Yale ASH 2021 Highlights: Cellular Therapies

April 01, 2022

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With presentations from: Drs. Iris Isufi, Stuart Seropian, and Lohith Gowda

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00:00Today we're going to give an update on
00:03cellular therapies and stem cell transplant.
00:08From ash, this session will be
00:12moderated by myself and Doctor
00:15Delgado and Doctor Stuart Seropian,
00:19who's our director of the stem
00:22Cell Transplant Program and Co.
00:23Director of the Cellular Therapy program,
00:26has also joined us and.
00:30Will help moderate the session
00:32together with low Heath and myself.
00:35So we will get started.
00:37The first, the first half of the talk
00:41will give some updates on cortisol
00:45therapy for hematologic malignancies,
00:48so I'm going to go ahead and get started,
00:51so thank you again for joining everyone.
00:54I will probably leave the
00:56questions for the end.
01:01So these are my disclosures.
01:06And just to to give everyone a little
01:10bit of a of a background today.
01:16I'm just going to show a general
01:18schematic for car T cells,
01:19so as you know, car T cell therapy.
01:23Has been approved in the last in the
01:26last five years to treat patients
01:28with him to logic malignancies.
01:30The the T cells are genetically modified
01:35to target tumor cells and this can be
01:38done in the absence of MHC one and two.
01:41Expression on the surface of the tumor cells.
01:44So there's a targeting domain.
01:47That binds to the antigen
01:49on the cell surface.
01:50There's a linker,
01:51and then there's a costimulatory
01:53domain that gives this car T cells,
01:56proliferative capacity,
01:57and AT cell activation domain.
02:02So we have currently multiple FDA
02:05approved car T cell therapies.
02:08It's hard to believe the majority of
02:11them are approved in the setting of.
02:15B cell lymphoma.
02:16So we have four products currently
02:20axicabtagene sailu so Brexit.
02:24Also counted in Merluza Lantis again coucil,
02:27and they're currently approved for
02:29patients with relapsed refractory
02:31B cell lymphoma after at least
02:34two lines of systemic therapy.
02:37Brecksville Cottage in was recently
02:39approved in patients with mantle
02:41cell lymphoma as well as in
02:43adults with relapsed refractory B.
02:44Cell A allows so these are two more
02:47recent approvals and then in the
02:49multiple myeloma arena the target
02:52is bmet and I'm happy to say that
02:57we not only have I decapped agenda
03:00cluzel approved in patients with
03:02with failed at least four lines of
03:04prior therapy but very recently.
03:06There's a new approval of Celtic
03:09captain or the Loosle in the same
03:12refractory patient population.
03:15So this is the summary of the
03:17efficacy after two lines of therapy
03:19for the currently approved products.
03:21As you can see,
03:23there are very high overall response
03:25rates from the three randomized
03:27phase three trials.
03:28Complete response rates vary anywhere
03:31between 40 to 58% and you can see that
03:35at two years about 40% of patients.
03:38There's a 40% progression free survival.
03:41Basically at two years,
03:43which is definitely not bad for.
03:47Refractory patient population
03:49that otherwise would have.
03:52Expected very poor outcomes.
03:56The toxicity is as you are
03:59familiar with by now are.
04:01Twofold cytokine release syndrome
04:04and neurologic toxicity, which.
04:08It happens in the majority of patients,
04:10however,
04:11grade three to four CRS and neurologic
04:14toxicity fortunately are less common,
04:17and there's some variability
04:18between the products in terms of
04:21the grades and severity of CRS,
04:23and neurologic toxicity.
04:27So what was exciting at this year's
04:32ASH was that there have been efforts
04:35made to move these CAR T cell
04:39therapies further up front in the
04:42treatment of patients with lymphoma.
04:44And you know the question arose well.
04:47Given that this type of therapy
04:49is doing so well in the relapse
04:52refracts that refractory setting,
04:54could it potentially replace autologous
04:56stem cell transplant so there were three
04:59studies that were presented and are
05:01currently published and those resume
05:03as seven with Axicabtagene sailu.
05:05So Belinda with the decision Cluzel
05:08and the transform study with Lisa
05:10Captain Marlow so and they looked at
05:13high risk diffuse large B cell lymphoma
05:15patients that were either refractory.
05:18First line treatment,
05:19which is usually our job.
05:21Or that relapse early after
05:24first line treatment,
05:25and patients were randomized to either
05:28cortisol therapy or the standard of
05:30care which is salvage therapy with
05:32autologous stem cell transplant.
05:37So I will start with Zooma 7.
05:41Basically, this is again an autologous
05:44second generation CD19 directed car T
05:46cell therapy that's currently approved
05:48after two lines of therapy and in the
05:52study design is that patients had
05:56relapsed refractory disease within 12
05:58months of adequate first line chemo
06:01immunotherapy and that were intended
06:04to proceed to autologous stem cell
06:07transplant so they were stratified
06:09by first line treatment response.
06:12And second line age adjusted it be
06:16they were in demised access L 2 * 10
06:20to the 6th chord, T cells per KG.
06:22After receiving some Lymphodepletion
06:24Kiem Lympho,
06:25depleting chemotherapy and cytoxan,
06:27or the standard of care which was two
06:30to three cycles of investigator selected.
06:33Usually platinum based chemotherapy.
06:34'cause that's what we use in practice,
06:37either rice or our depth.
06:40And patients that achieved either complete
06:43or partial response went on to achieve
06:47to receive a stem cell transplant.
06:50Whereas patients that did not achieve
06:52a CR or PR were off protocol and
06:56this is important as you'll see in a
06:59distinction with Belinda trial this
07:02the Zuma seven study did not allow for
07:05any bridging therapy prior to car T.
07:08And there was no crossover,
07:10so patients who did not respond and
07:13could not go on to transplant or
07:15did not crossover to the Axis alarm.
07:19Some of them actually 56% did receive
07:22subsequent cellular in no therapy.
07:23But that was not done on trial.
07:27So you know what happened to these patients?
07:29Well,
07:30you see that they enrolled 359 a
07:33180 received access.
07:35Actually,
07:36we randomized accela 179 the
07:38standard of care,
07:40and then when you look at what
07:42happened to them out of 100 and 8178
07:46underwent leukapheresis 172 receiving
07:49for depletion chemotherapy and 170
07:52received access selling fusion.
07:54So 94% of the starting patients.
07:57Actually received access out which
07:59they were randomized to,
08:02whereas in the standard of care
08:04arm out of 179 patients.
08:08Only about 64 of them received.
08:12Stem cell trench transplant,
08:14which is 36% of patients,
08:16and this actually is not uncommon
08:19in clinical practice because many
08:22of these patients end up for one
08:25reason or another.
08:26Not responding to the salvage chemotherapy,
08:29or they develop organ toxicity.
08:31They may not have.
08:33By that point, their lympho depleted,
08:35so they may not have fit T cells.
08:38They may not.
08:39They may not have fit stem cells
08:41for us to be able to collect.
08:43So a minority actually made it to transplant.
08:47So when we look at the
08:50baseline characteristics,
08:51they were pretty well distributed
08:54among the groups.
08:55As you can see,
08:5774% of patients were primary refractory.
09:00And then 26% of patients had
09:02relapsed within a 12 months.
09:04There were some high grade B cell lymphomas,
09:07including double and triple hit,
09:0917% duel over X pressers,
09:11and Mick rearranged patients.
09:15So when we look at the event free survival,
09:18which was their primary
09:19end point for the study,
09:20you can see that the 24
09:23month event free survival was
09:2540.5% in the access of
09:27ARM compared to only 16.
09:30.3% in the standard of care arm,
09:32and that was actually true when they
09:34looked at each of the individual.
09:37Subgroups by age response to first
09:40line therapy and whether they had
09:42high grades at B cell lymphoma,
09:44including double,
09:45triple hit or double expresser lymphoma.
09:48And when you look at the
09:51complete response rates,
09:53so overall response was 83% in
09:56the access alarm and 50% in
09:58standard of care and complete
10:00remission rates were 65 versus 32%.
10:06So there is some confounding in terms of
10:09looking at the overall survival benefits,
10:13because as I mentioned earlier,
10:1656% of patients in the standard
10:18of care arm received subsequent
10:20cellular immunotherapy of protocol.
10:22So this is the event free survival curve,
10:25here again showing a dramatic improvement.
10:29Median event free survival two months
10:32versus 8.3 months in the access alarm,
10:35the hazard ratio favored accessible
10:37for all of the different subgroups,
10:40including really high risk disease.
10:46Again,
10:46this is reflected in the progression
10:49free survival curves that separated
10:52and then when you look at the median
10:54overall survival was 35 months in
10:56the standard of care arm and it was
11:00not reached in the axle arm and.
11:03You know it,
11:04it's going again to be difficult to to see.
11:07It's curbs here that in terms of
11:10overall survival that are dramatically
11:13different from each other.
11:15So again,
11:17nearly three times more patients that
11:20were randomized to access L received
11:22definitive therapy versus standard of care,
11:25and there was a significant improvement
11:27in event free survival and response
11:29rate compared to standard of care.
11:31So this Soma 7 May actually mark a
11:34paradigm shift where you access L
11:36should be considered the new standard of
11:39care for patients with second line relapse.
11:42Refractory large B cell lymphoma.
11:45This is the transform study,
11:47so it looked at Lisa Captain Marlow,
11:49so I will not go into a lot of
11:52detail because it's very similar,
11:54but the I just want to point out that
11:57this car T cell therapy is slightly
12:00different from access L because
12:02there's a defined composition of CD8
12:04and CD4T cell components that are.
12:08Expanded separately,
12:09and then they're administered to
12:12the patient in equal target dosing.
12:15So when we looked at the study design,
12:19it's very similar.
12:20This did allow some bridging therapy,
12:23but then they.
12:25Performed a pet scan prior to
12:29LYMPHODEPLETION and Light and Lisle.
12:33And if there was no response by 9
12:35weeks or progression at anytime,
12:38a crossover to the lysis alarm was allowed.
12:44So when you look at the event
12:47free survival again with a median
12:49follow-up of six months,
12:51there was a significant improvement
12:53in event free survival of 63.3%
12:58compared to 33.4% at six months,
13:01and that held continue to hold at 12
13:05months even though there was some decline.
13:07So 44.5% versus 23.7%.
13:11Now again very similar results.
13:14So what we saw in Zuma 7?
13:17The complete response rates
13:20in the Lisle arm were
13:2266% versus only 39% in
13:25the standard of care arm.
13:30This is progression free survival.
13:32Again, even looking at 12 month
13:36data that is 52% in the Lisle
13:41arm compared to 33.9% in the in.
13:44The standard of care arm.
13:46So significant improvement in PFS median
13:49PFS in the light in the Lysol CAP to gene.
13:54The lysis alarm was 14.8 months.
13:59Versus only 5.7 months in
14:01the standard of care arm,
14:03which was the transplant arm and
14:07you know this is overall survival.
14:12Median overall survival was not reached
14:15in the Lisle arm and it was 16.4
14:18months in the standard of care arm.
14:24The third phase three study was Belinda,
14:29which this is kymriah.
14:31Basically the autologous CD19 CAR T cell
14:35therapy and this is the study design.
14:39Patients were looking
14:40for ease that screening.
14:42They did receive optional bridging
14:44with a platinum based chemotherapy and.
14:49The standard of care arm received
14:52salvage rice or or depth
14:56investigators investigators choice.
14:58They then underwent a week week six pet scan,
15:03and then they were they received
15:07either to sigend,
15:08occlusal or standard of Care now the
15:12difference here being that patients
15:14who did not achieve a complete
15:16remission actually ended up receiving.
15:19Multiple lines of platinum based
15:22therapy and including a different
15:24platinum based therapy altogether so
15:26they may have had two different two or
15:29three different salvage regimens here.
15:31By the time they actually made
15:33it to stem cell transplant.
15:37And.
15:40The fact that. They looked at this.
15:44They they based a lot of the UM.
15:48A lot of the criteria for non response
15:53on the Week 6 assessment actually did
15:56affect the outcomes as I will show you.
15:59So the patient characteristics
16:02were relatively equally
16:04distributed between the two arms.
16:07The median time from initial diagnosis.
16:10The randomization was similar
16:11about 8 months in both groups
16:14and the median time from the most
16:16recent relapse or progression to
16:18randomization was about 1.4 months.
16:20In the decision Lochloosa and 1.1
16:22months in the standard of care arm.
16:25So if you look now at,
16:28you know what patients are received.
16:30You can see that in the
16:33T sigend occlusal arm,
16:34almost 50% of patients received
16:37more than one cycle of.
16:40Chemotherapy prior to their lymphodepletion
16:43and then in the standard of care arm,
16:4797% of patients received multiple
16:49cycles of chemotherapy,
16:51and, importantly,
16:52the median time to the actual infusion
16:55of the T cells and that isagen occlusal
16:59arm was extremely long at 52 days and
17:02even in the United States was 41 days.
17:06But particularly in Europe,
17:08was longer at 57 days.
17:11So when they looked,
17:13surprisingly,
17:13when they looked at the event free survival,
17:16which was their primary endpoint,
17:18that was actually disappointingly
17:20the same in both the tisagenlecleucel
17:23and standard of care arm, so.
17:27You know why? Why did this happen?
17:29I mean,
17:30why was this study different from
17:32the prior to when you look at the
17:35Week 6 assessment that they did after
17:38these patients received bridging
17:40therapy or salvage chemotherapy,
17:42you can see that in that isagen
17:45lochloosa ORM.
17:4826% of patients actually had
17:51progressive disease compared to
17:5314% in the standard of care arm,
17:55so they progressed before they
17:57were able to receive the lympho
18:00depleting regimen and Corti.
18:03So they they investigators for
18:07the study did point that out,
18:11that the progressive disease at
18:13week six was more frequent in
18:15patients in that isagen lochloosa
18:17arm versus the standard of care and.
18:22There were multiple meetings and and
18:24experts in the field were asked about
18:27why they thought that Belinda failed to
18:31show an improvement in event free survival.
18:34And there are several factors for this
18:36that I'm sure will guide their the
18:39development of future trials for them.
18:41So the first was the longtime
18:43to infusion with that Kymriah in
18:46Belinda 52 days compared to 29 days
18:50with this card and Zuma 7.
18:52Abelinda allowed multiple
18:53lines of chemotherapy,
18:55as bridging therapy,
18:56which was different from
18:58Zuma 7 and transform.
19:01And Belinda also used lower
19:03dosing of lympho depleting agents,
19:06which are important for to obtain
19:08Disease Control in these patients
19:10that are not as heavily pretreated
19:13right because these patients had only
19:15received one prior line of therapy.
19:18So in Belinda,
19:19Cytoxan was only 900 milligram per
19:21meter squared over three days,
19:23and fludarabine was 75 per meter squared,
19:26whereas the other two trials had
19:29a higher cytoxan dose of 1500
19:31milligrams and 90 milligrams.
19:33Perimeter squared off loader being
19:36over three days. There were some.
19:38There were some differences
19:40in disease criteria.
19:41So Zuma 7 for example,
19:43enrolled only diffuse large B cell
19:46lymphoma patients whereas transform
19:48and Belinda allowed patients
19:51with 3B follicular lymphoma,
19:53which one could argue may be less aggressive.
19:56And the Belinda Trials definition of
19:59event free survival actually counts
20:02failure to achieve a response at the
20:05week 12 assessment as a negative incident.
20:08But due to the long gap to treatment,
20:11some patients may did not adequately
20:13respond to kymriah at that point,
20:16and they responded to kymriah after the 12
20:19week mark without any additional therapy.
20:23So several factors for White failed.
20:25So what is Novartis going to do?
20:27Are they gonna pursue another
20:30trial using the same product?
20:32You know,
20:33trying to mimic the other two studies?
20:36They have moved away from that.
20:37They have moved on and what they
20:40actually announced was this a next
20:43generation platform that's called
20:44T Charge that aims to revolutionize
20:47car T cell therapy and what it does
20:50is that it preserves T cell stemness
20:52the ability to self renew and mature
20:55that results in a product that has
20:58greater proliferative potential
20:59and fewer exhausted T cells and.
21:02They already presented at Ash.
21:05Now data from two first in human
21:09dose escalation trials.
21:11So Y TB323IN lymphoma and PHE
21:15885 in multiple myeloma.
21:17So there were two scientific posters
21:20that went along with the 1st in
21:23human clinical trials and what they
21:26basically showed is that this T cell T
21:29charge manufacturing process actually.
21:33Uhm?
21:37Give us a product that
21:39retains the immunophenotype,
21:41the of the input leukapheresis material,
21:43where naive and T central memory
21:48cells that are city 45 RO negative
21:51and CCR 7 positive are actually
21:54preserved as you see here.
21:57I don't know if you can
21:59see this here on the right.
22:01As opposed to the traditional manufacturing
22:05approaches where the cells are.
22:11City 45 Arrow positive CCR, seven negative.
22:17So the the thought is that these cells
22:21this is the time will reduce the
22:25manufacturing time basically to less than
22:28than two days because these cells are
22:31going to be able to go into the patient
22:35and expand and proliferate in vivo.
22:41So when you look again,
22:44these are called violent plots, there is.
22:49The. Y TB323 core T cells here actually
22:54showed very similar central memory.
22:56T cell phenotype and stemness gene
22:59signatures as the input material
23:01here in red compared to to the
23:05standard autologous city 19 product
23:08where there's more of a T factor,
23:10memory phenotype and.
23:14The Stemness high signature is retained
23:18in the the new product where TP323
23:21versus low stamina signature in the
23:25conventional autologous product,
23:26and this what this did is that it actually
23:30when you they looked at a tumor model,
23:32it showed better in vivo
23:34and to tumor efficacy.
23:36This is a traditional manufacturing
23:37and this is the T charge platform
23:40where you can see that even
23:42as low overdose as .1 times.
23:44Went to the six here shown in blue.
23:47Gives a response compared to .5.
23:50Times tends to the six in the
23:53traditional manufacturing so
23:54fewer cells are actually a car.
23:56T cells are required for tumor suppression
24:00and even when they looked at the expansion.
24:05The that they looked at in the
24:07blood by flow cytometry.
24:09These cells were were very potent and
24:12they actually had much better expansion.
24:15So there C Max was 40 times higher
24:18and AUC in the 1st 21 days was 33
24:22times higher for Y TB323 as compared
24:25to their traditional manufacturing.
24:27So this is what they used in the
24:30first in human study in patients with
24:33relapsed diffuse, large B cell lymphoma.
24:35And they saw some very encouraging data.
24:38They had two dose levels and
24:40they treated about 20 patients.
24:4315 patients who received this
24:46product at those level 2.
24:48They had a very high complete
24:51response rate of 73%. And they didn't.
24:55Importantly.
24:55Also they didn't see any safety
24:58signals beyond what was known and
25:01expected with the with the kymriah.
25:06So so.
25:08I think that all of the future studies
25:10that we're going to see coming out
25:13of Novartis will be utilizing this
25:15platform and at some point they will
25:17probably compare this to the standard
25:19of care which is autologous stem cell
25:22transplant and this eventually I think,
25:24will replace kymriah.
25:26So just to shift gears quickly
25:29towards multiple myeloma,
25:31as you know,
25:32bmet is highly expressed and malignant.
25:35Plasma cells and multiple myeloma,
25:37and then higher concentrations of soluble
25:40BCMA are associated with poor outcomes,
25:43and that's why this presented a
25:46very rational target for therapy.
25:49There's a lot of competition in
25:51terms of antibody drug conjugates
25:53and bispecific antibodies,
25:55but in terms of car T cell therapies.
25:58The advantages that hopefully
25:59it's a one and done deal.
26:01If you have a good product and you don't
26:04have to continuously infuse antibodies.
26:06So currently either captured in blue
26:09so and Celtic after Geno Deluso are
26:12both approved in patients who've had
26:14four lines of therapy exposures to
26:18immunomodulatory agent proteasome
26:20inhibitors and also anti CD 38
26:24monoclonal antibody like daratumumab.
26:26So.
26:28This is the phase one two data
26:31with BCM a
26:32directed CAR T cells in multiple myeloma.
26:36So BB 2121 was the first product approved.
26:39You see it has a 73% overall response rate,
26:4431% complete response rate in a
26:48heavily pretreated patient population.
26:50However, disappointingly,
26:51the median progression free
26:53survival was only about a year,
26:55and so people realize very early that.
26:59Uhm? Something else that needed
27:01to be done and that we need to
27:03improve upon upon this product.
27:06So Elk, RB 38 M is a car construct
27:10that actually has CV targeting
27:122 bfme epitopes instead of 1.
27:15So it targets both VH1 and VH two,
27:19and when they looked at the data,
27:22the overall response rate was 100%
27:24with complete response rate of 76%.
27:27And there's also another product where.
27:30Which is fully humanized,
27:33and that's enriched for early
27:35memory phenotype,
27:37so this kind of kills two
27:39birds with one stone.
27:40The cells hopefully persist longer,
27:43but because of their memory,
27:46early memory phenotype, but.
27:49Also,
27:50and being fully humanized,
27:53there is less development of of antibodies
27:57that result in destruction of these.
28:00Court T cells soak artitude one was
28:03a phase 1B2 study of Celtic catagen
28:06all deluso and they presented at ash
28:09their two year update and this is
28:13very similar in terms of leukapheresis
28:16lymphodepletion with fludarabine
28:17cytoxan and then they had the soul to sell.
28:21Infusion the baseline characteristics.
28:24Just important to note that 87% of
28:28patients were triple class refractory
28:30and 42% were pentad drug refractory so
28:33very heavily pretreated and resistant.
28:35Patient population.
28:37When you look at their overall
28:40response rates.
28:41I mean dramatic 97.9% and when you
28:46look at stringent complete response
28:49extremely high 82.5% the median
28:51time to first response was quick
28:54a month and median time to CR or
28:58better with two point 9 months.
29:00The percentage of patients that
29:02are remaining progression free
29:04at two years with 60.5%.
29:06So that was better than what we
29:09saw with the with Ida Captain Jean.
29:11Then you can see that this is important
29:14because basically for two years these
29:17patients did not get any other therapies.
29:20Which is you know important
29:22in terms of quality of life?
29:25And preservation of organ function.
29:27So when we look at PFS and overall survival,
29:30the two year PFS was a 71% median PFS
29:37and not reached compared to 60.5%.
29:43Uhm?
29:46Here in blue for patients who the all
29:52comers compared to patients who achieve
29:55stringent CR that did significantly
29:57better in terms of progression.
29:59Free survival at two years.
30:02So, so that's what denoted here in blue and.
30:05And as expected, the stringent CR
30:07patients would have better outcomes.
30:09And if you look at progression free and
30:12overall survival by MRD status again,
30:14significantly better.
30:16In patients who were MRD negative.
30:21And MRD negativity negative patients
30:25actually maintain their progression
30:28free survival beyond the year.
30:31So I'm going to switch gears
30:35now finally to a LL briefly.
30:38But importantly,
30:39we now do not have just the
30:43tisagenlecleucel approval
30:44for a LL up to 25 years old.
30:47We also have Rex Cottage in Auto Lusso,
30:49recently approved in adults
30:51with relapsed refractory B cell
30:55LALLLA much anticipated approval.
30:58So Ileana was in.
31:01Children and young adults are
31:03showing a significant improvement
31:05in event free and overall survival
31:08with this agenda Clouseau.
31:10In this patient population,
31:12including patients who did not
31:14go onto to receive an allogeneic
31:17stem cell transplant and this
31:19is zooma 3 with Brexit captain
31:22Jean with that showed 70.9% CR.
31:25Or CR with incomplete hematologic response.
31:29Pretty high in adults with
31:31relapsed refractory LL,
31:33so this has already previously
31:35been published.
31:36But to point out what was interesting
31:39at ASH is that patients are relapsing
31:43mainly because they're losing CD 19
31:47and so a lot of effort has gone into
31:50finding ways to mitigate that risk.
31:52So either by giving dual cars like City 1920.
31:56Two giving off the shelf CAR products or
31:58by re infusing CAR T cells in patients
32:01who may be at high risk of free labs.
32:04And so this was a study from CHOP at
32:09Upenn in children and young adults
32:11with relapsed refractory LL and they
32:14basically followed patients from.
32:17The time of their first scene,
32:1819 Carty and if they had,
32:21if they were minimal residual disease,
32:23positive if they relapsed,
32:25or if they saw that they had early B
32:28cell recovery and or city 19 hematogen's
32:31in the bone marrow they basically re
32:34infuse them with the autologous CAR.
32:36T cell products within six months
32:39of their initial treatment and
32:41you can see that in patients who.
32:45Were reinfused because of him at Agones.
32:49Actually the majority of them 76%
32:52achieved a complete remission and also
32:56patients who had early B cell recovery
33:00but did not have measurable disease.
33:02A good proportion of them achieved CR without
33:06needing consolidation with a transplant.
33:09However,
33:09patients who were reinfused for non
33:12response actually all of them pretty much.
33:15Did not respond to the car T product,
33:18so the clinical implications
33:22for this are that cortisol re
33:24infusions can prolong be sold.
33:26A plasia in a subset of patients
33:29with short car persistence and
33:31this can reduce risk of relapse.
33:34Rain fusions can induce remission
33:36in patients with prior relapse,
33:37but the remissions have limited durability,
33:40and really it does not make sense to
33:43reinfuse patients who were refractory
33:45the first time around because
33:46none of them actually responded.
33:49So this is just the class effects
33:51of the immune responses,
33:53CRS, and neurologic toxicity.
33:55You see that they're very very variable
33:58amongst the products in terms of
34:01both CRS and neurologic toxicity,
34:03and so then.
34:05The the less disease burden patients have.
34:08At the time of treatment at the better,
34:12the outcomes and and the less toxicity.
34:15And this is this is a lesson
34:17that we've learned.
34:17So the studies now are moving to
34:21incorporate these therapies earlier
34:22in the disease course or to debulk
34:25the patients before we actually
34:27give them the products.
34:28And and I think that's all I have.
34:31So what I'm going to do is I'm going
34:34to pass it over to to low heath.
34:36And then we'll do questions at the end.
34:58Good afternoon everyone.
34:59Anika I thank you for that
35:01beautiful presentation that
35:03really indeed is transformative.
35:05Yeah, these are the people who led the
35:07studies that I'm going to be presenting.
35:09Most of them have said this slides.
35:11I'm grateful for that.
35:13Objectives are DOC today would be
35:15to mainly look into the therapeutic
35:17avenues in which allogeneic stem
35:19cell transplant has been making
35:20progress in order to reduce some of
35:22the complications associated with it,
35:24which ultimately results in a better
35:26curative promise on the quality of life.
35:28I'm going to present a trial wherein we're
35:31going to use pre and post transplant.
35:34Uh, and I'll present some data from
35:37University of Minnesota that looked into.
35:39One Cody Anaconda troping.
35:41In addition to standard immunosuppression,
35:43for patients with acute GVHD,
35:45also present 2 two phase two trials looking
35:49a chronic DVT targeting different pathways.
35:53This this was a trial that was like that MGS.
35:55There was a multi site study
35:57led by Doctor Hobson team.
35:58Basically the study is looking to use
36:00of ruxolitinib which is a Jack anybody
36:02prior to during and after stem cell
36:04transplantation for patients with
36:06primary or secondary modified process.
36:08So for those of you who manage my life,
36:09I process.
36:10This is a very common slide.
36:11The disease can be classified
36:13into five different categories.
36:14Things on the left here usually
36:17get managed conservatively,
36:18or using cytokines and things
36:20symptomatic splenomegaly patients.
36:21We use ruxolitinib,
36:22and more recently the strike
36:23has been approved.
36:24Once they start coming intermediate
36:27risk or have bad gene signatures
36:29or higher very high risk.
36:31OK,
36:31those are the people if they're
36:33eligible for transplant,
36:33they'll be considered for stem cell
36:36transplantation of clinical trials.
36:37This is just a slide that
36:39shows that for the groups here,
36:40starting from grey, yellow,
36:42and blue median, overall survival is less.
36:44Those are the people that are
36:45normally considered for a stem cell.
36:47Transplantation based on clinical scenarios.
36:49So why is it that stem cell transplantation,
36:52although being curative,
36:53has been a little bit of a problem for us?
36:56Well,
36:56most of these patients have
36:57a ***** fibrotic condition.
36:58Have you know Mega League and patients
37:00who come in with splenomegaly at the
37:02time of transplantation generally
37:03tend to do poorly compared to others.
37:05You can consider options to take
37:07over spleen do variation,
37:09surgery and things like that,
37:10but it has its own infectious risk,
37:12robotic risk which ultimately
37:14decreases the promise of transplant.
37:16In addition,
37:17we've seen people have poor graft
37:19function graph failure rates
37:20can be up to 15%.
37:21That all adds up to the non
37:23relapse mortality and there
37:24are some transwitch reports.
37:25Pretty high rates of GVHD and on
37:27the left mortality for my life I
37:29process compared to other people.
37:30The real question is if regulating
37:32even the rest of the drugs which
37:34are now making foray into the
37:35field of my life I process,
37:36is it possible to continue
37:38this trucks in a longer term?
37:41Because, as I said,
37:43Jackie Ken has implications on
37:45symptomatic control for people who
37:47have multiple process can decrease the
37:49screen size or the last couple of years.
37:51We've learned that this drug is pretty
37:53active in both acute and chronic GVHD.
37:55Now we have a label for it.
37:57If people are being a Jack iffy and you
37:59start with prior to transplantation,
38:01there are some reports which suggest that it
38:03can manifest in cytokine release syndrome.
38:04Kind of clinical spectrum and there have been
38:07efforts to see if this drug can continue on.
38:09And there are also people who think
38:10if you suddenly stop it will rebound
38:12or bounce back and things like that
38:14which ultimately has negative impact.
38:15So the real question this study is
38:17trying to answer is, is it safe,
38:19effective to use a drug pre and post
38:22transplantation? This is a study schema.
38:24It included patients with mild fibrosis,
38:26both primary and secondary pre
38:27transplantation they would start a
38:29drug at 5 milligrams which is a lower
38:31dose around day minus 14 continued
38:33with conditioning regimen.
38:34Use it in the post transplant period.
38:36Reevaluate the patients at day
38:3830 post transplantation,
38:39at which time if the Council recovered,
38:41you bump them up to the 10
38:43milligrams vid dose,
38:43which is what we kind of use it in our set.
38:47The key inclusion for mainly adult
38:49patient population, as I said,
38:51both primary and secondary.
38:52This is a classification system.
38:53This is a dip system that intermediate
38:55one risk group in addition to adverse
38:57molecular markers or people greater than
38:59intermediate 2 running through that,
39:01they went with the Disney intensity
39:03regimen as receipts was 140 or lesser
39:06dose commonly used regimen prophylaxis.
39:08Methotrexate and climbers was
39:10applied in the set.
39:13Here is some characteristics.
39:14I know it's a busy slide,
39:16but all that I want you to focus
39:17on is that most of these people,
39:19about 85% of the people in this
39:21trial had a split omegle coming in.
39:22The study largely consisted of
39:24match related and unrelated donors,
39:26number of mismatched donors was less.
39:28The first thing that you think about
39:30when putting in a post transplant
39:32period is housing grafman.
39:33This is a pretty mild toxic drug.
39:36People can have deep cytopenias
39:38and here's a report and they thirty
39:4123124 patients had engrafted.
39:44On the platelet count tend to lag behind
39:46a little bit, whether it's the drug,
39:48whether it's the spleen.
39:49It's debatable,
39:49you follow them up today,
39:5160 neutrophils have recovered,
39:52or the platelets still lags behind by
39:55around a little more than 100 days,
39:57almost everybody recovers their
39:58platelet count.
40:01I'm here with the clinical
40:03outcomes that are reported.
40:04The one year OS is about 77% the
40:07one year cumulative incidence of
40:09relapse is about 17%. One year.
40:11Incidence of chronic GVHD is 14%.
40:14I think it's also important in the six
40:16months incidence of great leader for acute,
40:18which can be lethal. It's about
40:20four percent is kind of impressive.
40:22So based on this trial now people
40:24are starting to contemplate the C.
40:26Yes, this drug has benefits in
40:28pre and post transplantation
40:30setting in terms of the high risk.
40:32In population,
40:32maybe this can be translated into clinically.
40:36We will now just switch gears and
40:38go to an acute graft history that
40:41is presented by Minnesota Group.
40:43This was a phase two study
40:45a couple of years ago.
40:46They presented their phase one data that
40:48was published in Blood Advances, Dr.
40:50Holton and ET al had led this study.
40:53Basically, the rationale behind
40:55using human chorionic troepen and
40:57epidermal growth factor is that.
40:59Acute GVHD happens.
41:00It's usually in the setting of an
41:02immune attack due to the discordance
41:04between the recipient and the host.
41:06Communist therapeutic interventions that
41:08we apply are all deeply immunosuppressive.
41:10But by the time the immune cells have caused
41:13an destruction to the epithelial lining.
41:15In the absence of anything else,
41:17we continue to escalate him in a suppression,
41:19but here they're trying to come up with
41:21the concept of using tissue repair
41:23mechanisms by using growth factor support
41:25mechanisms like epidermal growth factors.
41:27We also know the concept of pregnancy.
41:29We've all known that HCG is
41:32kind of taller rising rising,
41:34it increases the regular population
41:36compared to conventional subpopulation.
41:37It also has impact on anabolic
41:39sides of metabol ISM,
41:41and as I said.
41:43GF also decreases and regulation,
41:47which is kind of being thought
41:49as a marker of inflammation in
41:51addition to promoting promoting it.
41:53More and more T cell metabolic
41:56studies suggests that bit rate
41:58seems to promote expansion,
41:59which is kind of a thing we like
42:01in the field of transplantation.
42:02Unlike neoplasms where T Rex are not
42:05well liked upon but to develop tolerance,
42:07we, like any agents that increases
42:10direct population.
42:11So based on their phase one design they
42:14now where they identified 2000 units.
42:17Sorry, 2000 units as appropriate dose,
42:20and they included two risk groups.
42:21In Minnesota,
42:22High Risk Group and the.
42:24Second line therapeutic group.
42:25I can give references for this
42:27at a later stage.
42:28They were used to drug subq every
42:30other day for seven days in
42:32addition to the high dose steroids,
42:34which is the commonest Firstline agent
42:35we use for the second line cohort,
42:38they would use this combination
42:39the same dose subq.
42:40Or if you're going to use it at 5000
42:42units for those who are refractory was
42:45given every other day for 14 days in
42:47addition to the standard of care and
42:49that standard of care was left with
42:51the physicians based on their choice.
42:54This is just a brief synopsis
42:55of what were the cohorts like.
42:57Largely,
42:57I wanted to focus on the fact
42:59that in the first line cohort,
43:00most of those people were stage
43:02three to four lower GI GVHD,
43:04which is what is more challenging
43:05to manage in the second line cohort
43:07that did have a few skin cases,
43:09that was stage three or four,
43:11they have some pictures in
43:12their presentation.
43:12I'm not showing that,
43:14but they were pretty bad skin stays,
43:16but regardless,
43:16most of them are a grade
43:18three to four acute GVHD,
43:20which is kind of challenging to manage.
43:23Here are the response rates
43:24in the acute GVHD clinical drug development.
43:2828 year responses being kind of validated
43:29as a nice marker to predict responses,
43:32so date 28 for all patient cohorts.
43:35There was a 57% CR and 11% had
43:38partial responses for the high
43:40risk Minnesota Risk Group to see.
43:41Our rate was 64% in the second line,
43:44it was 50% CR rates.
43:46And here's a non elapsed
43:48mortality can easily lead to that.
43:50This is for the entire cohort in the
43:52dark clients for the high risk group.
43:54And this is for the second line group.
43:55The P value was not significant,
43:57but based on those who are responding,
43:59CR or PR is not responding.
44:01There seems to be a train that the
44:03non relapse mortality at two years
44:05is declining with this information.
44:07And here is the same analysis for overall
44:10survival based on the whole cohort.
44:12And this is for those who are responding
44:14based on this kind of response
44:16we elicit with this intervention.
44:18When they presented the causes of that,
44:20it's really interesting that happens to be
44:22still a communist cause of death, right?
44:24About half of the patients had died,
44:26with a median follow-up of 17 months.
44:28Relapse is the second most common stuff,
44:30and infections and organ damage
44:32with common livery,
44:33and that didn't seem to be that much.
44:34But again, it's a small patient population.
44:37In summary,
44:38I think they show that the response rate of
44:4168 percent is pretty reasonably accepted,
44:43and day 28,
44:44and doesn't significantly impact on relapse.
44:46Mortality based on the fact that people
44:48are still dying with GST and relapses,
44:50they're recommending either using biomarkers,
44:53and they have some nice profile of
44:55metabolic stuff that they reported
44:57which I can talk to you later on,
44:59but it's kind of now in development
45:01in the field that we don't necessarily
45:03have to keep thinking about escalating
45:05immunosuppression,
45:05but now we need to start focusing.
45:07On getting the right immunomodulation in
45:12addition to tissue repair pathway drugs.
45:15In the other half of the talk,
45:18I'm going to talk about chronic GVHD.
45:21For some of us who do this on a daily basis,
45:23we see this in up to about 50%
45:25of patient population use of post
45:27transplant cyclophosphamide has
45:28brought that number down,
45:29but most people don't get it
45:31because cyclophosphamide does have
45:32some issues in terms of infection,
45:34cardiac toxicity and other things,
45:36and again it's largely applied in
45:38the setting of unrelated donors
45:39and not commonly used in massively
45:41donor transplantation.
45:41For those who develop,
45:43chronic steroids has been the workhorse
45:45for multiple multiple decades.
45:47About half of those patients
45:49eventually need second line treatment
45:50for disease progression.
45:51And they don't tend to do well at that stage.
45:54Up until a year,
45:55year and half ago really didn't
45:57have that many drugs in Brittany
45:59was approved a few years ago.
46:00Based on this trial,
46:02it's a boutique inhibitor.
46:03As you all know,
46:04the overall response rate was 67%,
46:06CR was 21% in that
46:08in the last 12 to 24 months.
46:10Now we have two drugs belimo saddle
46:12which is a rock to inhibition.
46:14That's not only has anti-inflammatory
46:16properties, but it also kind of
46:18targets the scarring part of it,
46:20which is kind of a novel mechanisms.
46:21Here the overall rate was 73% in the CR.
46:24CRA dispite being low the PR was
46:27high but based on the fact that
46:29it targets the scarring pathway,
46:31it's been approved recently.
46:32In addition to controlling gived.
46:35Uh, I spoke to you earlier on.
46:38Fracture GBST in the last six months.
46:40It's also been approved for chronic GVHD.
46:43Again, the rates of CR is close to about 50%.
46:46Most of these drugs are approved
46:48for people who fail at least
46:49two or more lines of therapy,
46:50but these lines of response rate
46:53suggests there is still more that's
46:55needed to optimize the speed.
46:57One of the yes,
46:59which is kind of not that commonly explored,
47:02but it's kind of.
47:03It's a welcome change.
47:04It's commonly,
47:05we think about jobs as a T
47:07cell mediated pathway.
47:08This work that was presented by
47:10Stephanie Lee's group from Fred
47:12Hutch is now looking into targeting
47:15macrophage driven chronic drug
47:17Physiology colony stimulating factor
47:191 receptor mediated pathways.
47:22Once someone is circulating,
47:23they can get into the tissues and
47:26then they can differentiate in either.
47:28I'm wondering 2 phenotypes of macrophages,
47:30which them one being pro inflammatory,
47:33this being anti inflammatory.
47:34But now people are looking into
47:36developing drugs against tests
47:37which promotes this differentiation
47:39to decrease the inflammation and
47:40the drug that I'm going to talk
47:42to you is a CC colony stimulating
47:45factor 1 receptor antibody.
47:47Inhibition of that is start to
47:48decrease 5 process and make bring about
47:51changes in collagen structure which
47:53kind of then has impact and tissue
47:55healing for people with chronic dry.
47:59The drug is exactly exactly map.
48:02As I said, it's a humanized IgG.
48:044 monoclonal antibody binds to
48:07CSF 1 receptor.
48:08In addition, it also binds to oil 34,
48:10which has informative properties in the skin.
48:13It's administered over 30 minutes
48:15for every two to four weeks.
48:16It's highly effective in decreasing
48:18the fiber optic signals on
48:19the nonclassical monocytes.
48:21In addition,
48:21using this intermittent dosing pathway,
48:23they found that you know gives
48:25opportunities to keep the drugs going
48:27frequently because the cells do.
48:29So in the mean time this was
48:31a phase one two study design.
48:33They wanted to test the phase
48:34one about 17 patients,
48:36a point
48:3915.5133 given over Q4 weeks at Q 2 weeks,
48:42and then they went to the phase
48:44expansion at 1 milligram per kilogram.
48:46That included a larger number
48:48of patient population.
48:49Presented here is a baseline
48:51characteristics for patients.
48:52A quick summary of this is that
48:54most of these people were heavily
48:56treated that more than half of the
48:59people in both phase one and two.
49:01I had four or more organs involved
49:04consistent with modern tactics.
49:05People have been exposed to Brittany and
49:08which is the rock number that I showed.
49:11I'm I'm there,
49:12basically show that there's no differences
49:14between Android patient populations.
49:16Uh, and the drug seems to be pretty
49:19well tolerated across both groups.
49:21The discontinuation rate,
49:23although seems to be high,
49:24but in this context it's pretty challenging,
49:26and about 30% in the phase one,
49:28and about 58% are still continuing.
49:30This drug in the phase two.
49:33More interestingly,
49:35is the response rate.
49:37Most of the responses we
49:38do show that responsive,
49:39especially with this one milligram per KQ,
49:412 weeks our sponsor seems to be pretty
49:44durable and same is the case with
49:46three milligrams per kick and when
49:48you look around their best overall
49:50response rates and time from responses,
49:51that's reasonably impressive,
49:53but time to responsive.
49:55One month it's something
49:57that you don't often see,
49:59and that's a welcome change.
50:01The next question people come commonly ask
50:03is how about organ specific responses?
50:06Well, light light Gray or blue ish
50:08is the CR rates in the dark ones.
50:10The PR lower GI?
50:12Everybody seems to have good responses.
50:14What what's of interest to us
50:16is the Giants and the skin,
50:17which seems to be PR based on
50:20its antifibrotic mechanisms.
50:21People ask me what happens to the lung,
50:23which is more common and challenging
50:25to handle?
50:26Seems like you know at least five out of
50:2815 patients is a reasonable one for CR.
50:30When it types the lung.
50:32And and and about 88% at serious
50:34skin sclerosis are baseline close
50:37to 16% on improvement in sclerosis.
50:40Another aspect that we tend to ignore
50:42is you might have clinical manifestation,
50:44but what about the quality of
50:46lives and symptom burden?
50:47And here's just a graph in somebody
50:49that's depicting that across the
50:51dose people had good responses
50:53in the symptom scale.
50:55In conclusion,
50:56I think the investigators were
50:57able to show that targeting
50:59monocyte macrophage pathway,
51:00the CSF one receptor ligand seems to be
51:04meaningful leads to decent response rates.
51:07Sclerosis seems to go down on it now.
51:10There's a trial that they're going
51:12to randomize different doses,
51:14potentially as a group with contemplating
51:16participating in this thing,
51:17but it's kind of opened up the concept
51:20of targeting monocyte macrophages in
51:22addition to the T cell thing that
51:24we commonly pursued in chronic GVHD.
51:26On the last day that I'm going
51:27to talk about is a better set,
51:29this was a study that was done at Boston.
51:31Abbott stepped as you all know,
51:34is a T cell costimulation modulator,
51:38the T cell receptors.
51:40After recognizing the APKS would
51:42interact with them and the CD 20 would
51:45normally interact with the CD 86.
51:48For this is necessary for T cell activation,
51:50proliferation and production
51:51of inflammatory mediators,
51:53whereas inhibits this pathway
51:55by targeting CD 1886,
51:57and this costimulation doesn't
51:59happen and the hypothesis here is
52:00that if you somehow can prevent
52:02this T cell costimulation,
52:03maybe the proliferation
52:04activation doesn't happen.
52:05That leads to decrease chronic dry.
52:08About six months ago I.
52:11I know I'm using the six months
52:12one year commonly because that's
52:14how frequently the drugs are
52:15getting approved in this space.
52:16Recently,
52:16the drug was actually approved
52:19for prevention of acute GVHD.
52:21Yeah, mainly for unrelated donors,
52:23so this is a study in the backdrop of that,
52:25but obviously the context
52:27is in a chronic dbcontext,
52:29so people are wanting to say yes.
52:30This is a drug that's not
52:32going to be commonly used.
52:33What happens in the chronic dry setting?
52:35So the design was this close to 40
52:37patients who had both are bleeding
52:39and reduced density transplants
52:40and declared themselves steroid
52:42refractory and the definition
52:43of that was persistent science
52:45and symptoms of chronic GVHD.
52:47Despite use of steroids,
52:48.5 mix perchik per day for
52:50at least four weeks.
52:51They were to be getting
52:52this to stand mix for cake,
52:53which is what was acute GVHD.
52:55Dose was every two weeks for three
52:56doses and then they would go on to
52:58get it for every four weeks for three
53:00doses based on the clinical response,
53:02there was no response will come
53:04off that a clinical response for
53:06their continuation was allowed.
53:07The aim was to look into the rates
53:10of overall response rates and
53:11see how things were playing out.
53:13And this is just a description of things.
53:15Go on the oral response rate was 49%.
53:18Unfortunately,
53:18CR was zero and most of them
53:21were PR responses.
53:22This is just a spread
53:24across different organs.
53:25In the interest of time,
53:25I'm going to quit that and this
53:27is the slide that basically shows.
53:29While look at response rates,
53:31its importance to Ryan has been the
53:33main drug that we've used quite
53:35a few other people were able to
53:36decrease down their dose of steroids,
53:38which has long term implications
53:40on their metabolic health,
53:41mental health,
53:42cardiovascular risk and things like that.
53:44So with that the.
53:47Investigators conclude now a 50%
53:49objective response rate or are in
53:52the cirrhotic factory is a welcome change.
53:54Importantly,
53:55there was a durable reduction in
53:57Prednisone dosing overtime infections
53:59were uncommon in this context,
54:01and infusions were pretty well tolerated.
54:03Their ongoing studies,
54:04correlate's and biomarkers,
54:06and things like that.
54:07With that,
54:07I'll end the top and thank everybody
54:09for coming and I'll open it up
54:10for the audience.
54:16So we're going to open this up to questions.
54:18Now you can feel free to ask them
54:21or or write them down in the chat.
54:25For each of the talks.
54:30And maybe in the. In the meantime,
54:32I'll just ask Lohith lohith.
54:35Do you think that given the good
54:39efficacy we've seen with ruxolitinib
54:41in patients with steroid refractory?
54:46Jigged, do you think that there's
54:48and given the safe the what seems
54:51to be fairly good safety profile of
54:54the human chorionic gonadotropin?
54:56Do you see a role for the combination
54:59of that with ruxolitinib and in
55:03terms of steroid sparing effects
55:06in this patient population?
55:08I don't know if there is such
55:10a trial that's already been.
55:11That University of Minnesota is doing or not,
55:14but that would seem like a
55:15reasonable trial to conduct.
55:18Yeah, I think I think that's
55:19that's a great question, Alice.
55:22Obviously, the CR rates around 60 to
55:2470% based on which trial you look
55:26around it or our response rate.
55:28Real question is the day 28 is the
55:32magic bullet, at least in most trials.
55:34How much are we going to?
55:38Miles suppressed?
55:38The good thing about this drug is it's
55:41not deeply Mila suppressive right?
55:42I think that's that's a great part of this.
55:45There's always been this concern in
55:47the field that if the inflammation
55:48kicks in and the tissue is wiped out.
55:51You're in a losing cause that that
55:54combination makes rational sense,
55:56but I'm not certain the group
55:58is pursuing this.
55:59Clearly,
56:00I think what it's showing is we just
56:02probably need to start thinking and
56:04deescalating immunosuppression sooner
56:05rather than keep harping on it,
56:07which is what we've done for many decades.
56:10Hopefully we'll get a good
56:12antimotility drugs, good tissue,
56:14healing, drugs going forwards,
56:15and this seems to be the right start.
56:18But there's
56:19a question in the chat about the
56:22the mechanism of rock
56:24two and Rock 2 inhibition. Can you
56:26tell us a little more about that? So.
56:32I think it's mass general
56:33identified a few years ago.
56:35They came up with this idea that.
56:39You know, just like most things you know,
56:42we have anti-inflammatory drugs.
56:43But we don't really have
56:46good antifibrotic trucks.
56:48I think this rock pathway has been
56:50shown in systemic sclerosis and,
56:52at least in this clematis GBST,
56:54most models targeting rock
56:57Pathway Rock 2 results in.
57:01Grease scarring, decreased fibrosis,
57:03and that was the rationale for that.
57:07Considering most of chronic GVHD,
57:09people have facial involvement,
57:11synovitis myositis and things.
57:13There's a lot of interest that's
57:15going on a couple of our dermatology
57:17colleagues and our banking.
57:18These samples at least my patients.
57:20Uh, trying to address what are the
57:23synergistic things that we could use?
57:25In addition to the rock pathway that
57:28further subprocess fibrotic mechanisms,
57:31because really,
57:32we do see that some of them come up with
57:34contracted arms and things like that
57:36and that has functional implications.
57:38More importantly,
57:39it's not deeply immunosuppressive,
57:40and that's a welcome change.
57:42Rates of infections are low and and.
57:45Stating that this is something
57:46that you had in the car,
57:48I say I've seen good responses
57:49even in lung GVHD,
57:51but I think as a special code I would
57:53like to see a little more to see if
57:55that brings up on field changing shift,
57:57but that's still a work in progress.
58:01There's also a question
58:02for Aris about immune approaches.
58:05Postcard T to enhance attention
58:08of cells for continued response.
58:11Thank you. Touched on that a little
58:12bit with that new Novartis platform.
58:15But people doing other things try and
58:16get car T cells to persist to work
58:18better afterwards that you heard of.
58:22Yeah, well, I mean so.
58:24So the humanizing party is 1 approach
58:29to for them to persist better.
58:31Again looking at the.
58:35Central memory phenotypes are using
58:38enriching for that particular patient
58:41population is another is another
58:44approach to to enhance retention.
58:47You know, the other thing is that they do
58:49have these Cortese that secrete cytokines,
58:52so that's another.
58:53That's another approach.
58:55And in fact there was actually an
58:57abstract at ASH that I didn't show,
59:00but I have a slide of with the BC MA therapy.
59:07Releasing, you know with AB Mccourtie
59:11releasing cytokines that enhance
59:13proliferation so so there are
59:16multiple approaches and actually.
59:20Come. You know, sometimes that can
59:22can be a double edged sword, right?
59:24Because these cells can proliferate
59:26very rapidly and then you have to
59:29think about a switch to turn them off
59:31because they can become a very toxic,
59:33but you can combine them.
59:35You can do basically like City
59:37Chen is doing at Yale,
59:38a dual knock in knockout, where you can.
59:42Knockout pretty one, so I mean,
59:44that's that's another approach, right?
59:46So so looking at the micro environment,
59:48can we actually can we actually.
59:53Get cells that are less exhausted
59:55by stimulating by by by affecting
59:58the micro environment.
59:59For example,
01:00:00those efforts are going on in CLL
01:00:02where there is a real problem with
01:00:04persistence of these court T cells,
01:00:06so those are all or or you
01:00:09know the other thing is.
01:00:11At CAR T cells like one of the
01:00:13labs is doing here with Sally Sue,
01:00:16you know,
01:00:17with the targeting low antigen density,
01:00:20for example T cells.
01:00:22So that's that's another approach
01:00:25so that once they they may.
01:00:28Progress after regular karty,
01:00:29or if you see decreased antigen expression,
01:00:33is to actually target them with the
01:00:35with the party that has higher avidity,
01:00:38so those are those are some of the
01:00:40approaches for to enhance the retention
01:00:42of these cells and continued response.
01:00:47So so I have
01:00:48one question for you is that?
01:00:52Why it has come up in there has
01:00:54already been a trial, but given the
01:00:56the favorable results,
01:00:57at least from the Zuma 7 trial.
01:00:59Do you foresee a time
01:01:02when Carty are used even?
01:01:05In high risk patients,
01:01:07as part of their initial therapy,
01:01:09as opposed to waiting for disease,
01:01:12refractoriness or relapse.
01:01:17Well, I mean different from the Zuma.
01:01:1912 so Zuma 12. For example, right?
01:01:21They took really high risk patients
01:01:23and they stratified them by pet after
01:01:26two cycles and patients that were pet
01:01:29positive went on to get to get Carty
01:01:32and the outcomes were pretty good.
01:01:35You know the problem is I think we need to
01:01:38get a little bit longer follow-up because.
01:01:44You know patients who have a positive
01:01:46PET scan after two cycles you know may
01:01:49still go on to achieve complete remission
01:01:51at the end of 6 cycles of therapy,
01:01:54so I don't know if it's ever going to
01:01:57make it to to frontline it. It may.
01:02:01It's not. We're not there yet.
01:02:03I think that what companies are doing now,
01:02:05though they are sponsoring trials where
01:02:08they pay for the collection of T cells
01:02:11early on in somebody's presentation.
01:02:13And they saved them in the event that
01:02:18patients do relapse and they will probably.
01:02:23Sell that information.
01:02:25Sell those to pharmaceutical companies that
01:02:27are designing that are designing trials.
01:02:31That's interesting, so so,
01:02:32so that's going on because I think
01:02:34it's really important to collect
01:02:36the cells as early as possible when
01:02:38they're when they're fit before
01:02:40people have a lot of chemotherapy.
01:02:43So so you know there may.
01:02:45I mean,
01:02:46the FDA hasn't even approved yet, right?
01:02:48For they haven't even approved access
01:02:51L or based on or Lisle based on
01:02:54the Zuma 7 and transform results.
01:02:56I think that's the next step.
01:02:58Because I think it should be approved,
01:03:00'cause clearly there's a PFS benefit in
01:03:03that patient population over transplant,
01:03:06so I think that's going to be
01:03:08probably the first approval,
01:03:09and then after that you know
01:03:11we're looking at.
01:03:12Yeah,
01:03:12potentially incorporating it in
01:03:14people with double hit lymphomas
01:03:16or primary refractory disease.
01:03:18Incorporating it early on.
01:03:22Alright, well we're a we're a
01:03:24few minutes after the hour,
01:03:25so, great presentations,
01:03:26great questions and discussion.
01:03:29Thanks everybody.
01:03:31Have a good weekend.
01:03:32Thank you everyone.