Targeting Innate Immunity to Enhance Anti-Cancer Immune Responses

May 21, 2020

Marcus Bosenberg, MD, PhD

Yale Cancer Center Grand Rounds | May 19, 2020

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00:00You know the areas that we're going to
00:04focus on today, or two critical ones,
00:07namely mute on Koleji,
00:09for which we really committed you centers
00:12and resources as well as computational work,
00:15which I think is critical in this next phase
00:18of Cancer Research in the 21st century.
00:21Anile open with our first speaker,
00:23as many of you know,
00:25doctor Marcus bosenberg is a leader in our
00:28Cancer Center professor of dermatology,
00:31pathology and Immunobiology.
00:32Co leader of the genomics genetics
00:35and epigenetics research program.
00:37Director of the else boren kins skin cancer,
00:41as well as a very active member
00:44of the faculty in theology.
00:46Enough leading nationally internationally
00:48recognized amount of pathologists
00:50and most most recently serving,
00:52really quite brilliantly as our interim
00:55leader and director of the L centerview know.
00:59Cology is really part of that launch.
01:03Marcus is research has been,
01:05as you know, prolific, focused.
01:07I pour it on the genetics and
01:10cellular changes that result in
01:12Melanoma while concurrently building
01:14innovative new laboratory models
01:16animal models to understand cancer,
01:19to define our immune response,
01:21responding and also even
01:23launching new centers.
01:25Precision oncology,
01:26precision cancer medison to help
01:28us define models to further the
01:31research of many of our faculty so.
01:34Marcus,
01:35thank you for volunteering to
01:36speak at our virtual form.
01:40Great, thanks so much Charlie.
01:42Thanks for the kind introduction.
01:44Just someone give me an odd that
01:47they can hear me and see the alright
01:50sounds good great so I'll start.
01:53Today's topic will be targeting innate
01:56immunity to enhance anti cancer
01:59immune responses and I think you know.
02:03What we've seen, even in the last decade,
02:06has been a remarkable transformation
02:08about how we think about treating cancer.
02:11A decade ago.
02:12You know, aside from area snow,
02:14if you look around Yale and other
02:17institutions, and there are a
02:19number of other people as well.
02:22But there wasn't that much
02:24interested in on Koleji.
02:25There have been longstanding
02:27efforts in a couple of cancer types,
02:30including Melanoma, such as IO2,
02:32systemic therapy,
02:33and adaptive transferring to
02:34Myrtle trading lymphocytes.
02:36On both of those sort of pioneered
02:38by Steve Rosenberg at NCI and then
02:41over the early 2000s CLI four and
02:43PD one PD L1 checkpoint blocking
02:46therapies were developed and if
02:48you look at the impact that this
02:50is had in terms of the number of
02:53cancer types where these are now
02:56standard of care therapies,
02:58you could argue that this is amongst
03:00the greatest advances ever and
03:02cancer therapeutics and resulted in
03:04sort of the first large decline.
03:07And cancer mortality over the last year,
03:10especially with the effects in
03:12lung cancer attributed to,
03:13for instance, the PD one PD,
03:16L1 blockade and this breakthrough
03:18was awarded the Nobel Prize in 2018.
03:21There's a nice video,
03:23the PBS that's made about Jim Allison.
03:26Related to that.
03:27That's just been out and following
03:29on that initial success,
03:31a lot of companies change their portfolios
03:34to try to do PD one blockade plus.
03:38Other drugs as the new sort of
03:40standard clinical trial that was
03:43instituted in Disappointingly
03:44the success of these approaches,
03:46was not really what had been anticipated.
03:49PD one blockade continued to have low,
03:52but real levels of effects
03:54in a variety of cancer types,
03:57but the addition of 2nd drugs almost
04:00overwhelmingly did not have significant
04:02benefit beyond PD one blockade,
04:04so there's a lot of interest in
04:07developing combination therapy approaches.
04:09In which cancer,
04:10me know therapy is a component of
04:12that and will focus a little bit more
04:15about targeting components of the
04:16innate immune system to enhance that.
04:18and I would argue here is that the
04:21mechanism of how these drugs work,
04:23and in general how anti cancer
04:25immune responses happen is really
04:27not well understood.
04:29Just to go back a little bit in
04:31terms of what's innate immunity
04:33and what's adaptive immunity.
04:35Most aspects of immunity have a
04:37strong basis in haematopoiesis and
04:39the cell types that are derived,
04:41at least in part from bone marrow and
04:43going from pluripotent stem cells
04:45to mile wooden lymphoid precursors,
04:47pretty much everything in the myeloid side,
04:50so the mass cells and all of these
04:53guys over here on the right are
04:56part of the innate immune system
04:58and T cells and B cells.
05:00Make up the primary component
05:02of adaptive immune immunity and
05:05So what are the characteristics of the
05:08adaptive immune system to sort of to
05:10get that out of the way while we're
05:13talking about innate immunity, well,
05:15somatic hypermutation of the T Cell Receptor,
05:18an amino globulin loci and recombination
05:20of those loci allow for billions of
05:23different clones within every human
05:25that have distinct reactivity set
05:27allow for the recognition of almost
05:29countless and diverse sets of.
05:31Antigens for which one can have a response
05:34that's either Pisati Seller B cell
05:36mediated and these responses typically
05:38associated with what's called memory,
05:41which typically means that after an
05:43initial exposure to a particular antigen,
05:46something that's recognizable by these cells,
05:48there's an increased response the
05:50next time that Amazon is encountered.
05:54How do you know whether T cells are B?
05:56Cells are actually important
05:57in any of these processes.
05:59What you're looking at here is a
06:01Kaplan Meier plot of a pre clinical.
06:04Tumor experiment,
06:05in which a line that we have developed
06:08number one point 7 is in Grafton,
06:10subcutaneously in a mouse,
06:11and if a mouse succumbs to in a large
06:14tumor that's resulting survival law.
06:16So there's no mice alive in mice
06:18that have had tumor outgrowth.
06:20However,
06:21if you have this line extend out the side,
06:24as it does here,
06:25that means that the mouse was cured of its
06:28tumor and lived life span up to 60 days,
06:31as illustrated here.
06:32Well, what can be done?
06:34In mice,
06:35which is not really typically
06:37ethical in humans,
06:38is that you can actually deplete
06:40certain components of the immune
06:41system or in graph tumors.
06:43In mice that are deficient for those
06:45components of the immune system.
06:47In this case,
06:48what you can see is treatment
06:50with the drug that was developed
06:52here at Yale by Aaron Rings Group.
06:55This is a cloud of project that's now in
06:57press in nature through owners group.
07:00This drug annihilating derivative
07:01result in about a 30% cure,
07:03depleting with CD8 anti CD 8 antibody.
07:06Prevented that cure rate and CD four
07:08also did at a little bit longer latency
07:11while blockade of NK cells didn't
07:13result in any extended survivals.
07:16So what I'm kind of bringing up now
07:18is a concept that if you really want
07:21to understand how these things work,
07:23it's typically useful to have a
07:25system to evaluate what functional
07:27components are at play here,
07:29and that's been a difficulty with
07:31the innate immune system,
07:33which will talk about second quick
07:35segue here to B cells and anti
07:37cancer immune responses which.
07:39Had a big splash earlier in the year
07:41where there were three papers in
07:43nature in January suggesting that
07:45the cells have a role in anti cancer
07:48immunity and I would say that this
07:50issue is still not really fully resolved.
07:52All of those patient papers tended
07:54to be a correlative and weren't
07:56really functional.
07:57Studies now show example of that in a
07:59bit what is known and has been known
08:02for awhile is that when you have
08:04elevated number of T cells and cancer,
08:06you tend to have elevated B cells as well.
08:09Uh, that correlation coefficient from
08:11an RNA POV is about a row of about .7,
08:15so it's a pretty high correlation in terms of
08:17be selling T celko infiltration into tumors,
08:20but that doesn't necessarily say that
08:22they're actually doing things there,
08:24and clinically we typically it's very
08:26common to use a drug called Rituxan Mab,
08:29which is a CD20 anti CD 20 in a body
08:31which results in depletion of B cells and
08:35the patients that are treated that way.
08:37And typically these patients don't
08:39have really much higher rates of
08:41cancers you might anticipate.
08:43If that were a primary method of
08:45restraining that particular arm
08:46of the immune system, however,
08:48I think there's still more work that
08:50hopefully will be done in this area.
08:52This is an experiment that I was
08:54referring to in which you can actually
08:57graph the same kind of tumor into
08:59a B cell deficient mouse.
09:01Here at LAX,
09:02the heavy chain that's needed prior
09:04to class switching of these cells
09:06and in a normal mouse say with PD,
09:08one therapy or spontaneous rejection.
09:10This is this curve here, or black sticks in.
09:13Black them you empty mice which lack B
09:16cells actually reject as well or better,
09:19while rag mice that lack both B&T cells.
09:22So a second way of evaluating whether
09:24lymphocytes more generally are
09:26needed results an outgrowth of the
09:28tumors so that you don't have that.
09:31This is a collaborative project with
09:33Harriet clickers lab by Bill Damski,
09:35who is going to be a new faculty
09:39member in dermatology in July.
09:42So what are the characteristics
09:44of the innate immune system?
09:46So it's typically a rapid response
09:49of system in which it's kind of
09:53hard wired to wrecking sentries,
09:55certain pathogen or pathogen molecular
09:58patterns that viruses or bacteria.
10:00Might happen or not typically
10:02present in eukaryotes,
10:03so it allows for almost
10:05like a barrier or reflex.
10:07If response to these type
10:09of molecules one recognize,
10:11but also the innate immune system
10:13can regulate enhance activation
10:15of the adaptive immune system.
10:17This has been known in vaccine biology
10:20and it's also known or understood
10:22the role within dirt excels.
10:24Play Witcher view to be part
10:27of the innate immune system.
10:29And their activation of T cells
10:32and T cell responses.
10:33So the question really is is what's
10:35the role of these various components
10:37in anti cancer immune responses and?
10:40It's useful to have an idea of what
10:42we're talking about here in terms
10:44of what the components might be.
10:45There's a lot of confusion and
10:47a lot of debate as to what.
10:49Sort of subsets of things that
10:51are related to macrophyllus.
10:53I'm not going to get into that.
10:55It's not enough time to really
10:57fully go into that.
10:58In this session there's different
11:00subsets of dendritic cells which
11:02a few of which are labeled here.
11:03Neutrophils are granulocytes down
11:04the bottom here and then there
11:06are some components of cells that
11:08are derived from lymphoid
11:09precursors, but kind of have some aspects
11:12of innate immunity in that they may
11:14or may not have the memory response.
11:16It's debated with some of these
11:18and also they have the ability to.
11:20Rapid respond to certain common
11:22molecular signatures which typically
11:23B&T cells don't do as regularly,
11:25so these are kind of a little
11:27bit in between depending on what
11:29aspect you're talking about,
11:31might fall in between the two.
11:33Errands group has also found some
11:35really interesting therapies that
11:36stimulate NK cells the same.
11:38When I was talking about you,
11:40wait for his talk to do that
11:42more and more depth,
11:43and he may have talked a little bit about
11:46that during this grand rounds recently.
11:48But I think there's a more
11:50of a story there that.
11:52And certainly can follow up with.
11:54So the question with innate immunity
11:57has been for awhile as is it actually
11:59fighting cancer or is it promoting
12:02cancer with certain aspects?
12:04and I think most people would view
12:06most components of the innate immune
12:08system to be promoting cancer,
12:10at least in some level.
12:12And how might we know that?
12:15Well,
12:15in certain cancer types where as a
12:17pathologist one sees something called
12:20metaplasia. So at the junction.
12:22Of the posterior aspect of the
12:24vagina and cervix.
12:25There's typically there can be inflammation,
12:28depending on the status of HP.
12:30The other things like that,
12:32which results in inflammation being
12:34chronically present at that site
12:36and for gastroesophageal reflux
12:38once he's also these changes of
12:40inflammation and alteration of the
12:42cell types that are there that are
12:44associated with higher rates of
12:46cancer in those particular spots.
12:48Also in a variety of models where
12:50when you induce inflammation,
12:52it tends to be cancer promoting.
12:55And the thought process that few
12:57people feel is is at at work there is
13:00that some of these inflammatory cells,
13:03like macrophages, secrete things like veg,
13:05F or other factors that are associated
13:08with growth or angiogenesis which
13:10then allow cancers to Co op that
13:12and then grow out and myeloid
13:15derived suppressor cells.
13:16Or the probably related M2 quote,
13:19Unquote subset of Macro
13:21Fages and in certain cases,
13:23neutrophils,
13:23which might also be viewed as
13:26the granulocytic MDC's,
13:27have been described as
13:28being potentially tumor,
13:29promoting by growth restriction,
13:31but also that they actively suppress the
13:34function of the adaptive immune system.
13:36And there are ways you can test this ex vivo
13:39and looking at T cell proliferation assay,
13:43zan secretion of cytokines, things that
13:45these cells might do against tumors.
13:47It's well established that natural
13:49killer cells have a large role.
13:52Uh,
13:52in eliminate ING cells that don't
13:54have MHT class one expressed on
13:56their surface and this is a little
13:58bit variable in terms of the balance
14:01between inhibitory and activating receptors.
14:03But there are thought to be the
14:05primary way where this occurs,
14:07and obviously they're called
14:08natural killer cells for a reason.
14:10They actually kill in a variety of Contexts,
14:13so some of those contexts can
14:15be against cancer,
14:16and there's also this thought that a
14:18certain subtype of macrophages can
14:20also participate in killing responses.
14:22Either through respiratory burst
14:24activity or secretion of cytokines
14:27locally in the micro environments.
14:30And so it's been attractive hypothesis
14:32for a while to try to target cells that
14:36seem to be promoting cancer formation
14:38and a few ways of doing that have been.
14:42It's been known for awhile,
14:44but the colonist stimulating
14:45factor 1 pathway,
14:47so CSF one and its receptor CSF one R are
14:50very very important and Macrophiles Biology.
14:53One way this was known as there is the so
14:57called osteopetrosis model of the opi model.
15:00In which CSF one is an inactive illegal
15:03in my so my Sutter home was I get for
15:07that particular allele oven on fully
15:09functional CSF one Lac macrophages?
15:12They also lack macrophage related
15:14cells like osteoclast,
15:15that remodel bone and teeth so
15:17these are hard nice to keep around.
15:20Then I'll talk about them in just
15:23a second a little bit more but
15:25that's one idea about how this
15:28pathway is relevant for Macro Fages.
15:31Um?
15:31And so there are small molecule
15:33inhibitors that this is a receptor
15:36tyrosine kinase that it can be
15:38inhibited by small molecules and
15:40it's also antibodies that block
15:42this receptor tyrosine kinase an.
15:44We've used both of these in the context
15:47of preclinical modeling and I'll talk
15:49about a clinical trial at the end.
15:51It's currently underway at Yale and
15:53you could have either of these two
15:55activities that's actually inhibited
15:57and somewhat disappointingly CSF.
15:58One R inhibitors as single agents have
16:01really not been particularly effective.
16:03There's one indication which I
16:05believe their FDA approved for
16:06it to so called giant cell tumor,
16:08which is really composed of macrophages.
16:10But I think they've been negative in all
16:13or nearly all other single agent indications.
16:15There typically also negative in
16:17combination with anti PD one blockade
16:20and one of the issues with studies of
16:22this type is did the drug actually.
16:26Affectively inhibit macrophages or even
16:29deplete macrofossils were typically
16:30very hard to deplete and so this is
16:33also called pharmacodynamics to see
16:35if your drug had the intended effect,
16:37and I think sometimes it's been a
16:40little less clearer that it's been
16:42full effect as opposed to a partial
16:45effect for some of these drugs.
16:47So can we use preclinical models to help
16:50define a role for makefiles in cancer?
16:53I had described an approach before with
16:56those Kaplan Meier plots where we use.
16:58Antibodies to deplete,
16:59for instance CDA, positive T cell,
17:01CD 4 positive T cells, or NK cells.
17:04Well, those approaches don't tend
17:05to work very well for macro fibers,
17:07and even using the anti CSF one R and
17:10nobody even with the right type of IgG,
17:13that would be typically more depleting,
17:15doesn't really tend to work in this subset.
17:17The genetic models which are
17:19actually probably not bad for this,
17:21and the Mets it off lab and others
17:23have used these in a cancer context.
17:26These are very hard models to work
17:28with as I mentioned before because.
17:30Even the teeth don't form properly,
17:32they don't breed particularly well
17:33suited to feed themselves Chow.
17:34You have to really, really baby them,
17:36like a watch them very closely
17:38to actually do a full experiment
17:40and then doing cohort type work.
17:42It is difficult 'cause they don't
17:43tend to live particularly long,
17:45even postnatally.
17:47And you can deplete in macrophages
17:48from spleen and peripheral blood,
17:50but within the tumor,
17:51if you look at them pretty carefully,
17:53they tend not to have been
17:55depleted in those areas,
17:56so this is an area obviously
17:58of interest in growth,
17:59so it's hard to know what the
18:01real role of these things are,
18:03but we have done some work looking at CSF.
18:06One R Inhibitors and we published a few
18:08years back with Mark Smith from Brisbane,
18:11Australia.
18:12A drug that Plexxikon had developed that
18:15wasn't specific just for CSF one R,
18:17but that was its highest potency
18:19towards that particular receptor.
18:21And one thing I'd like to bring your
18:23attention to is that wouldn't it be
18:26great if there were human models where
18:28you could actually see an effective
18:30anti cancer immune response and you
18:33could actually deplete macrophages?
18:34And we think,
18:35and we hope that we may have
18:37developed something like that.
18:39And this is with my colleague vision
18:41with zombie who directs the Center
18:43for precision cancer modeling at Yale,
18:45sort of preclinical testing core at Yale,
18:48in which we've taken tumor fragments.
18:50And we were seeing full
18:51checkpoint inhibitor response,
18:52including elimination of tumor
18:54cells within four or five days
18:56in a fully indietro model,
18:57this has been mouse first,
18:59but we're trying to build this up
19:01and towards a human setting an the
19:04overall goal is to, for instance.
19:06Flow sort the cells that make up these
19:08tumors and deplete macrophages that way,
19:11which will work in terms of getting
19:13rid of those and putting back the
19:15components that you think will be
19:17important for these anti
19:19cancer immune responses.
19:20So stupid too and hopefully
19:22that will be something else.
19:23Hear more about with overtime.
19:25So one thing I talk about briefly
19:27now too is CD 40 as a target
19:30which is on dendritic cells,
19:32macrophages and to some extent other cells,
19:34including in the filial cells.
19:37And CD 40 Los results in a B
19:39cell class switching defect.
19:41But it's been developed as an agonist
19:43CD 40 antibody, not a blocking.
19:46Anybody want it?
19:47Stimulates this particular
19:48receptor and Bob Vonderheide?
19:49Who is the Cancer Center director at Penn,
19:52has been developing this for over 10 years.
19:55For pancreatic cancer and with
19:57the former colleague Sukach
19:58and also with Catherine Miller.
20:00And more recently,
20:01we've published preclinical models
20:02looking at Agona CD 40 therapy,
20:04and I'd say at this point in time,
20:07the mechanism isn't entirely clear.
20:08Although we went into that a little
20:10bit with both of these manuscripts.
20:12But one thing that we can
20:14see here is that agonist,
20:15CD 40 plus anti PD one blockade in
20:18CSF one R blockade works a lot better
20:20than any of the other drugs alone,
20:22so it has almost 80% cure rates and
20:25this is the younger model as well.
20:27And then the doublet therapies were
20:29PD one plus CD 40 and so forth.
20:31Also, don't work as well as the triple,
20:34although in humans will see in a
20:36second that may be slightly different,
20:38but we're seeing this is pretty promising.
20:41Prickly on clinical evidence to support
20:43using combination therapies with CD40.
20:44One of the things that striking
20:46with this particular therapy
20:48relative to PD one blockade,
20:49or PD1 plus ETA four blockade.
20:51Here's the T sne plot of a single cell RNA
20:54seq experiment where you have two samples,
20:57one of which is a mouse which had an
21:00injection subcutaneously of a tumor model.
21:02Seven day or eight days before and
21:05then one day prior to this harvest,
21:07mice for either treated with the
21:10three drug therapeutic protocol.
21:11This-is Agassi, 40 anti PD,
21:13one anti CSF 1R versus not treated and
21:16for those of you who look at TI sneak lots.
21:20What's striking here is that
21:22there's almost no overlap.
21:23the T cell areas are down here.
21:26You can see by the Vijay areas over
21:28here and here that there's really huge
21:31expression profiling differences between.
21:33The various components of these
21:35tumor micro environments and
21:36we're currently chasing that down.
21:38There's also differences in
21:40clona type representation,
21:41which I won't have time to go into here.
21:45And so just to show a little
21:48bit of pathology as well.
21:50PD one treat tumors don't
21:52look that different from this,
21:54which is one day after initiation of
21:56there might be some slightly increased
21:58lymphocytes but not really extensive death,
22:01but with the CD 40 agonist
22:03containing therapies,
22:04we see Thromboses.
22:05We see extensive cell death
22:07even within one day,
22:08and the regression profile is you
22:11can see over here on the right is
22:14different from what we see with.
22:16Uh Anti CTF War anti PD one
22:18sort of combination therapies?
22:19So there's something that's unique here
22:21which also seems to have a vascular
22:24component which we don't see the
22:26typically with those other therapies.
22:27So an interesting thing too is that we tend
22:30to think about effects of immune therapies.
22:33We tend to think mostly on
22:35adaptive immune therapies.
22:36This is an image and a rag.
22:38My switch when we gave CD
22:4040 agonist therapy issues,
22:41we actually saw more toxicity in rag
22:43mice then we saw on while typing.
22:45I'm trying to figure out why that might be,
22:48including in Forks in the liver,
22:50and so he's her F 480 positive
22:52kupfer cells in the control rag,
22:55mouse liver and one day after treatment
22:57with Agnes CD 40 you can see that extensive.
23:00A mini granuloma formation of discover
23:02cells was slightly larger granulomas as well.
23:05Interesting high dose steroid
23:06treatment prevents this from happening
23:08even in the absence of lymphocytes,
23:10so there's a innate immune dependent
23:12aggregation of histiocytes.
23:14Also seeing large differences in
23:15the histiocyte expression profiles
23:17on a single seller,
23:18and I see,
23:19but I'd say that's a work in progress.
23:22One of the things we do see
23:25systemically is you can see here's
23:27cry about a 1000 to 10,000 fold.
23:30Increase in the chemo kind CX CL-10,
23:33which is a factor that recruits lymphocytes
23:35to the tumor microenvironment and
23:38you're seeing a large extension that,
23:40with the triple therapy and so some
23:43mechanism for the CD 40 agonist therapy,
23:46it's more rapid than what
23:48we're seeing elsewhere.
23:50We see a real big up regulation
23:53and systemic cytokines from Serum.
23:55We're not sure exactly which cell type yet,
23:58although macrophages and
23:59Dicesar certainly candidates.
24:01We're interested in the vascular effects
24:03were seeing next to endothelial cells,
24:05and I would say that this sort of suggests
24:07that cytokine cycling is obsolete.
24:09Very,
24:10very important in these responses,
24:11and that we will be getting a new
24:13you 01 grant with Catherine Miller
24:15Jensen as the contact P and me
24:18as a secondary API to evaluate
24:20single cell cytokine secretion.
24:21So RNA levels don't typically
24:23aren't very accurate for these.
24:25An actual looking at each cell and
24:27what cytokines it makes will be
24:29helpful in the last minute or so.
24:31I will briefly discuss.
24:32This is part of spore project for in
24:35our skin support and this is a trial
24:38that as led by Harriet cougar and Sarah Wise,
24:41in which an agonist CD 40 therapy is
24:44combined with anti PD one and then
24:46an anti CSF one R therapy and this
24:48is in patients that have progressed
24:50on PD one blockade in Melanoma and
24:53also non small cell lung cancer and
24:55renal cell carcinoma and I will kind
24:58of go through this so we make sure we
25:00have enough time for the second talk as well.
25:03Here's a brief description
25:05of the cohorts that are here,
25:07and we're going to move through this
25:09relatively rapidly and get to some of
25:12the neat stuff and mucosal Melanoma
25:14is notoriously hard to treat,
25:15tends not to have really high
25:18mutation burdens, and here is a
25:20patient who had progressed on C5,
25:22four plus PD one blockade,
25:23and you can see multiple liver
25:26lesions that actually cleared by the
25:28addition of giving an agonist CD 40,
25:30so the two patients I'm showing here
25:33didn't necessarily have the anti CSF 1 R.
25:35It had very clear responses after a PD,
25:38one failure or PD1 Pussy clip for further.
25:40So here's a couple more cases where
25:43there's a lesion here that's disappeared
25:45in a couple other lesions here that
25:48are not present at a later time.
25:50So this is a trial again by
25:53Harriet cougar and Sara Weiss.
25:55Part export project for the
25:56phase one is moving forward.
25:58I think the decisions now or whether
26:01or not to have the CSF one R inhibitor
26:04around for the next phases of the trial.
26:07But one thing that was interesting is
26:10that we are seeing a similar cytokine.
26:12Profiling is what we see in the
26:15mice with dramatic elevations.
26:17Avxl 10 in the triple therapy
26:19group with some elevations.
26:21In Co works that happened to have
26:23higher levels of agonist CD 40,
26:25and so these are the conclusions that I've
26:27I've already mentioned to you along the way,
26:30and one thing I'd really briefly
26:32like to say is that as part of
26:34the Yale Center for me on Koleji,
26:37we're starting a list of a set of
26:39working groups which are smaller
26:41groups around particular complex,
26:42and we're trying to be inclusive
26:44in these working groups,
26:46and I would suggest that you go to the
26:48website through Yale Cancer Center and.
26:51Elisa Matthews,
26:51which was ALLYSIA,
26:52is the person who is a scientific
26:55program director.
26:56She can get you set up so you can join some
26:59of these groups should you be interesting.
27:02And with that I'll just acknowledge
27:04especially arena quick by Eva,
27:06who's in my lab,
27:07who has done a lot of the pre clinical work.
27:11All of the trial work and
27:13writing and managing.
27:14That's all Harriet Kluber Inserra wise.
27:16Earlier work with Sue Kevin I mentioned
27:19vision with Asami as part of the
27:21center precision cancer modeling.
27:23And I'll stop there and just for,
27:24I guess,
27:25brief minute we can potentially
27:27take a question or two.
27:28Work
27:29is thank you.
27:30That's a terrific body of work.
27:32Yet let me ask a somewhat
27:35complicated question.
27:35Instead of multiple parts,
27:37which is, you know,
27:39you've clearly shown that targeting
27:41an innate immunity for this sort
27:43of PD one PD L1 responsive cancers
27:45potentially moves the needle higher,
27:48realizing that within that cohort
27:50there are patients who may respond
27:53to just PD one alone or PT1 hippie,
27:55or things like that.
27:57And so how do you?
27:59How do you see the work you're
28:02doing help differentiate that?
28:03Or do we just give everyone
28:05sort of the combination?
28:07Then Secondly,
28:07is a related note for the tumors that
28:10are not actually really benefiting
28:11and meaningfully from the current
28:13checkpoint inhibitors you know?
28:15Where do you see this approach working
28:18in that subset of tumors as well?
28:21But I I think right now the
28:23difficulty in evaluating new
28:25combinations of immune therapies is
28:26that if you do a standard of care,
28:29so your drug plus PD one blockade
28:31versus PD one blockade alone,
28:33those trials 10, and that's the reference
28:35trial that one might use at the end,
28:37take a very long time to complete
28:40and it takes awhile with.
28:41Follow up to know what those results are.
28:44Sort of the scenarios that I've just
28:46sort of illustrated at these anecdotal
28:48cases give one much better indication of
28:50whether there's some activity of an agent.
28:53And that's basically in the setting of
28:55failure of response to existing therapies.
28:57So in these cases it was PD
28:59one plus ETA 4 in one case,
29:02which we use more commonly in Melanoma.
29:05But also just with PD,
29:06one failure in and of itself.
29:08So in those clinical context,
29:09which regrettably are still pretty
29:11common in many cancer types,
29:12you have the opportunity to add on
29:14something like agonist CD 40 to evaluate.
29:16Weather is what would really be nice to
29:19have a biomarker to know when it would
29:21be useful to use these other therapies,
29:23and that's sort of lacking at the
29:25at this time point I would say,
29:27but having a better understanding
29:29of how these things work would be
29:31one step in the second step might
29:33be doing a more careful evaluation.
29:35Immediately after you started
29:36this new therapy,
29:37do you see the site of kind of response
29:39that you would expect to see in a patient?
29:42That's going to benefit and have
29:43him earlier cut off if they're
29:45not going to along those lines,
29:46but I think those are some
29:48of the thoughts that
29:49people are having at this one time and
29:51one other question that you sort of
29:53alluded to at the end of your talk.
29:55I know you had a recent publication
29:57sort of characterizing the sort of non
30:00traditionally son exposed class of.
30:01With respect to the biology and
30:03also their potential benefit or lack
30:05of benefit for checkpoint editors,
30:07can you just to share a little
30:09bit of insight from that work?
30:11Yeah, I mean this was kind of nice
30:13here 'cause the mucosal Melanoma
30:15that was the first case that we had
30:18shown in this would be an example
30:19of a relatively low mutation burden
30:21form of Melanoma is a pretty clear,
30:23at least correlation with tumors
30:25with higher mutation version being
30:27a little bit more responsive
30:28to mean checkpoint hitters,
30:29but it turns out that.
30:31There's a number of people in different
30:33venues that are looking for tumors
30:36that might have chromosomal changes,
30:38which are typically more common
30:39in low sun damage melanomas that
30:41those might induce trans locations
30:43and sort of not like transcripts.
30:45That sort of have random proteins
30:47that are expressed at reasonably
30:49high levels that might be very
30:51good targets for immune therapies,
30:53so it's not just whether you
30:55have mutation burn or not,
30:57it just whether you have antigens that
30:59your T cells can recognize or not.
31:02And right now we're not that
31:03great in any level of recognizing
31:05which cancers those might be,
31:06and it'll probably be different
31:08for every patient,
31:08so you can't just say well,
31:10this person has this particular
31:11peptide expressed or so forth.
31:13It's also their HLA haplotype and there's
31:14a lot of things along that that go into.
31:17Whether or not they'll be able
31:18to form a productive response.
31:22Well, thank you and thank you for that talk.
31:24Why don't we will turn it over
31:26now to our second speaker?
31:28As I mentioned, you know,
31:30clear area of priority for the Cancer
31:31Center has been in computational biology
31:33and were really very fortunate to have
31:36doctor more convene speaking to us.