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

Transcript

• 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.