"The Cell Therapy DART Solid Tumor Program" and "Cellular Therapies for Hematologic Malignancies at Yale- Clinical and Research Challenges"

March 24, 2021

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Yale Cancer Center Grand Rounds | March 23, 2021

Michael Hurwitz, PhD, MD and Iris Isufi, MD

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00:00Mike is a social professor of medicine and
00:03internal medicine and medical oncology
00:05shares patients or cancer patients,
00:07fraternity or cancers.
00:09As part of the smiling prostate,
00:11your logic cancer program.
00:14Alright, joining Allen 2009 Doctor Hertz
00:16was instructor of medicine at Harvard
00:18and attending physician in medicine at
00:20the Massachusetts General Hospital.
00:22MIKES graduate of Harvard College.
00:24He received his doctorate degree in cell
00:26Biology from Rockville University's
00:28medical degree from Cornell University.
00:30He completed a fellowship in Archology,
00:32Dana Farber and postdoctoral fellowship
00:34in Biology, the Masters in Massachusetts,
00:36Channel MIT Institution might still
00:38be talking about the silk yellow cell
00:41therapy program for solid tumors.
00:42Mike take it away.
00:44Thanks, Dan.
00:44Yeah, thanks everyone for inviting
00:46us from that from the
00:48therapy dog to talk.
00:50I'm going to talk obviously about
00:52the solid tumor side and then the
00:54other half is going to be here as
00:57this would be talking about liquid.
00:59So were the newest art.
01:01And we really started right
01:02before covid so we don't have
01:04a whole lot of trials open,
01:06so I think that this talk is
01:08going to be sort of short on data,
01:10but I hope it's going to be
01:13long on potential.
01:14OK, let me see if I can move my
01:17thing forward here in my disclosures.
01:20So the main therapies I'm going to talk
01:22about today are car T cells and till
01:25or tumor infiltrating lymphocytes.
01:26And I think that everybody is
01:28somewhat familiar with these terms.
01:30I know that a lot of people know
01:32a lot about these so far,
01:34but but they're really quite
01:36different therapies,
01:37and I do want to talk a little
01:39bit about the basic biology.
01:41So for those who are immunologists,
01:43bear with us.
01:44Maybe read the newspaper for
01:45a minute or two while I give
01:47you my very simple oncologist.
01:49View of immunology.
01:50So adaptive immunity is where T cells
01:53primarily recognize things that are
01:55foreign and used in attack them.
01:58Now,
01:58one of the reasons we don't attack
02:00ourselves is that we're always
02:02taking little chunks of our proteins,
02:05expressing them on the surface
02:06in something called the major
02:08history compatibility complex,
02:09and the T cell receptors.
02:11Basically,
02:12when when were you know your
02:14own a little bit?
02:15After that all the T cell
02:18receptors that we have the T cells.
02:20That that recognized groups.
02:23That recognize.
02:26The energy is well,
02:27get deleted,
02:28or at least they get turned off OK,
02:30so generally we don't respond
02:32to our own antigens,
02:33But if you get a foreign
02:35antigen like a bacteria,
02:36what happens is let's say
02:37if they go into a cell,
02:39the cell chops up the proteins.
02:41The proteins get put on MHC and
02:43the T cell receptor is going
02:44to recognize there's going to
02:46be a strong interaction,
02:48but that isn't enough to
02:49actually cause killing.
02:50It's only when you get something
02:52called costimulation OK,
02:53and that's via another pathway.
02:54Another set of receptors.
02:55And then you actually get killed all right.
02:58So how can we use that information
03:00to kill cancer cells?
03:01So let me say a little bit more and
03:04go a little bit more in depth into
03:06the T cell receptor signaling first.
03:09So this is a schematic of
03:10the T cell receptor,
03:12the Alpha beta chains are the ones that
03:14actually recognize the antigens and MHC,
03:16and there are signaling molecules,
03:17the Zeta chain and the associated CD3.
03:20So T cell receptors only recognize proteins.
03:22They only work if the antigen is
03:24expressed is presented by MHC.
03:26And they require Co stimulation.
03:27And as I said,
03:28the signaling are through these two things.
03:31Antibodies another way that
03:32we recognize things that are
03:34formed were quite differently.
03:35They can recognize any type of
03:38management doesn't have protein.
03:39They don't use MHC,
03:40and antibodies are much, much stronger,
03:43their interactions with their antigens
03:45and T cell receptors are with their
03:47antigen that makes the interactions up
03:50to 1000 and 10,000 fold stronger in fact.
03:52So someone had the bright idea
03:54of taking the back end of a T
03:56cell receptor and connecting it
03:57to the front end of an antibody.
03:59And we call those guys get chimeric
04:01antigen receptors and so this is
04:03the first generation car and this
04:05is actually in the 1990s.
04:06It was awhile ago so this is the antibody.
04:09OK on the outside of the cell and
04:11this is part of the solar spectrum.
04:13The inside of the cell worked a little bit,
04:16but not terribly well.
04:17A huge breakthrough though came
04:19in the second generation.
04:21And here what was done is they add
04:24a domain to the protein of CD 28.
04:26And what's that? Whoops,
04:27that of course is the costimulatory signal,
04:30and so when you put the customer
04:32let costimulator right in it,
04:33these are much, much more powerful,
04:35and these are really what
04:37we mostly use today.
04:38There are even stronger ones.
04:40The third generations that
04:41use two costimulatory signals,
04:42and there's the 4th generation,
04:44which is a combination of cars
04:46plus other genes that are put in
04:49to make the cells work better.
04:51So.
04:53When you actually the mechanics of
04:55this and in patients are complicated,
04:58just like all cell therapies are,
05:00whether it's transplant or
05:01something like this.
05:02In this case you need to isolate the T cells.
05:06They have to get activated and then
05:08their transduced with the chimeric
05:10antigen receptor and then expanded
05:12and then reinfused in the meantime
05:14patients get lympho depleted and
05:16the reason for that is that.
05:19Probably twofold reasons.
05:20For some reasons,
05:21you're actually treating the cancer
05:22to some degree by lympho depleting,
05:24but that isn't the case for all cancers.
05:27For some,
05:27you're doing it to have a niche for the
05:30T cells to actually live in and grow it.
05:33As you might imagine,
05:34this does not take a day.
05:36This takes several weeks,
05:37so one of the things about this kind
05:39of treatment is patients have to be
05:41well enough to survive those weeks and
05:43to be able to tolerate the therapy.
05:47I'm not going to go into this in detail,
05:50but there are a lot of toxicities
05:52associated with these treatments.
05:53The three famous ones are cited
05:55kind of release syndrome,
05:56which has to do with a lot
05:58of T cells at the same time,
06:00seeing antigen and then causing lots of
06:02cytokines to go into the circulation.
06:04There's also neurotoxicity called
06:06crests or cans and probably
06:08the most severe of these HLH.
06:10Alright, So what are we doing at Yale?
06:13We have one party study open
06:15right now for solid tumors.
06:17This is a kidney cancer trial done
06:20by the company, CRISPR Therapeutics.
06:22It's anti CD 70 which is highly
06:24expressed on clear cell kidney cancers
06:27and then there's some expression
06:29on a few lymphoid type of cells.
06:31Now it's very long name for the trial.
06:34The reason is that it's actually
06:36a little more complicated than
06:37even what I described before.
06:39'cause these are allogeneic engineered
06:41T cells. And what does that mean?
06:44So these are T cells that actually don't
06:46come from the patient they come from.
06:48Sort of healthy weight healthy donors
06:50in whom there they're having the car
06:53put into their own T cells and they
06:55this company using CRISPR CAS nine.
06:57I think a lot of us are familiar with
06:59that to knock out certain other genes in
07:02these T cells to make them work in us.
07:05So what do I mean by that?
07:08Well,
07:08if you take someone else T cells
07:10and put them into you,
07:12they will attack you and you will attack it.
07:15It won't be an effective therapy.
07:17They will get destroyed pretty quickly
07:19by the endogenous immune system,
07:20and they're going to have off target
07:22effects tube via their T cell receptors,
07:25potentially.
07:25So what they've done this CRISPR
07:27therapeutics is in addition to
07:29putting in the car to these T cells.
07:31They've also put in using CRISPR.
07:33They've removed the T cell receptor OK.
07:36They've also removed something
07:37called beta two microglobulin,
07:38which is part of MHC class one,
07:40and the result is is that our immune
07:43system doesn't recognize that it
07:44very well except by some something.
07:46All natural killer cells.
07:47It doesn't do that much,
07:49and it doesn't really recognize
07:51us except via the anti CD 7.
07:53Alright,
07:53so there are a bunch of advantages here
07:55of using T cells from someone else
07:58and not from the patient one is speed.
08:00These cells are waiting.
08:02The patients don't have to wait.
08:04Secondly,
08:04these cells are for someone with
08:06an immune with Acton intact immune
08:08system and a lot of patients with
08:10extensive cancers may not have
08:11intact immune systems and the T
08:13cells may be somewhat dysfunctional,
08:14and obviously it leads to the
08:16potential for more of a drug,
08:18something that can be done with
08:19high levels of production out there
08:21for everybody we've enrolled.
08:22One patient,
08:23we're going to be enrolling one patient
08:25another patient in a few months,
08:27or at the dose escalation phase,
08:28and we'll see how this trial goes.
08:30What else is going on at yelled,
08:32oh, oh, sorry before I, I go there,
08:35let me just. Say that So what?
08:37Some of the challenges are for car T cells.
08:40Specifically in solid tumors.
08:42Well, in general there can
08:43be an issue with persistence.
08:45The car T cells.
08:47They may not last,
08:48but these are big issues for solitaire.
08:51So one there is almost no answers
08:53in a solid tumor cannot lose.
08:55And when you give something like CAR T
08:58therapy against a particular antigen,
09:00it's very likely that the tumor
09:02will just mutate or or lower
09:05expression of that antigen.
09:06And become resistant to it.
09:09In addition to that,
09:10the micro environment of the tumor is
09:12very toxic to a lot of immune cells,
09:14including T cells.
09:15It's hard to infiltrate into a lot of tumors.
09:18There's a lot of necrosis.
09:19Many of the cells have low blood supply,
09:21etc.
09:22And finally,
09:22the toxicity is that that I sort
09:24of mentioned before.
09:25So one of the things that's being done here
09:28is being done by the lab of City Chen.
09:30His is the only 11 going to talk about,
09:33but it's worth pointing out there are many
09:35labs here working on car T type therapies.
09:37City Shuns Lab has developed.
09:39A modular,
09:40high throughput way of developing cartis,
09:42and it's the system that
09:43that again is very complex.
09:45There's a there's no time for me to
09:47for me to describe it and and be I
09:50wouldn't be able to do very well anyway.
09:53But this is a slide from from CD,
09:55but again,
09:56this is his own system that he is
09:58designed using adeno associated virus.
10:00To make parties,
10:02it enables rapid building of new
10:04modules because because modular we
10:06can put in many different cars into a
10:09lot of cells and look at them in parallel.
10:11And it also allows for knockout
10:13of other genes in the cell just
10:16to make to try to improve the
10:18cell's capabilities.
10:22And therefore we're looking for
10:24is superior cancer killing based
10:26on a lot of the platforms that are
10:28used now in the short term goal,
10:30of course, is to generate better
10:31parties against kidney cancer.
10:33He's actually looking at kidney cancer,
10:35which is great. 'cause that's a
10:36lot of what I'm interested in,
10:38and we're also working with
10:40Doctor Krueger on this area.
10:41Cougar, but also he can engineer in
10:44safety control so that if the T cells
10:46are causing some of these severe toxicities,
10:48they can be turned off.
10:51And you know the long term goal,
10:54of course, is to optimize better
10:56parties across solid tumors.
10:57Anan maybe liquid tumors too.
11:00In the first step of that,
11:02hopefully will be once his lab develops,
11:04but he makes a great car.
11:06Is for us to actually put
11:08it into trials alright,
11:09moving on to till let's go back
11:11very quickly again into immunity.
11:13So remember something for and it's
11:15a strong interaction by the T cell
11:17receptor and the MHC complex you get
11:19Co stimulation and you get killing.
11:21Alright,
11:22but how do you get a T cell that actually
11:24kills something that's not for it,
11:27right?
11:27As mentioned before,
11:28we don't interact very well with
11:30our own antigens.
11:31Now,
11:31cancer has sort of solved that a
11:33little bit for us in that cancer
11:35proteins are often mutated because
11:37cancer causing mutations and
11:38therefore the peptides actually
11:40can look for and and so you can
11:43actually get T cells to kill.
11:45As we all know though,
11:46it doesn't really work very well on its own.
11:49We need to give things like immune
11:51checkpoint inhibitors because
11:52of the toxic micro environment,
11:54so I thought that was developed
11:56began developing back in the 1980s.
11:57Was well,
11:58maybe if we take the two T cells out
12:00of that environment, grow them up,
12:03enhance their function with cytokines,
12:04maybe we can cause cell killing
12:06if we re infuse those T cells.
12:09And that's what 'til therapy is.
12:11So much like I described,
12:13the car T cells,
12:14you respect the tumors from patients.
12:16T cells are isolated from those tumors.
12:18They are activated an expanded in vitro,
12:21generally using Interleukin 2,
12:22but there are other interventions we
12:24use and then they reinfuse with the patient.
12:27In the meantime,
12:27agents have been limited depleted,
12:29which is extremely important for this
12:31therapy because we not only have to
12:34have a niche for the cells to go into,
12:36we have to get rid of T regulatory cells.
12:40And the Immune system Act
12:41as a sighted kind sink,
12:42sucking up all the good side accounts
12:44that we want to go to these T cells.
12:46'cause when we infuse these T cells
12:49we give patients in alluding to.
12:51Now before I move on with that
12:53with till I think a lot of the
12:55time when I tell people that were
12:57interested in cell therapies,
12:59they say oh it's cortisol therapy.
13:01But there's a huge difference
13:02is really between CAR T
13:04cell therapies and tilsen.
13:05I think of them is really entirely different.
13:08As some examples.
13:09You know, car T cells are MHC totally
13:11independent right there using an antibody,
13:13whereas 'til therapy is totally dependent.
13:15CAR T cells don't?
13:16They can look at sugars or other
13:19non protein antigens. Tills do not.
13:22Cars are pretty ineffective at
13:23looking at intracellular proteins.
13:25They're working on that,
13:26so maybe we'll get there one day,
13:29but right now they can't really
13:30recognize a lot of the proteins.
13:33And the key thing is that you know,
13:35till can look at any antigens that they see.
13:38So for example,
13:39when we take tumors out of patience and
13:42isolate the lymphocytes from those,
13:44that's going to be a diverse,
13:46diverse type of T cells,
13:48probably recognizing
13:48multiple different antigens.
13:49And, as I said before,
13:51a big disadvantage of car T cells.
13:53Is that you can lose the one
13:55antigen they recognized in their
13:56useless and that may not be as big
13:58of an issue with 'til therapies.
14:00And Lastly,
14:01there toxicities are quite different.
14:03Alright, So what are we doing at Yale?
14:06We have a trial right now for looking
14:09at triple negative breast cancer.
14:11This is an IIT that I'm doing
14:14with IMS Therapeutics.
14:15This is the first dedicated breast
14:17cancer till trial world we've been.
14:19We've enrolled two patients so far,
14:21and one of the reasons were interesting.
14:24Breast is that there's lab here.
14:26Tristan Park,
14:27who's a surgical oncologist here,
14:29an expert on breast cancer and
14:31on breast cancer cell therapies?
14:33Who's actually?
14:33Looking at the samples we get
14:36analyzing for the immune infiltrates
14:38and working with us on the trial.
14:41Just to say a little bit more
14:43about what it actually entails.
14:44It's there's a lot of for any
14:46sort of cell therapy.
14:48There's a lot of work that goes into
14:50it because these are complicated
14:51therapies that require a good timing so
14:54you know once a patient signs consent,
14:56they have to get their surgeries.
14:57Only then do you initiate.
14:59Of course the till culture,
15:00then it's going to be going
15:02for several weeks,
15:03and once you know the till
15:05is growing appropriately,
15:06only then are you going to
15:08limited Lee the patient and then
15:10infuse that into the patient.
15:11And then of course,
15:12as I said,
15:13these people require oil to afterwards,
15:14and they're going to be in the hospital
15:16for a lot of this because they're going
15:18to depleted and then once they recover,
15:20they go home.
15:21We follow them.
15:23So,
15:23so how might we improve some of these things?
15:26Well,
15:27I think infusion and reception isolation.
15:29That's not where the money is,
15:32but clearly we can maybe improve
15:34activating and expanding these
15:36cells and make them better killers.
15:38And the people who are the best at
15:40growing up and activating these cells.
15:42Of course that you are the people of the
15:45Advanced Therapy Lab run by Alexi Burst.
15:47Never die across and they
15:49have a huge amount of
15:50expertise over many years.
15:51Looking at till type therapies.
15:54They've grown up a lot of different
15:56cell products for use in patients,
15:59and I actually hold Inds
16:00for growing Melanoma till,
16:02but of course they actually did it
16:05and we're working together right now
16:07to grow up lung cancer till four,
16:09ideally to eventually put into patients.
16:13Just quickly to point out,
16:14they are very good at growing up selves.
16:17This is 1 experiment which they
16:19actually separated out the PD one
16:21positive from negative cells and
16:22show a lot of expansion in both of
16:25them and this just kind of shows one
16:27experiment of theirs that the cells
16:29they get are actually quite good.
16:31So here till they've isolated out
16:33and these are assays for interferon
16:34gamma production which is an essay
16:36of sort of it's a surrogate for
16:39cell killing and when you take this
16:41pill and you and you you put him.
16:44Alone,
16:44they don't make a lot of interferon gamma.
16:46As soon as you put them with
16:48autologous tumor,
16:49or they recognize antigens
16:50in the setting of MHC,
16:51they make tons of interferon gamma
16:53and then if you give them someone
16:55elses tumor that has emerged,
16:56they don't recognize they don't kill.
16:58So they're very good at making cells
17:00that kill and kill specifically,
17:01which is exactly what we need.
17:05So what can we do to actually improve things?
17:09To make these, what are we
17:11interested in doing here?
17:13Yale to improve these therapies?
17:15Well, the South therapy the AC T lab is
17:17doing experiments to look at adjusting
17:20the growth medium that that they do
17:23it in different cytokine combinations,
17:25different levels of cytokines and
17:27those experiments are ongoing.
17:28But. It's actually striking how
17:30little we know about what happens
17:32between when we take the cells out
17:34of a person and we expand them.
17:37We don't really know
17:38which cells get expanded.
17:39We don't know whether the T cell maturation
17:42states whether they are more naive or more.
17:44Effector cells dictate which
17:45cells that expanded.
17:46We don't know how this concept of T
17:49cell exhaustion relates to expansion,
17:51and we have very little idea about
17:52how homogeneous or heterogeneous
17:54that essential traits are between
17:55tumors or between tumor types.
17:57So and can we.
17:59Can we actually do experiments to
18:01figure some of this stuff out?
18:03And the approach that we're
18:05going to take here,
18:06and we've actually begun taking,
18:08is to do single cell RNA sequencing
18:10and paired with TCR sequencing so
18:12that we can follow specific T cell
18:14clones through growth and figure
18:16out which maturation phenotypes
18:18are the ones that grow the best.
18:22And whether exhaustion has an effect,
18:24and then we're going to do this
18:26across a number of subjects,
18:28so I should say that that's
18:29already been done a little bit.
18:31One it's being done beginning,
18:33and Sam Katz is lab by Sam Kerr,
18:35one of his graduate students,
18:37and I'll be doing some of
18:39these studies on long till.
18:40But really, the person doing this,
18:42Ben Lewin, the Hafler lab.
18:45I have no time around this,
18:46so I don't know where I am on time and
18:48someone told me I've got a little time.
18:50OK,
18:50good.
18:53So let me say one last set of
18:55experiments that are being done at Yale.
18:57Looking at some basic science that could
18:59have a big impact on T cell therapies.
19:01And by the way, I should point out that,
19:03you know, I've mentioned a
19:04few people who are doing work,
19:06but there are many others doing work at Yale.
19:09I they don't have time unfortunately,
19:10but but I don't mean to
19:12leave other people out.
19:13We're doing really vital stuff that
19:15in fact probably there are a lot
19:17of things I don't know about that.
19:18I wish I did.
19:19So one of the things that Sam Katz's
19:21lab is working on for quite awhile.
19:24So some invoices lab is Weismann's
19:26lab is working on is the idea
19:29of M RNA reprogramming?
19:30So he's using something called
19:32crisper I which is a crisper based
19:34technique to knock down genes but
19:36not to actually cause mutations
19:38or or or changes the actual DNA.
19:41The advantages of this technique is
19:43that you can do multiple RNAs at once.
19:46Sorry bout that. The.
19:49Other thing about this of course
19:51is when you do these things by RNA.
19:54RNA is temporary,
19:55so there are pluses to that
19:56and minuses to that.
19:57The pluses are that it's a lot safer.
20:00Not permanently altering itself.
20:02OK, the negative, however,
20:03is that it's only temporary,
20:05so if you want to have effects
20:07that last a long time,
20:09this might not be the method to do it.
20:13But you can imagine situations where using
20:15this kind of technique you could really
20:17turbocharge a cell for short period of time.
20:20So for example,
20:21we could have a car T cell.
20:25And you could use his technique
20:27to make the groups make them
20:29particularly proliferative at
20:30the time at inside accounts,
20:33for example to happen particularly powerful
20:35and killing stimulators of other things,
20:38you could have inhibitors
20:39of negative regulators,
20:40and in fact Sam is shown in his
20:43lab and from Weismans lab that for
20:46example they can at the same time
20:49using their CRISPR RNA I techniques,
20:52Christmas learning techniques
20:53to increase IL two in a cell.
20:56And decrease BCL type proteins
20:58which are made up tatic proteins.
21:00So again when you think about what
21:03I've talked about so far with,
21:05let's say the city Chen Lab in which
21:07they can do multiple different things
21:10to design sort of permanent T cells,
21:13that car T cells that are
21:15particularly powerful.
21:15You could also imagine adding in
21:17these M RNA's to those same cells and
21:20making turbochargers even more so.
21:22There's a huge amount of
21:24combinatorial things that we could do.
21:27To improve his cell therapies,
21:28and there's a lot of excitement
21:31for all those things.
21:32Last but certainly not least,
21:34I just want to acknowledge all that
21:37people have been doing a lot of work.
21:40So what first assault therapy DART 3 docs?
21:43Who do it right now or are nearest
21:46Stewart and I Alex is our CDT
21:48N as fantastic Sharon days
21:50are relatively new but also fantastic
21:53research nurse Ann Pavan or CRA.
21:55I'm not impressed but and then we
21:58have an amazing team here doing,
22:00you know regulatory and and pharmacy etc.
22:03Also, of course, the AC T lab.
22:07Which you know is really going
22:08to be the people developing.
22:10Sorry the next therapies
22:12that we that we do here,
22:14I mentioned the Melanoma team because,
22:16really, we've been doing till
22:17at Yale for very long time.
22:19And the person who got us started
22:21here was Mary Otional and a lot
22:24of the ideas that I talked about
22:26with regards to how to study these
22:28things really came from Mario.
22:30Harriet has done the most to have
22:32anybody here and has done a huge
22:35amount and Sarah Weiss has seen.
22:37A lot of the patients as well,
22:39Katrina Bezak,
22:40is is the person who is really a point
22:43person for a lot of salt therapies here,
22:46and she's actually also
22:48key for setting us up for.
22:50As I said,
22:51the very very likely approval
22:53of heart till in Melanoma people
22:55probably don't know this,
22:57but we have our own something called
22:59CDC which is for cell therapies.
23:01It's a committee to look at
23:03really usage and whether we have
23:06the capability and the capacity.
23:08To do all the different trials we want to do,
23:11none of this would be possible without
23:14the nursing staff on 11/12 North.
23:17A pheresis machine, Hendrickson the RSL,
23:19Audrey King, and of course, the lab.
23:21As I mentioned, and I should point out,
23:24that as I said,
23:25we're trying to get an Ind
23:26right now for long till.
23:28And that's based on funding
23:30we got from the office floor,
23:31and I think I'll leave it at that.
23:35Thanks everybody.
23:40My great presentation. Really excellent.
23:45Let's see if there any questions
23:47from the audience chat room here.
23:54So this is from God.
23:56Looks like you're so excited.
23:58Talk research on adding tablets and
24:00margin molecules or modules in T cells
24:03to get around challenging metabolic
24:04environment for exhaustion times.
24:06So there are there have been, you know, a
24:09lot of they're going to have a bunch of
24:12studies in mice that are really fantastic.
24:15Actually, some of the best ones.
24:17I think we're from Sue Keck,
24:19used to have a cancer biology lab cancer
24:23Menology lab here and now she's at.
24:25Assault or or scripts.
24:28I don't know which,
24:29but she's in California, but absolutely.
24:32So there's no question that in
24:34mice you can knock down metabolic
24:36certain metabolic pathways,
24:38making T cells much more tolerant of the
24:40toxic micro environment in the tumor.
24:42Now that hasn't yet been done in people.
24:45I don't think, or I should say,
24:48it's not entirely true.
24:49People have been doing screens to look
24:52at to make T cells more effective,
24:54and either party or till,
24:56and so there might be a company
24:58out there that has done that,
25:01or we just don't know.
25:03But absolutely,
25:03that's a huge area of research
25:05by a lot of people,
25:07and I think we will definitely
25:09at some point the future be seen.
25:11Carty cells that have metabolic
25:13pathways altered based on this.
25:16This is some recent data looking
25:19Dyson kinase and using that
25:21as a way of overcoming, I'll.
25:24Basic resistance checkpoint.
25:25There being no troubles me design right now.
25:30Look at this picture.
25:36Next comment is from Marcus Poison Bird.
25:38Nice presentation, just to mention.
25:42Let's try this myself.
25:43Every efforts include developing
25:45Massapequa tillmanns.
25:46Yes, absolutely.
25:46I need to talk to you.
25:49And Marcus, yes,
25:50very excited about that.
25:53Ask questions.
25:53Have party studies been performed
25:55patients in multiple Kartik
25:56loans simultaneously against
25:57multiple different energies?
25:58How many tourists again,
26:00is it generally available?
26:01Is detention targets in
26:02different types of solid tumors?
26:04So I don't know
26:05the answer to that,
26:07but I can tell you what I do now.
26:09So I think the idea of using
26:12multiple parties at once.
26:13I think there's a worry that when
26:15you do that and I think their data
26:18for this that multiple ones within
26:20a cell result in a decrement of the
26:22actual response that you need to have.
26:25A lot of the same.
26:29You need to have sort of.
26:33The same cars activate it all at
26:35once to really get a good response.
26:37We have too many androgens.
26:39It doesn't, I think,
26:40work as well like you basically
26:42dilute out the response.
26:43That's what I think.
26:45He basically diluted out.
26:46Now there are there have been people who
26:49are designing right now parties that are.
26:52Their heritage,
26:53their their heterodimers,
26:54so one of the antibody
26:56chains is to one target.
26:57One of the antibody chains to another
27:00target that's only going to work if you
27:02have really high levels of both antigens.
27:05Obviously on the cell,
27:06but those are inexperienced or those
27:08are being experimented on right now
27:10and we'll see how those those work.
27:12There's a real question about if you do that,
27:15you're not going to get the binding
27:18is not going to be as good regarding
27:21the number of tumor specific antigens.
27:23Again,
27:24it probably varies from from cell to cell.
27:28That the older studies seem to indicate
27:30that these are very old studies,
27:32so it's very hard to know what that means.
27:34But for the till studies in in some
27:36of the patients, when I looked at
27:38the ones who had really good responses.
27:41It did look as though.
27:43It was usually one dominant clone.
27:45Sometimes there were two dominant clowns.
27:49It's hard to know exactly what those data
27:51are was a very limited number of patients,
27:53and it's hard to know that they
27:55were looking at the right time.
27:57Like maybe the clone was there did
27:58a lot of what it's supposed to do,
28:01and then a lot of it disappeared
28:02from the blood for some reason,
28:04so it's very hard to know
28:05how much that's real.
28:06The last thing I would say, though,
28:08is that it looks as though the most
28:10important antigens are private neoantigens,
28:12meaning they're not these
28:13big targets that we do,
28:14and that's really a worry
28:15for car T cells in general,
28:17for solid tumors.
28:18So that is sort of a separate issue.
28:22Terrific Mike is always great presentation,
28:24so like to move on to our second speaker,
28:27Doctor IRA, Sufi doctor Susan,
28:29System Professor of
28:30Medicine and Hematology Co.
28:32Directed the adult Carty salty program.
28:34She received her medical emergency
28:36nurse in New York at Stony Brook
28:38and completed a fellowship at Yale
28:41University School of Medicine.
28:42Doctor seems clever work is in the
28:45area of hematological in season.
28:47Tallest algic stem cell transplantation
28:49for his commissions as part of New Sweden
28:52legacy programming transplant teams.
28:53She developed a strong interest
28:55in the president,
28:56promised she's focused her efforts
28:58in treating patients with aggressive,
28:59more focus as part of clinical
29:01trials solid in the response to
29:03treatment without August or outdated.
29:05Translate based on the specifics
29:08of specific seeds.
29:09As to director of the car T cell therapy
29:12product Spell Cancer hospital doctor Soupy.
29:14As part of a team that brings
29:16interview Milliman therapy treatments
29:18options to patients with certain
29:19types of blood cancers doctors.
29:22Thank you very much for having me.
29:36Can you see my slides?
29:40Now you know. Well, you know I have.
29:52Sorry, just have to share.
30:16Yeah.
30:19Yep, that's great.
30:22Thank you so my focus today is
30:25going to be in South therapist
30:27for him to logic malignancies and
30:30and what we're doing here at Yale.
30:34I'm a clinical investigator in
30:36lymphoma and cell therapies.
30:42I have a couple of bad disclosures.
30:47So the I'd like to update you today on
30:51some of the FDA approved indications
30:54for cell therapies and he malignancies,
30:58which are growing by the day.
31:01Some of our research strategies to
31:03improve response rates and prevent
31:06resistance to cell therapies.
31:08Some of the challenges we're facing
31:11clinically and research wise.
31:13And then I'd like to end the presentation by.
31:18I'm giving you an idea about the
31:21work that we're doing here at DL as
31:25part of our immune cell therapy dart
31:28for hematologic malignancies and
31:31then some of the Inter institutional
31:34research collaborations that we
31:36have started to work on.
31:39So, as Mike mentioned,
31:41there's been an evolution in
31:43chimeric antigen receptors.
31:45Overtime,
31:46the once we are still using in the
31:49clinic that are commercially approve,
31:53our second generation cars,
31:55but there is some innovative card
31:58design going on including suicide
32:00cars as a control mechanism for
32:04better toxicity management.
32:05This dual targeting cars that express.
32:09Two different antigen specific
32:11cars by specifics where you have.
32:15Add two linked SF Sfes within one
32:19core vector and then these TCR
32:23mimic cars that are important to
32:27address HLA presented antigen swear.
32:31You're directing the CFP domain
32:34against a peptide HLA complex.
32:40Initially the the target was CD 19 for
32:43B cell malignancies because as you
32:46all know it's a pan bissan marker,
32:49its expression is generally restricted
32:51to B cells and their precursors and
32:55represent it's it's it's surface molecules,
32:58so it's represented irrational target
33:01for therapy and he malignancies
33:04and so all of the agents that are
33:07approved for commercial use.
33:09Or directed at city 19.
33:12So we started initially back in 2019.
33:15The first approval with that DISA,
33:19gentle occlusal in pediatric LL and
33:22subsequent to that we've had a series
33:26of approvals including this agenda,
33:29Cluzel and Axicabtagene Silo Loosle for
33:32aggressive diffuse large B cell lymphoma,
33:36transformed follicular lymphoma and then.
33:40Lisso catagen merilou.
33:41So where you are giving the cells differently
33:45because it's a defined CD4 to CD8 ratio,
33:49so there is some novelty compared
33:52to the two previously approved
33:54products and then more recently Brexit
33:57catagen auto loosle just in the
34:00last year for mantle cell lymphoma.
34:03Anan, finally,
34:04you know just a few weeks ago
34:07Axicabtagene Silo Loosle for relapsed
34:10refractory follicular lymphoma.
34:12So the response rates that we
34:14see with these drugs,
34:16particularly in low grade
34:18lymphomas like follicular,
34:20are extremely good with very high
34:22overall response rate and complete
34:25response rates in pretreated patients,
34:27and then in diffuse large B cell
34:31lymphoma and aggressive deal BCL or
34:34transformed the complete response
34:36rates have varied anywhere from
34:3830 to 50% even though the initial
34:41overall response rates.
34:43Are very high,
34:44so these are still very good outcomes.
34:47Don't get me wrong for this
34:49group of patients,
34:50you know the predicted long term.
34:52Survival is typically less than 10% when
34:55they go on to get CAR T cell therapies.
34:59So we've really been able to to cure
35:01a good subset of those patients.
35:04But as you can see,
35:06you know we still have a long way to
35:09go in aggressive lymphomas be cause.
35:13Even of the patients were cheap
35:15complete remission only about 2/3 are
35:17able to maintain that, but it's very.
35:19It's very exciting because just in
35:21the last couple of years we now
35:24have all of these products that are
35:26commercially approved for use and
35:28that we are already using here at Yale.
35:32So the other rational target was
35:35BCM may in multiple myeloma,
35:38which is highly expressed on
35:41malignant plasma cells.
35:43And we know that higher concentrations
35:47of soluble soluble BCM mayor also
35:50associated with poor outcomes
35:53in in multiple myeloma.
35:55This is very essential in regulating B
35:59cell maturation and differentiation.
36:02And so there have been a series of phase
36:05one and two studies looking at PCM.
36:07A directed car T cells.
36:10And particularly the first one I did,
36:14captain be cluzel,
36:15is actually very close to approval.
36:18These were very heavily pretreated
36:20patients with a median number
36:23of treatments being about 6.
36:25And as you can see,
36:28the overall response rates are extremely
36:31good and even complete response rates.
36:34I'm.
36:36Are are very good and so.
36:40There is of course toxicity
36:43like we saw with anti CD 19,
36:46particularly cytokinin release
36:48and neurologic toxicity,
36:49but again this is a very difficult
36:53population of patients to treat.
36:55The majority of them were what we
36:59call triple refractory to emits an
37:02proteasome inhibitors and about 25%
37:04of patients were pent. Artifactory,
37:07including city 38 monoclonal antibodies so.
37:10These are extremely good outcomes for this.
37:13For this patient population.
37:16And there's now a race to
37:19get FDA approval in the USA.
37:22Not just only for I decapped
37:25agenda cluzel but but also for.
37:28For several other products and
37:30there are efforts being made to
37:33introduce them earlier in earlier
37:36phases of disease and comparing
37:38them to the standard of care which
37:41is autologous stem cell transplant.
37:43And then there are already efforts being
37:47made to mitigate antigen escape by combining.
37:50For example, PC MA Carty with CD19 CAR
37:53T or targeting other other antigens.
37:57So the same cannot be said for acute
38:02myeloid leukemia, unfortunately,
38:04which has been, you know,
38:07a great challenge over the years.
38:10And because many of the potential target
38:14antigens are actually intracellular,
38:17their tumor associated antigens
38:20or or NEO antigens and.
38:24And the proteins that are expressed on the
38:26surface of the malignant leukemic cells,
38:29like City 33,
38:30you know some of those markers
38:32are also expressed on.
38:35Hammer away **** stem cells and so.
38:40The trials going on have had to consolidate.
38:46Cortisol therapy or or rescue I
38:49should say the the mirror with an
38:52allogeneic stem cell transplant.
38:55So there are several critical
38:57and resolved issues with car T
39:00cell therapy in he malignancies,
39:03and I would categorize them in
39:06failure to achieve remission,
39:08disease, relapse,
39:09toxicities with car T cell and
39:12then some of the toxicity.
39:14Some of the challenges in moving beyond
39:18Bissell LL and diffuse large B cell lymphoma,
39:22two other diseases that may not necessarily.
39:28Have high expression of of surface markers.
39:31Easy to visit that are easy to
39:34target with with cortisol therapy
39:37or or certain diseases where.
39:40Malignant clone, residing inside a lymph
39:43node and not necessarily in the circulation.
39:46Like with Abyssal LL and so there's that
39:49challenge of the tumor microenvironment
39:52prohibiting the T cells from getting there.
39:56So. What is it that?
40:00Predicts outcome from a patient perspective.
40:03Ann and risk factors that we can outline
40:07before they go onto car T cell therapy.
40:10So there was this large study that
40:13looked at baseline factors that were
40:16associated with worse overall survival
40:18and progression free survival in
40:21patients who got standard of care.
40:23Axicabtagene,
40:24Sila Loosle and as you can see here,
40:27there were several factors that were
40:30statistically significantly associated.
40:31With worse outcomes and in particular.
40:37I would outline here patients that had high
40:40bulk of disease and patients that had,
40:44for example,
40:45elevated LDH levels pre transplant
40:48patients who required bridging
40:50therapy also were at higher risk
40:52of having worse overall survival
40:55and progression free survival,
40:57perhaps because both of these things are
41:00a surrogate for a higher disease burden,
41:04and then Interestingly some of the other
41:07factors that were associated with outcomes.
41:10Were younger age and also
41:13male gender and and that is.
41:16Very different from what we see.
41:20Included in our prognostic indices
41:23for lymphomas where actually
41:25older patients tend to do worse,
41:28and and this means that we need to really,
41:32really look at our prognostic markers
41:35in the era of cell therapy and
41:39and really redefine what relevant
41:42clinical risk factors are.
41:45So this is showing a multivariable
41:48model of Afexa cottage inside
41:51a looser treated patients,
41:54where again having.
41:57Poor performance status and
41:59also having high elevated,
42:01high LDH levels is associated
42:04with worse progression,
42:05free survival and overall survival.
42:09And then what about, you know,
42:12the the the disease itself?
42:14One of the things that we already know
42:18is that about 25 to 30% of patients
42:22who relapse after car T cell therapy.
42:27Experienced loss of CD 19 and
42:30this was demonstrated.
42:32Inazuma 1 trial and the US
42:35Carty Lymphoma consortium.
42:36So it's not the majority of patients,
42:39particularly in lymphoma,
42:40but it is a good subset and so you know what.
42:45What can we do?
42:48To prevent antigen loss and
42:51and then also this PD One PDL,
42:55one mediated cortisol inhibition and so.
43:00Because we know that PDL one up
43:04regulation is actually contributing
43:07to Carty exhaustion so.
43:10We have this publication nice
43:12publication in Nature Medicine from 2020,
43:15where.
43:17Nirav Shah at. In Wisconsin,
43:21actually looked at point of care manufactured
43:25by specific anti CD 20 and anti CD 19
43:27CAR T cells in relapsed malignancies.
43:30In some of these patients had already
43:34undergone anti CD 19 CAR T cell therapy.
43:37And they do see ongoing responses
43:40in about 40% of patients,
43:42I think out of about 60% that responded
43:46initially and they did not observe loss of
43:51CD 19 in progressing patients when they.
43:55Target at the tumor with the by specifics.
43:58So really very very exciting data.
44:00And then just this year.
44:03Just this past year at ASCO.
44:07They presented results of a first CD
44:1019 and CD 22 targeting Bicistronic
44:14which is dual antigen targeting.
44:18With humanized binders,
44:20to reduce image unicity,
44:22and in addition to 41 BB costimulatory,
44:26they also edit OX 40 to improve persistence.
44:31So based on that?
44:36Data they went on to do a single
44:38arm open label multicenter phase.
44:41One two study where they did tool
44:44dual targeting of CD 19 and CD 22.
44:47But they also added Pember Lizum app
44:50for relapsed refractory diffuse large
44:53B cell lymphoma and Interestingly.
44:56What they saw is there is a high rate
44:58of complete response is about 66%,
45:01although it's too early to say you know how.
45:04If they're going to be durable
45:06and how durable they will be,
45:08because right now they.
45:11They only have short term a data,
45:14but Interestingly there was very little
45:17toxicity with this particular construct.
45:20They did not see any grade three or four
45:24cytokine release or neurologic toxicity.
45:27And that perhaps really is
45:30a reflection of this.
45:32Really novel novel technology that they're
45:35using with a novel pentameric spacer,
45:38and this humanized binders so this
45:40data is very exciting because it's
45:43a therapy that we might be able to
45:46use if approved eventually in the
45:49outpatient setting and delivered
45:51in the outpatient setting.
45:53And that's where they're really
45:56going with this. So I'm.
45:59What else do we know about the?
46:04The disease aspect itself that may
46:08make response to cortisol therapy.
46:12Challenging,
46:12so this data from the Juliet study,
46:16which was the global phase two trial
46:19of tisagenlecleucel in relapsed
46:21refractory diffuse large B cell lymphoma.
46:24They looked at the Myc expression and
46:28tumor infiltrating T cells in that study,
46:31and what they actually found was
46:34that baseline mic negative status
46:36was actually associated with
46:39significantly improved outcome
46:40compared to Nick positive patients.
46:43And that included also longer median
46:46duration of response and overall survival.
46:50And when they looked at the
46:53tumor microenvironment analysis
46:54of the baseline biopsies,
46:57what they saw is that lack or low
47:00frequency of tumor infiltrating
47:02CD 3 positive T cells was also
47:05associated with short progression
47:08free survival compared to patients
47:10that had more than 3% CD 3T cells.
47:16In the tumor so taken together,
47:19these results suggest that make
47:22overexpression or an unfavorable
47:24immunosuppressive tumor microenvironment
47:26with a restricted T cell response
47:28may impact score efficacy in
47:31patients with large B cell lymphoma.
47:38And then this publication and
47:41Oncotarget looked at mutations or
47:44copy number losses of CD58 and TP53.
47:47Genes in diffuse large B cell lymphoma
47:50and showed that these are independent
47:54unfavorable prognostic markers so.
47:59What we know about City 58 is that.
48:05This is actually binds CD two and
48:08the T cells and T cell mediated
48:12cytotoxicity and also NK cell mediated
48:16cytotoxicity is actually quite important.
48:21And quite dependent on the
48:23expression of CD 58.
48:25On the on the tumor tissue.
48:28So in Ash 2020 they presented data
48:32looking at city 58 mutations and
48:35circulating tumor DNA is tumor
48:37DNA and they showed that this
48:41was associated with poor outcome.
48:44After Axicabtagene sila loosle.
48:47So these 358 mutations are or loss
48:50are common and they occur in about
48:5320% of patients with diffuse large
48:56B cell lymphoma and then in addition
48:59to that the protein City 58 protein
49:02expression is also directly related
49:05somewhere between 60 to 80% to 70% of
49:08patients with diffuse large B cell lymphoma.
49:12His do regulate have deregulation
49:14of the CD 58 protein expression.
49:17And as you can see here,
49:19they were able to show that loss of
49:22this expression was also associated
49:24with worst outcomes were in blue.
49:27Here you see 5058 wild type and
49:30in Red City 58 alteration so.
49:33Fewer patients that had loss of
49:36CD 58 expression actually went
49:39on to achieve complete remission.
49:41The majority either did not respond or
49:44they achieved only partial remission.
49:47And then they went on to to progress,
49:50unfortunately.
49:56So, meisner. Amazing group.
50:01Presented this data very,
50:03very interesting this year at ASH
50:06where they showed that integrating
50:09City 22 costimulation within cars was
50:12actually able to overcome City 58 loss
50:16in in tumor cells and they tried this
50:19both insists an entrance and it wasn't
50:23until they integrated it entrance
50:25that they saw that they saw these.
50:29These results so.
50:30This was very eye opening for us because,
50:34you know, we used to think that.
50:38All of the Co stimulation is
50:42coming from from other cells.
50:45And we didn't really realize how
50:49important actually ceded to City to
50:53was in in in car mediated cytotoxicity.
50:56So City 5862 was a very novel
50:59axis of car resistance that was
51:02uncovered through deep correlative
51:04studies in patients getting cell
51:07therapies and city 58 loss,
51:09or mutation pretends a poor outcome,
51:12but perhaps we can overcome that by
51:15engineering these cars that integrates
51:17it is 2 signaling in entrance and
51:20this is important because City 58
51:23Lawson mutations are also common in.
51:26Other cancers in are likely able
51:29to mediate resistance to other
51:31cars and immunotherapeutics,
51:33so it could perhaps be applied in
51:36other other malignancies outside
51:38of diffuse large B cell lymphoma.
51:42So I've spoken to you about
51:44the relapse reflect setting,
51:46but we are now doing studies pushing these
51:49cellular therapies in the second line,
51:51and even in the first line settings,
51:54Uma 12 looked at very high risk patients
51:57with high grade B cell lymphoma.
52:00With Myc, BCL,
52:01two and BCL 6 translocations,
52:03and they did pet directed therapy
52:06and for patients who still had
52:08disease after two cycles by PET scan.
52:11They actually went on to get their
52:15T cells collected and then receive.
52:18Car T cell therapy. So these are the results.
52:24They saw a very high 85% of the
52:27overall response rate with 74% CRS.
52:30This is a difficult group of patients
52:32for us to treat because F oftentimes
52:35they do not achieve remission and
52:38they progress right through therapy.
52:40And then Interestingly also or
52:43maybe as expected.
52:44The car T cell expansion was greater in this
52:48study when compared to Zuma one which were.
52:51Patients with relapsed refractory
52:54disease was were treated so so
52:57higher quality T cells with higher,
53:01with higher higher proliferation
53:04and higher expansion.
53:06So this has not.
53:07Obviously it's not prime time for us
53:10to change our decision-making and
53:12move this to to first line therapy,
53:16but there is definitely improved T
53:18cell fitness in first line treatment
53:21and this may be the wave of the future
53:25when we get more long term data.
53:28So just to sort of recap for you,
53:31some of the studies in relapsed
53:34refractory disease and.
53:36Also to include some data with
53:39CLL and mantle cell lymphoma,
53:41as you can see very high overall
53:44response rates across the board
53:47and then somewhere between 50 and
53:4975% complete remission rates in
53:52in relapse patients.
53:54So where are we going with this?
53:57As I mentioned,
53:58we're trying to introduce them earlier in
54:01the lines of therapies.
54:03So many phase three studies looking at second
54:06line for transplant eligible patients,
54:08randomizing them to transplant versus
54:11Carty and then and then perhaps eventually
54:14in the front line and then in a LL
54:18patients looking at patients one or
54:20MRD positive after one line of therapy.
54:23And then hopefully some of these phase
54:26three data in adults will result in
54:28an approval because we still don't
54:30have an approval in a LL for patients
54:33over the age of 25.
54:35So what about alginate cars is,
54:38as you know, there are some limitations
54:42with autologous CAR T cells,
54:44particularly in terms of cost harvesting
54:46and manufacturing failures and disease
54:49really progressing during manufacture,
54:51and we can really bypass a lot
54:55of that with donor derived.
54:58Sales where we can really reduce the time
55:01to infusion significantly and actually
55:03be able to take more patients to Carty.
55:07And there's an increased probability
55:09of healthy cortisol generation and the
55:12convenient of repeat dosing if necessary.
55:15So these are some of the investigational
55:17allogeneic CAR T cells for him malignancies.
55:23Targeting different antigens
55:24both in lymphomas AALL,
55:26but also in multiple myeloma.
55:28This is still early phase one phase two data,
55:32but I think that this is going to
55:36be the wave of the future in Carty,
55:40so I'm going to now shift gears to
55:43just briefly talk about our cortisol
55:46therapy program here at heel we
55:49started our efforts in 2018 and were.
55:52Able to eventually treat our
55:54first patients in January of 2019
55:57and then were able to actually
56:00achieve fact accreditation after
56:03extensive auditing of our program.
56:05So this is our organizational chart.
56:08As you can see, it includes.
56:14Collaboration between multiple
56:15different departments.
56:17Physicians nursing program self
56:19therapy with Diane and alexianne.
56:22Also a pheresis with it's
56:25neither and Jeannie Hendrickson.
56:28We have a really trained group of people
56:31being able to freeze the patients and
56:34then and then give the conditioning
56:37therapy and manage the toxicities.
56:40So what have we done in the last
56:43two years with 357 patients,
56:46some of them with axicabtagene, sidlu,
56:49sillence, amethys agenda, cluzel?
56:51We're just starting to actually
56:53expand to mantle cell lymphoma
56:55and then follicular lymphoma.
56:57And we've also treated 11 patients on
57:00clinical trial for multiple myeloma
57:02with anti BCMAM RNA CAR T cells.
57:05And as Mike mentioned there are
57:08some there is much less toxicity.
57:11But there are also challenges in terms of.
57:15In terms of the short life of the M RNA,
57:19and perhaps the need for frequent
57:22dosing or or maybe introducing this
57:24in earlier lines of therapy where
57:27patients do not have are not very
57:30heavily pretreated and do not have
57:32an extensive burden of disease
57:34with a new approval and multiple
57:37myeloma expected this year,
57:39there's actually an anticipated
57:40significant rise in numbers of
57:43patients that were going to be treated.
57:45And what that means is that we can
57:48collect a lot more data and and do a
57:51lot of a lot of studies on patient samples.
57:55So this is the yellow advanced cell
57:58therapy lab and then this is our
58:01immune effector cell therapy dart
58:03that Mike and I call lead and and
58:06we have a team as he spoke about.
58:09I won't belabor this,
58:10but we wouldn't be able to do what
58:13we do without their amazing work.
58:16So this is our portfolio.
58:18We have some studies that were
58:20opened and finished accrual,
58:22but as you can see we have a large number of.
58:26Pending studies at the majority of
58:29which are very novel because they
58:33are either by specific cars or their
58:36allogenic cars sitting 19 NK cars and.
58:43You know, really also these comparative
58:46randomized comparative studies introducing
58:48car T cells in the earlier lines of therapy.
58:51You know, we really took a set back with
58:54with Chobit, but we really hope to be able
58:57to open all of these studies in the next
59:01few months and start enrolling patients.
59:05So this is. These are some of our
59:10instruct intra institutional research
59:12collaborations with Doctor Mina Xuan,
59:14Doctor Jordan Pober in Pathology,
59:17looking at the vasculature in the
59:19human lymphoma nodal micro environment
59:22collaboration with shall issue.
59:24Looking at these phase cars for low
59:27antigen expressing B cell cancers and
59:30then collaborations with City Chen.
59:33So in the interest of time,
59:36I will just briefly.
59:38Discuss these collaborations, but.
59:41As you know.
59:44Getting the T cells to the tumor tissue
59:47and increasing homing is actually
59:50quite a challenge for most patients,
59:53and there have been several attempts
59:55overtime looking at how we can
59:58improve homing for lymphocytes.
01:00:00Including cell surface painting,
01:00:02for example,
01:00:03to insert alphabeta integrin
01:00:05into primary lymphocytes,
01:00:06including glyco engineering CAR T cells,
01:00:09for example,
01:00:10to enforce E selectin binding
01:00:13because as many of you may know,
01:00:15car T cells do not express sialyl
01:00:18Lewis X and do not bind deselecting,
01:00:22but we can actually achieve enforce
01:00:25their display on human CAR T cells by
01:00:28surface fucosylation and this will.
01:00:31Results in very robust E selectin
01:00:34binding even under conditions of
01:00:37hemodynamic shear and then also gene
01:00:41therapy using genetically modified
01:00:43lymphocytes targeting VEGF or two
01:00:47in highly vascularized tumors.
01:00:49But unfortunately all of this data is
01:00:52in mice and we don't really know what's
01:00:55happening in the human tumor vessels,
01:00:58and we do not have any idea about the
01:01:01spatial relations of these two of
01:01:04these tumor infiltrating lymphocytes,
01:01:06and so the aim of our study is to employ
01:01:09highly multiplexed immunofluorescent
01:01:10imaging of human lymphomas to specially
01:01:14specially correlate and phenotype.
01:01:16The infiltrating even of sites
01:01:18using formalin fixed and.
01:01:20Not been embedded tissue specimens,
01:01:22and then we want to apply these
01:01:25results to investigate the informer
01:01:27vasculature in car T patients.
01:01:29Pretreatment and posttreatment.
01:01:31This is Nathan Paulsen,
01:01:32one of the residents in pathology,
01:01:35and he's already looked at some.
01:01:38Or lymphoma tissue samples showing that
01:01:41there are differences in expression
01:01:43levels of vascular adhesion molecules.
01:01:45For example,
01:01:46between diffuse large B cell lymphoma,
01:01:49classical Hodgkin lymphoma and T cell rich,
01:01:52large B cell lymphoma.
01:01:53And so we want to do high dimensional
01:01:57phenotyping of these vascular cell
01:02:00in FPED identified tumor samples
01:02:03looking and all of these,
01:02:06all of these vascular markers and
01:02:08the we anticipate to find some
01:02:11correlation of the vessel phenotypes
01:02:13with the abundance and phenotype of
01:02:16the leukocytic infiltrates and to
01:02:19correlate there this with the patients
01:02:22outcomes post car T cell therapy.
01:02:25And.
01:02:27If we're lucky,
01:02:29we're going to be able to show that
01:02:32some two rationale for combining
01:02:34these CAR T cell therapies with
01:02:38antiangiogenic therapies, particularly.
01:02:42And this can be a launching point
01:02:44for us to
01:02:45actually eventually in the
01:02:47future consider a trial.
01:02:49So this is some of the data
01:02:52from Chalet Sues Lab where he's
01:02:55using these face cars where.
01:03:00Targeting specifically low density
01:03:02surface antigen and he's been able to
01:03:06show that car signaling is different
01:03:09from T cell receptor signaling and that
01:03:12it bypasses certain proteins like latch.
01:03:16And has a different pathway that results
01:03:19in acting polar MIS polymerization
01:03:22compared to TCR signaling, and he's.
01:03:26Actually using this information to
01:03:28develop these phase cars on lipid
01:03:31bilayers that he can modulate to
01:03:34recognize low density surface antigens.
01:03:37So this is again some of the data that
01:03:40he is generated in his lab where he's
01:03:43been able to show that Corti signaling
01:03:47bypasses this important scaffold
01:03:50protein promoting phase separation and.
01:03:55He's been able to build this face
01:03:57cars where they contain and you
01:04:00control modality that can leverage
01:04:02domains affecting phase separation to
01:04:05modulate Carty activity recognizing
01:04:07low density surface antigens.
01:04:10He's constructed Roger B cells
01:04:12expressing low to High City 19 and
01:04:16this is just some very preliminary
01:04:18data that he has showing that this
01:04:22point phase cars display superior
01:04:24activity compared to control parties.
01:04:26Again,
01:04:27low against low CD 19 so we are
01:04:31hoping to look now at some of our
01:04:35patients blood samples that have.
01:04:37Low CD19 expressing he malignancy's
01:04:40either at baseline or following
01:04:44treatment with CD19 CAR T cell therapy
01:04:47and and and showing how these pace
01:04:50cars will be able to to act against
01:04:53these low CD19 expressing tumors.
01:04:56And then we're also hoping the
01:04:59future to collaborate with City
01:05:02Chen looking at these dual knock
01:05:05in knockout CAR T cells that he's.
01:05:08Engineered in his lab targeting two different
01:05:12antigens on lymphoma cells and and.
01:05:20Doing PT one knockout.
01:05:24So this is our.
01:05:26This is our group and.
01:05:30Dedicated really dedicated
01:05:31group of people and I'm very
01:05:34thankful for their work and I
01:05:36went a little over time so I'm
01:05:38happy to answer any questions.
01:05:45So I don't think there's
01:05:47any questions on the.
01:05:49Chatroom at this point so.
01:05:52I was thank you for a
01:05:54terrific presentation.
01:05:55Thank you, thank you.