Yale SPORE in Skin Cancer presents: Rational Combinatorial Approaches with Immune Checkpoint Blockade for the Treatment of Cancer

June 16, 2021

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Yale Cancer Center Grand Rounds | June 15, 2021

F. Stephen Hodi, MD

ID6721

To CiteDCA Citation Guide

00:00Daddy, thank you so much
00:02for joining us today.
00:04So for today's grand rounds,
00:06I am thrilled to present our
00:08speaker to Steve Hardy from the
00:10Dana Farber Cancer Institute.
00:12Runs the Melanoma program and he also runs
00:15the immuno Oncology program up at the Farber.
00:18He's a professor of medicine
00:20and has an endowed chair.
00:22He's the Sharon Crowley market.
00:24Share in Melanoma.
00:26I've known Steve for many years.
00:29He's been on the faculty
00:31at Dana Farber since 1995.
00:33After finishing his
00:34medical school at Cornell.
00:35Great in his graduate education
00:37between the University of
00:39Pennsylvania and the Farber,
00:40Steve has made major contributions
00:42to the Melanoma field.
00:44He's lead author or first author on
00:46multiple publications in major journals
00:48such as the New England Journal of Medicine,
00:51Lancet, Lancet,
00:52Onkologie, and the like.
00:54He's made some similar
00:55breakthroughs in clinical.
00:57And care as well as in Preclinical Research.
00:59He's pioneered two approaches
01:00that I recall that have really
01:02changed the landscape of what we're
01:04studying and doing in Melanoma.
01:06One is combination of angiogenic
01:08therapies and immunotherapy,
01:09and the other one is combinations
01:10of GM CSF with with immunotherapy,
01:12and I believe you'll be talking
01:14at least about the letter.
01:16He has a few other very novel gene
01:19therapy approaches that he's using,
01:20which I think he will be talking
01:22to us about as well,
01:24so we actually originally wanted
01:26Steve to come down last June.
01:28Marcus and I invited him as
01:31part of the skins for.
01:34Administrative core,
01:34but unfortunately wasn't
01:35able to come last June.
01:37Glad to have him here today and
01:39we look forward to seeing him in
01:41person sometime in the near future.
01:43So without further ado,
01:44I'd like Steve to take the
01:46screen over and take it away.
01:48And if you have any questions for Steve,
01:50please put them in the chat box.
01:56But thank you very much, Harry,
01:57for the very kind introduction.
01:59And I do hope that we get
02:02to see everybody very soon.
02:04Let me just get. And if you can verify,
02:08you can see slides and everything,
02:10OK, yes, we're seeing it.
02:11Well, great. Thanks.
02:12And I do hope we can all
02:14see each other again soon.
02:16Everyone is doing well so it's a
02:18pleasure to join you all today and I'm
02:21going to be kind of talking a little
02:23bit of leading up to some ways to
02:25think about rational combinations of
02:27combining with checkpoint blockade.
02:28So as a clinical investigator,
02:30think of of cancer therapeutics
02:31and such that cancer and people
02:33are present for a long time,
02:35so there's an opportunity
02:36for antigen recognition.
02:37There may be slightly different than what
02:39we see in the transplantable tumor models,
02:42the transplantable tumors being
02:43key to understanding mechanisms.
02:44But we've also found in most more
02:46recently that the translation into
02:48into people may be challenging.
02:50Some of the aspects really to
02:52agonist targets and other things
02:53in terms of the rate from ecology
02:55is also fairly challenging,
02:57so in the world in the world
02:59we're living in the checkpoint
03:00world that we're living in.
03:02Why do anti tumor responses are not do
03:05not happen in order to clear cancer,
03:07so they've either never developed?
03:09The immune cells are too few in
03:11number or there are exhausted,
03:13and this obviously the exhaustion
03:14is very important within the
03:16PD one we're living in,
03:17they could physically be excluded
03:19from the tumor or the antigen.
03:21Presenting machinery is somehow disrupted
03:22with engine loss or or the machine itself,
03:25such as MSE loss,
03:26which we're going to try to address.
03:28Most of these over the next hour or so.
03:32So in the beginning there was appealing
03:34map antisocial foreign just to use
03:36Melanoma as as the paradigm example.
03:38Traditionally Melanoma would have about
03:3911 months median survival for brain Mets,
03:41six months or less an now we have
03:44with hippie the 22% of patients
03:46now having a long term survival
03:48with over 10 years of follow up and
03:50notice on the survival curves that
03:52there's an inflection point or on
03:54the two and after three year point
03:56and then the flattening of the curve.
03:58But we also interesting we see with
04:00no volume app anti PD one this is the.
04:03Going to combine data,
04:05little bit of mixing apples and
04:07oranges in terms of dose and schedule.
04:09All previously treated patients
04:10then now those patients,
04:12about 35% are living long term with
04:14no volume AB monotherapy and then
04:16moving on to the most recent update of
04:19the Checkmate 067 trial in Melanoma,
04:21which was a phase three trial that
04:24combine Knievel plus it be and
04:26compared it to Epyx alone Evo.
04:27Plus it be compared to niveau.
04:29It was not designed.
04:31The caveat here not designed to
04:33compare Niveau.
04:34Happy to Nivo but now with six years
04:36of follow-up you again see this
04:38inflection point around 2:00 and after
04:40three years flattening of the curves
04:42with needle plus Tippy, now 56 percent,
04:4457% of patients to living a long
04:46long term with the disease.
04:48So so the question is,
04:49with this kind of as the the new baseline,
04:52how can we improve upon these results?
04:55And we look at very important biomarker data,
04:59so the the importance of CD
05:018 and the invasive margin.
05:03So it's the tumor stromal
05:05interface and the proximity.
05:07The closeness to the PD one PD
05:10interaction is highly predictive of
05:12responses to anti PD one therapy again
05:15in Melanoma and also that PDL one
05:18is a mark biomarker in now with the
05:21numerous diseases that PD one is looked at.
05:24PD1PD1 target therapies.
05:25The back seat when expression
05:27on immune infiltrating cells.
05:29So the new cells themselves,
05:31mostly macrophages,
05:31are also predicted responses to hear
05:34anti PDL one because it was a mad
05:36in patients with lung cancer and now
05:39other countries with kidney cancer.
05:41So to briefly summarize other aspects
05:43that could be applied to improving upon
05:46those results quite a few years ago now,
05:48Glenn Dranoff,
05:49my longtime mentor and friend,
05:51and I did some anti slip or anybody trials
05:54looking specifically in patients who had.
05:57Received a prior GMC based vaccine,
05:58but notice pathologically when they received.
06:00If you limit map that
06:02there was this in panel,
06:03a area central necrosis with the
06:05room available to around the outside,
06:07and that room available tumor was
06:09heavily infiltrated with CD4CD8 CD 20s.
06:10But we notice throughout the tumor
06:12that there was an immune attack
06:14of the vascular vessels feeding
06:16the deposits depicted in panel F,
06:17and that this these lymphocytes were
06:19attacking the blood vessels when the
06:21product will be in the center and
06:23probably leading to this TNF like
06:25effect that we virtualized in pathology.
06:27And so it raises the question of the
06:30combination as he was alluding to
06:32of combining anti angiogenesis and
06:33immune checkpoint in the importance
06:36of hypoxemia.
06:36If 1A making veg F that not only
06:39involved into Genesis but Veg F
06:41being a very potent suppression
06:42of dentrix cell maturation.
06:44Another important myeloid as important
06:46suppressor cells that you might like.
06:48My Lloyd Wright suppressor cells
06:51also make important engineering
06:52factors such as Veg F that lead
06:55to also this suppressive feature
06:56and whether there was a role for.
06:58Andrew Genesis,
06:59in terms of not just being blocked
07:01for for blood vessel formation but
07:04also its role in immune activation
07:06and immune suppression.
07:08So we looked into this further
07:10summarizing some work from a few
07:12years ago of combining simplified
07:14paid with entry into Genesis based
07:17on the vasculopathy that we saw.
07:19I thought the pathologically the
07:21role of veg F and decrease in
07:23the Newcastle maturation work by
07:25George Lucas and others.
07:27Overcash Jenna natural.
07:28Also had shown that blocking Veg
07:30F and proved himself trafficking
07:32across Endothelia and we worked with
07:35Jed Walchak memorial looking at pre
07:37treatment levels of Veg F which were
07:39associated with the higher the bowls with
07:41poor outcomes.
07:42Both less responses and less reliable.
07:44Again guilt by discussed by association.
07:47Then Jeff may play a role with
07:49the new checkpoint blockade.
07:51So this is just kind of some summary of that.
07:54Here's a pet scan of a patient on the top.
07:57The CAT scan portion shows his liver
08:00metastasis and then that is lit up by pet
08:02and after just a few months of treatment
08:04delivery tasks hasn't changed in size,
08:06but it has become metabolically cold
08:09and this trial would it be alone had a
08:11response rate of about 35% and 50% of
08:14patients doing doing well with controlled
08:16the disease for six months or more.
08:19So this is a background.
08:20I think the correlatives give you the
08:22basis for this for this combination,
08:25and that we look at the pre and on
08:27treatment on the left and comparing
08:29to patients who received it be
08:32alone on treatment on the right and
08:34some some control samples and the
08:36patients received Bevis is a map.
08:38Anti Veg F had changes in the
08:40endothelium as depicted by CD 31,
08:42where they morphologically look plumper,
08:44columnar and biochemically were
08:45activated with up regulation of E.
08:47Selectin.
08:48These morphologic and biochemical
08:49changes and then to filium.
08:51Were associated with kind of
08:52a robot robust in brisk,
08:54lymphocytic infiltrated on the larger insets.
08:56Here you can see that some red cells
08:58in the center of the endothelium and
09:01lymphocytes complete surrounding it in
09:04comparison to what we see with it be alone,
09:06which is really very little
09:08changes and aphelion.
09:09In addition, the endothelium with with veg.
09:12F blockade would be versus a mad had
09:14upregulation of other important anchor
09:16molecules such as the Cam and I Cam that
09:20you can see highlighted and Ethereum here.
09:22That also suggests that by
09:24blocking Veg F you can improve,
09:26potentially improve the trafficking of
09:28lymphocytes into the to my crime and in
09:31this approaching one of the concerns
09:33we had at the beginning of the talk,
09:36which was whether the lymphocytes
09:37immune cells can actually make
09:39it into my environment,
09:41or if they were excluded.
09:42So based on this then check went
09:44on to do some bevacizumab trials
09:46and they did something very smart.
09:49They gave a single dose of bevacizumab
09:51before combining with checkpoint.
09:53Did biopsies before and after above
09:56an fortunately showed that the
09:58Bev the Veg FA blockade by itself
10:00had changes in the endothelium.
10:02Ann had improved lymphocyte
10:03trafficking cross.
10:10Is your one and also the fact that
10:13the Arnie seek in the tumors that
10:16had a myeloid signature seems to do
10:18better when they receive this map.
10:21Again, tying in that myeloid suppressor
10:23function in the veg F function with the
10:26suppressive aspect of the immune system
10:29and that those patients who had those
10:32those myeloid cells there and receive Bev
10:34had a market improvement in their outcome.
10:37So this concept has very rapidly progressed
10:40and obviously in important issues such
10:43as kidney cancer that is driven by hip
10:471A and in Genesis here is anti PDL,
10:49one to value map plus.
10:51XD Neb better far,
10:53123 inhibitor TKI showing that
10:55that combination improvement
10:57over soon to be alone.
11:00Another day to Pember Lism AB
11:02plus extended so anti PD 1 + 54.
11:05One 2-3 and innovation versus
11:06ended up having improvement in both
11:08progression free and overall survival.
11:11And this kind of concept has expanded
11:13very quickly to non small cell lung
11:16cancer with some data showing improvement
11:18with angiogenesis combinations
11:20and either will or has probably
11:23checkpoint plus anti Andrew Genesis be
11:25approvals in hepatocellular carcinoma,
11:27anamitra carcinoma and with other many
11:30combinations being being developed.
11:32So one of the questions we had is what
11:35is the role of the immune system in
11:37this anti into Genesis in terms of the
11:40role of anti genesis and it distract
11:43effect on on immunity and so in some
11:45of our patients we have a banking
11:47aspect we collect from the biopsies,
11:50try isolate Melanoma cells.
11:51We also collect tumor associated fuel
11:53cells and also to associated comma stem
11:55cells in a very simple experiment,
11:57Western blot or mean blinding here looked
12:00at before and after treatment with.
12:02Anti introduces checkpoint combinations
12:04and found that patients post treatment
12:06from their human immunity had either
12:09recognized new an energy targets
12:10or had higher antibody titers to
12:12certain targets and just of note
12:14the bottom left hand corner is that
12:17these two are individual cells.
12:19Do make tube formation so they are
12:22functional that and so we were interested
12:24in trying to isolate what those
12:26targets are because they were seeing
12:29someone else somewhere seen actually
12:31on the endothelial cells themselves.
12:33Calls other medical mental illnesses
12:35and it comes stem cells within
12:37the tumor micro environment.
12:38So one of the factors that were
12:40found in in in doing our kind of
12:43Sidney expression library screening
12:44of endothelial cells with this other
12:47energetic factor in your put into
12:49an so it kind of shows that patients
12:52can at least make any bodies against
12:55another engine factory here at age 2
12:57and age 2 is involved with in Genesis
13:00through spreading and edit this on migration.
13:02It's involved with actually anchoring
13:04the ilium to parasites and kind of
13:07a scaffold of the deathly.
13:08For them to gain structure,
13:10and it's also been shown to be
13:13involved with resistance to bed.
13:15This is a map,
13:16so in many trials mostly chemotherapy.
13:19Those pieces who developed resistance
13:21had higher levels of Angel
13:23Queen too, as a kind of a resistant I
13:25now to tie in the Ender Genesis back
13:28with the potential for immune regulation
13:31and repeating 2 not only signals by
13:34that I receptor found on endothelium,
13:36but also tide to accept it,
13:38which can be found.
13:40Onto your training monocytes and macrophages.
13:42So again, the myeloid component
13:44here being tide in as well as
13:46the link between angiogenesis,
13:47an macrophage biology and immune suppression.
13:50So there could be a dual role for entropy
13:52into both in terms of the androgenic
13:54component as well as immune regulation,
13:57so we were further interest in just
13:59kind of taking a look at this and
14:02found for number of combinations that
14:04Angel Queen 2 levels were associated
14:06with outcomes to treatment so so
14:08patients who had higher levels.
14:10Andrew Queen 2.
14:11Or changes in between 2 levels did
14:13worse and that patients who developed
14:16antibodies to interpret into did better,
14:19showing both for patients with
14:21it be on the bottom here.
14:23And for patients who received it be plus
14:26businesses map on the top right hand corner,
14:29which is the ratio of antibodies.
14:32Change two afterwards to pre levels.
14:34There are a couple of patients
14:36who had high titer antibodies and
14:39whether entropy to go up there.
14:41They had the highest danger point
14:43to any bodies that were present,
14:45so the one of the questions is
14:47whether the humoral immunity being
14:48developed is actually functional an
14:50we have some data that the patients
14:52who are making any bias to interpret
14:54into some of those antibodies can
14:56actually block Type 2 signaling both
14:58on endothelium and in macrophages,
15:00so so the immune system may be very
15:02smart in terms of actually making
15:04functional antibodies against
15:05an engineering factor here,
15:06such as interpreting 2.
15:09So here is some of the data showing
15:11that as a function of treatment
15:13patients get higher levels of
15:16agent into anybody's he both with
15:18patients received hippy dippy Bev.
15:21We have data showing anti PD one patients
15:24also developed any bias to injure
15:27Queen 2 as a function of treatment.
15:30So one of the questions again,
15:32maybe goodbye Sociation is is
15:34is the expression of a gene two,
15:37which seems to be suppressed by Veja
15:39blockade at times associated with these
15:42myeloid cells in the tumor microman
15:44now in preclinical animal models,
15:46people find M1 macrophages as more tumor.
15:49Sidell M2 is more suppressive in humans.
15:52It's a bit more challenging to
15:53define M1 versus 2 and it's really
15:56more functional characteristics,
15:58but he wanted to look at.
16:00Patients received if he alone would be Bev.
16:03So we had these samples to look at
16:06Angel Queen two expression before
16:08and after treatment and what we
16:10found is that with businesses amab,
16:13if you look both in the tumor and
16:16and acylium that you get decrease
16:18in entropy into expression as
16:20a function of the decade.
16:22But with hippie alone endocrine
16:24two seems to increase in both the
16:27tumor cells and in the endothelium.
16:29We then correlated the level of.
16:32Of Andrew Queen two that we could
16:34find in the ilium, to see 163 cells
16:36in the tumor marker firemint, CDC.
16:38Once we can be a marker for my Lord
16:40suppressor cells, or dendritic cells,
16:42and what we found in the dozen or so cases
16:45that there was a seems to be a correlation
16:48with age 2 expression in CD163 cells.
16:50So the higher the age 2,
16:52the more CD wants 3 cells that were noted.
16:55The tumor marker aren't these city
16:57wants 3 cells would be the cells that
16:59had the Type 2 receptors on them and
17:02would part of the myeloid suppression.
17:04And so there was kind of a correlation
17:06between that levels of age 2 in the
17:08my suppressor cells and tumor marker.
17:10Violent again giving data to suggest that
17:13maybe this would be an important target
17:15to consider from both an androgenic
17:17standpoint and from immune regulation.
17:19So moving on to some other plan today,
17:22working with Summer Amanar Group whose
17:24therapist in geologist we preceded
17:27with a Phase 1B study that tested
17:29the activity of PEMBLE is a map anti
17:32PD one with TRIBUTED which is in a
17:34Pepto body that blocks both Angel
17:36Green one and interpreting two now.
17:39The goal here would be hopefully to
17:41get the interpreting to blockade.
17:43Black entropy and one would maybe
17:45potentially do a slightly different effect,
17:48but we know that both veg F in this
17:51cartoon here as well as age 2 have some
17:54overlapping functions into distinct
17:56functions both on their veg F and H2 effects.
17:59On myeloid suppressor cells,
18:00making important factors of style
18:0210 and such the potential role for
18:05PDL 1 onto associated macrophages
18:06in the role that the entropy do in
18:09twin two increases that expression on
18:11tumor social macrophages went back
18:13to one day regional.
18:15Slide showing how PD one
18:17immune cells into my crime.
18:18It was predictive of a Tesla smab
18:20responses to in lung cancer and other
18:23myeloid cells such as neutrophils and
18:25that are becoming more highlighted in
18:27terms of their role in immune suppression.
18:29So we're going to show you the first
18:32group of patients that were rolled
18:34in this study were 17 microsatellite
18:36stable patients with clinical cancer.
18:38All had been heavily pretreated meeting
18:40time of 2.6 years since her diagnosis.
18:43In this trial there are no DLT's in
18:45that 30 mixture kid was was determined
18:48to be the MTD for the the Pepto body.
18:52There were some truly adverse events.
18:54Download distention,
18:55diarrhea of some some adima which has
18:57been shown with injury and inhibitors.
19:00That did you get a little bit of
19:03third spacing some level of Tita
19:06abnormalities but but nothing there
19:08was there was dose limiting.
19:11This is the dose escalation for those
19:13treated on the left with multiple
19:15different cancers and then on the on.
19:17The right is the colorectal cancer court.
19:20Specifically in the first quarter pants
19:22record, so in the dust escalation,
19:24a number of cancers were treated,
19:26including colorectal cancer,
19:27ovarian renal cell, showing that there
19:29were a couple of partial responses include
19:31rectal cancer and some stable disease,
19:33and the writer the spaghetti
19:35plots for spider plots showing the
19:37clinical activity in patients with
19:39colorectal cancer who received.
19:40This combination in the color
19:42took or hurt the meantime.
19:43Depression was 2.8 months that the
19:45meaning of survival of nine months.
19:46We're going to go through a
19:49little just now with this.
19:51So we applied site off which is looking
19:54at at staining immune cells in the from
19:57the purple blood using any bodies that
20:00have heavy metal conjugation which,
20:03as opposed to doing flow cytometry,
20:05are permitted to do 3540
20:07markers at at a time,
20:09and this is looking at patients with
20:12the 1st 12 weeks of cycles of therapy in
20:16specifically focusing on the colorectal
20:18cohort and in splitting up patients who.
20:21Received clinical benefit as defined
20:23as either response or stable disease,
20:25lasting six months or more.
20:28What we found is that there were
20:30certainly higher CC-3 positive cells
20:32in patients with clinical benefit
20:34following their first mission therapy.
20:36Both C4G8 cells decrease in patients
20:38that did not have clinical benefit.
20:41CD 8 effector cell,
20:42specifically,
20:42the memory phenotypes decrease the
20:44patients that do not have clinical
20:46benefit in both the CD four and
20:498603 cells decreased in patients
20:51who had no clinical benefit.
20:53In particular,
20:53was noted in patients who had rapid
20:56progressive disease that these cells were.
20:58Were quite were quite low in decreased,
21:02almost non detectable.
21:04We're looking at other phenotypes
21:06in terms of an NK cell analysis.
21:08Those and we're going to think
21:10further discussed the potential
21:12role for innate immunity here.
21:13So this is going to be the first
21:15kind of hinted that there are
21:17trends that increases in the city.
21:20Fix ceases, Dim CD,
21:2160 negative cells in patients
21:22with no clinical benefit,
21:24and that is in the CD.
21:2616 positive cells were higher in
21:28patients with clinical benefit,
21:29which goes along with the potential
21:31indeed aspects.
21:31There are no differences in the
21:33CD fix excels.
21:34According to the cycle or clinical benefits,
21:37it didn't seem that it was had
21:39to do with timing over treatment
21:42and the CD 56 positive cells were
21:45higher in patients clinical benefit
21:47as well as the NK marker Pete 3056
21:50positive cells were higher in
21:52patients received clinical benefit.
21:54This was consistent across really
21:56all of the patients with the
21:58significance look in my Lloyd cells,
22:00which you would assume that the Pepto
22:03body might be affecting my itself.
22:06That Mila cells increased in
22:08patients with no clinical benefit,
22:09but the myeloid derived suppressor
22:11cell phenotypes seems to increase
22:13in patients with no clinical
22:15benefit in the classical monocytes.
22:17Also,
22:17increasing patient clinical benefit these.
22:19The M2 like macrophages,
22:21which the markers again are not
22:23as well defined in humans,
22:25trended to be higher inpatient
22:27clinical benefit but did not
22:29reach statistical significance.
22:31So the activity of anti PD one
22:33plus the end
22:33two pepta body probando combination
22:35may be hindered by increasing the
22:38price of my life cells leading to
22:40decrease in memory and effector
22:42T cell populations interesting.
22:43There was an association between
22:45baseline NK cell activity,
22:46an expansion of the cytolytic NK
22:48cells and think that the role of
22:50the of checkpoint and other things
22:52on a native beauty needs to be
22:54fully explored will talk about
22:56it a bit and we're currently in
22:58the midst of another enrolling.
23:00Another group of 25 patients.
23:02At Microsoft stable,
23:03colorectal cancer that that core is just
23:06about finished enrolling right now and
23:08hope to get further analysis coming out.
23:11So I think in general the role
23:13of angiogenesis and combinations
23:15is very important.
23:17It has the immune activation
23:19seen by Vjet blockade.
23:20The benefits and efficacy
23:22across multiple cancers,
23:23except taxes are manageable,
23:25but also to further consider
23:27other targets an Angel into
23:29being the next potential target
23:31serum age 2 levels increase.
23:33Increase their social worse
23:34outcomes that veg appliqued me
23:36temporarily decrease into expression
23:38in effect things into my Chrome.
23:40It needs to be a mechanism for resistance
23:43to checkpoint blockade that that I
23:46think is deserving of further studies.
23:48So one of the questions and that
23:51Harry was alluding to is how can
23:54we improve the therapeutic index?
23:57So one of the aspects is bringing
24:00bring back the concept of cytokinin.
24:03So if you think about the original
24:05reports for SQL Blockchain frequent
24:07battles by Jim Allison that the
24:10effect of C2 for blockade wasn't
24:13really well understood or appreciated
24:15until it was combined with GMCS
24:18screening tumor cell vaccines.
24:20That the really demonstrated the
24:23synergetic simplistic potential in
24:25preclinical animal models and that
24:27work that Glenn Dranoff and I did.
24:29Together with James accept subpoena to
24:31missile vaccines with checkpoint blockade.
24:33Suggested a potential synergistic effect,
24:35but work by Craig Sling off and
24:37others and many others have had
24:39concerned that GM may induce
24:40negative regulatory aspects of the
24:42immune response by promoting Mayo.
24:44It's impression cells or T regs
24:46that are in specific in a number
24:48of studies have been done,
24:50so that was kind of the concern
24:52going into this. So originally.
24:54Again, going back to just things in Melanoma,
24:57as a proof of principle,
24:58and if he is the first proof of principle.
25:02We did this randomized study that.
25:04Combined,
25:05hippie noted to be here 10 mix working
25:08which is higher than the approved dose
25:11and had a maintenance portion to it
25:14with systemic GM CSF versus it be alone.
25:17An date is been published.
25:19Progression free survival between
25:21the two arms was not significant,
25:24but interestingly overall survival
25:26was significant for the GM's arm
25:29with the one year rate of survival
25:31for it be alone being 52.9 versus
25:3416.9 for the combination.
25:36Sargramostim or GM CSF.
25:37What will talk about this potential in just
25:41a moment when we looked at side effects.
25:43Usually when you combine things you
25:46have control over more side effects
25:49but we looked at the GMR mscramms to
25:52arm versus it be alone.
25:53The patients in the combination
25:55had fewer high grade adverse
25:57events compared to be alone,
25:59and specifically when we looked
26:01at the toxicity types there was a
26:04profound decrease in GI toxicity.
26:06Diarrhea colitis in Poly toxicity
26:08so colitis diarrhea is the biggest
26:10concern for Epyx itself in.
26:12In pneumonitis, lung inflammation
26:14being a primary concern for NTP,
26:16one based therapy so found
26:18that these two target organs,
26:20having improved benefits with the
26:22combination, fairly intriguing.
26:23So what is the potential mechanisms
26:25that GM improves survival but does
26:27not improve pressure free survival?
26:29So GM recruits todrick cells,
26:31macrophages, and presentation,
26:32and when you combine this with
26:35counteracting introductory elements
26:36such as would simply for blockade,
26:38you could see if surgery happening there.
26:41Maybe Jim improves depletion of
26:43of of regulatory cells that could
26:46be that there would be important
26:48when the President GM that's that
26:51was suggested by Alan Korman.
26:53The importance of of C play 4 in
26:56terms of depleting regulatory cells
26:58could be amplified by GM in this UN
27:01coupling of overall survival and progression,
27:05free survival has been previously
27:06described for other GMC based
27:08immunological therapeutic approaches,
27:10specifically supercell.
27:11Tea and prostate cancer
27:12dendritic cell vaccine has,
27:14as part of its component GM put into it
27:16and there was a also a disconnection
27:19between progression free survival and
27:21overall survival with an improvement.
27:23Overall survival in those studies
27:24that included super Salty,
27:26so it's teen prostate cancer.
27:28So there's another basis for
27:29this observation in the past.
27:31But when we look at the possible
27:33mechanisms of improved Palmer TX,
27:35is Glenn Dranoff had had done the GM
27:37knockout mouse and and those gym mice
27:40develop significant lymphoid hyperplasia.
27:41This around the Airways,
27:43in the lung vasculature.
27:44They're really clearly demonstrates
27:46the role of GM in Palmer home stasis,
27:49and you can see in panel A is
27:51a normal mouse lung and panel
27:54B being the GM knockout mice,
27:56showing the profound inflammation
27:58in the Airways.
27:59In addition,
28:00GM is a cytokinins involved in
28:02the coastal homeostasis in in
28:04really promotes GI equal healing.
28:06The knockout mice have colitis and
28:08this can be partially reversed with
28:10administering systemic James half.
28:12If you look at idiopathic bowel
28:14inflammatory bowel disease.
28:15Jim may have a role there,
28:17so there are trials of giving GM
28:19to patient with Crohn's disease.
28:21They have shown improvement,
28:23a subset of patients with Crohn's
28:25disease have high titer neutralizing
28:26antibodies to GM.
28:27They show a mechanism weijia may be
28:29important in some inflammatory bowel disease.
28:32Patients actually have decreased
28:33levels of GM receptors,
28:34again making this combination.
28:36So we moved on to doing a randomized
28:38phase two three trial of submission
28:41or GM CSF plus nivo it be versus
28:43Navy would be alone.
28:44The primary endpoints were overall
28:46survival relapse, free survival.
28:48In in potential reduction
28:49toxicities Anne's hair and I were
28:52talking right before this.
28:54The trial is ongoing in the
28:56midst of phase three,
28:58so I think the role of GM is interesting,
29:02possibly from exclamation point,
29:04but particularly from his possible
29:07reduction in in side effects
29:09in that cytokines may behave in
29:11different organs differently,
29:13so the lung and gut,
29:15which is the mainstay of protection.
29:18Against invading microorganisms,
29:19GM may play a very important
29:21homeostatic role there,
29:22and they play different roles systemically
29:24throughout the other parts of body,
29:25and this is other areas were
29:27interested in looking at.
29:29So what what drives response to
29:31checkpoint blockade is kind of next
29:33next question and we set up some
29:35site off panels looking at patients
29:37who had received it be alone and
29:40receive PD one alone and spent a
29:42long time saying these panels up.
29:44And would you find out with the site
29:47offers that doing the experiments
29:48may may become much easier,
29:50but the analysis of the data from
29:53computational biologist endpoint
29:54can be quite onerous and and such,
29:56but these are some of the Disney plots that.
29:59Be a established looking at the
30:01different subsets of cells that
30:03we could look at in the purple
30:05blood and again focused on patients
30:07who had received it be alone.
30:08Initially in Pembroke alone.
30:11And what we found is that patients
30:14who between those those two chords,
30:16lymphocytes and monocytes frequencies
30:18very much differ between responders and
30:21non responders where you can you see
30:24with patients who responded to Penn Bro,
30:27there's actually less lymphocytes
30:28in the purple blood.
30:30Well,
30:30if that's not the case and that there
30:33also are higher monocytes in patients
30:36responding in the blood to Japan bro.
30:39And then.
30:40Sanders and that is not the case with 50.
30:43One of the things that kind of
30:45fell out in the data set is that
30:48patients who failed response to anti
30:50PD one had lower expression of CD.
30:5269 would be in case also kind of
30:54activated circulating NK cells
30:55in the peripheral blood an we've
30:57subsequently have a couple of other
30:59other datasets working on the kind
31:01of has confirmed these observations.
31:02It really brings out the question of
31:04what the role of innate immunity is.
31:06Here we know that in case cells
31:08have PD one in the surface,
31:10but when you the most profound
31:12effects have been on these.
31:14Circulating activated CD-69 that
31:16would be positive NK cells in the
31:19peripheral blood that seems to be
31:21associated most with pembrolizumab
31:23efficacy in normal.
31:25So with that as a basis,
31:28we wanted to say what other aspects of
31:31the tool micro vironment contribute to.
31:34Maybe Check Point resistance or
31:36efficacy and there we could have many
31:39lectures on all the areas investigation.
31:42We've seen that ACR Anasco recently
31:44of areas are looking at quote unquote
31:47resistant mechanisms to PD one blockade,
31:50so we talked the importance of having
31:52seen infiltrate the importance of interferon.
31:55In the two microenvironment and then
31:57things such as beta two mutations
31:59that may be part of the APC machinery
32:02or Jack mutations.
32:03Part of interferon signaling that they
32:05may be important resistant mechanisms,
32:07but we were further interested
32:09in looking into that.
32:10My work with Scott Rodick was simply
32:12want to look at the protein level.
32:15What class one and Class 2 as part
32:17of the APC mechanisms are doing
32:19as part of this resistance in
32:21relative to checkpoint blockade.
32:23So we took advantage of this study.
32:25The so called Checkmate 064
32:27Study investigation study.
32:28That randomized patients untreated
32:30patients mellema to either receive
32:32first niveau induction followed by
32:34a four switch to Epyx induction,
32:36or the other half of patients
32:39received it be first induction for
32:4112 weeks followed by NIVEAU and
32:44then after both induction periods,
32:46all the patients got needle maintenance
32:49and everyone got biopsies before hand.
32:51In between the two inductions
32:53in falling induction,
32:55two as well as a collection
32:58of peripheral blood samples.
33:00And we want to look specifically
33:02at the protein level,
33:03so this is work and penalty by Scott
33:05Rodick and looking at class one
33:07expression in the left hand column in
33:09Class 2 expression in the right hand column.
33:12And there's a little bit of our part to this,
33:15so if you look in a room normal 1/3
33:17and five you have high levels of
33:19class one expression which you should
33:21see in all nucleated cells, right?
33:23All nucleus should have high class.
33:25My expression three is decrease and
33:27five is almost absence of of class one.
33:29But interesting in this tumor.
33:31You have your control cells there.
33:33You have immune cells there that
33:35have class one.
33:35That kind of show you,
33:37I think,
33:38fairly profoundly that the tumor
33:39itself is last class one and then
33:41on the right hand column for 246
33:43you have Class 2 expression of
33:45high Class 2 expression,
33:46which is typically not all
33:47that common in cancer Melanoma.
33:49You have medium and then you have no Class
33:522 expression in panel 6 on the bottom.
33:54Figure what we've done is we've
33:56color coded on the top the the level
33:58of class one expression across all
34:00the tumors that were evaluated.
34:01So the darker has the highest
34:04class my expression.
34:05Approaching level all the way down
34:07to kind of complete loss of classics
34:10pressure on the right and then right
34:12below that is by HC is Class 2 expression.
34:14Then we looked at both Arnie
34:16seek and whole exome sequencing.
34:18For these samples and so the middle
34:20panel shows you Barney seek class
34:22one expression HLA B&C and on
34:24the bottom shows you where there
34:26are mutations and the things that
34:28you would be most interested in,
34:30such as beta two and Jack Stack.
34:32So of note there were very few.
34:35Mutations and beta to attract Staten.
34:37Actually one of the major mutations.
34:39If you look at the left hand portion
34:41and purple where there was a detective
34:43beta mutation actually had very
34:45high level of classification by
34:47Etsy and we when we look into there
34:49that that that actually patients
34:51tumor had about was estimated about
34:537% of reeds had abated mutation,
34:55so most of them did not,
34:57but it was probably a minor
34:59population and maybe suggest
35:00mechanisms of acquired
35:01resistance going down the road.
35:04So we looked at the initial response
35:06to patients who either on the top
35:09here received hippie first or so
35:11simply for blockade on the bottom,
35:14received niveau or anti PD one and
35:16what we found is that the patients
35:19who had reduction in class one
35:21which was determined to be 50% or
35:24more reduction class one did really
35:26poorly to CFO blockade tippy while
35:29patients with reduction class one
35:31did not seem to affect the response
35:34rates for outcomes to Geneva.
35:36Interestingly,
35:37patients who had any Class 2 expression
35:40as defined by 1% did really well to
35:43Nivo had improvement in outcome to Nivo,
35:45but do not seem to affect all
35:49their clinical outcomes to
35:50see full blockade with hippie.
35:53So these are the Catman.
35:54Alesis and Gray are.
35:56Some patients were not a valuable
35:58few patients an an here we have,
36:00the blue being patients who
36:01had intact class one.
36:03So if greater than 50% or intact class
36:05one in the red being patients who had a
36:08reduction of 50% or or loss of Class 1.
36:11The patients who received it
36:13be first and went to Nivo.
36:14You can see here did much much better.
36:17Who if they had class one intact
36:19if they had reduction class
36:21we did very poorly in red.
36:23And actually took us a little while
36:25to figure this out because there were
36:27a number of patients who received
36:29it be first who are quote unquote
36:31in not not valuable at 1st and the
36:33reason is because some of those
36:35patients who had the lowest class,
36:37one expression or complete loss of
36:39classic session unfortunately never
36:40made it to the first set of staging scans.
36:42They either progress very rapidly
36:43or passed away early on in their
36:45treatment course.
36:46This is compared to a panel on the
36:48right who received niveau 1st and
36:50there was no difference on their class.
36:52One expression on outcomes to Nevo.
36:55Here's Class 2 expression again
36:56on the left patient,
36:57receiving it be first in the right place.
37:00For seeing you go first,
37:01there was a slight trend, but not squeeze.
37:03Some big difference for me first,
37:05but the patients who had any Class
37:072 expression did really well to
37:09niveau as depicted by the blue
37:11line on the right hand panel.
37:13So we.
37:13Had the Arnie seek data and we
37:15want to further kind of investigate
37:17what genes could be related with
37:20a focus on the patient.
37:21Received Niveau 1st and these are the
37:23top top jeans that were so sheated
37:26with with with good outcomes but had
37:28low class one expressions and many
37:29of these are in a fair and target genes.
37:32As you can see as you would expect
37:34and of no down near the bottom is
37:37I'll 15 which would be a target in
37:39case it was also significant in that.
37:42So we looked at the interferon.
37:44Genes are associated with outcomes
37:46in the patients receive needle
37:48first. We also had the interference
37:50publishing secure from from
37:52mercantile we visited, looked,
37:53would they looked at Penn Bro.
37:55We had our top 25 jeans and of course
37:58any good computational group would want
38:00to have their own their own signature.
38:03So they develop their own infernal legions.
38:06Was had some overlap so that on the
38:08left or patient received needle first
38:10on the writer page received it first.
38:13In the patients who had these
38:15signatures and had low class,
38:17one expression still did very well to niveau,
38:20but the expression of these genes
38:23most of interferon target genes
38:25do not affect their outcomes to
38:27Epyx and so this would is what you
38:30would have would have accepted.
38:32When we looked at the patients receive me,
38:34go first and had low class one
38:36expression and looked at what other gene
38:38signatures were associated with that.
38:40The patients again who got needle first.
38:42There were some gammadelta cells that were
38:45associated with outcomes as well as an in
38:48case signature as depicted on the left,
38:50and those signatures were not
38:51influential for patient received
38:53it be first in terms of outcomes,
38:55we were able to in those patients
38:57who had low class one expression and
38:59good outcomes were able to identify
39:01in the two mark apartment by C.
39:03Both Gamma, Delta and in case files.
39:05There were few,
39:06but they were detectable in those
39:08in those patients by HC.
39:10Anne's kind of hinted before I'll
39:1215 specifically in the patients
39:13who had low class and expression
39:16or single first was associ with
39:18better outcomes in on the left.
39:19Here an we're not influencing the outcomes
39:23to page received it first on the right.
39:26So we were interested trying to
39:27confirm in some way another group
39:29of samples that were well clinically
39:32annotated for outcomes and went
39:33to the Checkmate 069 study,
39:35which was a study that had got
39:37the proof on evil Epion Melanoma,
39:39and so there was one Group A source evil
39:42it be an another group that received it,
39:45be alone and had samples available
39:47for analysis.
39:48While we were able to show is that
39:50the patients got it be alone who
39:52are downregulation of class one
39:54basically had 100% negative predicted
39:55value for for both response and
39:57an for poor clinical outcomes.
39:59So if they had loss of class one
40:01again they did very very poorly
40:03for the patient seen evil.
40:05Plus it be there were there were
40:07trends but there was nothing stuff.
40:09Again.
40:09Obviously this is not ideal that it was
40:11combination that is hard to dissect out.
40:13There was a trend toward the
40:15Class 2 being beneficial,
40:16but it does not reach.
40:18Sickle significance.
40:19Here are the the mayor analysis for
40:22patients with class one expression,
40:24again high versus low class profession
40:26with iffy on the left and evil clip
40:28in the right and you can see the
40:31difference received it be with low
40:33class xpression doing very poorly.
40:35It was no difference for patient received
40:37new needle plus it being.
40:39Nearest Class 2 expression that
40:42again reached had a trend but
40:45did not reach significance.
40:48So it appears that secretly for blockade,
40:50responses are dependent on MHC class
40:53one expression while PD one blockade
40:55is not entirely dependent class
40:56one but is improved with Class 2
40:59expression and with also previously
41:01described interference signatures,
41:02they really show the importance
41:04of interfering there.
41:05I think this raises a lot of questions
41:08and on what other aspects interest to do.
41:11We are interested in looking at
41:13other other cancers in the Class
41:152 component which has been also
41:17reported by other groups importantly.
41:20Suggest that maybe CD four cells
41:22making game in assure on could be
41:24very important for for for PD one
41:26blockade dependence on class one.
41:28For 64 we've always been interested in using.
41:31This is a predictive marker.
41:33Prognostic studies and are looking at
41:35other groups of patients both needle,
41:37plus if it in order to to try to really
41:40say if patient has downregulation
41:42class one which should it be considered
41:45or not as part of the regiment?
41:48So we're really now applying newer
41:51technologies to understand the spatial
41:53relationships with immune cells,
41:56tumor environment,
41:57doing both MIDI and other other
42:00important imaging techniques,
42:01sisyphe and others to understand the
42:05interactions of these immune cells.
42:07Myeloid cells CD4 CD,
42:09eight other other aspects,
42:11as well as the APC machinery
42:14nearest neighbors to understand the
42:17interaction between requirement.
42:19We think it's important to better define
42:21the role of Class 2 and CD4 cells as
42:24well as the potential for Nate immunity.
42:27We have some hints there,
42:29both from their early site off as
42:31well as some of the aspects and
42:34looking the difference between needle
42:36versus AP or simply for speedy
42:38one or the control for NK cells.
42:41Even with checkpoint blockade,
42:42important role of cytokines,
42:43both the efficacy as well as some
42:46examples of possible reduction
42:47in in toxicities combination.
42:49Drink factors and really using data for
42:51rational combinations of checkpoint
42:53blockade based therapies in the future.
42:55So many of the things I've discussed
42:57with you today were investigating
42:59initiated and it's always very
43:00hard to do investigation studies.
43:03And this is just a list of the many
43:05folks that were involved with these
43:08studies in the approaches that the
43:10result for them and I just want
43:12to pay pay thanks to them.
43:15And these are my disclosures too.
43:23Thank you.
43:26Thank you Steve.
43:27I'm going to ask folks to please
43:29enter questions into the chat box,
43:31but while folks do that I will
43:33start with one or two.
43:35That's OK with you.
43:38So first question was the dose
43:40delivery better when you gave the
43:41AP and the GM CSF versus APLON?
43:43In other words,
43:44were you able to get more cycles in?
43:47Now that's a very it's very good question.
43:50So when and when we looked at that and in
43:52response to some of the reviewers comments,
43:55is there was good question there
43:56done not seem to be a significant
43:59difference in number of cycles
44:00there were between the two arms,
44:02so so that's a great question.
44:04So if you reduce the we
44:06know that super blockade,
44:07we know that if he is dose dependent, right?
44:09We know going from 3 to 10 you have
44:12more toxicity and more responses,
44:14and so the question is great
44:16question is whether you could
44:17just get more more Dragon and.
44:19Watching at least between the storms,
44:21do not seem to be a significant
44:22difference between between that,
44:23but that's a great question and something
44:25we need to continue to look into as
44:27we move on to the needle at the study.
44:30Let's not thank you.
44:32Expression is So what
44:34directions are you planning
44:35on taking for class one?
44:37Deficient melanomas.
44:39Yeah, we we number one have been
44:41interested in looking at whether the
44:43class one observation is important.
44:45Other cancers Sony would be is now
44:47a lung cancer and kidney cancer and
44:49we've been trying to gain access to
44:52some of them just to see you know,
44:54does does class one influence that?
44:56So that's the first thing.
44:58The other thing is we were kind
45:00of interested to look at a just
45:02even a biomarker driven trial
45:04for classroom expression to say,
45:06should patients who have low
45:08class work session.
45:09Getting it be,
45:10or if there's an efficacy change,
45:11we just haven't been able to
45:13get traction to do such trials
45:15and logistical standpoint.
45:16Yeah,
45:17it's very complicated and you
45:18got a lot of them going on,
45:20so there's a question from the
45:22audience from Antonio Muro.
45:23Thank you for your presentation.
45:24By the way, thank you for
45:26the presentation is awesome.
45:27It's going to end up with that,
45:29but in the GBM trial,
45:30comparing neighbor versus
45:31Beth patients with PD,
45:32L1 expression survived longer
45:33if they received bags.
45:34Do you have any ideas as
45:36to why that could be?
45:39Yeah so. One of the questions that could
45:43be confusing is whether the PEO expressions
45:45on the tumor on the mileage component
45:48so in in brain tumors you gonna have the
45:50myeloid like cells or run that probably
45:52have a lot of people and expression,
45:55and so one of the hints from the Genentech
45:58trial is that the immune cells express PD L1.
46:01The myeloid cells also for both markers.
46:03For predicting this to improve outcomes
46:05to budget blockade and so depending upon
46:07you know sometimes maybe more myeloid
46:09dependent on my my Lord Rich and others.
46:12Include by blocking veg F for engineering
46:14factors you actually having a greater
46:15effect on that myeloid suppressor
46:17compartment that my suppressor effect
46:19then then actually on the tumor itself.
46:21So that would mean without having
46:22a definitive answer,
46:23that that would be one of the hypotheses
46:25is that you're when you're blocking with
46:28Bev that you that you may be affecting
46:30both your immune cells that are pretty
46:32one positive as well as as well as
46:34the myeloid component that affects,
46:36and so if the tumor is is is more dependent
46:39on myeloid cells or in such that you.
46:42Milo suppressive cells.
46:43You may be having a benefit
46:45by blocking benchev there.
46:46That's again something that needs to be
46:49more definitively determine in patients,
46:51but I think a reasonable hypothesis.
46:53Now then, maybe Antonio can respond to
46:55the question of whether it's actually
46:57primarily expressed in the my load
46:59cells or in the glioma cells themselves.
47:01'cause I've seen some really strongly
47:04positive gliomas tumor cells.
47:06It is interesting,
47:07then why folks into other questions.
47:09I'm going to ask you a question about your
47:11early date on the vasculopathy with the CTA.
47:14Four at that pic.
47:15That figure that your shoulder
47:16is actually quite stunning.
47:18Do you think that that's organ dependent?
47:20More likely.
47:20See it in the liver or whatever.
47:22Or do you think and maybe you've
47:24had a chance to look at that now,
47:27so we've so, at least in
47:29that very early stage.
47:30Way back when they do not seem
47:32to be organized and we had,
47:34we saw the best drop, the many different,
47:36many different organs that were biopsied.
47:38And. In so we've also as many are looking
47:43at tertiary lyford's liquid structures.
47:45That anti interests may
47:46also be influenced in.
47:47So we actually saw a large I didn't
47:50think into this into much detail.
47:52A number of tertiary lymphoid
47:53structures associated with that,
47:55and you think that maybe those are
47:57making any bodies and those mission
47:59with good outcomes, but that,
48:00but as we're looking at for these
48:02traditional infrastructures,
48:03we also saw these vast properties
48:05in many different organs,
48:07so there's different degrees of it,
48:09but but but it does not seem to be working.
48:12It.
48:13Interesting, and then if you followed
48:16followed up on your studies of the angio,
48:18the edge two expression in the Tigers
48:21in patients who got deep in Eva.
48:24No, there's blood studies that your
48:26shirt yeah yeah yeah, yeah.
48:28So we so with evil if he also and we
48:30do have some data that we're putting
48:33together that while the antibody titers
48:36are not as the increase in anybody,
48:39titers are not as high.
48:41If the patient had received which.
48:43Maybe again suggest maybe there's
48:45some humanity effects to anti
48:47Backdraft patients who did develop
48:48antibodies to enter into an evil.
48:50If he did seem to do better
48:53than patients who did not,
48:55but the waiting to do our
48:57confirmatory cord right now.
49:00That's great, and then so you're
49:01planning on following up on those
49:03studies with the engine point,
49:05and we wanted to inhibitors
49:07in other cancers or with EPI
49:09Nevo as opposed to a dragon.
49:10Yeah, so I heard you're always my therapist.
49:13It's always been challenging to gain
49:15access to these drugs for grade to do
49:18some of the the stage you want to,
49:20so that's been one of the challenges,
49:22but there are. There are some companies
49:25that are looking at at dual veg F.
49:27H2 inhibition in cancer,
49:28and I think that those studies will probably.
49:31People shed further light,
49:32so when you block veg F,
49:34Ange two goes down temporarily and then
49:36H2 comes up is kind of resistant mechanism
49:38and so the question is whether you
49:41whether the blocking age 2 would would
49:43also be beneficial with veg F and likelihood.
49:46It probably would be in terms of
49:49if these hypotheses are right,
49:51but effect PFS because because you'll be
49:54blocking into an once resistance comes out,
49:56so those some of those trials
49:59are being done early on.
50:00H2 inhibitors that were studied were
50:03many of the companies have shelved that
50:05as a target because the inhibitors,
50:08when combined with chemo, didn't seem
50:10to do any better than blocking VEGF,
50:13combining chemo, and so there was,
50:15I think, less enthusiasm.
50:16At that point,
50:18hopefully some of the mechanism questions
50:20and the questions and combining with
50:23checkpoint blockade may may give a
50:26little bit of impetus to to look at
50:28this further in in cancer therapeutics
50:30by combining with checkpoint and and
50:33the complexities of indigenous actors,
50:35so hopefully there will be
50:37some reinitiation of that.
50:38So what happens
50:40to entry point into levels when you
50:42give of edge of receptor inhibitor?
50:46As opposed to especially
50:47The Dirty inhibitors, yeah,
50:49I don't. I don't think I haven't seen any
50:52data that specifically looked at that.
50:55We went yeah yeah but I think yeah
50:59yeah so I think that you know
51:02the the kidney cancer and and.
51:05The all those, all those states
51:06could look at the issue levels.
51:08I have not been able to look at that,
51:10but that's a very good question.
51:13Maybe even even the Lebanon studies have
51:15been coming out in Melanoma and others
51:17are also very interesting in Aladdin.
51:20Bullhead veg F receptors,
51:21also FGF in those studies.
51:23Some of them just recently presented
51:24at ASCO are also kind of indicative
51:27of this of this combination,
51:29so then looking at other its effects,
51:31another energetic factors age 2
51:32I think would be an opportunity.
51:37So Steve is a final question for you.
51:39What do you think the next big
51:40hit is going to be in Melanoma?
51:42Let's put aside the leg 3 because
51:44we already know about that one.
51:47Yeah, I, I think that the live Adam data
51:49also looks very interesting, right?
51:51In terms of combinations where that
51:53fits into the portfolio of options for
51:56patients in terms of line and such,
51:58it will need to be kind of further detailed.
52:01I do think that as a field
52:03for me in therapy in general,
52:06making hints to it that we have to
52:09understand the role of an aide,
52:11immunity and that so some of the targets
52:13for NK cells and targeting my light
52:16cells I think are interesting very.
52:18Early in development,
52:19but will Melanoma and other cancers have?
52:21P1 is a base will be an opportunity to
52:24test those aspects with innate immunity.
52:26It's not a matter of getting
52:29the innate immunity started,
52:30but I think more of how how durable
52:32that those interactions are.
52:34So in case else, or may be interesting,
52:37but how do you propagate them long
52:39term so I would say like 3 looks good.
52:42I will say in Genesis looks good.
52:45We'll see what GM does,
52:46but that the future interest
52:48in other excitement.
52:49In addition to the checkpoints
52:50would probably be how we manipulate
52:52innate immunity to to help patients
52:54with cancer in the future.
52:57Steve, I think that there
52:58are no other questions.