Targeting Innate Immunity to Enhance Anti-Cancer Immune Responses

Transcript

• 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.