Cell Therapy and Transplantation

Transcript

• 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.