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

Transcript

• 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.