Cell Therapy and Transplantation

February 19, 2021

Information

February 19, 2021

Presentations by Drs. Lohith Gowda and Iris Isufi

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00:00Disclosures.
00:03An outline for my talk today would be to
00:06briefly talk about 6 important studies.
00:08One is a randomized trial comparing
00:10best supportive care against
00:12allogeneic transplant for patients
00:13with MD S between ages of. 50 to 75.
00:16Yes second study would be looking into
00:19an owl way of mobilizing stem cells.
00:21Studies 3, four and five are
00:24addressing pharmacologic and cellular
00:25manipulations to decrease the
00:26risk of graft versus host disease.
00:29Post allogeneic stem cell
00:30transplant and the final study.
00:32We will briefly talk about evolving
00:34role of what consolidation is prior to
00:36allogeneic stem cell transplantation.
00:38In modern era,
00:39we will not focus too much about
00:41autologous transplantation because my
00:43colleagues in lymphoma and myeloma section.
00:46I have tested on that concept and once
00:49the arrows done I'm going to pass on
00:51the talk to Iris for chimeric T cell talk.
00:55So the first study was a BMT CTN 1102.
00:58This randomized study was a
01:00biologic assessment study to be
01:01biologically assigned to receive
01:03another public stem cell transplant.
01:05People should have identified
01:07a donor between the 90 days of
01:10consenting for this MDS study.
01:12Math sibling donors and matched
01:14unrelated donors were load.
01:15They were all expected to undergo stem
01:18cell transplantation within six months.
01:21Subjects between ages 50 to 75 were included.
01:24Only primary Arduino MD S with the
01:27intermediate two or high risk by
01:29PSS were included in the study.
01:32All these candidates were meant
01:33to be in a traditional sense be
01:36acceptable to undergo reduced
01:38intensity transportation study.
01:39Randomized people to either get randomized
01:42260 questions to transplantation,
01:44or 124 patients.
01:452 best supportive care or whatever
01:47other options individual centers
01:49would offer to those.
01:55So here are the results from that study.
01:58The primary endpoint of the trial
02:00was a prior overall survival.
02:02Looking into the donor and the
02:04no donor arms here 3 or estimate
02:07overall survival was 47.9% for
02:08those who had a donor against at
02:1126.6% for people who did not have a
02:13donor at the time of randomization.
02:16Game when they do the sensitivity analysis,
02:19excluding subjects,
02:19are assigned to the node on around
02:22who either died or withdrew prior
02:24to the 90 research window.
02:26For the sooner the eventual outcome did
02:28not change with the adjusted overall
02:30survival of 48% for the donor arm
02:33against the 28.1% for the non donor
02:35when they specifically looked into
02:37the different subgroups for analysis.
02:39Use of rat hyperventilation agents.
02:41Age groups less than 65 against
02:43greater than 65 duration of MBS,
02:45less than three months or greater than.
02:47Reminds I PS is risk groups that
02:50donor am sent it to do better
02:53for the overall survival.
02:55One of the secondary endpoints of this
02:56video is to look into leukemia free survival.
02:59Understanding the risk of my
03:00latest plastic syndromes.
03:01Clonal evolution here.
03:02They don't around again came out superior.
03:05Three year leukemia free survival
03:07of 35.8% compared to the node
03:10on around which was 20.6%.
03:12Adjusting with the sensitivity analysis
03:14again the leukemia free survival was 35.9%.
03:17The donor arm against the 21.8%
03:19for the node and are similar to
03:21the prior slide within subgroups
03:23for all different variables that
03:26looked into leukemia.
03:27Free survival advantage was
03:30seen with the transplantation.
03:32This is a slide that is
03:34showing as treated analysis.
03:35Again,
03:36showing the superiority for both overall
03:38survival and leukemia free survival.
03:40Absolute improvement for
03:41overall survival study,
03:42one point 4% for the transplantation
03:45arm was 28.4% for the leukemia free
03:47survival again for the transplantation.
03:53So one of the conclusions of this
03:55randomized study for a very long time,
03:58the field of Miller Park,
03:59stem cell transplantation
04:00and who to transplant,
04:02who not to transplant was based
04:04upon Markov decision modeling.
04:05This is the first randomized trial
04:07comparing best supportive care of
04:09best available care against the
04:11random against allogeneic stem cell
04:13transplantation in a randomized manner.
04:15Specifically, in a Common Age group
04:17where we encountered this disease,
04:19so such patients,
04:20if they have a suitable donor,
04:22this leads to improved overall
04:23survival through leukemia free
04:25survival and again after we ask our
04:27patients to undergo transplantation,
04:28a question that gets asked is can you know,
04:32is this covered by Medicare?
04:33There's most of these patients
04:35are greater than 65.
04:36Historically,
04:37we had to report those outcomes
04:39now within the subgroup analysis,
04:41we're clearly able to show that for
04:43people greater than 65 in less than 65.
04:46Transportation is a good option.
04:47I think that goes against transportation.
04:49Is there are reports that talk
04:51about decreased quality of
04:52life post transplantation,
04:53so the study had designed.
04:55I didn't show you that like the study.
04:57I designed a quality of life measurement
04:59at different time points for both the
05:01arms and it shows that the quality of
05:04life was no different or definitely
05:05was not included in the transportation.
05:08Finally,
05:09as I want to emphasize that overall,
05:11there's a very strong advantage
05:13for stem cell transplantation,
05:15particularly to have a match sibling donor
05:17or a mass unrelated donor identified
05:20early in the course of their treatment.
05:23I have next study talks about
05:25how to mobilize stem cells at.
05:28Traditionally we walked in stem
05:29cell sources through several modes,
05:31either with G,
05:32CSF mobilized the donor bone
05:34for bone marrow transplant ago
05:36for bone marrow aspiration,
05:37or resemble cord blood transplants.
05:39There are many different limitations
05:41for each one of those things,
05:43but the communist platform is G.
05:45CSF mobilized peripheral blood graphs.
05:48Usually, in order to achieve that,
05:50we have to give about four
05:51to five days of injection.
05:53This is kind of a time sensitive
05:55process and with every day we keep
05:57giving G CSF phenotype of sounds that
06:00we generate along with Democratic stem
06:02cells changes with those T cells that
06:04are then more likely to induce both
06:06acute and chronic graft versus host disease.
06:09Currently there is an urgent need rather
06:11than unmet need for rapid mobilizing agents.
06:14One compound that we tend to use
06:16Explorer EXE firing people who
06:18do not mobilize with G CSF.
06:20It's a CX here for inhibitor.
06:22It does generate a lot of cells.
06:24But can only mobilize adequate number
06:26of cells that we feel are desirable
06:28in about 60 to 65% of patients.
06:30So in order to come with a rapid solution,
06:32people have been looking for alternative
06:34options in terms of how to do.
06:36CXE R2 seems to be a potential target,
06:39so here in this study that we should
06:41have presented by the audience they
06:43using akcija to organist MDT at
06:45145 along with product support to try
06:48and see if a single day mobilization is
06:50possible to generate * **** wit emitter
06:53Partick stem cells in addition to Olympus
06:55suppressive properties of the T cells.
06:58So here is a condensed version of
07:00the results that I'm presenting.
07:02The study included healthy volunteers,
07:03about 12 of them, of which 92% of
07:06those volunteers mobilized 20 CD,
07:0834 cells per microliters combination.
07:09That is the M GTA145 plus player
07:12XFR compared to only 57% of the
07:14patients achieving the same target
07:16with single agent product so far.
07:18Just in case you're wondering what is the
07:2020 CD 34 cells for Michael later before
07:23the subjects are put on a fresh this machine,
07:26we do a peripheral blood CD 4 count.
07:29Most centers would not put people in
07:31machine if the count is less than 10.
07:33Here it's showing that they've
07:35got a decent number of count 2020
07:37CD 34 cells per microliter,
07:38suggesting that the eel,
07:39what we can predict preparing the machine.
07:42This is a decent deal,
07:43expecting a good outcome for decent
07:45collection at the end of the day.
07:48The Peaks cell concentration that
07:50we found in the peripheral with the
07:52combination was 40 CD 34 cells from Mike
07:54later again that suggest that the robust
07:56aggressive the cells that they were
07:58able to achieve with this combinations.
08:00Eight of those donors went voted
08:02the combination underwent a phrases
08:04and the median sell those that were
08:06collected was 4,000,000 cells per cagey
08:08of their sippy and what's expected.
08:10So that's a very good number in
08:12terms of the overall picture.
08:14How we look at it. Then the design.
08:17Some industry.
08:18Most experiment with the primary transparent
08:20secondary transplant on the left hand side.
08:22There able to show that using this
08:24combination they were able to show at
08:2623 fold higher engraftment compared to
08:28using donors were mobilized with just
08:30five days alone or plexi for single agent.
08:33The graph on the right hand side
08:35basically show the survival for such mice.
08:37Post engraftment was pretty good
08:39compared to the alternative options.
08:41This study has kind of been an exciting
08:44development in that now people are
08:46now exploring alternatives to G,
08:48CSF and basically trying to mobilize
08:50a phenotype of cells that are
08:52immunosuppressive to make sure
08:54the graph can stain.
08:55But at the same time they're able to
08:58generate enough of HSBC's to re populate
09:00post updated conditioning therapies.
09:04For the next three studies were going to
09:07talk about graph versus host disease,
09:09as many of you know,
09:11allogeneic stem cell transplantation
09:12is a curative intent treatment,
09:14but the graph versus host disease
09:16complication that ensures can have
09:17significant mortality and morbidity,
09:19especially chronic graft versus host disease,
09:21can be seen in about 30 to 70% of
09:24the patients main frontline therapy.
09:26For these patients,
09:27we do use corticosteroids.
09:28Approximately about 50% of patients,
09:30either dependent on it or
09:32eventually become refractory.
09:33The only FDA approved drugs in their second
09:36line setting is the drug in Brittany.
09:38People in the CLL vertebrae familiar
09:40with this truck and that study was
09:42not based on randomized trial is
09:44based on a single arm study where
09:46they study about 42 patients.
09:47The overall response rate was about
09:4967% in that in the CRL about 21%.
09:53It's interesting to note the
09:55median time to response was close
09:57to three months on that study.
09:58However,
09:59there was a D.
10:00Saint reduction in Cortico steroid
10:02use from .29 two .125 again pretty
10:05late in the game by up by both
10:07Week 49 after initiating at a
10:09median follow up for 14 months.
10:11In that study 71% of the patients at
10:14discontinue the drug due to toxicities.
10:17Again,
10:17the other important point to note
10:19here is that there are currently
10:21no drugs approved in this space.
10:23Based on the randomization.
10:24This led to the reach three study which
10:27was studying ruxolitinib against best
10:28available therapy in patients with steroid,
10:31refractory or steroid dependent.
10:32Chronic graft versus host disease.
10:34This was a multinational
10:35trial led by Doctor Zaiser.
10:37Here's the study.
10:38Design included patients greater
10:39than 12 years of age who either
10:42had steroid refractory independent
10:43chronic graft versus host disease.
10:45It had to be moderate to severe,
10:47as defined here below.
10:48That is lack of response or disease
10:50progression after Prednisone greater than
10:52a MacBook per day for more than a week,
10:55or disease progression with
10:56Prednisone greater than point,
10:58buy mixed bag per day are a
11:00milligram per kilogram every other
11:01day for greater than four weeks are
11:04increasing the dose of Prednisone
11:06to greater than .25 milligrams.
11:07Today,
11:08after two unsuccessful attempts
11:09to taper the dose,
11:11obviously you're worried about
11:12the graft rejection.
11:13So prior to the study enrollment,
11:15we had to confirm everybody
11:17had decent engraftment.
11:18The randomization was stratified by
11:20chronic graft versus host disease.
11:22Great people were allowed to go either
11:24on ruxolitinib 10 milligrams to be ID
11:27those on the backbone of steroids.
11:29Percent minus calcineurin inhibitors
11:31or best available therapy.
11:33About six cycles.
11:34Were given in the intervention
11:36alarm and then the analysis was done
11:39correctly to the start of summer cycle.
11:42At the end of 6 cycle people around
11:44the best available therapy are what
11:46allowed indeed to crossover the excellent in.
11:49If there was a need,
11:50the primary endpoint of the study
11:52was overall response rate at Week
11:5424 as defined by the NIH consensus
11:56criteria and the key secondary
11:58endpoints were failure free
12:00survival and
12:00modified lease symptom scale.
12:02Assessing the responses at Week 24.
12:05This is just a slide to show that
12:09across the two arms age, sex, TV,
12:12IDF, chronic GV HD the criterias
12:14on the score were well matched.
12:19The overall response rate,
12:20when assessed after six months or weeks 24,
12:23was higher in the proximity bomb.
12:26It was 49.7% almost doubled
12:27compared to the 25.6% seen with
12:30the best available therapists.
12:31The CRH was about 6.7% or says 3%.
12:34Achieving a CR in the
12:36setting is extremely hard,
12:37although it may look like the
12:40sea animals aren't that high.
12:41What we really need to take into account
12:44is the OR or are you know when you
12:47talk to people who take transportation.
12:50It will be agrees that this
12:52is a good endpoint.
12:53Rather than focusing on CR alone.
12:56When they looked into failure
12:57free survival at week 24,
12:59failure fix around being defined as a
13:00time to the earliest of recurrence of
13:03underlying disease or the start menu.
13:04Systemic treatment for chronic
13:06GV HD or death.
13:08But the rock selection of
13:09arm it was not raised,
13:11but as it was 5.7 months
13:13with the observation log.
13:17One thing that is often
13:19understood understood,
13:19he did incorporate that is
13:21the symptom scale modified.
13:23Lee Symptom Scale is well validated
13:25in chronic GV HD setting,
13:27investigators were able to show that
13:29for patients who are investigational
13:30arm had a better quality of life as
13:33is being measured by the symptomatic
13:35score with a 24.2% here compared
13:37to the 11% the controller.
13:41Which is the best overall response
13:43rate right? But again,
13:44with the intervention arm with excellent
13:47and M it was 76.4% compared to 60.4%.
13:49But the best available therapy are
13:52the median duration or best overall
13:54response was 6.2 four months unpaid but
13:57was not reached in their excellent in a bar.
14:01In conclusion this is the first
14:04successful randomized phase three
14:06trial for the chronic GV HD space,
14:09or excellent in a demonstrated significantly
14:11higher overall response rate at Week 24.
14:14There was improvement in failure
14:16free survival significantly
14:18improved symptom improvement.
14:19There was hype.
14:20It was the highest best overall
14:23response rate at Week 24 with excellent.
14:25The most frequent adverse event
14:27seemed the setting was similar to what
14:29we've seen in acute GBS resetting
14:31when we use our excellent name,
14:33namely anemia and thrombocytopenia.
14:34Based on this finding,
14:36there is increasing enthusiasm to start
14:38using this drug as a second line setting.
14:42The other important progress in the
14:44chronic GV HD space is in studying this
14:48pathway called the rock Pot Rock here
14:50stands for through associated coiled
14:53coiled coil protein kinase pathway.
14:55Rock essentially comes in two isoforms,
14:58rock one and Rock 2.
15:00These are sitting three on TuneIn kinases.
15:03Most of this study is coming systemic
15:06sclerosis, another autoimmune
15:07disease models where altering rock
15:09to re balance the immune system,
15:12which down regulates drugs
15:13that's blocking the rock.
15:15Two parter.
15:16Basically, downregulate proinflammatory
15:17side intensity at 17 and it also
15:20increases your Excel production.
15:22In addition,
15:23what is interesting about this
15:25pathway is that it also controls
15:27multiple pro fibrotic processes,
15:29including myofibroblast activation.
15:31Rock is a downstream of major Pro.
15:34Fibrotic mediators mediate
15:35stress fiber formation.
15:36It also regulates transcription
15:38of several pro fibrotic genes.
15:40It is important because when
15:42you study chronic GV HD,
15:44there are milder versions of GV HD where
15:47people are just ocular or oral GST,
15:50which is not really that much of morbid GST.
15:53In contrast, that sclerotic,
15:55longer sclerotic pericardium,
15:56those are the most serious one
15:59where inflammation with fibrosis
16:00eventually lead to bad outcomes.
16:02So a drug which controls inflammation
16:05alters the fibrotic trajectory
16:06is a big welcome into the field.
16:10Study results are being eagerly awaited
16:12in the field for the last couple
16:14of years based on its mechanisms.
16:16And here's a slide on the right
16:18hand side that was presented
16:20initially in as 2018 and that ECT.
16:23And they're trying to find the dose.
16:25That intention to treat analysis
16:27about 59% of the patients showed
16:29overall response rate in that state.
16:31The inclusion criteria included people
16:33or greater than two prior lines of
16:35therapy and a significant number of those
16:37have more than four organ involved,
16:40and many of those are traditionally
16:42classified as what we call as
16:45a severe chronic GV HD.
16:46This lady is recapitulating what
16:48the study design was on the left
16:50of the eligibility criteria,
16:52which is basically age greater than
16:54to all active chronic Jamie ST2
16:56to five prior lines of therapy.
16:58They were allowed to go on the one
17:00of two arms either once a day.
17:02Those are twice a day.
17:04Those you would continue to tell
17:06clinically significant progression
17:07or unacceptable toxicity with the
17:09primary endpoint looking in four
17:11or R as per the consensus criteria
17:13and secondary endpoints with safety
17:14duration of response, at least symptoms care.
17:17Can you free survival and overall survival?
17:20The study population was well
17:21balanced for both the once a day dose
17:23and twice a day dose on the right
17:25hand side is giving you the overall
17:27output for all of those things.
17:29There was nothing significantly
17:30different between these two groups,
17:32but what is of interest here?
17:34Ways there were several people.
17:36Approximately 30% of the patients
17:37had used up ibrutinib.
17:39Other option ruxolitinib bugs are option,
17:41suggesting that the drug the the design
17:43of the study should be interpreted taking
17:45into account what are currently approved,
17:47or at least what's commonly
17:50used in the field.
17:52Here is the safety and tolerability
17:54of the of the study design.
17:56It has issues with gastrointestinal
17:58stuff in terms of diarrhea, nausea,
18:00which is a common thing that we
18:03encounter in our patient population.
18:05When we looked at specifically the
18:07great prior higher events, pneumonia,
18:09hypertension, hyperglycemia,
18:09or some of the common events
18:12that might come across.
18:13Again,
18:13keep in mind chronic GV HD patients
18:16are highly immunocompromised and
18:17infections are not uncommon.
18:20The primary endpoint was easily
18:22met for both the arms.
18:24It was 73% with once a day,
18:26those 77% with the twice a day dose.
18:29What was presented in this Patch
18:32was basically the 12 months follow
18:34compared to the previous presentations.
18:37Offered to show that seven patients
18:38were able to reach a CR Interestingly
18:40median time to the response in
18:42the studies four weeks,
18:43which is a welcome change.
18:46Here's the responses across the different
18:48subgroups they were interested in,
18:49no matter whether using it once
18:51a day or twice a day.
18:53Whether they had severe chronic
18:55GV HD screening or not,
18:57but it was refractory and refractory
18:59number of organs involved.
19:01Number of prior lines of therapy
19:03prior originate are excellent in it,
19:05this drug was able to show
19:08good overall response rate.
19:10The duration of Response rather than
19:13median duration of response was 50 weeks
19:15and about 60% of the patients maintain
19:18responses for greater than five months.
19:20Can you see survival
19:22Rasterizer reported six months?
19:23This ones reporting at 12 months of
19:26failure free survival at 58% is an
19:28extremely encouraging data for this field.
19:31Overall survival again is impressive,
19:33but 89% understanding the mortality that
19:35comes with chronic graft versus host disease.
19:39Additional endpoints that they talk
19:40about is reduction in the doors.
19:42They were able to show that the main
19:45cortico steroid dose reduction was
19:47possible in about 44% of the people.
19:49It was higher in those who responded.
19:52Obviously 52% and lower in those who are
19:54not responding about 17% in addition
19:56to the steroids calcineurin inhibitor
19:58dose reduction was also possible with.
20:00More patients in the treatment arm able
20:02to do that with compared to what we've
20:05seen historically in other trials.
20:07Symptoms scale The least scale
20:09as I presented you earlier on.
20:11Again,
20:12it was a meaningful difference with both
20:14responders or nonresponders achieving
20:16improvement in their symptoms scores.
20:18In conclusion this drug element Bell
20:21incident is well tolerated and has
20:24achieved clinically meaningful outcomes.
20:26Response rates are greater than
20:2870% with both treatment arms,
20:30including in patients who failed
20:32ibrutinib and Jack inhibitors.
20:36Switching gears will talk about the cells.
20:38The reason for graft versus host disease
20:40or the T cells that are coming here.
20:42The trial initially done at Stanford
20:44is explored to see if we can isolate
20:47self populations to decrease after
20:48sostis is historically the way
20:50we've tried to diploid cells are
20:52XY or we try to extract pantycelyn,
20:54plead or use drugs like ATG Witcher invite.
20:57We're depleting agents toxin is more recent
20:59addition to the field of transplantation,
21:01which kinds of depletes the cell in the
21:04setting of haploidentical transplantation?
21:06What investigators at Stanford Ed.
21:08Was in the preclinical models.
21:10Initially, they showed that regulatory
21:12cells which in the PD 1 field with
21:15solid tumors as a different meaning,
21:17is a welcome change in the post
21:20transplantation setting because it
21:21in users tolerance decreases GV HD.
21:23So the design the study with the my
21:26love letter transplant setting wherein
21:28you would give your chemotherapy
21:30or radiation and then subsequently
21:32confuse equal volumes of regulatory
21:34T cells and conventional cells.
21:36So basically.
21:37And a -- 2 prior to transplantation.
21:39Amateur quite stem cells and T.
21:41Rex cells were extracted out,
21:43kept and then infused,
21:44and a 0 two days later the conventional
21:46cells were then infused into the recipient.
21:49Here instead of a conventional two or a
21:52combination of suppression regiments,
21:54they were able to show that single agent,
21:56even a suppressive.
21:57Agents like tacrolimus was adequate.
22:01The amount of total cells that
22:03they chose would 3,000,000 T cells
22:05and almost everybody got more than
22:06two million CD 34 positive cells,
22:08which is what we normally like
22:10in the transportation context.
22:12Extrapolating the data,
22:13they now went at a multi site level and
22:17showed that when you try to go commercial,
22:20it's feasible showed on the
22:22left hand side the CD 34 purity.
22:24Here XL doses anti Rexel purity when
22:27taking into account the logistics that
22:29comes with it for mobilizing the donor.
22:32Collecting at a site shipping it to
22:35this company would then analyze extract
22:37HSP season T Rex to one bag and then
22:40conventional T cells to another back.
22:42They were able to show that that process
22:46work efficiently and the rest of this,
22:48like basically show the clinical data,
22:50were able to show this interphil
22:52engraftment later engagement and
22:53time of hospital discharges,
22:55or all favoring this novel approach.
22:57What is more important,
22:58or patients is graft versus host disease,
23:01both grades two or higher acute graft
23:03versus host disease and chronic GBS T
23:06as shown on the left hand side here was
23:08significantly lowered when they use
23:10this design of infusing regulatory T cells.
23:13Along with the conventional
23:15cells at different time points.
23:17GPS direction is important,
23:18So what happens to the relapse?
23:20A good out point for that is what
23:22we call the GFS on the right hand
23:25side there able to show that GFS was
23:28significantly better with using this
23:30novel approach and TRM was almost
23:32nonexistent with this approach,
23:33suggesting and paving way for future
23:35study designs for cell manipulation to
23:37decrease graph versus host disease,
23:39with a special emphasis on regulatory
23:42T cells.
23:43In this last light,
23:44we're going to talk about how they
23:46feel if consolidation is evolving.
23:48Loading my colleague presented a couple
23:50of weeks ago and this interesting
23:52trial from oral is cited in in
23:54terms of how this is a game changer
23:57to the field of transplantation,
23:58the drug has now been approved.
24:01To recap,
24:01essentially patients get intensive
24:03chemotherapy at the time of recruitment.
24:05These people are all in the older
24:07age group and were thought not
24:10eligible to receive transplantation,
24:12but 44% of the patient get one cycle
24:15of intensive chemo consolidation
24:16and 38% get second layer of chemo
24:19consolidation and then their random
24:22honest to get either placebo osrs
24:24study agent which was CC-486 which
24:26is or a laser sighted in in that
24:29there was overall survival advantage
24:31as shown in the right top corner.
24:34I adore you present it as an extension of
24:36that people have now done subgroup analysis,
24:39coming back to the left hand
24:41side here Doctor Way and up to
24:43remind you are able to show that.
24:45Irrespective of consolidation,
24:47whether they got consolidation or not.
24:50Are they got one consolidation
24:52or greater than or equal to two
24:54consolidation there showing that
24:56CC 4X6 was able to improve overall
24:58survival and relapse free survival?
25:00I'm not showing the slide but
25:02in the more recent
25:04ECD a couple of weeks ago as
25:06an extension of this study,
25:08investigators showed that many
25:10people in the placebo arm.
25:12Went on to get eventual allogeneic
25:14stem cell transplantation and they
25:16make a case suggesting that we
25:18are getting more transplantation
25:19at higher frequency in that arm.
25:21Basically did not alter the
25:23eventual overall survival, however,
25:24we should keep in mind the study was
25:27not designed to answer that question,
25:29so that leads us to the next
25:31segment of this as to how we can
25:34address limitations and propel.
25:36Understands of allogeneic
25:37stem cell transplant,
25:38so in this coming year ALR several study
25:41designs to do this in the backdrop of.
25:44Was that animal study design
25:45working with Doctor Probie?
25:47We have a multicenter study
25:49that we we initiating's,
25:50been supported by Celgene.
25:51That is basically looking
25:53into the potential role of
25:55novel consolidation regiments.
25:56We all know that reaching CR
25:58is a major milestone in AML.
26:00The question is,
26:01how long do you need to consolidate
26:04them prior to you get them to the
26:07allogeneic transplantation in that premise,
26:09using some immunological correlates
26:10will be studying the role of
26:12epigenetic priming post consolidation.
26:14And also using the concept of Fortaleza
26:16cited in increasing regulatory T
26:17cell output to decrease GV HD in
26:19the post transplantation setting,
26:21we have designed a study that
26:22will look into an extended period
26:24use of over laser setting prior
26:26to transplantation and post
26:27transplantation with the hope of
26:29decreasing both GST and relaxed
26:30survival and that would start recording.
26:32So this study has implications to
26:34the satellite centers because many
26:36of these patients after transferring
26:37will go back to you as primary and
26:39that's something you guys would be
26:41able to get access to the drugs
26:43and treat them in the practice.
26:45The other two studies of interest
26:47is led by my boss that are open.
26:49We looking into the role of allogeneic
26:51stem cell transplantation for patients
26:53who are relapsed refractory setting.
26:54There are many new drugs that are coming.
26:57I didn't have a chance to talk all
26:59about them up for all of them,
27:01but I have is 1 set strike which is
27:03using Radionucleotide radionucleotide
27:04to target CD 45.
27:06Comparing against the conventional
27:07care which is currently ongoing and
27:09there's also a multicenter trial.
27:10As you know,
27:11afflict Rena bitter guilty name is
27:13approved to treat relapsed refractory AML.
27:15But now we're studying that in a
27:17randomized fashion to see if preventing
27:19relapse is better rather than treating
27:21relapsing relapse refractory AML.
27:22And that's a study that's
27:24currently ongoing with that.
27:25I'd like to thank you all and.
27:28I would ask you all to hold your questions
27:30at the end of it while I pass on.
27:33So the more interesting phase of T cell
27:35engineering talks by my colleague,
27:36Doctor Sophie,
27:37thank you very much.
27:45Thank you, Louise.
28:03So I'll focus my talk today on cellular
28:07therapies for B cell malignancy's.
28:10These are my disclosures.
28:11And I'd like to start by reminding
28:15everyone of the approved city
28:1719 cortisol products that are
28:20currently on the market for B cell.
28:23Non Hodgkin lymphoma is we have
28:26exit Captain James I'll alusil
28:28targeting City 19 with the city 28
28:31costimulatory domain tyssa gentle
28:33occlusal also targeting CD 19 with a
28:36four one baby costimulatory domain.
28:38The newly approved lie.
28:40So Captain Jean meluso.
28:42With a four one baby costimulatory domain,
28:46these are all approved for large cell
28:49lymphoma and transformed follicular lymphoma,
28:52whereas T Sergeant occlusal is
28:54currently the only approved product.
28:57Also for the treatment of relapsed
29:00refractory pediatric LL and then
29:03finally a recent another recent
29:05approval last year of Brexit captain
29:08Jean Autolux so in mental relapse,
29:11refractory mantle cell lymphoma.
29:13Targeting CD19 with the CD 28
29:16costimulatory domain for relapsed
29:18refractory large cell lymphoma,
29:21transformed follicular lymphoma.
29:23The overall response rates seen
29:26in clinical trials have varied
29:28between 50 and upwards of 80%.
29:31Complete remission rates, however,
29:34are only in the order of 40 to 50%.
29:38This is significantly improved
29:41compared to the previously
29:43established standards of care.
29:45But still leaves some room for
29:48improvement and then with Brexit
29:50catagen and mantle cell lymphoma.
29:53Also very remarkable results with
29:55overall response rates of 93% and
29:58complete response rates of 67%.
30:02Looking at studies of these cellular
30:05therapies and some of the risk factors
30:09associated with worse progression,
30:11free survival and overall survival,
30:14it has become clear that there are
30:17some factors that are patient related
30:20and some that are treatment related.
30:23For example, having a very poor performance,
30:27equal performance status prior to
30:29receiving car T cell therapy and also.
30:33Very elevated LDH have actually been shown
30:35to be very poor prognostic markers for
30:38progression free and overall survival.
30:41Post car T cell therapy.
30:44And and this is a study just published
30:47in JCO this year where they did
30:50multivariable models in patients
30:52treated with AXI cottage inside alusil.
30:55And again they really showed clear
30:58distinction between the progression free
31:01survival and overall survival curves
31:03in patients that had poor performance
31:05status and high disease burden as
31:08represented by elevated LDH levels.
31:12You know what about what about
31:15the biology of the tumor itself?
31:18What we know now is that anywhere from 1/4
31:22to 30% of patients with relapsed refractory,
31:25large cell lymphoma,
31:27who progress after cortisol therapy.
31:311/4 of them will have loss of
31:33CD 19 in their tumor biopsies.
31:36So not all patients,
31:37but at least in some this is
31:40responsible for their for their relapse.
31:43So how can we circumvent that?
31:46A very important study published in
31:49Nature of Medicine also this year by
31:53Nirav Shah at University of Medicine,
31:56Wisconsin, looked at by specific anti
31:59CD 20 and CD19 car sales for relapsed
32:03diffuse large B cell lymphoma and
32:07they have seen a 40% of patients
32:10having ongoing response rates.
32:12There's the.
32:13The follow-up is still short on this study,
32:16but there were definitely
32:18complete remission rates,
32:19including in patients with
32:20previously received CD 19,
32:22car T cell therapy,
32:23and they did not see loss of CD 19 in
32:27any of the progressing patient tumors.
32:31In addition to antigen CD 19 antigen Escape,
32:35the tumor micro environment
32:36is very important as well,
32:39with PDL one upregulation which can
32:41contribute to car T cell exhaustion,
32:44and so this brings me to a very
32:47important study called Alexander
32:49Auto Three that was presented.
32:54Initially at ASCO where they
32:56looked at targeting Bicistronic,
32:58assisting with a bicistronic vector
33:01target targeting CD 19 and CD 22 and
33:05the importance of this is that there
33:08are two independent cars that are
33:10delivered in a single retroviral vector.
33:13They have humanized binders and in addition
33:16to the four one baby costimulatory domains,
33:20there's also an OX40
33:22costimulatory domain, which.
33:23Would lead to improved persistence,
33:26and so from this study presented at
33:29ASCO now we have the Auto 3 Alexander
33:32study that was presented at this
33:34year's ASH where in addition to dewali
33:37targeting CD 19 and CD 22 they also
33:41edit Pember Lizum app in relapsed
33:43refractory diffuse large B cell lymphoma.
33:47They had a cohort of patients that
33:49received the cortisol therapy
33:51alone and then they had another
33:54cohort that received three doses
33:56of pembrolizumab every two weeks,
33:58as well as a third cord that received
34:02just one dose of Pembroke on day
34:06one following conditioning and.
34:08Based on the.
34:10MTD that was established from the phase one.
34:14There is currently an ongoing phase
34:16two looking at efficacy for relapsed
34:18refractory diffuse large B cell lymphoma.
34:21So these are some of the characteristics.
34:24As you can see,
34:25the median age was 59 years,
34:28but they did give this cortisol therapy
34:31to patients up to the age of 83.
34:34The majority of them had high risk features,
34:3755% were double hit,
34:38dual overexpresses or even triple hits.
34:41At the majority, 71% had stage four
34:44disease and the majority were relapsed.
34:48Actually,
34:48about 50% were both relapsed and
34:52refractory and interesting, Lee.
34:54With this novel technology,
34:56they saw that great three of
34:59cytokine release syndrome,
35:01or grades three and above of
35:03neurotoxicity were quite low.
35:05So CRS over grades three and above.
35:09Only 2% and neurotoxicity City
35:11green above only four percent.
35:13Importantly,
35:14none of these patients received any
35:17prophylactic measures to prevent the
35:19development of CRS or neurotoxicity.
35:22An overall,
35:23the number of patients that received
35:26tocilizumab was low at 16%.
35:28And an patients did not receive steroids.
35:33So what are the results?
35:35As you can see, particularly if
35:37we go to the higher dose levels
35:40of the cell therapy product,
35:42the overall response.
35:44Rate is 87% with 73% complete response rates.
35:50It's still early,
35:52so durability remains unclear,
35:54but the patients, particularly the patients,
35:57were achieved.
35:58Complete remission actually
36:00have had ongoing complete
36:02remission beyond three months.
36:06And also when we look at the cellular
36:09kinetics by best overall response,
36:11you can see that.
36:13Particularly in patients who achieved
36:16CR PR as designated here in green,
36:20they have ongoing persistency
36:23beyond 18 months.
36:25So CRP are associated with higher
36:28expansion and longer persistence.
36:29So in conclusion, auto three is
36:32well tolerated with low rates of C,
36:35Rs and neurotoxicity.
36:36Particularly higher grades.
36:38They did also include an outpatient
36:40cohort and more than half of the
36:43patients were managed in the outpatient
36:46setting without requiring admission
36:48of the patients who got admitted.
36:51None of them were into baited,
36:53and the complete response
36:55rates were particularly high.
36:57Especially if we look at the
37:00higher cortisol dose levels.
37:02With a CR rate of 73%.
37:07Um?
37:09So the next study that I will
37:12talk about that I found very
37:15interesting and I will just give
37:18you a bit of a background here,
37:21is that about 20 to 30% of these
37:24relapsed refractory diffuse large
37:26B cell informers were actually
37:29found to have either mutations
37:31or copy number loss in City 58.
37:34And there was this study that
37:36was published in Uncle Target.
37:39That has looked at TP 53 and 358 and
37:42here just to focus on wild type CD
37:4658 versus mutated both in terms of
37:49progression free but also overall survival.
37:52Both patients who had mutations in
37:55city 58 and patients who had copy
37:59number loss actually had a much
38:01poorer progression free and overall survival.
38:05And why is that important?
38:07Well,
38:07it turns out to be 58 is actually
38:10the receptor of for the city.
38:13Of the city to molecule that's
38:15expressed by T cells and also
38:18by natural killer cells and its
38:21expression is necessary for T cell
38:23and NK cell mediated cytotoxicity.
38:26So in this study published,
38:28it actually presented as
38:31an oral abstract by Misner.
38:34Stanford group.
38:35They looked at city 58 mutations in
38:38circulating tumor DNA by cap seek and also
38:41looked at a city 58 expression by email,
38:44history,
38:44chemistry and as you can see,
38:47patients who carried these city 58
38:49mutations in their tumors actually had
38:52much worse progression free survival
38:54compared to wild type patients and
38:57also when it looked at city 58,
38:59expression by IHC.
39:01And again this is a pre treatment.
39:04Precarity and this is.
39:07Post treatment with Corti
39:10in the study that looked at.
39:13They had used exit captain Jean style Alusil.
39:17What they saw is that the complete
39:21remission rates were actually much
39:23lower in the patient group who had.
39:27Low levels of CD 58. Expression and.
39:32Even though even in the patients with a
39:35C 58 loss who responded to treatment,
39:39at best they had a short PR and
39:42then they progressed. And so, um.
39:47So this was very interesting.
39:49So how can we circumvent that and
39:52how can we probe the biology of
39:55the car T cell responses towards
39:57tumors that are lacking?
39:59This functional city 58 So what the
40:02authors did is they generated the
40:05city 58 knockout via CRISPR and they.
40:09Integrated a city to Costimulation
40:11within cars so when you look here on
40:15the left they actually generated.
40:18They looked as a control it either
40:21CD19 or CD22 targeting cars that were
40:24similar to exit cottage inside Alusil or
40:28Tisagenlecleucel that are on the market and
40:32and they actually did not see any response.
40:36However, when they integrated a city too.
40:39Costimulation here represented in red
40:42what they saw is that that actually
40:45overcame the loss of CD 58 in tumor cells.
40:48And when you look at the percent
40:52survival that was significantly
40:54higher in the cells that had.
40:57That contained CV 2 and you know initially
41:01they incorporated city two in SIS and
41:04that did not result in any responses in vivo.
41:08However, when they introduced it in
41:12trends that actually did the trick.
41:15So they put in an additional,
41:18so to speak.
41:19City two receptor entrance,
41:21and that's what mediated significant
41:23antitumor activity in in Vivo Anet
41:25overcame the city 58 knockout.
41:27So this data was actually extremely
41:30important, in my view,
41:32because it it shows us that City two Co.
41:35Stimulation is very important.
41:37This wasn't known before we,
41:39we thought that these car T cells were
41:43already endowed with all the necessary
41:46costimulation that they needed.
41:48However, we now know based on this study,
41:51that there are other Co stimulators
41:53on the surface of the tumor cells,
41:56such as CD 58 that also really matter and
42:00that they can drive car T cell efficacy.
42:05So this CD 5832 is a novel
42:08axis for car resistance.
42:11It's important in large
42:13cell lymphoma because,
42:15as I said to you 25 to 30% of patients
42:20will have either city 58 loss or mutations.
42:24And if we engineer cars,
42:26integrating City two signaling
42:29entrance we can overcome this city 58.
42:32Lawson reestablished car efficacy.
42:34And and this is important because there
42:37are other cancers like multiple myeloma,
42:39Hodgkin lymphoma as well as solid tumors
42:42like colon cancer for example that
42:45do carry city 58 loss and mutations,
42:47and we expect that in the next
42:50couple of years there will be.
42:54Cortisol studies looking at this.
43:01In humans. Another study that I found
43:06of interest was also this abstract.
43:101194, where they looked at Amick,
43:13expression and tumor infiltrated the
43:16cells in patients who received his
43:19agenda cluzel in the Juliet study for
43:23lymphoma and what they were able to
43:26show was that having a baseline Nick
43:29negative Myc positive studies make
43:31positive study was actually here in blue.
43:35Associated with a worse probability of.
43:39Survival and then also having fewer tumor
43:43infiltrating CD 3 positive cells were
43:46was also associated with poorer outcomes.
43:50And particularly,
43:52if those infiltrating cells had.
43:56Exhausted immunophenotype
44:00so I I talked to you about you know how
44:03this works in the relapse refractory
44:06setting and what we can do in that
44:10setting to to overcome resistance.
44:12But what about patients who never go into
44:15remission with their frontline therapy?
44:18So this study Zooma, 12,
44:20looked at exit cottage inside Alusil,
44:22in patients with very high risk,
44:25large diffuse large B cell
44:27lymphoma in the first line.
44:30Um and and at ash they
44:32presented the interim efficacy,
44:34safety and PK data,
44:36so patients qualified for this
44:38study if they had high grade B
44:41cell lymphoma with Mick and BCL,
44:43two or BCL six translocations,
44:45so double hit or triple hit large cell
44:49lymphoma with an epic score of three
44:52or above before enrollment they had to
44:55have had at least 2 lines of an anti CD.
44:5920 monoclonal antibody.
45:01Sorry not 2 lines but two cycles and
45:04enter second containing regimen and they
45:06had to have had a positive PET scan
45:09after two Step 2 cycles of treatment
45:12they enrolled them look at free stem.
45:14They had the option of getting some
45:17non chemotherapy bridging such
45:19as radiation or maybe REVLIMID.
45:21And then they give them flu
45:23side conditioning and a single
45:25infusion of access cell.
45:28Again, median was 61 years old,
45:30but they treated patients
45:32up to the age of 86.
45:35They all had advanced stage disease,
45:3753% were double hit or triple
45:40hit as determined by fish.
45:42A 72% had.
45:43Keeping score of greater than or equal to 3.
45:49And when they looked at overall
45:52response rates, remarkably high 85% and
45:54CR rate for these patients was 74%,
45:58and they have followed them.
46:00The median follow-up was a 9.5 months,
46:03so not very long follow up yet,
46:06but it's important to realize that
46:08the majority of these patients with
46:11double or triple hit INFORMALS will
46:14actually relapse within a year.
46:16Post initial therapy.
46:17So so you know, really.
46:19Really great outcomes and the
46:21most common grade three and above
46:24adverse events were encephalopathy.
46:26In 16% of the patients and cytopenias
46:30there was one grade 5 adverse event that
46:34occurred on the study due to COVID-19.
46:38When they looked at cortisol
46:40expansion and compared that to their
46:42Zuma one study where people had
46:45had relapsed refractory disease,
46:47what they saw is that the car T cell
46:51expansion was significantly greater in
46:54this study in summer 12 compared to Zuma one.
46:59And that perhaps,
47:00maybe because these patients had very little
47:04treatment before they went on to party.
47:07Um?
47:08And in Zuma 12.
47:12There was higher frequency of CCR seven 3045
47:15RAT cells in the pre infusion product which
47:18was associated with a greater expansion.
47:21Again, this is suggestive of improved T
47:25cell fitness in the first line treatment.
47:28So it's this study you know well
47:31doesn't have very long follow up.
47:34It does provide us with some
47:36insights into the pharmacology
47:38of access L for patients who are
47:41exposed to fewer prior therapies.
47:43Now I'm going to shift gears to relapse
47:46refractory indolent non Hodgkin lymphoma.
47:49I'll present you the data from Zuma
47:51five with AXI Cap to Gene and then from
47:56ilaris study with tisagenlecleucel cell so.
47:59In this study zoomify,
48:00they looked at follicular and marginal
48:03zone lymphoma patients who had relapsed
48:05after two or more lines of therapy.
48:08This was the study design.
48:10Again,
48:10very standard flu Cy followed by by Access L.
48:14They all had to have had anti CD 20
48:17monoclonal antibody plus an alkylating
48:20agent with their prior therapies.
48:2368% of the patients had refractory
48:26disease and importantly,
48:27over half of the patients had
48:30actually progressed within two
48:32years from their initial therapy,
48:34which is this P OH,
48:36D20 four group that we now know
48:39is associated with worse survival
48:41in both follicular lymphoma and
48:44marginal zone lymphoma when they
48:47looked at the overall response rates
48:49very high again in the above 90%.
48:53And CRA,
48:54it's also very high anywhere
48:56from 70 to 80% progression free.
48:59Survival was actually noted to be
49:02longer in the follicular lymphoma group
49:05compared to the marginal as opposed
49:08to the marginal Zone lymphoma group.
49:11But the response rates importantly were
49:14consistent across all of the subgroups,
49:17including Flipi score,
49:19high tumor burden or prior therapies.
49:22And the median duration of response,
49:26particularly in the follicular lymphoma
49:28Group, has not been reached and.
49:33Is a 78% duration of response in
49:38patients who, with follicular lymphoma,
49:42who achieved a CR.
49:47There were important to note a
49:50grade three and above adverse
49:52events in 86% of the patients.
49:55Most of them were cytopenias
49:57and infections and their worst
50:00three Grade 5 adverse events,
50:02one of which was related to multisystem
50:05organ failure with cytokine release
50:08syndrome and another one due to
50:11coccidioidomycosis infection.
50:12So the the other important thing to
50:16note is that 82% of patients experienced
50:20some grade of cytokine release syndrome.
50:23The only 7% experienced
50:25grade three and above.
50:28Almost half the patients received socialism
50:31AB and 17% received corticosteroids.
50:36As far as neurologic events,
50:3860% at any grade,
50:40neurologic events an almost 20% had
50:42grade three and above neurologic events.
50:4536% of patients received steroids
50:48for neurologic toxicity,
50:49so when they looked at serum cytokine levels,
50:53they saw that cortisol peak levels were
50:57associated with grade three and above
50:59CR S and then some of the other side.
51:03It kinds like interferon gamma L6 TNF Alpha.
51:07Were also associated with grade
51:09three and above neurologic events.
51:12So the response rates were very high,
51:16but as I've just shown you there is still
51:20significant toxicity with this treatment,
51:23particularly for follicular
51:24and marginal zone.
51:26Lymphoma is where we now do have available
51:29other available therapeutic options.
51:32This is a sort of a similar design study.
51:36The Ilara which looked at this urgent
51:40occlusal for follicular lymphoma and.
51:42And I will not spend much time.
51:45Suffice it to say that the complete response
51:48rates and overall response rates were
51:50extremely high with this therapy as well,
51:53but it was better tolerated,
51:55and indeed they did not have any cases of
51:58Grade 3 or above cytokine release syndrome.
52:01There was very little use of anti
52:04cytokine therapy and very low rate of
52:07severe neurologic events of only 1% so.
52:11You know,
52:12it's important to again keep in
52:14mind that these treatments are
52:16not created equal and that there
52:18are differences between them,
52:20some of which have to do with
52:22the costimulatory domain,
52:24but many of which have to do
52:26with other parts of the design.
52:28So toxicities are very different
52:30and and there's much work to be
52:33done to see how they will stack up
52:35against other types of treatments,
52:37particularly these novel.
52:40Body drug conjugates or or CD20
52:45CD 1963 by specifics.
52:49I will now briefly shift gears
52:52to mantle cell lymphoma,
52:54which also remains an unmet need.
52:57As you can see with one year and
52:59five year outcomes relative in terms
53:02of relative survival that are worse
53:05compared to follicular lymphoma
53:07in marginal zone lymphoma and
53:10certainly lower cure rates compared
53:13to diffuse large B cell lymphoma.
53:16So this is the study that got.
53:20Actually, that got Brexit.
53:22Captain Jean approved,
53:23published in New England Journal
53:26in 2020 targeting CD 19,
53:29where you see that the overall
53:32response rate was very high,
53:3493% and 67% of patients actually
53:37achieved complete remission.
53:39These were patients that had relapsed
53:42refractory disease and the duration
53:45of response is quite durable,
53:47with with a plateau in this curve.
53:51I'm reaching three years now.
53:54As so, um, this is the transcendent study.
53:58The mantle cell cohort.
54:00This was just presented at ASH
54:02and this is looking at lysosome
54:05now in mantle cell lymphoma.
54:07This product is different from AXA
54:10capture Gene because it has a defined
54:13composition of T of CD8 and CD4T
54:15cell components that are administered
54:18separately at equal target doses.
54:21So flu Cy conditioning lies to
54:23sell and they had two dose levels.
54:2970% of patients had more than or
54:32equal to three prior therapies.
54:35A 75% had received prior ibrutinib,
54:38including 31% that were
54:40refractory to ibrutinib,
54:4125% a quarter had received prior Boneta
54:45klaxon there were 16% of patients that
54:48were also refractory to prior Boneta clocks.
54:52There was a significant number of patients,
54:5541% that had blastoid morphology,
54:5822% with P50.
54:59Three mutations and the majority of patients.
55:022/3 of patients actually had an elevated key.
55:0667 proliferation index,
55:07which we know is associated with worse
55:10outcomes in mantle cell lymphoma.
55:12When we look at the toxicity.
55:15I'm with Lisa cell CRS grade three
55:20and above very low 3% and Grade
55:243 or above neurotoxicity 12.5%.
55:29When they looked at response by subgroup,
55:32again remarkable that the overall
55:34response rates and complete response
55:37rates in patients with High Ki
55:3967 blastoid morphology or P53
55:41mutations are actually quite so.
55:44Miller to the group that does not
55:46have any of these poor features.
55:50The median follow-up is still
55:52relatively short 5.9 months.
55:54This type of therapy works fast
55:57within a month. You see the responses.
56:01And when they looked at the
56:04cellular kinetics,
56:05what they saw is that at one year
56:08sick there was life cell persistence
56:11in 67% and 33% even out to two years.
56:16Am so now they are ongoing with
56:19enrollment at the higher dose level.
56:22Dose level 2.
56:25And and again,
56:27this is remarkable for mantle cell
56:30lymphoma with with no significant toxicity,
56:34grade three toxicity.
56:38What about CLL?
56:41This study transcend CLL 004,
56:44looked at lice or sell in
56:47relapse CLL and very interesting.
56:50Lee had very high complete response
56:54rates of 45% and and really
56:57high rates of undetectable MRD,
57:00both in the blood flow and in
57:03the bone marrow by NGS and even
57:08when they looked at patients with
57:11failed BTK here in the second.
57:15Bar what failed BTK or or phonetic lacks.
57:18They had a very impressive
57:20rates of complete response,
57:22so so this was already presented at
57:25Ash of 2019 and what was actually
57:29presented this year at Ash was.
57:32A combination of lice,
57:33a cell with a brute nip based on
57:37preclinical data that shows that
57:39imbrued nip can improve car T cell,
57:42anti tumor efficacy and reduce the
57:45rates of cytokine release syndrome.
57:47So so this was the study patients
57:50had progressed on ibrutinib or they
57:52had mutations of BTK and they had no
57:56contraindication to restarting ibrutinib.
57:59And they were again very high
58:02risk patients in all groups.
58:04100% had some high risk features
58:07like deletion 17, P 53,
58:09mutation complex karyotype,
58:11100% had had priori brute Nip,
58:14100% were relapsed refractory
58:16to ibrutinib and.
58:19Half of the patients had
58:21actually seen vanetta clocks,
58:22in addition to two BTK inhibitors.
58:26When we looked at grade three
58:28cytokine release syndrome,
58:29only 5% again and or logic
58:32toxicity grade three and above
58:34similar to mantle cell lymphoma.
58:36Only 16%.
58:37Um,
58:38complete response rates,
58:40particularly when you look
58:42at dose level 200%
58:44overall response rate 67% complete
58:48response rate and the majority of
58:51patients had undetectable MRD.
58:54In their in their blood.
58:57So in summary, you have very rapid responses,
59:00high overall response rate, high rates
59:03of CR with lysis cell and ibrutinib.
59:06And even though this is no direct comparison,
59:10it certainly looks better than
59:12the data with lysis cell alone
59:14for relapsed refractory CLL.
59:16So I just wanted to I know
59:19we're running out of time,
59:21but for people who treat leukemia,
59:24I did want to mention some of the upcoming.
59:28Studies in a allow that are important,
59:31including the comparison of tisagenlecleucel
59:34cell versus plain attuma Bob or I know,
59:37choose a map, Osaka mice and this
59:40is the Auburn phase three study,
59:43Cassiopeia,
59:44which looks at his agenda occlusal in
59:47patients who are MRD positive after
59:50first line therapy and then also summa
59:53for looking at exit cap to gene in
59:56patients with relapsed refractory LL.
59:58So so with that,
01:00:00you know I'd like to end and and
01:00:03I'm happy to take any questions.
01:00:17OK. So, Doctor Gordon Dr Sophie.
01:00:20Thanks for those great reviews.
01:00:23We do have a number of questions.
01:00:25All remind people who are listening.
01:00:28If you have questions,
01:00:30submit them in the Chatter Q&A section.
01:00:33I and. I'll start with some
01:00:37questions about Milo dysplasia,
01:00:39starting from the top.
01:00:41This is for Doctor Gowda.
01:00:44And I'll just, I'll paraphrase this,
01:00:47given the results of the randomized
01:00:49trial led by Doctor Cutler.
01:00:52Mild displeasure.
01:00:54Should we in?
01:00:55This isn't naturally to donor.
01:00:57Should we be considering
01:00:58haploidentical transplant in older
01:01:00high risk MD's patients low?
01:01:01What do you think?
01:01:04It's
01:01:04a great question, I think.
01:01:06It was an exclusion criteria in this trial,
01:01:08so that's the number one point.
01:01:11Essentially, this pistol betas
01:01:12lingered on for as many years
01:01:14as we've all been doing this.
01:01:16That haploidentical outcomes similar to
01:01:19match siblings and matched unrelated donors.
01:01:22There has never been a randomized
01:01:24study in this population.
01:01:25There are multiple registry studies
01:01:27that have shown feasibility's.
01:01:29And then also just studies that shows
01:01:31you kind of laid these people so you have
01:01:34to take all those with a pinch of salt.
01:01:37I would say enter specific protocol based.
01:01:39Certainly worth considering that the
01:01:41reason that prospective study that says
01:01:43in elderly people Apple may not be that
01:01:45great for email from the registry again,
01:01:47but there are at the same time you do the
01:01:50mismatches in the registry limitations.
01:01:52There are equal numbers that
01:01:53suggest it's efficacious.
01:01:54So if you think there's a high risk
01:01:57disease and there's no really good option.
01:01:59I would certainly get an
01:02:00Apple down and go forward.
01:02:03OK alright thanks Doctor Assoufia
01:02:06question about car T cells.
01:02:08Given the encouraging Zuma 12
01:02:11results or were car T cells child
01:02:15at all and frontline setting
01:02:18for high risk lymphoma. So
01:02:21this is this is the first study
01:02:23that I know of where this is
01:02:26being tested in up front,
01:02:28in upfront lymphoma and that's why
01:02:30they chose such a high disease risk.
01:02:33Group of patients that had double
01:02:35or triple hit disease or were
01:02:37primary refractory on PET scan.
01:02:41I'll follow up with my own question.
01:02:43Do you think this data is sufficient?
01:02:46We should consider this.
01:02:49Or this requires further study and
01:02:51end insurance approval, of course.
01:02:54Yeah, I mean, I think that
01:02:56the the duration is short,
01:02:58we need longer duration,
01:03:00at least beyond the year.
01:03:02For these patients, you know.
01:03:04That being said,
01:03:05we we have treated here and also
01:03:08other institutions have reported that
01:03:10PET scan after two cycles of therapy
01:03:13does not have the same prognostic
01:03:16significance in large cell lymphoma
01:03:18that it has in Hodgkin lymphoma,
01:03:20and that indeed we are able to cure.
01:03:24Um, many of those patients when we
01:03:27complete six cycles of therapy so.
01:03:30I certainly don't think
01:03:32that based on these data,
01:03:34you know we would change standard of care.
01:03:37I think that this requires you
01:03:40know further further follow up.
01:03:43Right, and I think that most importantly,
01:03:45we really need to see the data
01:03:48in relapsed refractory disease.
01:03:49As to how this stacks up to too high dose
01:03:52therapy and autologous stem cell rescue,
01:03:55I think if indeed there is an improvement
01:03:58in cure rates with that approach.
01:04:00For these patients,
01:04:01I think that will be a stronger push to
01:04:05move it to frontline for high risk groups.
01:04:09Right, right?
01:04:10OK couple of questions on the
01:04:14graft versus host disease studies.
01:04:18I from Doctor Challace,
01:04:20do we have a sense of what?
01:04:23Best alternative therapies patients received.
01:04:26Monoclonal antibodies.
01:04:27Did any receive a brute nib?
01:04:32And now it's just.
01:04:34Did anyone receive rocks?
01:04:35Although that may refer to the crossover.
01:04:39Hello diary,
01:04:39I probably also know the answer to this.
01:04:41I don't know if you want me to
01:04:43feel this one or.
01:04:44Yeah, sure yeah.
01:04:45So yes.
01:04:46It says it says.
01:04:48Why was the local investigator on
01:04:50this study so best alternative?
01:04:53Therapy was a long list of standard
01:04:55non FDA approved treatments 'cause
01:04:58there aren't any FDA approved
01:05:00treatments for for chronic GV HD,
01:05:03but they did include ibrutinib.
01:05:05They included photo pheresis.
01:05:07Those were common ones.
01:05:08Other agents for Mycophenolate
01:05:10sirolimus occasionally and the
01:05:12brute name was added to this trial.
01:05:15Pretty early on,
01:05:16and so patients did receive many of
01:05:18those best alternative therapies.
01:05:22In comparison, and that was up to
01:05:24investigators choice, corollary,
01:05:26question, how do you recite decide
01:05:28between ruxolitinib and a brute
01:05:30knipfer GV HD based on this phase,
01:05:32three data looks like.
01:05:33Take a stab at that. Yeah, I think
01:05:36we should understand that I put in the
01:05:39beta was approved based on Phase 1B.
01:05:42Phase two study design.
01:05:43In another, we really didn't have many drugs.
01:05:46Well, certainly it's challenging.
01:05:47You know, practice.
01:05:48We see a lot of cases with Orange
01:05:51ebstein a little bit of Raskin GV HD.
01:05:54Those stones care of us.
01:05:55I'm really excited about this
01:05:57new drug that Katie, 025,
01:05:59especially for what we traditionally
01:06:00called the marleybone versions of GST,
01:06:02including highly fibrotic questions of
01:06:04that and those are the ones that kill.
01:06:07Your patience is defining it
01:06:08highly immunosuppressive, right?
01:06:09So, coming back to her then,
01:06:11I think I might be tempted to use it
01:06:14earlier on again in a clinical trial design,
01:06:17because.
01:06:17It's not a prude,
01:06:19although we are waiting for the approval
01:06:21to come through anytime I might be
01:06:22tempted to try that if it's a highly
01:06:25fibrotic question earlier on but.
01:06:26Side effects of reboot.
01:06:27Your name can be significant
01:06:29in my personal biased opinion.
01:06:31Set opinions with Rocks is an issue,
01:06:33but again,
01:06:34in this trial the show that
01:06:35quality of life cytopenias taking
01:06:36all that into account rocks was
01:06:38way better compared to the other,
01:06:40so I may be tempted to use that
01:06:42up front and we're already doing
01:06:43it in some of our case this,
01:06:45but it's not studied in a randomized fashion.
01:06:47It's worth studying it.
01:06:48If somebody sponsors that kind of a study.
01:06:53So when you short answer the data support for
01:06:56ruxolitinib is probably a more active agent.
01:06:59The I'll add the ibrutinib study required
01:07:02inflammatory erythema in the skin or oral
01:07:04GV HD is entry criteria. So as you said,
01:07:07it was probably a group of patients.
01:07:10Might be a little bit easier to treat
01:07:12those particular clinical scenarios,
01:07:14whereas ruxolitinib seems to be a
01:07:16more broadly active agent and it
01:07:19doesn't cause atrial fibrillation,
01:07:20which is an issue with the brunette.
01:07:23Um? OK, another Milo dysplasia question.
01:07:29Given the recent randomized study from
01:07:31MD Anderson showing no improvement
01:07:33in outcome with maintenance,
01:07:35Ivy is a sighted in versus placebo.
01:07:38This is post transplant in AML and MD S.
01:07:43Do we think or Eliza would be different?
01:07:48So I'm glad I'm with paying attention
01:07:50to MD Anderson clinical trial output
01:07:52very closely, and I guess he likes
01:07:55those results with that background.
01:07:57I think we should first
01:07:59dichotomize those two things,
01:08:01So what battle showed was.
01:08:03Every every come are getting
01:08:05randomized and they've only median
01:08:07of 4 four cycles of that was given.
01:08:09As for the trial right?
01:08:10And it was it was tested in a randomized
01:08:13fashion that turned out to be negative.
01:08:16We can argue that Ivy and oral,
01:08:19despite mechanistic things,
01:08:20are not the same drug.
01:08:22What we're trying to achieve is
01:08:24couple of two different things.
01:08:26There's some confusion now with the
01:08:28CC-486 clinical trial data as to what
01:08:30is the right timing for the transplant,
01:08:32because it's very cleverly
01:08:33articulated by the company in terms
01:08:36of how this needs to be done.
01:08:37So we all agree CR one is
01:08:39a major entry point,
01:08:41especially for intermediate
01:08:42and advanced rest.
01:08:43How many cycles of consolidations are needed?
01:08:45It's an open field,
01:08:46unlike the hydac for the good risk groups.
01:08:49So if we can create outpatient
01:08:51based regiments with oral
01:08:53set aside in equal and drug.
01:08:55And the rationale that we build
01:08:56for the trial is the initial
01:08:58scandura trial from Cornell,
01:09:00where they show that epigenetic priming
01:09:02enhances cancer test is an antigen
01:09:04exposure now antigen expression that
01:09:06then makes the T cell attack better.
01:09:08You generate a lot of tumor infiltrating
01:09:10lymphocytes with epigenetic priming,
01:09:12so you kind of also make the
01:09:14people less fragile coming into
01:09:15the transparent by rather than
01:09:17giving hydac equivalent intensity,
01:09:19you make it better.
01:09:20Third,
01:09:21in the pre transplantation
01:09:22setting this synergy when you
01:09:24prime with epigenetic agents.
01:09:25Bracton Alcalay to yourself
01:09:26and cyclophosphamide.
01:09:27So those are the 3 three concepts
01:09:29in the pre transplantation setting.
01:09:31The post transplantation setting.
01:09:32When you continue that
01:09:34as a maintenance again,
01:09:35that's the dichotomy between
01:09:37BI tools file and mine.
01:09:38Is that increase the regulatory
01:09:40T cell expressions,
01:09:41which is beneficial for GST.
01:09:43But there's also a lot of data that
01:09:45epigenetics increases hedging idea or
01:09:47expression which then makes it easier
01:09:49for the T cell attack that makes
01:09:52relapse less likely because there's
01:09:53an ongoing TNR GVL surveillance so.
01:09:56We're redefining consolidation differently.
01:09:57Trying to get into the space of a
01:10:01traditional hydac plus hydac against
01:10:03probably lower intensity therapy,
01:10:05which can be given an extended
01:10:06period of time at the target on
01:10:09decreasing events downstream,
01:10:11either due to relapse GST so that those
01:10:13are some of the subtle differences
01:10:16in how this can be interpreted.
01:10:20OK, one last question.
01:10:22I were there patients with
01:10:25bronchiolitis obliterans and the
01:10:27Rockstar study an important question.
01:10:30Alright, do you recall?
01:10:32It's not clear to me. I mean, I
01:10:35think this is abstract.
01:10:36I want to look at the paper
01:10:39myself to see what it is,
01:10:41but the initial dose finding
01:10:42study they said greater
01:10:44than four organ involvement.
01:10:45And there was a lot of multiple
01:10:48people at severe chronic GV HD.
01:10:50I'm assuming there was some
01:10:52representation of Bill,
01:10:53but I want to look at the fine
01:10:55print before it comes out,
01:10:57especially for all the noise it's
01:10:58making saying it's antifibrotic
01:10:59and anti-inflammatory.
01:11:00That would be a breakthrough.
01:11:04Right, so I think we we
01:11:07probably need to wrap up.
01:11:08There's a kudos to Doctor Trophy
01:11:11for pronouncing the Carty names.
01:11:14I'm sure I was.
01:11:15I was very impressed actually and
01:11:18thank you so much buddy else.
01:11:21Can do that? Yeah yeah thank you so
01:11:24much Stewart for moderating such a,
01:11:26you know, a very lively Q&A.
01:11:28And thank you Doctor Sufyan doctor
01:11:30Gowda for such amazing talks.
01:11:32I would also like to thank
01:11:34me go day to work very
01:11:36hard behind the scenes to get this
01:11:39series going and this is recorded as
01:11:41we discussed all of the
01:11:43recordings will be available.
01:11:44You can claim CME credit if you
01:11:46provide us some feedback about how we
01:11:49can improve this going forward and.
01:11:51Hopefully next year we will have
01:11:54a hybrid model of in person and
01:11:57virtual component and looking forward
01:11:59for a great 2021 for everybody.
01:12:02Thank you so much and looking
01:12:04forward to next year post Ash.
01:12:07Thank you. Excellent, thank you.