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

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

March 24, 2021

Yale Cancer Center Grand Rounds | March 23, 2021

Michael Hurwitz, PhD, MD and Iris Isufi, MD

ID
6337

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.