Yale ASH 2021 Highlights: Cellular Therapies

Transcript

• 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.