31fantastic contributions,
00:32including very important drugs
00:34that have been approved both
00:36in acute myeloid leukemia and
00:39plastic denritic myelo neoplasm.
00:42So she received her Doctor of Medicine
00:45from the First Pavlov Medicine
00:47Institute in Saint Pittsburgh in Russia,
00:50and then got a PhD in experimental
00:53hematology from the Federal Institute
00:55of Hematology and Blood Transfusion.
00:57So Doctor Konopliva's research
00:59has focused on patients with
01:01hematologic malignancies both
01:02including acute myeloid leukemia,
01:04acute lymphoblastic leukemia
01:05as well as high risk MD's.
01:08And her research,
01:10as I mentioned,
01:11have led to important not only
01:13science and advancing,
01:15but also therapeutic translation,
01:17especially venetoclax,
01:18which really has changed the landscape
01:21of how we treat patients with the AM, LCLL,
01:25potentially MD's and other conditions.
01:29And on a personal level,
01:31I think Doctor Konopleva is very known
01:32in the field to be a fantastic mentor.
01:34She has mentored some of the most
01:37productive researchers in the field
01:40as well as being a very nice and
01:42very good person to interact with.
01:44So I encourage as many of you to
01:46talk to her if you can today.
01:47Thank you so much for coming.
01:55Thank you, Amir,
01:56for this very kind introduction.
01:57I'm happy to be here.
01:58This is my first time at Yale
02:00and I'm looking forward for the
02:02day and meeting a lot of you.
02:04And so today I wanted to take
02:07you through our story on Biso 2.
02:09I know this is like a general grand
02:11round for both human solid malignancies,
02:13but I think targeting cell death is
02:16probably important for including
02:17for the solid tumors as well.
02:19And I'll show you some of the kind
02:20of ways we think about that as well.
02:25So these are my disclosures and as
02:28you all know, the resistance to cell
02:30death is one of the hallmarks of cancer
02:33and it's largely governed by the B22
02:36family proteins which are listed here.
02:38It's quite complicated.
02:39I'll show you later how the system works,
02:42but essentially there's over
02:44expression of different B22 family
02:46members depending on the tumor type.
02:48For example in myeloid malignancies
02:51and we have mainly B so 2IN TALL.
02:54We also have B cell XL and B so two
02:56and M So one is kind of ubiquitous
02:58and I think in SO2 must B cell XL is
03:01a primary anti apoptotic molecule.
03:04The way the system works is by
03:06dimerization of anti apoptotic with a
03:09propoptotic family members and there are
03:11quite a few of those as well So bags.
03:14I will talk to you several times in my talk.
03:17So this is what we call execution
03:19of cell death protein.
03:20So essentially kills the cells by making
03:22pores in the mitochondria membrane
03:24and inducing cytochrome C release.
03:27And then there are a lot of this will be A
03:29share only proteins which essentially bind B,
03:31so two or others and inhibit their function
03:34because it works through demoralization.
03:36You can actually inhibit the function
03:38of B so 2 by inhibiting the protein
03:42protein interactions between for
03:44example B so two and some of this
03:47protest proteins and as a result you'll
03:49have a release of this propagatoric
03:51members and killing of the cell deaths.
03:54So this was pioneered in the first attempt.
03:58This was a paper back in 2005.
04:01At the time the company was called Abbott
04:04and they designed the first protein
04:07protein inhibitor which was called Abt 737.
04:10So this was a work from Steven,
04:12Fasig,
04:12Sol Rosenberg and others that
04:15effectively inhibited the BCL two.
04:17So the structure here is
04:19actually the structure of BCL XL.
04:21So they used the NMR based technology to
04:24engineer this molecule and green protein
04:26here is one of this proteins called back.
04:30It's not even here but it's one of the BHA.
04:33On your proteins there's some critical
04:35critical rates reduced how it binds
04:37to B cell XL and this is the actual
04:39molecule which you can see it sits
04:41into that pocket and this mimics the
04:44B back interaction with B cell XL.
04:47In this matter there's another structure,
04:50this is pretty large molecule about
04:53960 KD but this was the 1st and I
04:56think the most successful protein
04:58protein inhibitor interaction.
04:59I think the only other class that I'm
05:02aware of MDM 2P53 inhibitors but they
05:04still not approved due to toxicities.
05:07Now this molecule was A2 molecule
05:10and it's analogue called Navidoclax
05:12did go into clinical trials,
05:15but because it blocked both BCL
05:17XL and BCL two,
05:18it encountered some toxicities in the
05:21form of thrombocytopenia because BCL
05:23XL is important for plated production.
05:26But I'll get back to you in the end.
05:27I think BCL XL targeting is very
05:29important and there
05:31are other ways of safely inhibit BCL XL.
05:33So Nabilox is still not approved.
05:36And so moving forward in 2013,
05:40the same company now it's called Abbi
05:42engineered the original molecule and
05:45they got rid of BCL XL interaction.
05:48So apparently this aspartate one
05:50O 3 is a critical residue which is
05:53different between BCL two and BCL XL.
05:56And so they engineered the new
05:58molecule that had now very specific
06:00BCL two only properties.
06:01So it only bound BCL two was about
06:0410 times more important than original
06:06nebidoclax and it did not inhibit BCL XL.
06:10And this is what we now know
06:12as the neto clocks,
06:14the drug that is approved for several
06:16types of hematologic malignancies.
06:18And of course it's paid playlists
06:20because it did not inhibit B cell XL.
06:22So I said I work on B.
06:24So too when I came to us,
06:26that was my first project at the time.
06:28We initially used the antisense,
06:29but antisense didn't make it in clinic.
06:31They were not effective enough,
06:33not specific enough.
06:34And then when the original
06:36camp compound came out,
06:38we developed the story on
06:40AML and BCO 2 with ABT 737,
06:43which were published in 2006.
06:45And then when the new compound came out,
06:48because Nevada clocks never
06:49made it to AML trials,
06:51again,
06:51AML patients as you know have
06:53all low platelets to start with.
06:55So it was kind of impossible at the
06:57time to transition into AML trials.
07:00When the newcomer came out,
07:01we teamed up with a Tony Litais lab
07:03at Denif Harbor and we worked for
07:05a year between two of our labs and
07:08published a cancer discovery paper
07:10in 2014 showing that the Nanoclax is
07:12highly effective in acute myeloid
07:14leukemia pre clinical studies.
07:16So,
07:16so these are just I'm not going
07:18to go through the paper or data
07:20that's all published,
07:21but these are just mRNA level for B,
07:24so two amongst different types of
07:26leukemia and the red line represents
07:28to the normal uninvolved bone marrow.
07:31This was from a Hyperlux MLL collection.
07:34So you can see that majority of
07:36AML this is log scale have upper
07:38related mRNA for BC2.
07:40There's some examples here,
07:41some some some that don't.
07:43For example this inversion 3 AML do not,
07:45but majority have high levels of BC two.
07:49We also show that it's expressed
07:51on leukemia stem cells and then
07:53we show that if you target BC two,
07:55you eliminate AML blasts and AML
07:57stem cells to some extent.
08:00And also the compound had efficacy in vivo,
08:02although by itself it,
08:03it was not curative and it wasn't
08:06curative in patients either.
08:07So this work in conjunction with
08:11the CLL data that Amar mentioned.
08:13So that time the Netflix was already
08:15in CLL trials and was very effective.
08:18It caused tumorlysis and actually they
08:20had some deaths because of tumorlysis.
08:22So it's CLL is super dependent on B, so true.
08:25So it's like the primary B,
08:27so two dependent disease,
08:28but we already knew the dose,
08:31we knew the safety profile of
08:33this molecules was fairly safe
08:35besides this tumuliser syndrome.
08:37So it was sort of sufficient based
08:41on this work to take venetoclax
08:43into AML relapse refractory study.
08:46So this study was conducted between
08:49different institutions and was published
08:52in cancer discovery back in 2016.
08:54So initially we projected that we're
08:57going to treat 50ML patients and we
08:59were hoping for response rate around 40
09:02to 50% based on our preclinical work.
09:05And I have to say that this did not pan out.
09:07So we learned that AML is way too
09:09complicated and probably our preclinical
09:11models do not really faithfully
09:14recapitulate the response in in patients.
09:16So the response rate,
09:18objective response rate in the trial
09:19was only 19% with the CRCRI rates,
09:23but about 50% of patients did
09:26have blast reductions as shown
09:28here on this waterfall plot.
09:30And then there were some subsets of patients
09:32who tend to be more sensitive to that.
09:34For example,
09:35patients who had IDH 1-2 mutations,
09:37they generally had response and the
09:40response among those was about 32%.
09:43So that was encouraging.
09:45And in fact,
09:46we enriched the study for the IDH
09:481-2 mutated patients because at
09:50the same time the paper came out
09:52from Stanford showing that this
09:54subset of AML is highly be so
09:55dependent and that turns to be true.
09:57Till now this patients respond very
09:59well to nine, 8:00 to 9:00, sorry,
10:02but essentially that was encouraging,
10:05but it was clearly not enough for
10:06to get this drug approved as a
10:09single agent in the salvage setting.
10:11And of course for me as a researcher
10:13that was disappointment because I
10:15thought this was like the best drug
10:17I ever had in the lab and still
10:19it's not you know curing people.
10:21The duration of responses was also
10:23pretty sure about three to six months
10:25and all patients progressed after that.
10:27So fortunately the story did not
10:29stop at this point as you know.
10:32And so why we think that AML
10:35in AML target and B,
10:36so two alone is not sufficient?
10:39Well,
10:39first of all,
10:40because there's a redundancy and
10:41expression of BCL two family proteins.
10:43So if you just look at this western blood,
10:45this is from Andrew Ways publication
10:48and BCL two is almost ubiquitously
10:50expressed at high levels.
10:52BCL XL is usually not expressed
10:55or low expressed.
10:56But I'll tell you which subsets
10:58do have BCL XL And then there's
11:01MCL one which is mildly specific
11:04sort of BCL two family member,
11:06it's ubiquitously expressed as well.
11:09So you can imagine that if
11:11you target only be so true,
11:13you leave some other members untouched
11:16and therefore cells probably quickly
11:18adapt to the this effect and they
11:21rewire and they become resistant.
11:23So how can you get around that?
11:25So the next thing is that any
11:27type of chemotherapy can actually
11:29in the setting of wild type B53
11:32can induce expression of this
11:34proprietoric family members that
11:36I mentioned before what we call BHA
11:38only proteins and this PH3 only
11:40proteins can in fact inhibit MCO one.
11:43So as you can envision,
11:46you can have synergy between
11:48venetoclax and pretty much any type
11:50of chemotherapy that would induce
11:52this response and then you inhibit B.
11:54So two, so you sensitize the
11:56cells and then there's bags back
11:58interaction and the cell death.
12:00So practically speaking this went into
12:02development in all the AML patients
12:05unfit for chemotherapy because for
12:07younger patients we had 7 + 3 which
12:10we still have and they were doing
12:11pretty well with the transplant.
12:12But for all the patients there was
12:14really like no standard of care
12:16low dosa turbine or hypermethylene
12:18agents have been used.
12:20So I have to say that based on the
12:23clinical need more than the signs,
12:25the combination trials were with
12:27hypermethylene agents and low dose
12:29Iturbin and all done fit there
12:31for chemotherapy AML patients.
12:33And this were the results of the
12:35initial Phase 1B study when the
12:37Vanetta glass was combined either
12:39with azacitidine or with a decitabine,
12:42hypermethylene agents or even with
12:44low dose Iturbin which by itself
12:47has very little activity in AML.
12:49And you can see here that well you know
12:51this was a newly diagnosed patients.
12:53So was very rapidly was transitioned
12:55to the newly diagnosed CML which I
12:58think was another difference with
12:59the original trial that we used
13:01where we used phonetically where
13:02it was relapsed refractory setting.
13:04But you can see that you know majority
13:07of patients in fact responded and
13:10they did achieve like true CRS.
13:12There was some of those escalation
13:14findings as well,
13:14but eventually 400 milligram ended
13:16up the right dose for the HMA
13:19and 600 for the low dose,
13:21high turbine combination.
13:22So the responses,
13:24the responses tend to be durable
13:25and there was very little toxicity.
13:28So suddenly the all the patients
13:30which for which we didn't really
13:32have QS before in one month
13:34that we're going into remission,
13:36the infections and mouse suppression
13:37was still the main toxicity.
13:39But other than that we didn't see
13:41like much effects on the kidney,
13:42liver or anything which was to me always
13:45the most surprising thing because B
13:47so two is so ubiquitously expressed.
13:49So who could imagine that
13:50targeting B so two is so safe.
13:52I think before we go into clinic,
13:54we can never really predict what happens.
13:57And then eventually this resulted
14:00in the randomized phase three study
14:03called VLA study where VENESA,
14:05what we call venetocide was randomized
14:08to azacide and placebo control.
14:11It was 2 to 1 randomization and
14:13this was for all the patients with
14:16AML ineligible for chemotherapy.
14:18The median age was close to 70
14:21years old and you can see that
14:23there's far as response rate,
14:24majority of the patients achieved
14:26response it was which was
14:28in the range of 60 to 70%.
14:30There was lower in PPG mutated
14:32AML which we learned later is a
14:35a prom for this approach.
14:36But overall there was high response rate,
14:39but most important there was survival
14:41advantage compared with ASA with medium
14:44overall survival of about 14 months and
14:46compared to nine months with ASA cited in.
14:49So this LED in 2018 to the accelerated
14:53approval of the Naglo X and AML and
14:56subsequently to the full approval in
14:58combination with the chemotherapy
15:00low Dosa turbine is also approved.
15:02But even though they missed
15:04the primary endpoint,
15:05but the overall survival was still better.
15:07But I think it's very rarely used
15:10in United States and this survival
15:13is shorter only about nine months.
15:15So this is like what Amar said is
15:18considered to be breakthrough.
15:19But you know if you look at the curves,
15:21you can say that is this really like
15:23a breakthrough because majority of
15:25the patients are still you know,
15:27dying from their disease.
15:28Initially it seemed to be like
15:30plateau here at 30%.
15:31So now the curve dropped down to about
15:3420 to 25% with about four years of follow up.
15:36So it still stands,
15:38but clearly you know it was not a
15:42curative approach and that kind of
15:44prompted our lab and many other groups
15:46going back to the kind of drawing
15:48board and trying to understand how
15:50we can improve on that and what are
15:53mechanisms of resistance and how
15:55we can combine with other agents.
15:57So in the rest of my talk,
15:58I will show you like several like
16:00examples from our lab how we kind of
16:02developed the new agents for the combination.
16:04Some of them are in trial,
16:06some of them are hopefully getting to
16:09approval soon and this is sort of a
16:12summary how we can think of potential
16:15combinations and resistance mechanisms.
16:17This figure was done by one of our
16:20fellows and again going back to
16:21like how the drugs work, right.
16:23So again you have BSO 2,
16:25you have it pre complex with BHA
16:27only protein which allows you to
16:30block this interaction.
16:31And this is a drug venetoclax,
16:33it's called BHA mimetic because
16:35it mimics PHA only proteins.
16:37So it binds here,
16:38it displaces this BHA only and then this
16:41products have to activate backs and back.
16:44So again backs and back are very
16:46critical because without that there's
16:48no cell death and they have to go
16:51into the mitochondrial membrane
16:52and they induce sacrum C release.
16:55So one thing that I already
16:57mentioned that there's a redundancy,
16:58so if you have a regulation of
17:00this other B SU-2 family members,
17:03you can get resistance right?
17:05Because they can even though you
17:06do have displacement,
17:07what happens is that this BHA only
17:10protein instead of going to the bags it
17:12will go and bind this other protein members.
17:15So how can you get this app regulation?
17:18Of course it may have
17:20been before pre-existing.
17:21For example in monostatic AML there's
17:23app regulation of MCL one because of
17:26the lineage dependency on MCL one.
17:28But then there are a lot of
17:30mutations and this
17:30mutations we call them signalling mutations
17:33which we now can up regulate both MCO one,
17:35BCL XL and BCL 12A1 and I'll
17:38show you some examples of those.
17:40So this will lead to resistance
17:42and of course you might want to
17:44think of targeting those mutations.
17:46So the other major mechanism of
17:48resistance is the P53 loss and I
17:50already mentioned that PhD is critical
17:53for BHA only proteins induction.
17:55But on top of that P53
17:57transcriptionally controls Bax,
17:59so BAX levels are lower and P
18:03and P3 lost AML and there's also
18:05other mechanism of resistance.
18:06So this remains unmet need
18:09in the field of AML and MD's.
18:12And then there are some other mechanisms.
18:15For example,
18:16Yanis offenders group has published
18:18the mitochondria resistance to the
18:21venetoclax through our regulation of
18:23some of this crystal proteins such as
18:25Glib B and also mitophagia kind of
18:28selection of the healthy mitochondria.
18:31And there's some effort as far as
18:34drug discovery in that field as
18:36well going back to the patients.
18:37So what did we see like from this mechanisms?
18:40What did we see as far as the
18:43resistance development?
18:44And before that I have to say that we
18:47also developed in the lab habanero clocks,
18:50resistance cell lines.
18:51So we decided to take some of
18:53unbiased approach and we generated
18:554 vein resistance cell lines.
18:58They're available for anyone who
19:00wants to use them by prolonged
19:02exposure to the drug in the tissue
19:04culture lab and took only about
19:063 months to generate the cells.
19:07So about the same time as our
19:09patients to progress.
19:10And then we did all kind of metabolomic
19:13genomic proteomic profiling and
19:17epigenetic profiling as well.
19:18So one pathway that came out kind of
19:20screaming at us, which was not a new pathway,
19:23but it was something that we already
19:25knew from before.
19:26It was MEP kinase pathways.
19:27So it was upregulated on the RNA level.
19:30And then we confirmed that in
19:32the by immuno blotting analysis,
19:34you can see application of some of
19:36this MEP kinase pathway proteins
19:38and as a result MEP kinase can
19:41stabilize MCL one proteins.
19:44So it's not transcriptional but on
19:45the level of the protein and we did
19:47see that in all the three cell lines
19:50M so one levels were up regulated
19:52as you would expect And then if you
19:54use the either M so one inhibitors
19:56or knockout of M so one you get
19:59tremendous synergy with venetoclax
20:00and the cells are are dying off.
20:03So I'm not going to talk about M
20:04so one inhibitors but suffice to
20:06say that they are not approved
20:08because of toxicity.
20:09So again like thinking why B so two so
20:11safe and M so one is not safe so M so one.
20:14Tends to be very important for the heart
20:17muscles and so patients treated on the
20:19clinical trials with MC1 inhibitors,
20:22they have what we call Troponin leak and
20:24potentially you know cardiac toxicity.
20:26So that Hanford the whole like
20:29development of MC1 inhibitors
20:30and it's not clear whether they
20:33actually have therapeutic windows.
20:34So, but in the lab, these are the
20:38great sensitizers to Vanadacolexa.
20:40So then we went back to patients and
20:42we know that in patients Ras mutations
20:44are fairly common in AML on their own.
20:46They don't have prognostic significance,
20:48but they can arise at the
20:51time of progression.
20:52And so when we looked at the patients
20:54treated on the HMA venetoclax
20:56trials at the time of relapse,
20:58they had like expansion of this Ras, K,
21:01Ras and Ras clones also PTPN 11 clones,
21:05which is not shown here fairly
21:07quickly within like 6 months or so.
21:09This has single cell DNA sequencing data.
21:13We also looked at the sort of
21:15patients by immunoblotting.
21:16So we did show up regulation of
21:18MCL one and the approgation of
21:20MAP kinase pathway and this is
21:21on the histochemistry level.
21:23At the time progression MCL one was
21:26up and BCL two was down regulated.
21:28The problem of course that in
21:30AML we don't have Ras inhibitors.
21:32We are really hoping that we can
21:34get them from the solid tumors.
21:36But the companies have been so
21:37focused on the lung cancer and they
21:39have been reluctant to go into AML.
21:41So we are still trying to convince
21:44them that Pan Ras inhibitor would be
21:46a great thing to have an AML and we
21:49actually have data with the in the lab
21:52that the combination is really striking,
21:54the papers submitted.
21:55But right now we don't have anything.
21:58So we also did the engineer this in the lab.
22:00So we put the NRAS G12D into AML
22:04cell line which was dox inducible.
22:07We showed that the cells become
22:09resistant to another clocks.
22:10But again the MCL one inhibitors
22:12work alone on combination.
22:14We did the mouse study with MCL
22:161 inhibitors and there was a
22:17reduction of the tumor growth,
22:19but we don't have MCL 1 inhibitors
22:20and we don't have resin inhibits.
22:21So we are like at a loss right now,
22:24but we're working on that.
22:27So this MEP kinase upregulation I
22:28think is one of the major kind of
22:31resistance when you use HMA Van.
22:34It's not an issue when you use chemotherapy,
22:36van,
22:36because Rascalone is very sensitive
22:38to the regular chemotherapy,
22:39which is kind of a relief.
22:42And this data we have sort of confirmed
22:44that this was a large analysis.
22:46I think the paper is under review from Viali,
22:49a study looking at different genomic
22:51subsets of patients who are and time to
22:54progressional this is rather survival.
22:57This was presented at by Hartman
22:59donor at the last ASH.
23:01And so they basically show that the
23:03classical kind of ELN classifications
23:05do not predict very well the
23:07response or duration of response.
23:09But when they did looked at
23:12different genomic subsets,
23:13again P50 mutated AML did very poorly.
23:16So survival was only about 5 months here,
23:19same as you get with HMA.
23:21But this intermediate cohort,
23:23it actually included patients with Ras
23:25mutations. So Ras mutation was confirmed
23:27to be like resistance factor for the HMA
23:30band and also another mutation signaling
23:32mutation F FLIX free FLIX free ITD mutation.
23:36So this data are being sort of refined that
23:38I told you a little about the Ras story.
23:41Now Flix 3 is another very common mutation,
23:43about 30% of patients have Flix 3 mutation.
23:46Unfortunately we have drugs for
23:48those that are being approved.
23:49So of course like we jumped into that
23:52very early on and in fact we saw that
23:54even in the original phase one study
23:56where which showed up regulation of
23:58this or selection of the clones with
24:00the Flix 3 IT do or as mutations and
24:03people who relapse or wear primary
24:05fracture and very similar this like
24:07selection of the Flix 3 ITT clone with a
24:11therapy using the single cell tapestry
24:13sequencing and the sort of why Flix 3
24:16ITT the story is very similar to Ras.
24:18So here you have you know the
24:20same Ras map kindness pathway.
24:22You also have a prolation of some other
24:25ones that five PS3 kines AKT but eventually
24:27it all comes down to this MCL one.
24:30So MCL one phosphorylation is regulated
24:32by both MAP kinase and also there's a
24:36stead pathway dependent phosphorylation.
24:38So when MCL one is phosphorylated it's
24:41stable so the levels are increased
24:43and the product cannot be degraded
24:45otherwise it's short lived protein.
24:47So essentially there's also some
24:48B cell XL component,
24:49but I think it's a minor,
24:51but the nice thing is all downstream
24:52or Flix 3 ITD.
24:53So it's OK if we're here Flix 3
24:55what happens with MCL one.
24:57So we used Quizactinib for that matter and
24:59we showed nice inhibition of the Flix 3 MCL.
25:02One did go down by wasn't that
25:04huge up down regulation.
25:06But we also show that the protein
25:08called BEM was induced and BEM
25:10can is a prop of Tory BC on a
25:13protein that can inhibit MCL one.
25:15So the combination of these two
25:18makes cells sensitive to venetoclax.
25:21And this is BHA profiling essay
25:23which I have time to explain in
25:25detail by essentially you throw
25:27the peptides on the cells and see
25:30which dependence that they have.
25:32But the point here is that if you
25:33treat cells with Flix 3 inhibitors,
25:35you have huge up regulation of B.
25:37So two dependency to the peptide
25:39or to the actual venetoclax drugs.
25:42So you have synergy in vitro.
25:44And in this model,
25:45which there was like a subcutaneous model,
25:47not a great model for AML,
25:49but we subsequently publish also PDX models,
25:51we show like essential cures
25:53of the mice for that matter,
25:55when we use the Quizad,
25:56snip and Venetoclax combination.
26:00So this did go into clinical development.
26:02And for the trials another flixster
26:05inhibitor second generation
26:07guilt treatment was selected.
26:09And this paper is now published in
26:12JCO by MD Anderson Group and many
26:15other collaborators where there was
26:17combination of venetoclax and guilt
26:19retina for relapse refractory Flex
26:213 mutated AML.
26:22And there was quite significant response
26:25rate in all patients or in those
26:28who failed prior Flex 3 Tki's alone.
26:31And if they went for the transplant,
26:33they actually the survival looks fairly good.
26:37The data by Kathy Smith showed
26:39that the Flixtree clones were
26:41extinguished after this combination.
26:42I have to say that she did show
26:44that Ras clones were coming
26:46up in patients who progressed.
26:47So Ras is still a resistance
26:49mechanism even in that setting.
26:52But again,
26:54this was quite impressive sort of
26:57advance in the field of Flixtree mutated AML.
27:00Now of course we all know that treating
27:03patients is best at the time of diagnosis.
27:05So for all the patients we
27:07cannot use chemotherapy.
27:08So Ambiencin's group has
27:10pioneered what we call triplet.
27:12So triplet is essentially Azovan
27:14which is a backbone and then you
27:16add the third drug in this case
27:18is guilt written and this paper
27:20is also now accepted in JC or now
27:22this is single sounded trial.
27:24There's a lot of discussion on Twitter
27:26whether it's like you know true or not,
27:29but at least you know data from
27:31Indiannis and look very impressive.
27:34Now when you see 100% response rate,
27:36you always kind of pause,
27:37but that's what they reported and 30
27:40newly diagnosed patients with AML and
27:43they estimated survival at two years was 70%.
27:46So this is like way better
27:48than what we had before,
27:50but they had to like reduce a
27:52lot of duration of the drugs and
27:54work out the schedule because the
27:56combination is mild suppressive.
27:57So the major like heme toxicity of
27:59venetoclax is mild suppression.
28:01So Neutropenias because Mallo
28:03itself express B so too.
28:06And so when you use the vanadium
28:08clocks in combinations,
28:08you have to cut back and that's
28:11continued discussions with FDA
28:12because the approved scale is 28
28:15days of vanadium clock.
28:17So there's a randomized study right
28:18now ongoing which hopefully will
28:20kind of solidify this question run
28:22by a Stellas and AbbVie where the
28:25same combination is being used in
28:27the frontline all the AML settings.
28:29So we'll see how that goes,
28:32but again what do we do about Ras.
28:34So this is like very early preclinical work.
28:38We're working with Everest Gavasitis at
28:41Einstein and he developed the RAF inhibitor.
28:44So kind of downstream of Ras that inhibit
28:47is allosteric RAF inhibitor that he
28:50is about to publish in solid tumors.
28:53But we show that P in cell lines
28:55with K or N Ras mutation is highly
28:58effective drug using inhibition
29:00of the pathway and there's some
29:02additive effects with venetoclax.
29:04So we kind of continue working on that.
29:06So hopefully we'll get either
29:08Ras inhibitors or RAF inhibitors.
29:09We did test the MECH inhibitors.
29:12I didn't show you that we published that.
29:14We went all the way into clinic,
29:15but MECH inhibitors caused a lot of
29:18GI talks and so the trial was unsuccessful.
29:21So it was stopped for lack of
29:24efficacy and high
29:25toxicity. So we can't really use the Mac
29:28inhibits unfortunately in this combination.
29:30So work to be continued on this topic.
29:34So there are a lot of other
29:36combinations with banana glass
29:37that have been sort of published.
29:38This is just some nice summary that
29:41was presented at last EHA and the
29:44the combination with IDH inhibitors
29:46that are now in clinical trials and
29:49both in AML and MDSI have to say
29:52there's many inhibited combination
29:54which looks super exciting.
29:55Of course, I'm still 1 went to to trials,
29:58but it's struggling.
29:59There was McGraw mop combination
30:02which we pioneered,
30:03but right now McGraw mop is
30:05all the trials have stopped.
30:06So I'm not going to talk to you about
30:09that today and but I want to show some
30:11data with the immune approaches in
30:13this case is antibody drug conugate.
30:15So kind of a little bit different
30:17story with venetoclax.
30:18So, so we used the,
30:21we looked at CD 123 because CD 123 is
30:24a subunit of all three receptor alpha
30:27and it's ubiquitously expressed in AML.
30:30Also this other level of my
30:32BPDCN and in some ALR as well,
30:35it's expressed in stem cells based
30:38on Craig Jordan's work and it's
30:40sort of the only antigen right now
30:42that we kind of trying to target as
30:44far as immune therapy and EMLMDS.
30:46There are other efforts but none
30:48of them have been successful yet.
30:51So we've been working with this
30:53company Immunogen that developed
30:55the antibody drug Conugate.
30:57So they have the antibody gain C123
31:01that's through the linker is bound
31:04to the alculator that produces
31:06the single strand DNA damage.
31:09So obviously it's internalized and
31:12and you know kills the cells for
31:14the DNA damage kind of chemotherapy
31:17but in a targeted fashion.
31:19So it had the good single agent
31:22activity and BPDC and then EMO
31:25the company has filed approval for
31:27BPDC and patients a second line.
31:29So hopefully we get this drug
31:31approved pretty soon.
31:32And so we of course asked the question,
31:34can we combine the two because
31:36this is like you know the immune
31:37therapy that seems to be working.
31:39So we've done quite a bit
31:40of preclinical work.
31:41It's not published yet,
31:42but we show that the compound is fairly
31:45specific. So these are AML cells.
31:47This in red is CD123 expression.
31:50So again,
31:50majority of cells do express it and
31:53they're being killed by this drug,
31:55but then the cells that don't express
31:58there's no killing and KG one is resistant.
32:00We're not quite sure why,
32:02but it seems to be specific.
32:04And then we ran the combinations
32:06both with another clogs and
32:08azacitidine and the triplet because
32:09now we're in the triplet era, right?
32:12And you can see here.
32:13So these are different cell lines.
32:15I have to say that ITD cells
32:17have high expression of C123,
32:18which is why we selected those
32:20for the combination trials.
32:21But especially with the triplet,
32:23there's quite a bit of synergy.
32:27What about PPG mutant AML,
32:30So these are wild type cells,
32:31so they're sensitive and they mutant or loss,
32:35PPG loss, we see less activity.
32:38There's still some induction of cell does,
32:40but it's actually quite resistant
32:42to both of the compounds.
32:44We're not quite sure how that is affected.
32:46So for some reason the cells
32:48had very high expression of MSL.
32:49One, we're still working on to understand
32:52that because we did see induction of
32:54DNA damage in both knock down cells
32:56and the wild cap cells and there's a
32:59part cleavage but it's less killing and
33:02that is also reflected in the trial.
33:04The PhD media patients didn't
33:06do as well as you can imagine.
33:09The drug abolishes the S phase.
33:11So this is like IMGN alone and the
33:15different concentrations and then
33:16when you combine with the Vanasa you
33:19essentially you kill off the S phase
33:21cells so you don't have anything left.
33:24You do get activation of gamma H3X
33:26as adna damage and Cliff cast space.
33:29So then we try to understand the mechanism,
33:31how that works.
33:34And so one thing is we know that
33:36again I'm Gen.
33:37inducing the single cell DNA strand breaks.
33:40So we showed the phosphor P53UP
33:43regulation which was the same
33:45with or without venetoclax.
33:47But then we saw that the drug inducing
33:50the DNA repair pathway phosphor check one
33:53and it seemed to be less with venetoclax.
33:56So we are,
33:57it's kind of off story,
33:58but we are trying to understand if
34:00BCL 2 inhibition can actually be
34:02involved in the control of DNA damage,
34:04which is hard to understand because
34:06it's cytosolic and this is DNA.
34:08But we are kind of working through the story,
34:11still trying to figure out all
34:12the parts of the DNA pathway.
34:15But it has some like clinical,
34:16preclinical implications because if you
34:18use IMGN first followed by the nether class,
34:22you have very striking synergy.
34:24This BLISS index is 18.
34:26If you do the reverse then
34:28first followed by IMGN,
34:30there's very little synergy now in
34:32the clinic it's given concomitantly.
34:35So I think it's fine but and nobody's
34:38interested in understanding the kinetics.
34:40But I think the biologically this
34:42is interesting phenomenon and
34:43perhaps something to do with DNA
34:45damage repair that we're working on.
34:47We also showed that the IMGN primes
34:50towards be so to inhibition.
34:52So I didn't I have a lot of like
34:54mouse data which I didn't show you,
34:56but the clinical trial has been
34:58reported at ASH and the paper is
35:01also now accepted in JCO.
35:03So this is a triplet.
35:05So again the drug is now called
35:08Pivacomab P VAC.
35:09We abbreviate that it was used with
35:12Azovan in newly diagnosed AML.
35:14All the patients,
35:15you know majority were unfit,
35:18but there were some fit patients as well.
35:21So it was fairly safe.
35:23So again the drug has some toxicities,
35:26but generally speaking it was well tolerated.
35:30And then the response rates where I
35:32would say similar to the ACE event,
35:34but what was impressive
35:36was MRD negativity rate.
35:38So the depths of response was you get about
35:4240% with ACE event it was about 76% of 79.
35:45So almost doubling the depths of response.
35:48Now we don't know yet if that
35:50translates into survival,
35:50which will be a critical question.
35:53So now Immunogen is bought by ABB vie.
35:55So we're hoping that this will continue
35:57and to randomized phase three study
35:59and maybe we'll have that triplet in
36:01a few years fully characterized that.
36:04But if you look at this like 3 subsets
36:07that I showed you before, so again,
36:09the good kind of prognostic patient
36:11that respond well to to azavan,
36:13they did really well.
36:15This response rates in PVC mutant,
36:18there was about 20% full CR rate,
36:21but 50% overall response rate.
36:23So maybe there's kind of,
36:25you know some signal again with PVC mutation,
36:28we are kind of really at loss.
36:29So that you know,
36:31but again this will be developed
36:33hopefully further and we'll see a few
36:36years from now where that lens now P 53.
36:39So I already told you several times that this
36:42is like a major unmet need in AML and MD's.
36:45All the drugs that we had in phase
36:47three have failed for the most part.
36:49And even from the very initial studies,
36:52we've showed that this was a major resistance
36:55factor to venetoclax as well unfortunately.
36:57So patients who again relapsed
36:59or who were primary fracture,
37:01they had high rates of 17 P loss or P50C
37:07mutation or both and why that is the case.
37:11So first of all if you do like
37:13single cell DNA sequencing,
37:15this is from Andrew Way's paper
37:17you showed you know all this
37:19clones are being selected for.
37:21So it's almost like a pressure to select
37:23this clones for that because they do
37:25not get killed by venetoclax cell.
37:27And what he showed in this paper is
37:30that while in parental cells venetoclax
37:33induces backs activation by this essay,
37:36there's much less in the PVC knockouts also.
37:39And you can sensitize it by MC1 inhibition.
37:43But again,
37:44we don't have MC1 inhibitors in the clinic.
37:46So what do we do about that?
37:48We we don't really know.
37:49But I want to show you some clinical
37:51data from our Einstein program that
37:53was developed before I got there
37:56using a different approach.
37:57So the approach that they decided to go
38:01forward was really developed by Jogan.
38:04I cannot promise the last name,
38:05but that at Cleveland Clinic.
38:08So he is I think,
38:08the most knowledgeable person
38:10in HMAI feel that.
38:12So essentially he published
38:14the first study in MD's,
38:15as I'm sure Amara knows very well.
38:17And he compared the traditional dosing of
38:20decybin with what he calls metronomic dosing,
38:23which is once a week like 1/5 of the dose.
38:25So really like tiny doses of decybin.
38:28But he showed that this is
38:31enough to deplete DN MT3DMT1.
38:32So you don't really need to induce this,
38:35you know, constant cytotoxic
38:37DNA damaging response of HMAS.
38:40And then he showed in preclinical work
38:42that it can induce differentiation
38:44of P53 novel loss clones.
38:46Now the resistance to the decided
38:49men is mediated by approvalation
38:52of pyramid and synthesis.
38:54Again, this is all his work and
38:57he had some preclinical data
38:59that Veneto clerks can in fact
39:02reduce the pyramid incentives.
39:04So there may be potential synergy there.
39:07So based on this sort of
39:10preclinical rationale,
39:11the team at Einstein have
39:14developed this metronomic dosing
39:16of Decidabin and Veneto clerks.
39:18So now you have a newly diagnosed
39:20patient with Amalo MTS who comes
39:22to clinic and gets once a week
39:24injection of the SIBIN subcutaneously
39:26and one dose of another class.
39:28So I'll say I had hard time
39:30believing that when I got there,
39:32but I think now I'm so converted and
39:34that we are continuing the development
39:37of this in the prospective trial.
39:40So again this is like a schedule,
39:42this is like traditional what you do,
39:44you give another class for 28 days
39:45and you give the SIBIN for five days
39:48or ASAP for seven days and then you
39:50repeat the cycle and he is like once a week.
39:53So the idea is really to get away from
39:55the DNA damaging response because we
39:57know that Pfc mutated cells are only
39:59being selected by any DNA damaging drugs,
40:02they don't care and get into
40:04this hyper misleading effect.
40:06How that works, we don't know right?
40:08How many agents mechanism of actions
40:10is still not fully understood,
40:13but the idea was can we like really use
40:15that approach and at least have some benefit?
40:19So they published this paper,
40:20this was retrospective study using
40:22this regimen and now as I said,
40:24we are in the prospective study.
40:26I'm sorry,
40:26it's a it's a bit difficult slide
40:28but the point is that there was
40:31no really like mouse suppression
40:33but the response rate was quite
40:36significant and CR rate was 57% which
40:39was fairly similar to the VLA study.
40:42And then when we looked at the small
40:44numbers again this is all like very
40:46early on of PVC mutated patients,
40:47the survival was about 10 months
40:49and a lot of patients actually
40:51achieved full remission,
40:52became transfusion independent
40:54and they did very well.
40:56They relapsed like a clock at 10-11 months.
40:59So it's not curative approach but
41:00at least you know we can extend the
41:03survival again and reality is five
41:05months survival. Many other studies.
41:06Now this is 10 months.
41:08Again, small number non randomized studies,
41:10so with all the Kevas,
41:12but we're quite excited about
41:14that and we are thinking of what
41:15can we add to that to really like
41:17capitalize on this approach,
41:19you know using this metronomic dosing.
41:23So one thing is like in the lab we are
41:25trying to use some of the BAX activated.
41:28So I told you several times the
41:30BAX is really like critical and
41:31the BAX is not working with PP,
41:33she's lost. So we have a collaboration
41:37with again Everest and also Jerry
41:40Chipok would develop the direct
41:43Bax activators or Bax modulators.
41:46So we are thinking maybe
41:47if we use those compounds,
41:49there's a preclinical stage we
41:51can overcome the PVC mutant loss,
41:53but this remains to be seen.
41:56OK. So switching gears,
41:58so this was PVC new dated AML and
42:00now going back to the chemotherapy.
42:02So as I showed you before,
42:04there's like very good rationale to
42:06combine the Netherlands with the
42:07chemotherapy and AML and there are
42:09a lot of trials which have been
42:11already reported and now we're getting
42:13the response rate of about 90%.
42:15So this is like like was unheard of before,
42:19but when you add the Netherlands
42:21to chemotherapy you really get
42:23tremendous synergy.
42:24So in our centre we have this
42:26also IST that is run by Doctor
42:28Manzaris where we use the standard
42:30Sam plus sheep plus another class,
42:32different durations and so forth.
42:35The trial is still ongoing,
42:36but again the response rate are about
42:3890% is still like short follow up.
42:40So we don't really know like survival,
42:43but we are quite excited about this
42:45approach except PVC MUDA patients,
42:47they relapse and they don't do well.
42:49So we stopped using this for even
42:51younger PVC MUDA patients because all
42:54patients, 5 patients were treated with,
42:56they're all relapsed and they died
42:58from despite the fact that some
43:00of them achieved remission.
43:02So again, PVC remains an issue.
43:04So we're looking at the stem cell
43:07extinction with the therapy and
43:08doing a lot of research with that.
43:11And in the last 10 minutes of my talk,
43:13I'll go back to BCL XL,
43:14which may be of interest more
43:17broader kind of auditorium.
43:19So BCL XL is a cousin of BCL two
43:23and it's less expressed in the AML,
43:25but it's expressed in solar tumors,
43:28it is expressed in the TELL subsets.
43:30So this was work from Tony Lataev
43:33now a few years ago,
43:34a number of years ago that showed
43:37that the typical TELL actually
43:39depends on BCL XL and if you use this
43:42Navitoclax drug that didn't make it,
43:44you actually get very good responses.
43:46There's a subset that is B,
43:48so two dependent,
43:48but I'm not going to go into that.
43:51Now.
43:51I already told you that the
43:53liability of B cell X inhibitors is
43:56thrombocytopenia because platelets
43:57depend on B cell XL for survival.
44:00So you get on target toxicity and of
44:03course it's challenging to those.
44:06So and you know this is just a
44:08couture published review recently.
44:10So Nevito clocks right the drug
44:12that is still not approved,
44:13it was just as the venetoclax so
44:16inhibits the complexes inducing bags
44:18back but it causes thrombocytopenia
44:21killing the platelets.
44:22So the way around that at least
44:25that's ongoing work is to use the
44:28degraders for BCLXL degraders.
44:30So,
44:31so we have been collaborating with
44:34the team from Dalhoung Zhou who
44:36was before University of Florida
44:38and now he
44:39moved to the San Antonio.
44:40So he developed this Protac BCL
44:44XL degrader where the legend
44:47is essentially native o'clock.
44:48So same drug, but then there's a linker
44:52that links it to the VHL E3 ligase.
44:54So you can ask why that is
44:56better than inhibitor, right?
44:58First of all, it's huge molecules.
44:59So it's has a pharmacological
45:01properties issues.
45:02But The thing is that this E3 ligase
45:05is not expressed in platelets.
45:07So you're not getting degradation
45:09of B cell XL and platelets.
45:11And therefore you can see here
45:13there's no B cell cell degradation
45:15in platelets with this drug.
45:17But it's like a TLO tumor cell line,
45:20it's very nice degradation.
45:21So this is just the schematics of that.
45:24And again as a result,
45:26you can kill the tumor cells
45:29but you don't kill platelets.
45:31So this drug right now is in clinical
45:34trial in solar tumors and it's actually
45:37completed the phase one portion of it.
45:40They did see some drop in platelets,
45:42but there was much less than whenever
45:44the clocks I think because the drug
45:46still binds to some extent and still
45:49inhibits a little bit of BCL XL function,
45:51but it was reversible and
45:53no other toxicity was seen.
45:55We published that it's quite effective
45:57and the TL models and recently we
46:00also moved towards the dual BCL 2XL
46:04product which is not yet in the clinic
46:06and we published this work in AML
46:10and we showed that this dual product,
46:11we call it 753-B,
46:13it was actually quite effective in all
46:15primary AML samples including those
46:17that were resistant to venado clock.
46:20So there's you know there's
46:23degradation of BCL XL as you would
46:25expect basically didn't see much
46:27degradation of BCL 2IN primary cells
46:29but it was seen the cell lines.
46:31So we think that's potential for using
46:34dual BCL 2XL inhibitors in AML as well.
46:38And the other aspect of it that is
46:40very kind of popular and the solid
46:42tumor literature is that the role of
46:45B cell excel in senescence cells.
46:47So what we know the senescence cells,
46:49the cells that survive chemotherapy
46:51and but they can kind of revert back
46:55and become chemo resistant and the
46:57metastatic cells in the setting of
47:00breast cancer or lung cancer and so forth,
47:03It's much less known in senescence in EMO.
47:06But there was a paper by Ari Melnick's
47:08group that showed that chemotherapy
47:11can actually induce senescence cells.
47:13So this is like essay you use for
47:15the C-12 FDG where you can show that
47:18within the viable cells a fraction
47:21of them are actually senescence and
47:24the senescence cells they depend
47:25on BCL X cell for survival.
47:27So when we sorted out the senescence cells,
47:29we showed that BCL XL was up regulated
47:31which was which was consistent
47:33with the literature.
47:34And then when we looked at the markers
47:36of senescence, this is cell line.
47:38So chemo is inducing all the
47:39senescence phenotypes.
47:41But when we use this BCL XL
47:43degrade that we
47:44can reverse that and
47:45they showed here as well.
47:47So we think that there's a potential
47:49efficacy of BCL XL inhibition and this
47:52dormant senescence cells plus with
47:54it's really hard to like identify them
47:57and patients like you know the the
47:59essays are not very well established.
48:02But I think there's a lot of interest
48:04using BCXL inhibitors as synolytic
48:05in a variety of different sort of
48:08conditions including sorry tumors,
48:10leukemias and so forth.
48:11And the finally,
48:13like I told you that there's some
48:15AML subsets that are BCL Excel
48:17dependent and this is one of them.
48:19So this is like totally horrible
48:21entity called acute Erythroid,
48:22Erythroid leukemia.
48:23And now Doctor Xu here has done
48:26a lot of work on that,
48:28but it's in the old classification
48:30is the MLM 6 and it has all of this
48:34Erythroid markers and it has very
48:36high rates of PPC mutation, right.
48:38So I already told you that the NOW
48:40class does not work for PPC mutant AML.
48:42And sure enough in all clinical
48:44trials patients who were AEL patients
48:46who were treated with Venetoclax,
48:47they progressed very quickly.
48:49So that's not a solution,
48:51but there was a,
48:54we collaborated with the work with
48:55a group at University of Helsinki
48:57and they they published this very
48:59nice paper last year and blood.
49:01So they looked at the dependency
49:03and AEL using the Crispus screens
49:06or drug screens and one of the
49:09top one was actually B cell XL.
49:10This is a gene called B cell
49:1312/1 that controls B cell XL.
49:15And you can see that it also was
49:17true for the drug screen as well.
49:19They show this and they confirm that
49:22and the cell lines and if you use a
49:25different like gene expression data sets,
49:26so again this is old M6 also
49:28M7 which is megacaric leukemia,
49:31they have high expression here,
49:33very high expression and this
49:34is Saint Jude Court as well.
49:36So they have a high expression of
49:38BCL XL on a transcriptional level.
49:41So The thing is because the
49:43erythroid cells have you know
49:44naturally utilizing this protein
49:45for survival and this is preserved,
49:48they also showed some efficacy
49:50in the in vivo models.
49:51So we are interested in using the
49:53product for this indication and
49:55within mechanistically it makes a lot
49:57of sense because again in Aristo it
50:00says the main transcription factor
50:02that drives kind of development
50:04is gutter one and we show that
50:07there is a very direct correlation
50:08between B SO2L1 and gutter one.
50:11This is activity from the gene expression
50:13analysis and both different data sets.
50:16This was collaboration with Saint Jude team,
50:18so there's no correlation with BCO 2.
50:20So really in Ali think there's
50:23transcriptional up regulation
50:25and dependency on BCL XL.
50:27Based on some of the prior work published,
50:30we know that this got the one
50:32directly binds the BCO 2L1 locals.
50:34And we have now also data in
50:37AL in collaboration with again
50:39Ilaria from Saint Jude
50:41and they're using this degrader.
50:44So this is original BCL XL degrader.
50:46This is like a next generation.
50:48We showed us the cell lines that are
50:51completely resistant to the netoclocks
50:52here and green they can be nicely
50:55killed by this B cell cell degrader.
50:58We also tested this in fuel primary
51:00samples that you know failed all kind
51:03of regiments including macrolimab and
51:05the we show the B cell degradation
51:08here and very nice response.
51:10So again, this is preclinical work.
51:12We're trying to get the drug if we get
51:15funding for the trials is still ongoing,
51:18but we feel that this is a hopeful
51:21and in fact I learned that every
51:24just approved the nabito clocks
51:27for the subset of AL between MSK
51:30and the MD Anderson Cancer Center.
51:33So there will be a small pilot
51:34trial at least testing the proof
51:36of principle that B cell XL is a
51:39driver in this horrible disease.
51:40We also see very similar phenotypes in MPN,
51:43but I didn't have time to
51:45show this data as well.
51:47So I'll end here.
51:48And I would like to postulate
51:50that AML is generally B,
51:52so two dependent disease,
51:53but then there's some subsets that are
51:56depend on B cell XL or M cell one.
51:58And of course we love the drug because
52:00it kind of lowers the threshold.
52:02So you can see the synergy with pretty
52:05much anything you use and then you can
52:08kind of go back to lab and figure out why.
52:11But but this was really like you know
52:13born in the clinical trials where I
52:16showed you synergy with chemotherapy,
52:18with the hypermethylene agents,
52:20with thyristine kinase inhibitors and
52:22you know the the fuel has really like
52:25exploded using this drug as a sensitizer.
52:28Some of the you know trials that I
52:31mentioned are ongoing and immune
52:33therapies I mentioned to you before
52:35now resistance is obviously as a major
52:38issue and it's largely driven we think
52:41by PC laws or signaling mutations.
52:44And you know I showed you what
52:46we're trying to do about that.
52:47But then the subsets that are B cell
52:50excel dependent and we are quite
52:52excited about using this B cell excel
52:55inhibitors or products in this setting.
52:57So I'll end here.
52:58So I have many,
52:59many Co workers collaborators from
53:02both my MD Anderson lab that has now
53:07only partially moved to Einstein.
53:08So I have a new lab at Einstein and
53:11my clinical collaborators at MD
53:13Anderson especially Courtney who led
53:15AMLVLA trial now who has done a lot
53:17of triplet combinations and many
53:20other investigators of course Dr.
53:22Contagion who has been really like
53:24pushing ABVI to go forward with this
53:27HMA event trial despite the fact that
53:30single agent was not as efficacious.
53:32And a lot of collaborators from
53:35Montefiore Einstein,
53:36we're developing this new programs
53:37that I showed to you and many
53:40collaborations with the companies
53:41but also academic collaborators.
53:43So I would like to acknowledge
53:45Tony Li Tai
53:45who has been really like,
53:47you know, developed this first
53:49approach with me in the lab.
53:52And you know, we think that because of
53:54that work and algos really went into AML
53:57and we have collaboration with Andrew
53:59Way at Melbourne and with the Saint
54:01Jude team and Dao Hangzhou for the product.
54:04So I'll end here.
54:05Sorry, it's like 5 minutes before
54:06the end of the hour,
54:08but I am happy to take questions.
54:10Thank you. Maybe I
54:19can start.
54:22You have questions in Zoom
54:26a fantastic talk.
54:28Very few people actually bridge
54:30the the clinic and the lab like
54:32you do clinical trials and lab,
54:34which is amazing.
54:35So I know this is not
54:37primarily your research,
54:38but why would you think the metronomic
54:40use of HMA with venetoclax would
54:44actually work for TP50 TP 53
54:47while regular dosing would not?
54:50I think the regular dosing induces
54:52DNA damage and essentially leads
54:54to the selection of P53 lost cells,
54:57so you kind of lose your hypermethylene
55:00advantage, whatever that is.
55:02Again, I don't know how the hypermetalline
55:05agents work in PhD muted EMLO,
55:07but I think what happens with the
55:09regular dosing, there's DNA damage,
55:11which was shown by Steele,
55:12Gore and others before.
55:14And the cells,
55:15they're just like being selected for.
55:17So all you get is selection of
55:19cells that are like PHC mutated.
55:21They're resistant to DNA damaging drugs.
55:23And so there's very limited like advantage.
55:26Well, with metronomic dosing you
55:28really like rely on hypometallic
55:30effects of the drug and then
55:32you know you you get benefit.
55:34But again you know it's
55:36a hand waving argument,
55:37but we are encouraged to see that
55:40in the prospective trial with
55:42the you know about 10 patients
55:44treated that the data stand.
55:45So this you know again they're going
55:47to remission about like 5060% and as of
55:50right now survival is about 11 months.
55:52But again like short follow up,
55:54you know it's a small number of patients.
55:56So I'm like you know,
55:58I've been hesitant presenting
55:59this data till I actually,
56:00you know, saw the survival data,
56:03but we're hoping that you know this
56:05will stand, but again it's not curative.
56:07So we definitely need something
56:08else to add to that.
56:10Thank you,
56:17very nice talk. I was curious
56:19about what's being done towards
56:22tissue specific MCL ONE inhibitors.
56:25So in order to avoid the cardiotoxicity,
56:28you talk beautifully about BCL
56:29XL for example. Unfortunately,
56:32nothing that I'm aware of.
56:35I heard that there's some approaching
56:38making approaches making the ADC.
56:42I haven't had yet chance to
56:44get any of those to my lab.
56:46So people are thinking about that.
56:49I think it's probably ongoing,
56:51but I'm not aware yet that
56:52there's any like you know,
56:53compound that is close to clinic,
56:55but I think that would be the way to go.
56:58Now the VHL is expressing the heart.
57:02So you know,
57:03there's also effort by Stephen Fazek,
57:06who is now at the Vanderbilt to look
57:09at all 600 ubiquitin ligase and try
57:11to understand the tissue specificity.
57:14Obviously, if I'm so one,
57:15we have to avoid the heart.
57:17I think that effort is still
57:18ongoing as far as the products,
57:20but I think perhaps using the antibodrap
57:25conugate maybe is the way to go.
57:27You know there was the B7 HCB cell Excel
57:31conjugate that went into solid tumor trials.
57:34It somehow didn't make it,
57:35but kind of similar approach
57:36perhaps can be used in Amo,
57:38but nothing close to clinic yet.
57:41Thank you.
57:44Thank you for that. Thank you.
57:48Looking at the evolution on the
57:49clinical slides that we show on track
57:51right single agent one of the plaques,
57:53we are very modest activity in AML
57:56That phase three study that you show
57:58with Curtney in the first three months
58:00ASA one curves don't separate after
58:03that the curves start to separate but
58:06everybody needs a CR after one cycle.
58:09I think what are we doing there
58:12I think the probably the people don't
58:14die with ASA after first month either.
58:17So they still you know this well with
58:19ASA side is about nine months right.
58:21So they even though they don't get
58:24intermission, they are still, you know,
58:26alive and they continue on study
58:28and so they curve separate later.
58:31That's my guess. But you're right.
58:33You know, remissions happen after one to
58:35two months with the vanilla clocks and
58:37there are no remission with azacitidine.
58:40But it's because I guess they're still
58:43kind of able to maintain people alive with
58:45all our supportive care and everything.
58:47They they are still there.
58:50That's my understanding
58:52because you know if you go back into
58:53that paper that you're a part of the
58:55Curtis paper that frankly presented
58:57at the older NPM on positive.
58:59I have a feeling when Nick presents
59:01the data after that combination,
59:02they're highly choosing NPM on positive
59:05patients that is chemosensitive
59:07or mild suppression sensitive.
59:09And then they're tagging it up with
59:11the fixed data because they're seeing
59:13a flat like that kurtish paper
59:15you have the first three months,
59:16it's a flat drop, drop,
59:18drop and we know what addition of three
59:21class of frequently liberals done too.
59:23And
59:25the point being is AML being all legal
59:28flow now, how much emphasis can we
59:31give just the BCL component in looking
59:33into resistance because the minor
59:35suppression component takes care of it
59:37for three to six months, very good.
59:39We don't have anything to that extent
59:41compared to cytotoxic in the past.
59:44Garcia within a recently in the post
59:46transplant period in the other one has
59:48maintenance even there the curves first
59:50three to six months and then drop,
59:51drop, drop, you don't have a
59:53leukemia there at that stage.
59:55So now when I'm going to fight stem cells,
59:57what do you think the resistance is in
59:59that context when you're using either
01:00:00one in the post transplant context?
01:00:03Oh I I don't think I'm able
01:00:04to answer that question. So
01:00:09I'm not sure what the you know.
01:00:12I don't think that this is just mouse
01:00:14suppression causing people to die,
01:00:15but there's really like relapses going on,
01:00:18right? And I assume that this is
01:00:20still escape of some of the clones
01:00:22that are not being eliminated.
01:00:24But I don't know the data that well.
01:00:27But yeah, the point is well taken
01:00:28that you know the triplet, the data.
01:00:32As far as like you know,
01:00:33there's a lot of discussion
01:00:34if you have MP1 free, St.
01:00:36Commutative clone can be eliminated
01:00:38with Venetoclax alone or not.
01:00:40The data are not very clear,
01:00:42but at least from VLA data
01:00:44we know that Flixtree mutated
01:00:45patients even if they had MPN one.
01:00:48This is not published,
01:00:49but I looked at that in the rest context.
01:00:52The survival is still shorter than
01:00:54for those who have only MPN 1.
01:00:56So there's still that contribution
01:00:58of the Flixtree clone to the
01:01:00like relapse earlier Relapse,
01:01:01despite the fact that you target the,
01:01:03you know, presumably stem cell MPN,
01:01:05one clone with Venetoclax.
01:01:07But I don't know really how like
01:01:09Clonal Dynamics happened there,
01:01:11but I do think that triplet adds in
01:01:13that sense that it will target the
01:01:16fixture clone within even MP one.
01:01:18But again, you know,
01:01:19I don't have data to that.
01:01:22So maybe one last question,
01:01:24given your extensive work with drug
01:01:27development in AML and you alluded to
01:01:29the Twitter wars on some of these data.
01:01:32I think one big question that
01:01:34keeps coming up is if if an agent
01:01:37has no single agent activity,
01:01:38does it can it have realistically a chance
01:01:41of being synergistic in a combination?
01:01:44Some people pointed to Vinito
01:01:45Clacks as the rule that this,
01:01:47but actually Vinito clacks as you
01:01:48said does have single agent activity.
01:01:50It's not much,
01:01:51but it does have activity and
01:01:52some people took a Victory lab
01:01:54with Magrolimab because it has
01:01:56zero single agent activity and all
01:01:58the fuss about the combinations
01:01:59and then the face reasoning.
01:02:00So so is your sense that if you
01:02:04have no single agent activity,
01:02:05can you really be synergistic
01:02:07in combination as a general?
01:02:09Yeah, I think it was like general question.
01:02:13I would probably be very worried about
01:02:15going to phase three with a drug
01:02:17that has no single agent activity.
01:02:19As you said the NOW class did have activity
01:02:21you know reduced blast in 50% of patients
01:02:24and the the data also in the front line
01:02:27setting where they did the bone marrow,
01:02:29they did seven days venetoclax pretreatment
01:02:31just single agent and they did bone
01:02:34marrow that was done in Australia and
01:02:36they also showed reduction or even like
01:02:38remission in about 50% of patients.
01:02:40So it does have single agent activity
01:02:42but also like different mechanistically
01:02:44because it's like a sensitizer, right.
01:02:46So you can, you know,
01:02:47think that even if you didn't
01:02:49have that single agent activity
01:02:50in combination you might have had.
01:02:52But I personally like I'm very
01:02:54worried that you know, I I'm,
01:02:56I'm not sure I would develop the drug that
01:02:59has absolutely no single aging activity
01:03:01and combinations, you know, going forward.
01:03:04I might be wrong.
01:03:06Thank you so much.
01:03:08Thank you everybody.