Immunotherapy for Hepatocellular Carcinoma: Promises and Challenges

June 24, 2020

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Chen Liu, MD, PhD

Yale Cancer Center Grand Rounds | June 23, 2020

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00:00Thank you all for
00:03joining us it's a real privilege
00:06today to welcome our new chair
00:09of pathology at Yale,
00:12Doctor Chen
00:14Liu is the Anthony N. Brady Professor of Pathology
00:18who joined us on March 1st?
00:20So really right
00:22into the thick of it.
00:26And in the short time he's been
00:29here he has
00:31Collaborated with all of us,
00:34particularly in his efforts to
00:36champion the testing efforts that were
00:40essential in our response to COVID.
00:43Chen received his training in China
00:46received his postgraduate training
00:49at Peking Medical College,
00:52his PhD in pathology at University of
00:55Pennsylvania and most recently had
00:59served as the chair of pathology immunology
01:02and Laboratory Medicine,
01:03as well as the chair of the center
01:07of dermatology at the Robert Wood
01:10Johnson Medical School in New Jersey.
01:12Chen's career has been focused on the
01:15work in viral hepatitis liver cancer
01:17immunotherapy graph versus host disease,
01:20as well as cancer epigenetics,
01:22where he's made important
01:24contributions in all of these areas.
01:27Really understanding mechanisms of
01:29carcinogenesis defining cancer
01:30biomarkers and equally importantly developing
01:33new therapeutic approaches and
01:34we're really so privileged to have
01:37Chen not only as the new chair,
01:39but as a member of our Cancer Center,
01:42and this really gives us, I think,
01:45really great additional expertise and
01:47strength among the talent we have here.
01:54Thank you very much Charlie,
01:56for that
01:57nice introduction and also more
01:59importantly, thank you for the
02:01opportunity to present this talk.
02:25Just briefly, I am a liver
02:28GI pathologist so I'm actually practicing
02:31in the clinical
02:33service and I'm also a pretty
02:36good mouse pathologist in general,
02:38so I think basically I serve
02:40as a sort of expert
02:43consultant.
03:30So today
03:31I would adjust the
03:33top one of the you know.
03:34You know main research project
03:36and you might laboratory,
03:38which is sort of how to divide
03:40up how to developer mode.
03:42Effective email Sara pay for
03:45hyper cellular carcinoma.
03:47OK, so good.
03:48So uh, as you know a better seller cars.
03:52Nobody is very deadly disease.
03:54You know it's actually really they
03:56will come and you know we have almost
03:59600,000 new cases a year globally.
04:02In contrast to many other type of cancers,
04:05you know.
04:06Mostly theology is a relatively well not.
04:09For instance,
04:09you can see it's almost 80% of those
04:12cases are caused by two viruses,
04:15hepatitis B and hepatitis C virus is,
04:17and then the other,
04:19so you know it's a toxin alcohol awesome.
04:22Recently fatty liver disease and
04:24some metabolic liver disease.
04:25You know you know all contributed to
04:28the etiology of hyper server carcinoma.
04:30I think one thing in common is in
04:33majority of the cases an there
04:35is long standing.
04:37Monitor liver disease and
04:38then develop chronic.
04:39You know you know hepatitis
04:41and also cirrhosis,
04:42which is almost like a
04:44precancerous condition,
04:45and then become my father Cellular
04:47Carcinoma because of this uniquely
04:49theology and the pathogenesis there at
04:52least two things we can think about.
04:54Why is the best way to eliminate it's,
04:58you know cancer is really with it is emitted,
05:01the ideology. So in this case,
05:03if you can eliminate hepatitis B,
05:06hepatitis C with.
05:07Pretty much he limited 80% of the of
05:11the cancer, so hepatitis B vaccine has
05:15been practice of over multiple decades.
05:18I think the data is already show because
05:21of the widespread you know like seen
05:26vaccination against hepatitis speed,
05:28the incidence of liver cancer indeed has
05:32seen trending down in the hepatitis B.
05:36Prevalent regions and so the other thing is.
05:41Question is because there is a
05:44longstanding process for, you know,
05:46from the initial lever insult to the
05:48cancer formation is you already talked?
05:51We're talking about a 20 to 30 years and
05:54then we do have very high risk population,
05:58so we know this high risk population,
06:01so this provides a window of opportunity for
06:04us to develop ball markers or something.
06:07Therapeutic interventions.
06:08In other words,
06:09we can identify the underlying pathogenesis
06:11and hopefully we can identify targets.
06:14And to intervene to prevent out trade.
06:18Now I've had this order carcinoma,
06:21so currently you know.
06:23Unfortunately the you know,
06:25liver cancer therapy is really behind
06:28too many of other solid tumors.
06:31We did not have really big progress.
06:34You know,
06:35for hyper server carcinoma therapy
06:38and there is absolutely unmet
06:40need in this cancer,
06:43so we were transplantation can be
06:45considered as a curatives therapy.
06:48If we had identified the tumor
06:50earlier and also there is a lever
06:53available for their patients,
06:55those can be considered cured.
06:57Killer and the surgical resection is,
07:00you know,
07:01has been performed by the recurrence is,
07:04you know it's almost 70% of patients
07:06after the surgical resection.
07:08So overall,
07:09with the typical therapy currently,
07:11you know the three year survival
07:14is still less than 20%.
07:16And, uh, in about a 10 years ago that,
07:20uh, one first therapy was approved,
07:22which is arrive in a, you know.
07:25So resonator is terrorism Chinese
07:27inhibitor and so that only showed moderate
07:30effect in the small number of patients.
07:33And all only the pasta two or three years
07:36we have seen in another momentum which
07:39is a checkpoint inhibitors role in the
07:42treatment of other Cellular Carcinoma.
07:44So we can talk a little bit more about the
07:48checkpoint inhibitors in nice to feel slides.
07:52So first of all,
07:53these are the tires in kind is
07:55currently being tried and approved
07:57of tested in hypothetical carcinoma.
07:59So rifle name wrecker ever made
08:02neighbor which is basically another
08:03version of the revenue and then
08:05the other tools also tested.
08:07But all of those types and kindness is.
08:10It's really more broad inhibitors
08:12rather than specific target,
08:13so it's been believed.
08:15You know those kind of.
08:17You know the haters.
08:19But you hate this kinase activity,
08:22and you know inconsequence surprised
08:24to know vascularization or really
08:27play some sort of anti angiogenesis
08:30effect so you know we have
08:33actually also shown that you know,
08:35for example, survivor name can also
08:38interfere. The mitochondria is in a
08:41particular carcinoma. In other words,
08:43they're probably multiple mechanism for
08:46the tyrosine kinase mechanism of action.
08:49We have had our cars in them and I would
08:52like to show you this slice and this is a uh,
08:56you know, you know, uh,
08:58the slides made by a charmer and Addison,
09:01so this tell you,
09:02you know how you know the therapy.
09:04You can see the chemotherapy,
09:06you know this is for cancer as a whole.
09:09So one thing you can tell you
09:11can see the email server which
09:13represented by this green line is,
09:16you know, certainly is superior
09:17to any other sort of monotherapy.
09:20However, if you combine the
09:22Indian up check behind it,
09:24therapy with more targeted,
09:26you know genomically targeted agent,
09:28you can see dramatic improvement,
09:30so that's probably why you know the
09:33email therapy attract such attention.
09:35I think as you know over the past
09:38decade we have been talking a lot about
09:40the email therapy and particularly
09:43the clinical application of female
09:45checkpoint inhibitor really created
09:48this momentum for cancer therapy.
09:51Alright,
09:51so with that background,
09:53will see you how to look at the liver.
09:56So what is the unique aspect unique
09:59aspect of carcinoma?
10:01So this I have to say we have not much
10:04understanding on the overall immunology
10:07or you know biology of the liver as
10:11well as the hypothetical question.
10:13So we were had.
10:14It has been considered as a
10:16immunologically tolerant organ,
10:18and that means you know there
10:21are data shows all the humans.
10:23Activity cells actually are
10:25eliminate in liver.
10:26In other words, in the liver is,
10:29well, very well protected.
10:31And the dancing in the in deliver,
10:34you know you have a wait.
10:37There are a lot of energy
10:39and presenting cells.
10:40However,
10:41there are data shows.
10:42Most of the antigen presenting cells
10:45actually induced or you know Tara
10:47Jennifer phenotype rather than,
10:49you know,
10:50activate the cellular immunity and as
10:52well as I mentioned earlier majority
10:54for the hyper Cellular carcinoma is
10:56actually rising from the background
10:59of chronic viral infections,
11:00hepatitis B, hepatitis C.
11:02So this has been known.
11:04All has been extensively studied.
11:06Long standing chronic very affection,
11:08actually rendering T cell exhaustion.
11:10So this is another challenge is we
11:13have to think about when we talk
11:16about how to develop more effective
11:18immunotherapy for Heather Cellular
11:20Carcinoma so that you know that.
11:24Also HTC, you know it has a very
11:27higher expression of PD L1.
11:29You know?
11:30P DL1 is alignment for PD one.
11:33So those engagement
11:34actually surprised that I.
11:36Activated you know anti tumor teazles.
11:39That's probably why this is,
11:41uh,
11:41you know how you use.
11:43You know you can actually use
11:46checkpoint inhibitor to block this
11:48interaction between TDLPDL One and 51.
11:51The other aspect is there are many
11:53regulatory T cells in hypothetical carcinoma.
11:56So we have shown you know that
11:59there is a higher number of
12:01regulatory T cell as well as as
12:04myeloid derived.
12:06The tumors surprise if TS LMDS sees,
12:08so those are the challenges
12:11we have to consider.
12:12And then you know when put
12:15all these things together,
12:16you know the probably we need
12:18to think about the multiple
12:21strategy to really develop a more
12:24effective immunotherapy for HTC.
12:26And now you know,
12:28staying is more broadly.
12:29Currently in clinical application
12:31also has been very exciting.
12:34Is a checkpoint in Hibbett are
12:36you see the impact will check
12:39component inhibitors really is act
12:42on multiple spy type of the middle.
12:45You know regulation most
12:47specifically blocking PDYPTL.
12:49Interaction.
12:49So the other so you can think
12:53about is to really eliminate.
12:56Also at least inhibit
12:58regulatory T cell in the cancer,
13:00and the other is so more exciting.
13:03You know,
13:04that's what I'm going to
13:06talk about a little bit more.
13:09Is adoptive cell transfer therapy
13:11for those adoptive transfer therapy.
13:13We really can't think about Tuesday.
13:16Why is non antigen specific, you know?
13:19Autologous tiles,
13:19for example, in case hours,
13:21all tumor infiltrating the
13:23emphasize and then the other,
13:25is actually another modified
13:26version of adoptive cell transfer.
13:28Transfer therapy is engineering T cells,
13:31so this will be the car T cells.
13:34Also, I will spend a little bit time to.
13:37Another thing is,
13:38think about if we can identify
13:40tumor specific antigens.
13:42We can think about is to use to developers.
13:46So actually this probably more ideal
13:48because you will be able to induce.
13:51Kilmer space saving other immunity.
13:52So we had done some working in this area
13:56so I will show you what we have found.
13:59OK, this is just the introductory
14:02slide you know for what we are.
14:05You know, you know,
14:06for this audience you probably
14:09all very well now what you know,
14:11the started for email.
14:13Check it.
14:14Check Point inhibitor therapy for
14:16example is really blocking these two
14:19inhibitory molecules PD L1 and the CD L4,
14:21so those are inhibitory.
14:23So basically with the variables develop
14:25all kinds of Therapeutics called
14:28checkpoint inhibitors is blocking those two.
14:30Inhibitory pathways under treated
14:33as a way to activate the T cells.
14:37So for liver cancer, as you know,
14:39at least right now I mean this.
14:42You know the update is I say
14:44this is updated today.
14:45Maybe it will be changed.
14:47You know very soon as well,
14:49because for right now we have
14:50at least three FDA approved.
14:52The trackpoint inhibitor is when
14:54the pipe and temporal needle and
14:56the other one is against the
14:57CTLA is I believe mad.
14:59So those are three FDA approved and
15:01certainly there are many in the pipeline.
15:03You see how busy this lies is,
15:06you know you see those.
15:07Those are the current.
15:09In Eagle trials registered away is,
15:11you know, a clinical trial data.
15:14And those are the space three trials
15:17with all kinds of transforming hitters,
15:20so you will notice is the most of
15:22the trials actually is looking
15:25at the combination therapy,
15:27particularly with tyrosine
15:28kinase inhibitor also entity.
15:30EG Eiffel you hitters as well as
15:33the combined with some, you know,
15:35a local regional therapy or
15:36surgical resection so you can
15:38see the estimated releasing date.
15:40You know complete, complete,
15:41complete completion date.
15:42It will be in the next year or two.
15:45We're going to see a lot about you
15:48know the you know the results you know
15:51related to checkpoint inhibitors for HTC,
15:53so this is really you know the
15:55exciting part of you know for
15:58the in this field right now.
16:00So now let me try to talk about a
16:03little bit more like other approach
16:05which is active investigation by
16:08quite a number of groups in the world.
16:11So which is really adopted cell transfer,
16:14you know, therapy.
16:15So for those you know this concept
16:18was in the really knew.
16:19So the first tumor,
16:21infiltrating lymphocytes, are paid.
16:22As you may know,
16:24it was divided decades ago by
16:26Rosenberg at NCI.
16:27So in that case you know he isolated tail.
16:31Infiltrating lymphocytes for isolated
16:33fuel from Melanoma patients and
16:35reinfused ourselves back to the patient.
16:37But now over particular,
16:39over the past few years,
16:41more and more evidence point of the
16:44really efficacy of this sort of therapy,
16:47and also most recently you can actually,
16:50you know culture.
16:52Certain cells in X-ray invaluable in
16:54Mitchell and stimulative certainty cells,
16:56and to induce so-called settle
16:58toxic T cells and then refilled.
17:01So cells back to cancer patients.
17:04And another is really the
17:06innate immune response arm,
17:07which is in case else,
17:09you know by definition in case else
17:12it's the main biological function
17:14is really as a surveillance.
17:16Places Seville's role in the
17:18party at that will check out
17:20all the auto kill tumor cells.
17:23So there are a lot of attention
17:25on empty cells as well,
17:27so I will share a little bit of data we
17:30have written that down within himself
17:32and of course the excitement coming
17:35from the engineer T cells which is party.
17:38So those are we'll just talk back so.
17:41So let's first to look at it.
17:44This how we can induce more.
17:46After specific immunity.
17:47Alright,
17:48so in this case you know
17:50you probably won't find out.
17:52Is there any tumor antigen or is
17:54there any specific tumor energy
17:56you had asserted carcinoma?
17:58So indeed,
17:58you know over the years we know
18:01Alpha fetal protein is one of the
18:03first tumor antigen associated
18:05with hypothesize are carcinoma.
18:07However with multiple different
18:08groups of trying to use Alpha
18:10Fetoprotein for email therapy,
18:12the results are really mcleese mixed
18:14because maybe the Alpha fetal protein is.
18:17Really highly expressed in embryo
18:19Genesis and also in some other
18:21highly proliferating cells,
18:23so it's great it louder challenge
18:26so this slide show that you over
18:29the years and actually for hyper
18:31disorder carcinoma.
18:33Fortunately we do with you know
18:35we did find a variable to render
18:38gene called glide different three.
18:41You can see this is likely country
18:44expression.
18:44You know fairly specifically
18:46specifically expressing.
18:47Carcinoma So what is great because
18:50way so this clapping series X you know
18:53it's you know it's an X chromosome,
18:57so it's highly expressed in the Amber
19:00Genesis and stuff you know in adult
19:03issue and then re over express in more
19:06than 90% of hypothesized personal.
19:08So unfortunately we really do
19:11not understand the role of the
19:13life agents rate at the moment.
19:15I mean I had two graduate student
19:18had dedicated their season.
19:19Trying to figure out what is the
19:22biological role of glycogen 3.
19:24After disappointing,
19:25you know we have say it looks like
19:28the gladness re somehow interact with
19:31other growth factor and to create a
19:33micro environment on the cell surface
19:36and it would direct the downstream
19:38safely to regular cell growth.
19:40Interestingly enough gladly constraint.
19:42And now there is a general like a genetic
19:45syndrome which is a Simpson Globby,
19:47you know a Homer syndrome.
19:50I have never seen temptation like
19:52this is only rated from textbook,
19:54so this is a syndrome actually.
19:56Is that loss of function of by pigments
19:59rate so you can see it in overall if
20:02you look at the syndrome is it looks
20:05like deletions of glycogen straight
20:07create some sort of overgrowth.
20:09Alright,
20:10so this you know that it has been
20:13confirmed in the now customize.
20:15Look at this.
20:16Now customize the embryo is just
20:18the much larger than the white type
20:20so this is almost the antithesis
20:23for us to think about.
20:25If it's a delight,
20:26beacon three can somehow as you
20:28know looks like tumor antigen mold,
20:31cancer formation but somehow during
20:33development is actually typing.
20:34Three seems to act as surprising
20:36function and to check the development.
20:39You know during the.
20:40And then if you look at it,
20:42overall expression pad network IP gains
20:44rate there, it's really you know,
20:46three major organs expressed,
20:48blindness Ray and organize.
20:49Well,
20:49I you know the highest one
20:51actually is a play center, right?
20:53So the play center has highest
20:55expression of the clapping.
20:57Answer it,
20:57but that's why I think that just last
21:00month I went to see and Harvey Doctor Harvey,
21:03Claimant,
21:03who is really the leading expert in press
21:06enter here at you and I talked with him.
21:09So I said, You know?
21:11Let's figure out what is it.
21:13Skype,
21:13even serious role in place and are right.
21:16I know what the other organisms,
21:19fatal liver you see.
21:20This looks pretty express
21:22and then also fatal lock.
21:24And then I add other tissue.
21:26Long is completely zero expression.
21:28I thought you know like make
21:30sure they were tissue.
21:31Now normally they do not express flight
21:34PS3 but however is expressed in.
21:37Is the you know the email,
21:39his chemistry, you see all the you know,
21:41the cancer cells expressed those things.
21:44You know the proteins on the cell
21:46membrane and actually this is one
21:48of the market you know in full
21:50pathologist will liver pathology.
21:52Sometimes when we question
21:53about whether this is cancer or
21:55not, we tend to do email history,
21:58chemistry to confirm, you know,
21:59to help us to make a diagnosis of hypothesis,
22:02elder personal. Alright,
22:04so this is also we checked with all
22:07the different cancer cell lines,
22:10tissues and both at mouse and human.
22:13So Interestingly, the mouse,
22:14iPad or cellular carcinoma does not express.
22:17Could I pick three and only in the
22:19humans of different cell lines we
22:22have checked and the overexpressed
22:24clapping in the normal hypothesize.
22:27But does not express,
22:28so this is a because of the mouse
22:32had a salad or carcinoma does not
22:35express quite happy constraint.
22:37Actually created item vantage for us to
22:41create some model to study this date.
22:44Potential human or therapy.
22:45Because when we talk about it,
22:47we want to do emails Arabic.
22:50You know we have to create a model and
22:53see how we can test some of our ideas.
22:56So this is just the last, you know,
22:59sort of a last slide of Truth demonstrated
23:02the collective Pickens Research,
23:04you know, expression and its role in,
23:07you know.
23:07You can see it so here is, you know,
23:11almost exclusively expressed in HTC and
23:13the same time you can see it is correlation.
23:17It seems to be correlated with
23:20worst personalities.
23:21So now,
23:22as I mentioned,
23:23that has turned to see how we built
23:25this model because we have over
23:27the years and longer we built this
23:30model which is the Bob semis totally
23:32immune are committed and then we
23:34have this person normal cell like
23:36original derived from optimise.
23:38So as I mentioned earlier so this cell
23:41line does not express any guy picking three.
23:44So what we did is to overexpress human
23:46like Bacon three in the mouse outline
23:49and then inoculate through this minus.
23:51And it will see you know whether
23:54we can have a model to test the,
23:56you know anti tumor immunity.
23:58So this is,
23:59you know just a slide to show you here.
24:03For example whenever you introduce this
24:05cell line to the opposite minus you see.
24:08This is why type spleen and then
24:10this is the tumor. Very mouse split.
24:13This is a bother significantly
24:15large sometimes you know obvious
24:17between 3 to 5 four,
24:18so the indicating indeed the
24:20Bobbsey might will see this.
24:22Far into Hypersolar Carcinoma
24:23ISO for in the summer.
24:25Hawk trying to Mount immune response,
24:27but at the end the tumor wins because
24:30within two or three weeks there is.
24:33You know, big tumor produce.
24:34Either,
24:35you know when we do the subq injection
24:37or we do the also topically rejection,
24:40you can quickly develop this HTC in the
24:43box emails and then we look at the worst.
24:46The cells in the privacy you know.
24:49Certainly we have all the different type of.
24:52Salsa peace out most of the T cells,
24:55but actually if you will be
24:57further phenotype of those cells,
24:59most of those actually there is
25:01significant regulatory T cell
25:02components and also MD SC components,
25:05so indicating so in this box model.
25:07Indeed there is email,
25:09surprised phenotype and so that's
25:11why the tumor wins and two produces.
25:13So we think this probably is very
25:16good model for us to look how we
25:19can develop a model to test some
25:21of the ideas we wanted to detach.
25:24'cause I'm wiser, circular.
25:25I've seen the others.
25:27We want to also think about how
25:30to manipulate manipulate the
25:32different immune system and to check
25:34to see if we can have some more
25:37effective and the tumor immunity.
25:39So first you know, as I mentioned,
25:42the clapping and straight,
25:44you know this highly expressed tumors.
25:46It'll specific energy.
25:47So when we did that,
25:49go in the traditional method that you say,
25:52OK, we will just be recreated.
25:54Called in and trying to you know,
25:57you know,
25:58build recombinant protein both
25:59in front bacterial from the East,
26:01and then use the protein.
26:03As you know energy and to email those
26:06mice so this data show you just show
26:09you after we immunize those mice,
26:12and then we check,
26:13you know,
26:14we did not really see any significant
26:16changes into in terms of humor
26:19side before and after vaccination,
26:21and then we check the cellular immunity
26:23and humoral immunity and overall.
26:25Conclusion from that is we
26:27tried multiple times.
26:28If we just inject eclectic and straight
26:29to the mice with another really created any,
26:32I need two more community in this,
26:34at least in this mouse model.
26:36And then we say, you know, you know.
26:39Then we check the tumor within
26:41our really see any you know,
26:43tumor infiltrating emphasize as well.
26:45So then we just tested this
26:47idea to see how about.
26:49You know,
26:50we think that different approach.
26:51So why I'm proud that we feel is maybe
26:54we should think about how to allow the
26:57light beacon St guide to the real,
26:59you know the immune organs in case like go
27:02to the split or go through the lymph node.
27:05So one idea we did try,
27:08you know at that time sort of
27:10thought about it is you know,
27:12how about we conjugate?
27:13Collecting three with lymphocytes so using
27:16this chemical I do not try to pronounce it,
27:18you know.
27:19CC and uses conjugate.
27:21Basically we conjugated the glide Pickens,
27:23reporting with lymphocytes.
27:24So that hypothesis hypothesis was to use in
27:28the table in full size carry this protein,
27:31the energy and the lymphocytes has
27:33this natural homing capability and
27:36they will go to the right email.
27:38Oregon.
27:38Maybe that will excite, you know,
27:41to initiate, and the tumor immunity.
27:43So actually that's indeed it was the case.
27:46So this is just to show you.
27:49You know we conjugated and emphasize with,
27:51you know, with the protein,
27:53and then we inject, you know,
27:55enjoy the back.
27:56Those info size you know to the mice,
27:59and then we look at the tumor.
28:01You fancy the conjugated what
28:03so you can efficiently surprise
28:04the tumor growth and this will
28:06different treatment protocol.
28:07You can see it's really time dependent,
28:10and so this is very exciting.
28:12And then we say, OK,
28:13let's check it was, you know all
28:15the cells and different components.
28:17So this just to show you which acted like.
28:21This is an ileus part,
28:22definitely compared to the control,
28:24you can see a lot of activated T cells.
28:27More importantly exciting
28:28is after this congregation.
28:30Actually we can see the lymphocytes
28:32actually infiltrated into the tumor.
28:34So this is a boy.
28:36We believe.
28:36This is probably why we you know this
28:39sortable bikes vaccination approach works.
28:42So again,
28:43this is just another different data.
28:45I you know to show you
28:47you know how this country,
28:49you know that just this is
28:51just demonstrated indeed,
28:52although the fact that we have seen
28:54is related to the conjugation between
28:57the lymphocytes and the collective
28:59history protein so so for that this
29:01is but anyways summarize this data,
29:03so we think you know later
29:05on we actually purified we.
29:07Initially we just use the total invoice size,
29:10but now actually we test it's just isolated.
29:13These results and it was a tease out,
29:16so this is a work is ongoing.
29:18So basically is what our working
29:20model of our working hypothesis.
29:22We want to continue to try.
29:25That is we are using T cell
29:27as a carrier for tumors,
29:29therapeutic vaccine delivery.
29:30So this is where we're testing
29:32this in hypotheticals.
29:33Normal,
29:34I think there's a possibility so those
29:36can be become a sort of platform 40 sell.
29:40You know like you know.
29:42So this is a work I'm going
29:44to get my laboratory.
29:46Now let me you know,
29:48share it with you or some of the other
29:51things which will also cellular therapy
29:53related and this one is the Carty.
29:56So we didn't develop find,
29:58you know the valuable gladness
30:00riccardi cells.
30:00So this is just a diagram to
30:02show you we use the landing
30:05viral vector and then basically
30:07created this Jeep 3 car T cells.
30:09So right now we created both in the T cell.
30:13Sales and also we you know we
30:16created this platform using NK
30:18cells which I will talk a little
30:21bit more in the next few minutes.
30:24So those hasn't been shown.
30:26You know this is another diagram.
30:29Other group also developed this.
30:31Party and then they use a different regions.
30:34They're focusing on the sea.
30:35Turn up the protein and then we
30:38decided to focus in on the end
30:40terminal because the end terminal
30:42is on our side of the cell
30:45membrane with believe you know,
30:46the in terminal may have better access,
30:49so this is our party.
30:51Construct and then we.
30:52Basically this is also called a third
30:55generation that you know a platform.
30:57We divided both in the lending
30:59virus as well in collaboration with
31:01another factor that rockers you know,
31:03don't do so.
31:04He has a virtual various platform.
31:07We actually work together and also
31:09make made made this construct in the
31:12regional various platform as well.
31:14So then you know, testing again,
31:16test this party in in Rachel.
31:18So it seems to work very well.
31:21And also we test it in the animals.
31:24You know this just show you a different
31:27types of satellites and this is actually
31:301545 is immortalized hypothesize,
31:32set, immortalized levers, allies,
31:33developer in my laboratories of
31:36the basis serve as a control.
31:38You can see though.
31:39Also the target because this
31:41tells you know does not have the
31:44you know the the 1545 cells does
31:46not have a clapping's resort.
31:48There's no target and the others
31:50you know the commonly used a
31:53cellular carcinoma cell address
31:54themselves and those type 2 so
31:57show significant killing effect.
31:58So this is this is in cell culture
32:01and then then we also decided to
32:04introduce it into into animals.
32:06And indeed you know they were treated.
32:09Those animals this.
32:10Our volume compared to the controls.
32:13And at the Cardinal applicants repartee.
32:15Indeed, so very effective,
32:17very effective,
32:18and also lost almost two months.
32:20You know, this is really exciting,
32:22and I think we pretty much feel
32:25very confident in this construct.
32:27But now The thing is, you see,
32:29you know,
32:30certainly eventually will need to bring
32:33this to human trial and to see if this this,
32:36you know construct will be actually
32:38showing the effectiveness in human.
32:40So that's certainly you know need a lot.
32:43Effort and also some other you know
32:46funding and that will get this stuff.
32:49So this is a really you know,
32:52exciting and also we tested the similar
32:54Carty using PDX mouse model because
32:56to develop that you know that's
32:59another thing I mentioned earlier.
33:01We are very happy to share
33:03with people you know working on
33:05hyper disorder carcinoma also.
33:07Edit cancers as well.
33:09But we build a multiple PD exercise and
33:12over the years not only we have the PDX MI,
33:15so we also have the corresponding cell card.
33:18Sterilize so you know,
33:19for you know for both liver cancer,
33:21pancreatic cancer,
33:22and we also have other tumors PDX as well.
33:25So this is just to give allow
33:27us in future to developer mode.
33:30You know, you know,
33:31I would say precision of personal
33:33email therapy because this way
33:35we can see if we can derive some.
33:37More specific hydrogen,
33:39and from this particular patient,
33:40and then from that platform to
33:43build a specific artifice, patients,
33:45certainly, that's what he,
33:46what you know in the future.
33:48Endeavor for that.
33:49Alright, so the last section of my talk,
33:52you know it's just one share the lights.
33:55Turn attention to the you know
33:58another inmate.
33:58Email cells which is encased in HTC,
34:01so you probably ask why we are
34:04so interested in today.
34:05So if you look at the.
34:08The human body.
34:09The organ contains the highest
34:10numbers in case ours is a liver.
34:13If you look at the liver almost 2%
34:15of the Leeward nucleated cells are
34:17in case of you probably say it's very,
34:20you know, surprised you know.
34:22Actually it's you know, but it does.
34:24In case I'll do indeed work is very I.
34:27I would say to say minimum
34:29is poorly understood.
34:30Alright, so however, over the years,
34:32so you see back to even 1990s.
34:35So people already shown
34:36that if that you tested.
34:38In case files from the hypothetic are
34:41still like compared to the non tumor cells,
34:45they show the empty cells.
34:47Had this dysfunctional in terms,
34:49they have lice killing effect
34:52and this also reached 2013.
34:54Another group also reported this,
34:56but very few later Richard to really show.
35:00It's a strong evidence.
35:01Say what is it?
35:03The NK cells function in
35:04hypo thyroid carcinoma.
35:05Alright, so as I mentioned,
35:07it's a such a big pop.
35:09You know they have more.
35:11In case else that many other
35:13lymphocytes in the liver.
35:14So that question is how we can find
35:17that was in his house would do in
35:20those are the others, you know.
35:22So this is some people also just very reason.
35:26You know shredded.
35:27They were recently recorded.
35:29If you expand the NK cells and then you
35:32know you feel so badly in the mouse model,
35:36actually expand it out.
35:38In case else does precise anti
35:40tumor activity in mouse models.
35:42So this will be like an invisible experiment.
35:46So it's just indicate you know NK cells
35:49after expansion they still maintained.
35:51Activity I think that's a very
35:53critical for us to talk about.
35:55You know,
35:56if we ever wanted to make in case
35:58out to PSR building platform,
36:00we have to make sure the expanded
36:02engage cells would hire that function.
36:05Right, This is, you know,
36:06a couple years ago and this is also
36:09in collaboration with another faculty.
36:11Don't found in rockers,
36:12and so we decided.
36:14Just let's start, you know,
36:16some of the basics of NK cells in HTC.
36:19So what the platform we use so is,
36:22you know we,
36:23you know we had a transplant program there.
36:25So we basically for any HTC transplant
36:28fever so will get the tumor and then we will,
36:31you know,
36:32isolate NK cells from the tumor and isolated.
36:35You know from the adjacent that you know
36:37zone we call the adjacent alone from the,
36:40you know,
36:41the Beamer tissue and also isolated
36:42the NK cells from the non tumor.
36:45You know,
36:45like you said,
36:46Mount tumor distance period I
36:48DS 5 centimeter away from the
36:50tumor and we isolate all those NK
36:52cells and then we expand it.
36:54Also in case cells and that's all what
36:56we do in the same time we get the blood.
36:59You know patients per for blood in case else.
37:02And then you know to compare
37:04with different orders at least.
37:06Oh groups and see what's the function
37:08or was the basic plan in case out.
37:11So what do you know?
37:13After we did that so we did quite
37:15a number page and yet you know the
37:19most common transplant deliveries,
37:20hepatitis C liver and also the other,
37:23is alcohol induced cirrhosis?
37:24And so that's how we literally focusing
37:27on HC deliver an also alcoholic.
37:29So with that will do the functional I
37:32say and then we did a lot of irony.
37:36Take try to see you with any changes in
37:39those cells and then later out toward you.
37:43Know quantitative PCR to
37:45determine certain specific jeans.
37:47So this. All right?
37:50OK, thought to make a Long story
37:53short because the timing so I will
37:56not get into the killing I see.
37:58So basically what we find is that
38:00there are significant difference
38:02between all the NK cells we
38:04isolated from different liver.
38:06So that might be interested enough.
38:08It's TV related liver NK cells and
38:10the alcohol related liver cancer.
38:12They are also different in terms of function.
38:15You know they have light
38:16skin activity in alcohol,
38:18but how interesting they have
38:20even higher connectivity.
38:21HC way.
38:21Which isn't really surprising to us compared,
38:24you know.
38:24So we that suspension with it artistic
38:27and then you got all the data,
38:29but we still have sitting on large amount
38:32of data is still waiting to be analyzed,
38:35but at least right.
38:36The moment I can share,
38:38you know this really very fairly recently.
38:40Just few months ago with that we
38:43actually identify the CD 62 L of
38:45course share cell or I also liked.
38:47So this has been really
38:49significantly changed.
38:50You know, between all those different.
38:52So here the summary.
38:53We can see really tabley how
38:56for whatever reason in NK cells
38:59isolated from HC be related.
39:01HTC you know the HC way related
39:04HTC you actually have a higher
39:06expression of selected and.
39:08However in the alcohol related NK
39:10so you have lower expression so
39:12this will be the hours they put
39:15all the guys average as a baseline.
39:17So it's really interesting.
39:19You know how this dichotomy,
39:21which by itself may not be very
39:23surprising because the difference
39:25is if you look at the Histology
39:28between the cancers arising from
39:30HCV and the cancers arising from.
39:32Alcohol, the big difference is is you know,
39:35in the HTV Kaiser or background
39:37deliver as well.
39:38You always have the inflammatory
39:40activity going on.
39:41In other words,
39:42you have the inflammatory Emilio
39:44within those levers,
39:45which in alcohol induced liver
39:47cancer or liver cirrhosis.
39:49You have minimum inflammatory activity.
39:50So I think this is sort of
39:53a exciting we want.
39:54We are thinking about is right now.
39:57It's really easy to further
39:59and you know exactly what's the
40:02actual role of the CD 62.
40:04All out selecting the role in this
40:06in case sales particularly is,
40:08we wanted to see if the inflammatory
40:11thing all hepatitis virus itself
40:14contribute that to to that is different.
40:17So this is our model right now,
40:19so this is a working model we
40:22are actively pursuing that.
40:24As I mentioned,
40:25this summarize with all our
40:27current data with NK cells.
40:29What do you see?
40:30The in case are higher expression,
40:33what actually they are?
40:34Higher higher killing capacity.
40:36So those are mainly from the
40:38HC way steaming the HTC, right?
40:41That's very interesting.
40:42And however, in contrast,
40:43the alcohol induced the
40:45HTC that will lower CD 62.
40:47And also lower kidding capacity.
40:49So that's really, you know.
40:51Allow us to think about if we ever do.
40:54You know the next step in the future?
40:57If we develop a therapy?
40:59Maybe this is where if we understand
41:01more about the Rover LCD,
41:03you know you know the CD six tool and
41:06we potentially can think about is you
41:09know how we can turn this CD6 tool.
41:12You know, lower expression one and to
41:15get together them to be more active against.
41:18HTC in the alcohol siding
41:20because of all the HC way.
41:22However,
41:23I don't think for this stimulation
41:25by CT62 will be good idea,
41:28because if they already have a
41:30pretty strong in as you know,
41:33HC way you know for this way
41:35they already have higher.
41:37In case our activity and I was also
41:40higher city 6 two expressions as well.
41:42So we may have to think about if you know
41:45what other strategies for HCA Induces.
41:48So this is a working hypothesis.
41:50As I mentioned,
41:51we need to do more cases and
41:54then to see if we can,
41:56you know,
41:56find something most specific and
41:58to treat you know HTC this is
42:01the bottom line is I think more
42:03and more we see this trend which
42:05is the tumor heterogeneity.
42:07So we can outline some of the HTC altogether.
42:10You know, apparently you know for HTC,
42:13you know differently etiology.
42:15It seems like to have very different.
42:18Biology, so we thinking about it,
42:20developing therapeutic strategy,
42:22we have to really think about it.
42:25Take that into a consideration.
42:28But on the Furthermore,
42:29I decide you don't mention that
42:32those two testing that model
42:33will be the movie thing.
42:35It might be the HDD itself with
42:37somehow engage the NK cells.
42:39So this is our current very
42:41preliminary is out here.
42:43We basically culture the HIV positive
42:45because we can grow hepatitis C in
42:47those tumor cells and then do code stimulate.
42:50We called priming the NK cells.
42:52You know,
42:52in this case we can just use another.
42:55You know the NK cells and
42:57testing the targets.
42:58But you know, like a 50K562 cell lines,
43:02so that sell you can
43:04clearly see after coaching.
43:06In other words, it's the priming
43:08the monkey cells with hepatitis C.
43:11Indeed,
43:11in deals that you know NK cell functionality.
43:15But now the question you know
43:17come to the point.
43:19I say even you have a strong
43:22and creating activity in iPad.
43:24HC,
43:24they induce Apple cider carcinoma somehow.
43:27The HCS, you know, take CC is still prevail.
43:30So In other words.
43:31So maybe this is by itself is not enough,
43:35or maybe because remember
43:36what we have so far.
43:38Test data is all in the
43:40individual isolated condition,
43:42so this is really coming to the
43:44point that there may be some other
43:47immune surprising signal type in the
43:49micro environment which even in visual
43:51you know the NK cells maintain their.
43:54In and out, and as you
43:56know anti tumor activity.
43:57But however in the.
43:59Imil surprising micro environment.
44:01Those are simply just cannot function,
44:03so that's really tell us you know
44:06when we deal with HTC is causing by
44:09C virus versus you know like a narco
44:12versus the alcohol costs the HTC.
44:14We have to think about differently
44:17so this is really, you know,
44:19just the game with this idea in
44:21a long days and we are actively
44:24investigated the possibilities.
44:25Alright so I think my time
44:28is almost up and I think.
44:30This will be the summary and I will say
44:33you know you can see you know this.
44:35From both you know,
44:37patients and mice,
44:38so there is an email response in HTC.
44:40That's good sign.
44:41That means that there is engagement between
44:44the tumor and then they and ominous.
44:46Not in the music thing,
44:48so this created opportunity for
44:49us to develop an you know,
44:52better therapy so that it seems
44:54like this email surprising cells
44:56are dominant in HD situation and
44:58about human patients and also adding
45:00models and we demonstrate uniform.
45:02Our own study.
45:03Also,
45:04many other people study also show
45:06the tumor explanation of specifically
45:08molasar PewDiePie scene and those car
45:11T cells in case cells are indeed promising,
45:13you know, a therapy.
45:15And as you know.
45:16Imagine that in the last section
45:18of other than in case also we see
45:22the differences between the HC way
45:24induce the HTC and alcohol induced
45:26ACC really tell us we have to think
45:29about a personalized email therapy approach.
45:32We have to really see if we can
45:34separate those cancers with you
45:36know what cording to their ideology
45:39and then see developper you know
45:42more effective therapy accordingly.
45:44So now the challenge is, you know
45:46there is another easy to get this done,
45:49but I think many are really, you know,
45:52not just in the confined within.
45:54You know liver cancer.
45:56Actually you can have this probably
45:58multi other cancers as well.
46:00I think this is one area we all
46:02need to think about how to do this.
46:05So certainly biomarker for
46:07getting service absolute liking.
46:08So even though therapy specially but
46:10you know we're making inroads right now.
46:13For example. Total tumor.
46:14Antigen burden, you know.
46:16Like the microsatellite instability is,
46:17as you know,
46:18has something demonstrate you know as
46:20a predictive marker for more fighter
46:22effective therapy for check for me.
46:25Hey, better so that's the right direction.
46:27But we still need to think about more
46:30specific file markers for different
46:31cancers and see how to get everything.
46:34And then obviously we almost no.
46:36There will be some sort of
46:38tumor resistant coming out,
46:39so that's where you know we need
46:42to pay attention or be at least
46:44consider the possibility of the.
46:46That the veloppement of resistance and
46:49its potential mechanism that causes high,
46:51particularly women,
46:52sing about personalized email therapy.
46:54We all know that tumor Hitler genetix
46:57really does dimension as well,
46:59but and the other is is really, you know.
47:03There is a very active field right now
47:06is a target and you understand you
47:08know the new energy income information
47:11because that you can induce new
47:14energy through radiation therapy.
47:16Awesome tumor, like original local
47:18regional therapy for hyper disorder,
47:20carcinoma injecting chemotherapy,
47:21agents of radiation, you know,
47:23create a new energy and so those new
47:26editions probably will be able to serve
47:29as a target for us to develop more.
47:33Like the potential 80 factor.
47:36You know emails are paid approach OK,
47:38so with that I would say you know
47:41thanks to people who are working
47:43in my life in especially houses MD,
47:45PhD student, graduate student ID TS.
47:47Who did all this in case our work and
47:50Frank and layout with the post office.
47:53We did also by tumor vaccine work so
47:55have a lot of collaborations tools.
47:57Thanks from you know by you know
47:59really the priority institution
48:01University of Florida and also ruckers
48:03University and especially assigned
48:05don't phone bill who is actually.
48:07That they did not email about,
48:09you know shared his eyes,
48:11speaks parties with us,
48:12and also the regional viral vector
48:15system to build better effective
48:17party and also my long term
48:19collaborator animal clinic in the.
48:21Again,
48:22you know saying You know the Funding
48:25Agency for support our work over
48:27the years so I will stop there.
48:29and I welcome questions,
48:31ideas from the audience. Thank you.
48:33Thank you all for your attention.
48:37A chain thank you and thank you for a
48:39terrific talk as well as you know the
48:42work you're doing in this very challenging
48:44malignancy and and folks should submit
48:47their questions on the chat button.
48:49But let me if I may start. Yeah please.
48:52You very nicely identify the potential
48:55differences in immune response between
48:57alcoholic associated legacies as the alcohol
49:00associated legacies as opposed to viral,
49:02where given the rise in the role
49:05of non alcoholic stay out of the
49:08tightest Nash in HTC pathogenesis,
49:10where do you see that aligning compared
49:13to the models you now been studying?
49:16Yeah,
49:17so
49:17my so that's that's a thing.
49:20There are two issues here alright.
49:22So yes, Nash Associated
49:24Hypersolar Carcinoma, you know.
49:25But these are epidemiologist study
49:27has seen the rising incidence.
49:29However, in practice we seem
49:31very little of those cases,
49:33you know, because you know,
49:35I think that's the thing, because you know,
49:38we use in the liver transplant as our model.
49:41You know, we get those sites
49:43where it without that issue.
49:45I think this is it common.
49:47We just do not have a lot of cases.
49:50Actually human tissue cases.
49:52I would say HTC arising
49:54from the Nash patients.
49:55To really it was studied in detail,
49:58but there are, but they each center
50:01they will have a really a fuel in.
50:04The implication is very hard to to do.
50:08The study.
50:09Second point is you know if
50:11you look at it in terms.
50:14You look at the Histology so the
50:16alcohol related cirrhosis probably
50:18will have more resembles to the Nash
50:20Associated Cirrhosis or carcinogenesis
50:22because they both contributed.
50:24For example, how alcohol.
50:26Induce enough cirrhosis
50:27and apparel carcinoma,
50:29probably by messing up the metabolic
50:31pathway within the liver, right?
50:33So that's the same way you know.
50:36Nice related thing.
50:37It is basically part of
50:39the metabolic syndrome,
50:41so I would think if we want to guess,
50:45I will assume those probably
50:47more or less related to the to
50:50the alcohol induced the HTC,
50:52which is less information.
50:54So that's the key difference if.
50:56If we look at that issue,
50:58you have very little information
51:00in in Nash or alcohol related
51:03liver injury or hepatitis C.
51:05You always have this.
51:07I'm going chronic inflammation.
51:08I think that's the key difference.
51:11I mean,
51:11it was sort of a surprise was
51:14may not be a good surprise.
51:17Become actually see the NK
51:19cells behavior differently
51:20in there supposed to groups.
51:23Interest rates are we don't know,
51:25so you know to complete with complete
51:28and know that yeah yeah,
51:30so a number of our members of
51:32audience of submitting questions.
51:34I'll start Marcus bosenberg is
51:36asking have you considered making
51:38Carty to either hepatitis B virus,
51:41hepatitis C virus antigens expressed on the
51:43cell surface? So we haven't because the
51:46reason we haven't you thought we really
51:49worry about that kind of therapy as a
51:51matter of fact, if you look at the viral
51:54distribution in the liver, we need,
51:56you know you have more very expression
51:58in the non tumor cells and tumor cells.
52:01You know, for example used in the liver.
52:04Sample I haven't I disappear if
52:06you look at the hepatitis B.
52:09But you know, engaging expression in both
52:12the tumor tissue Anna noun tumor tissue.
52:14You tend to have higher expression.
52:17In the non timit liver tissue.
52:19So we really worry about it.
52:21You know you created this type of a target.
52:24You probably wipe out the liver
52:26instead of locating the tumor cell.
52:28So I don't see those are really
52:31again assumption as part of the
52:33say that's probably part of the
52:35reason we haven't really seen.
52:37People reporting are making those
52:39hepatitis B or C in a car key yet.
52:43Yes,
52:43thank you so question from
52:45damper chain are the the T cell
52:48infiltrating cells in the tumor?
52:50Are they different from the T
52:52cells in the adjacent hepatitis
52:54C infected liver and related
52:56to that would be the effect of
52:59immune checkpoint therapy on the
53:01background liver vis-a-vis the tumor.
53:03If they are different.
53:06Right, so that's you know,
53:07uh, you know greater point,
53:09let's see first so you know,
53:11for the first part,
53:13so we didn't have to really
53:15look at the overall generic key.
53:17Infiltrating the middle size.
53:18So we basically we did not sign the
53:21whole T cells compared, you know,
53:23the tumor and the non tumor liver.
53:25So we really focusing on the NK cells
53:28because we decided just focusing
53:30on K cells and for different,
53:32you know for number reasons
53:34I mentioned so we don't know.
53:36The total tease out difference between
53:39humor and the surrounding labor.
53:41In Hep C and also in alcohol cirrhosis.
53:45So that's what they II you know.
53:48A question is whether or not
53:51you know the for this way,
53:54the information you know driven
53:57T cell weather.
53:58You know you will be able to see
54:01you know in the inflammatory
54:03citing and how those are behave,
54:05so we really don't know at this one.
54:10Her thank you question from
54:12under whose and are asking.
54:14Given the differences in tumor cell
54:16biology and immune micro environment
54:17between HTC of different etiologies,
54:20how do you think about modeling these
54:22ideologies in animals to more reliably
54:24test immunotherapeutic approaches?
54:26Yeah, that's a great point, but I
54:29think at this moment I don't see we have
54:32a good model to test that, particularly.
54:35You know if you look at the mouse model.
54:38I mean we we. Also created hypothese,
54:41transgender demise but we've
54:42never been able to recapitulate
54:44the similar similar pathogenesis.
54:46Yes, if you have hepatitis C,
54:48you know like a transgenic mice,
54:50but somehow you do not have
54:53all the information you would
54:54otherwise see in the human model.
54:57The reason is when you build a
54:59transgenic mice, you basically create
55:01this tolerance for the antigen.
55:03You know, for example,
55:05so that means that the minds of
55:08the host will trade that rise.
55:10Transgender put in.
55:11And as a Nitro, you know,
55:13own protein,
55:13so we never be able to initiate
55:16those kind of inflammatory model.
55:18The other model,
55:19Israel chemically induced the model.
55:21You know,
55:22you know to look at the personal Genesis.
55:25It's really not the same as all
55:27because in that in those cases
55:29you have more liver damage rather
55:31than actually information driven.
55:33So for that question,
55:34I don't think you know we have really
55:37good model to to look at the email now.
55:41Check on inhibitor.
55:42So for that matter,
55:43alright,
55:43so you know the one we divided the
55:46Bobbsey Miz will be good to look
55:49at the email check only hitter but
55:51again in that setting you know.
55:53The difference is is we don't.
55:55There is no hepatitis infection
55:57in that system.
55:58We actually trying to get
56:00hepatitis C virus windows privacy,
56:02HTC and trying to do that,
56:04but for some some reason we still cannot.
56:07In a, you know,
56:09recapitulate the inflammatory response.
56:10You know in that, in, in,
56:12in, in, the in the system.
56:15So again you know like you know just
56:18like them, please ask the earlier.
56:20So for those you know differences.
56:22You know whether you have inflammatory.
56:24Changes in HTC of lice inflammatory
56:27transition alcohol induced that HTC will
56:29be when you use trackpoint in Haverhill.
56:31How they behave?
56:32We don't know for whatever the reason.
56:35If you look at the clinical trial
56:37they conducted the network T service
56:39out because actually hoping serving
56:41as a reviewer when this separated.
56:43You know some middle ground.
56:45I say can you tell me can
56:47you separate this out?
56:49Can you say alcohol, HTC patient you know?
56:52And also HC? Wait patience when you use.
56:54Checkpoint inhibitor,
56:55do they behave differently?
56:56Out behavior? Say I mean with them.
56:59I mean,
57:00I guess probably you know the case number.
57:02Overall,
57:03you know you'll still have a relatively
57:05fewer numbers of people with alcohol.
57:07HTC I think majority the patient is still
57:10is like a HC way or HP way related HTC.
57:14I think that's really important
57:16because I think that you know.
57:18What you got the checkpoint inhibitor
57:21should absolutely considered an I in
57:23in the sighting of Nitro I will say
57:26to you know physiological difference
57:28in terms of the path biology,
57:30for example whether or not
57:32they have the indulgence
57:33inflammatory milio or macro
57:35environment or not I think that
57:37could make this huge difference.
57:39I think this is actually one
57:42of the area I was saying is.
57:45We should have really look at the
57:47difference between the two groups
57:49for tumors and when we use the
57:51checkpoint inhibitor that we can
57:52probably learn a lot because one,
57:54as I said, almost no information.
57:56The others has a lot of information.
57:59Yeah I need to see more
58:02data on that. Yeah and last question
58:05from Jeff Score is DPC three
58:07expressed in Cholangio Carcinoma?
58:09And what about cells and HTC
58:13that show cholangiocarcinoma
58:14differentiation? As a feature of
58:17HTC. No, it doesn't.
58:19You know a guy picking 3 does
58:22not express in Columbia Personal.
58:25And when you know with the mic style tumor,
58:28you know we call it the.
58:30You know, the mix type 2 in both.
58:32So you have hypercellular
58:34at Michelangelo Carcinoma.
58:35In that exciting?
58:36Yes, some other hypercellular carcinoma
58:38can be staying for clapping and
58:40three so I have to say that I think
58:43this is we haven't done that yet.
58:45So this is all this idea
58:47to the audience you know.
58:48So in the later literature they have
58:51demonstrated by email his chemistry
58:52they have seen like a certain
58:54percentage of prostate cancer.
58:56Breast cancer colon cancer also
58:58expressed like if we say 10 between
59:005 to 10% of those cancers also
59:02expressed clapping and three right
59:04so those are in the literature.
59:06Those really any doctor type
59:08of report out there.
59:09We never look at it ourselves,
59:11but for some of you know anybody you know.
59:14You know if you are interested in that,
59:17it may be you know you can
59:19look into some of those.
59:21I mean, it's not surprising that guy
59:23pick once we also exploiting some tumors.
59:26Because this is just one of those,
59:29you know.
59:30Amber Amber,
59:31Genesis type of property got re
59:34express and in the in cancer.
59:37So just through this information
59:39out there. Thank you, that was really a
59:41superb talk and we're so fortunate now
59:43to have you as a member of our cancer.
59:46Centers are welcome and we look forward.