Immuno-Oncology

October 26, 2020

October 21, 2020

Presentations from Yale by Marcus Bosenberg, MD, PhD, Grace Chen, PhD, Roy Herbst, MD, PhD, Akiko Iwasaki, PhD, and Aaron Ring, MD, PhD

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00:00We're going to start with a few
00:03introductory remarks from the
00:05head of our Cancer Center, Dr.
00:07Fuchs, and then we'll go into a few
00:09short presentations by really outstanding
00:12panelists from our center and also
00:14Doctor IRA Melman from Jeanetta.
00:17And after that will be opening up
00:19the program to questions and answers
00:21and hopefully a freeform discussion
00:24to cover some of these topics.
00:26We really know.
00:27We know that that in order to treat.
00:31To effectively develop cures for cancer,
00:33there has to be a collaboration between
00:36industry, academics, government.
00:39It's really very, very important,
00:41and we designed this session specifically
00:43to build connections between your medicine,
00:46Yale science and industry leaders.
00:48We've collected your questions in
00:50advance and we invite you to submit
00:53your questions at during the time
00:55of discussion in the chat room.
00:57We also encourage you to share
01:00your questions with everyone.
01:04Heading into engaging in the discussion,
01:06we know that we have a wealth of
01:09expertise in the audience today.
01:11Not only do we have outstanding panelists,
01:13we have an amazing list of
01:16participants from industry.
01:18Will review the chat room
01:19throughout and will pull a number
01:21of the questions for for ants.
01:23For discussion in the question and
01:25answer portion of the session will
01:27also have a staff member monitoring
01:29the chat room and if we're unable
01:32to answer your question today,
01:34will try and follow up as soon
01:36as as possible.
01:37And please also know that the
01:39webinar is being recorded.
01:40Let me now just welcome doctor Charlie Fuchs.
01:43He's the head of our Cancer Center.
01:45He's a Richard Sackler and Jonathan
01:48Sackler Professor of Medicine.
01:49And professor of chronic disease
01:51Epidemiology.
01:51As I said,
01:52he's a director of the Yale Cancer
01:55Center and also the physician
01:57in chief of Smilow Hospital.
02:00Charlie has brought an amazing vision
02:02of building science at this Institute
02:04is be immeasurably successful.
02:06Charlie please.
02:08Error, thank you and thank you
02:10for your leadership and I want to
02:14welcome or many attendees today to.
02:16What is the 1st of a new series,
02:20namely Yale engage cancer which is
02:22really intended to be to stimulate
02:25discussion and collaboration in what is
02:28our mutual interest in combatting cancer?
02:31And this first one, I think,
02:33really highlights the great
02:35depth at our center has.
02:38Enemy know biology and Immuno Oncology.
02:40Mario certainly are our
02:42leader for the session.
02:44Has has really had an incredibly
02:46accomplished career in science and
02:48drug development in Iowan recently.
02:50The president of the Society
02:52of immunotherapy and cancer.
02:53But obviously, as you'll hear,
02:55we have assembled Marios assembled
02:57an extraordinary talent to team to
03:00really engage in this discussion.
03:02You know, we I joined the Kansas
03:04center about four years ago,
03:06and you know what attracted me here was the.
03:10Great depth of talent and accomplishment.
03:13The science here is really unparalleled
03:16in terms of genetics, cell biology,
03:18pharmacology among others,
03:20and most notably,
03:21today Immunobiology and beyond that
03:23I think the clinical operation.
03:26Frankly,
03:26the 10th anniversary of swallow cancer
03:30hospital has enabled an incredible
03:32growth of a clinical operation it now sees.
03:3648% of all cancer patients in the
03:39state of Connecticut and is enabled
03:41a fourfold increase in trials,
03:43clinical trial enrollment,
03:44and Moreover, actually this year.
03:46Yale had studies that have that have enabled
03:494 new drug approvals in the cancer space.
03:52You know,
03:53obviously,
03:53we're in the midst of a pandemic,
03:56and we're focused on kovid.
03:58But we all recognize that
04:00in the 21st century,
04:02cancer is really the great landscape for
04:04for what we want to accomplish in medicine.
04:07And I think I owe.
04:10Is an important leg that's going
04:12to get us to where we need to be.
04:16We really value the partnerships that
04:18we develop at Yale with our colleagues
04:21and industry and so many of you.
04:23Perhaps all of you with
04:25backgrounds and industry,
04:26an biotech and related areas are obviously
04:29sharing a mutual interest in this fight.
04:32You know,
04:32we welcome your participation in this forum.
04:35But Moreover,
04:36either during or even after the webinar,
04:39we would like to.
04:40Engage with you in terms of
04:41conversations and collaborations.
04:44'cause first and foremost,
04:45we know it takes a village to
04:48combat cancer and we hope with
04:50this does beyond other things.
04:52Is actually enable new collaboration.
04:54So please reach out to me.
04:56Mario or the other panelists because
04:58we want this to be the beginning of
05:01conversations and new engagements
05:03as we work together to leverage
05:05the great work in Immuno Oncology.
05:07So Mario, thank you for allowing me to.
05:11To share a few thoughts and I
05:12look forward to this symposium.
05:15Thank you Charlie.
05:17I just again want to repeat that our
05:19format today will be a combination
05:21of brief introductory comments by
05:23our panelists and then a moderated
05:26discussion including your questions.
05:28We've invited our faculty to
05:29briefly address several questions,
05:31including what their core expertise says,
05:33what questions are driving their research,
05:35how can we work with the corporate
05:38sector in order to address this disease,
05:40and finally, what types of resources,
05:42capabilities,
05:43and partnerships align with those brought
05:45to bear by the corporate sector to advance.
05:48This work remind all the speakers
05:50that you have 5 minutes to speak
05:52and then I will cut you off.
05:55Very nicely because we want to get
05:58on to the discussion afterwards.
06:00After the Yale speakers,
06:01I'll then introduce Doctor
06:02IRA Melman from genetic.
06:04So with that,
06:05let me just go ahead and proceed.
06:07Our first speaker will be
06:09doctor Marcus Bosenberg.
06:10He's The Professor of dermatology,
06:12pathology and Immunobiology
06:13at the El School of Medicine.
06:15He's currently the interim director
06:17of the Yale Center framing oncology
06:19and he's also the director for
06:21the Center for position cans
06:23for modeling and the director of
06:25the elsewhere in skin cancer.
06:27And also the Co leader of the genetics,
06:30genomics and epigenetics.
06:31So I've now taken up almost all
06:33of the five minutes with Retitles
06:35Marcus and I'll turn it over to.
06:40Thanks Mario would have the
06:41next slide that be great thanks.
06:43I had the great pleasure of working
06:45with Mario on a regular basis
06:47as part of the Melanoma team.
06:49As a practicing dramatic
06:50pathologist and I think you know,
06:52the Yale Center for immuno
06:54oncology in this session is
06:55really focused on Immuno Oncology.
06:57Is kind of at the center of a hub of a
07:00number of very important pieces at Yale.
07:03So doctor Fuchs really nicely
07:04summarized some of the really
07:06impact that the Cancer Center has.
07:08I think many of you are aware
07:10of the sort of world.
07:12Leading world renowned capability of
07:14the Immunobiology Department at Yale,
07:16traditionally with real strengths in
07:18basic immunology but now branching
07:20out toward human translation.
07:21Menology Ann.
07:22Really one of my jobs is to try to
07:25bring folks into the realm of IO from
07:28that Department which has really been,
07:32I think,
07:32a great success so far.
07:34A couple of the talks here from doctor
07:38ring and Doctor Wisocky sort of are
07:41related to some of those efforts.
07:44Also kind of giving you a feel for
07:46the landscape and this is really just
07:49an introductory session with myself.
07:51There's also the advanced cell therapy
07:53lab that Diane Kraus directs and
07:55had established an it's a full GNP
07:58facility that can harvest to multithreading.
08:00Lymphocytes expand and then allow
08:02that product to be reinfused into
08:04patients runs clinical trials.
08:05This is a real opportunity for Yale
08:08to move forward on the scientific
08:10front with regard to cell therapies
08:12and we're really positioned well.
08:14To do that,
08:15doctor Herbst will be talking
08:17right after me about some of the
08:20translation TLE efforts at Yale,
08:22and I'll let him do so.
08:24As doctor snow mentioned in my role
08:27in as directing the Yale Sport and
08:30skin cancer with Harriet Cougar,
08:32there's really excellent access
08:33to patient samples,
08:35patient materials through now.
08:36Doctor Hertz will explain 3
08:38now spore grants at Yale,
08:40and we're coordinating these efforts,
08:42especially with regard to Iota
08:44getting access to specimens.
08:46Which I think will be important for
08:49industrial academic collaborations
08:50in my role now too.
08:51I also tend to be at a lot of the
08:53discussions related to industrial
08:55academic collaborations between
08:57other entities, aniele with respect.
08:59And, you know, oncology Ann,
09:00I really enjoy that interaction
09:02an obviously try to move those
09:04things forward in the way that's
09:06most productive for both parties
09:08in each of those interactions.
09:10So if we can go on to the next slide,
09:13I'll talk about the remaining thing on the.
09:16We'll hear so,
09:17and that's the Center for
09:19precision cut cancer modeling,
09:20which I also direct with vision
09:22with Sammy and what this is,
09:24is a state of the art
09:26preclinical testing facility.
09:27It's really focused on Immuno Oncology.
09:30And we will do testing of agents
09:31with respect to syngenetic models and
09:33other things that have been developed
09:36at Yale that are unique to Yale.
09:38We have sponsored research
09:39agreements with some members
09:40who are on this call related to
09:42things like class one deficient
09:44models that were uniquely developed
09:46at Yale that don't have to be
09:48licensed out as a result of that,
09:50and we have a lot of experience which
09:52some of which will hear about in
09:54later talks just after me looking at
09:57responses to IO agents in these models,
09:59what were particularly.
10:00Cited about right now is the idea of
10:03doing patient derived explant studies to
10:05evaluate human immuno oncology agents.
10:07So the idea here is you take
10:09fragments of tumors,
10:10embed them in a proprietary 3D matrix
10:13and then use agents that might be
10:15biologics that are using humans to
10:18test responses in those samples and
10:20on the right you can see this is
10:22an example of a mouse based tumor,
10:25but one in which when we gave a
10:28checkpoint inhibitor we see a
10:30compute complete curatives response.
10:31And so we're looking at readouts
10:33for these systems.
10:34But the idea is to have personalized
10:36immunotherapy where you can actually
10:37look at different combinations in a
10:39patient in real time and decide what
10:41might work best for that patient.
10:43And we're not fully there yet,
10:44but we think we're pretty close and
10:46hope to have this available for others
10:48within the next six months to a year.
10:51So I'll stop there and allow
10:52the next speakers to go on.
10:58Argus tanky, with the next
11:00speaker is doctor Roy Herbst.
11:02He's the head of medical oncology,
11:04Yale Cancer Center and smile cancer
11:06hospital and The Associated Cancer
11:08Center director for Translational
11:09research and a professor of Medicine
11:11and professor of pharmacology, Roy.
11:15Thanks Mary, and thanks to
11:17everyone for being here today.
11:19So in my role as the associate
11:21director of Translational Research,
11:23I just want to describe, you know,
11:26a little bit about your disease
11:28programs or so-called darts and what
11:30you can see is UCR disease programs,
11:33immunology, population Sciences,
11:34Developmental Therapeutics,
11:35microbiology, cell signaling,
11:36radiation genetics,
11:37and all of these disease
11:39programs are amazing,
11:40but we want to interact them with the
11:43clinic with the clinical teams have.
11:45Access to patient specimens move move
11:47new drugs from the the lab to the clinic,
11:50and I think we're doing that quite
11:52well and we form these darts.
11:54Diseased aligned research teams
11:56and that's where we build our
11:58industry alliances in our spores
11:59and we have a number of industry
12:02alliances right now with Genentech,
12:03Astra Zeneca,
12:04Eli Lilly to name a few and these
12:06darts promote translational research
12:08through the scientific discovery.
12:09We test new discoveries in
12:11our clinics as I mentioned and
12:13really take ideas back and forth.
12:15We've worked very hard this last year
12:17too and to improve integration to
12:19increase the number of investigator
12:20trials that we have at Yale.
12:22Now in this day and age,
12:24investigator initiated trials can
12:25be where we hold the Ind or it can
12:28be a small trial with industry
12:29where they hold the Ind.
12:31But at least we are closely involved
12:33in the correlative studies or it's
12:34built on Yale Science and we want to
12:36build clinical basic teams to move forward.
12:39So in the next slide I'll just show you.
12:43We've been very successful in this,
12:45and you know,
12:46there was already an existing
12:48Melanoma spore here 10 years ago.
12:50But now with the support of the darts and
12:53with some monies that we were able to supply,
12:56Marcus and Harry have renewed the skins for,
12:59so it's a third renewal now.
13:01A third span.
13:02For that we formed a new
13:04lung cancer spore myself,
13:06with leaping as leaders.
13:07We did this now six years ago.
13:10We just renewed it building a large
13:12part on the immunology from his lab.
13:15One of the trials that really,
13:17I think propelled this forward was a
13:19signal 15 for which it was developed
13:21in the lab paper nature medicine,
13:23and then of course,
13:24clinical trials ongoing.
13:25Really proud that Barbara Burtness,
13:27who actually was recruited
13:28in the last 10 years,
13:30built a head and neck program and
13:32with support working with surgery,
13:33working with some of the
13:35great scientific leaders,
13:36now hasn't had an export and we actually
13:38have a group that's working in brain cancer.
13:41They've submitted.
13:42They're working on it.
13:43Pat Larusso,
13:44who I think you all know.
13:46Or many of you will know has been working
13:48on something in phase One South DNA repair,
13:51so we have many many translations
13:52from lab to clinic programs and these
13:55are great opportunities for specimens
13:56to work with industry for new drugs.
13:58We these things will only survive if we
14:01have alliances with the outside next slide.
14:03So I just want to give one example
14:05today and I know iris on the
14:07phone and he's going to speak.
14:09So I've known IRA for quite some
14:11time longer than either of us.
14:13Would like to know.
14:14Actually took a course at
14:15Rockefeller University as a student
14:17when he was a guest lecture.
14:19But of course, IRA has a history with Yale,
14:21so I was approached nine years
14:23ago with a drug called MPL 3280.
14:25It was a PDL one inhibitor.
14:27We already knew that these
14:29drugs sort of work.
14:30The PD one inhibitors cause Mario
14:32his office right across the Hall,
14:33but we studied this drug and you can
14:35see on the left you know activity.
14:37You know your complete response
14:39in a patient but will yell was
14:40able to offer along with many
14:42colleagues from around the world.
14:43It was a multi national study
14:45but we were able to get biopsies
14:47and this was the work of Katie
14:48Poletti and Scott Gettinger and
14:50others so we could actually define
14:52the adaptive immune response.
14:53So I think if we hit one more
14:55time so we actually could see
14:57what happened in a patient that.
14:59Responded but we also could see what
15:01happens in patients that didn't.
15:02And you know,
15:03this was an important observation.
15:05Working closely with Iran,
15:06the team danshen this was actually
15:08published in nature and it really
15:10defined some of the parameters
15:11of immune resistance and now of
15:13course the challenge is to use this
15:16knowledge in the future prospectively
15:17with combinations of agents,
15:18and that's something we're doing
15:21right now on the next slide.
15:23And we had the opportunity to
15:25take it further.
15:26So then, you know,
15:27as a lung cancer investigator and
15:29having a very robust long group,
15:31you know doing phase three all the
15:33way from phase one with a spore.
15:35As I mentioned,
15:36we were the lead site for this trial.
15:38The empower 110 trial which actually
15:40look at this drug and PDL 3280
15:42became a Tesla Zimride compared
15:44with chemotherapy and this trial
15:45if we hit again this trial just
15:47recently reported in the New
15:48England Journal of Medicine two
15:50weeks ago was a positive result and
15:52actually resulted in the drug being
15:54approved in the frontline setting.
15:55The reason I showed this,
15:57if we go to the next hit is we
15:59will look at some of the different
16:01PDL one markers in this.
16:02So we were able to move one metal up.
16:05It wasn't the first drug approved
16:06in this space the 2nd but were able
16:08to look at SP142 and 22C3 which are
16:10different biomarkers but even more
16:11critical not known to many on this call.
16:14Kurt shoppers now working with these
16:15specimens with some amino quantitative
16:16studies that he's developed here at Yale.
16:18So now we have randomized data
16:20that we can look at even more
16:22exploratory biomarkers and then
16:23on the very final slide we're
16:24anxious to work with all of you we.
16:27No, here this is very interesting story.
16:29I forgot to put this in.
16:31This is looking at tumor mutational burden.
16:33This is blood based tumor mutational
16:35burden as done by Foundation
16:36Medicine and you can see when
16:38you have TM be greater than 16.
16:40You can see that in this trial.
16:42That's a predictive marker
16:44with significance for activity.
16:45For intensive over chemotherapy.
16:46So new markers being developed.
16:48So then on the next slide.
16:51This is what I, my final slide.
16:52We have a whole office of Translational
16:54research and this actually expands now
16:56throughout the Cancer Center 'cause
16:58we work with other teams but with Ed
17:00Captain who's been just a wonderful
17:01colleague and friend for now 6 1/2 years.
17:03We've really built this office where
17:05we have the ability to bring these
17:07proposals in and then to execute you.
17:09It's very easy to make the deal,
17:11but to actually execute on the deal
17:13is important so I'll stop there.
17:14Happy to answer questions later.
17:16Anxious to work with as many
17:18collaborators as makes sense.
17:19Thank you.
17:20Right, thank you. I'd like to
17:22introduce the next speaker ehrenring.
17:24He's an assistant professor of email biology,
17:26one of the most creative minds I've met.
17:29Among all the wealth of talent that
17:31we have here, Aaron, you have some
17:33very interesting things to describe.
17:35Please please proceed.
17:37Yeah, thanks so much Mario.
17:39So the focus of my research is to use
17:41structure based protein engineering
17:42to develop pharmacological tools
17:44that we can use to dissecting probe
17:47complicated immuno regulatory pathways.
17:48That's a mouthful.
17:49I should say what we're really
17:51primarily focused on are these
17:53proteins called cytokines,
17:54which are small hormone like
17:56molecules of the immune system
17:58have exerted very powerful effects
18:00on nearly all aspects of immune
18:02Physiology and biology is really cool,
18:04but what's really important
18:05in the context of cancer?
18:07Is the study kind for the very first
18:10agents that prove the principle that the
18:12immune system could be a target of cancer?
18:15And that's evident from this this very
18:17semanal report on the activity of high
18:19dose interleukin two and Melanoma,
18:20and you can see that a small fraction of
18:23patients actually had very durable responses.
18:25In fact, you could call them cures and you
18:28see that first tail in the survival curve,
18:30and I'll just note that you know
18:32a major leader in this work was,
18:35of course, our colleague,
18:36my good friend Mario snow.
18:38You know who's been leading the way so
18:40we can advance the next slide, please.
18:42So in the past four years,
18:45my lab has gotten really interested
18:47in one particular cytokine,
18:49called Interleukin 18.
18:50What makes this study kind compelling
18:52is it has really strong activities in
18:55vitro in a dish on two key cell types.
18:58Tumor infiltrating T cells,
19:00which recognize specific tumor
19:01antigens in are proven to be
19:03the some of the most important,
19:05if not most important targets
19:07in cancer immunotherapy.
19:08I liked it.
19:09Also stimulates another class of
19:11cells called natural killer cells,
19:13which are emerging.
19:14As key immune effectors,
19:15particularly in the setting of
19:17immune checkpoint resistance,
19:18as Roy was just alluding to in the
19:20setting of image C Class one loss,
19:23if you can advance one click
19:25that was really shocking,
19:26though,
19:26as we dug into the biology violate
19:28teams that have been tried in clinical
19:31trials before GlaxoSmithKline had
19:32taken it through a phase two trial
19:34of over 60 Melanoma patients.
19:35What they found was that it was
19:37very well tolerated for cytokine,
19:39but it completely bombed due
19:41to lack of Efficacy.
19:42Only one out of 60 three
19:44patients had a partial response.
19:46Next slide,
19:46please.
19:47So what we discovered in my lab
19:49is that the activity of Alateen is
19:52highly restricted by a molecule
19:54produced by tumors within tumors
19:56called Interleukin 18 binding protein.
19:58This is an ultra high affinity inhibitor.
20:00Violating that binds.
20:01I'll 18 inhibits its ability to
20:03interact with its receptor on,
20:05till and NK cells.
20:06And So what we did is we use directed
20:09evolution to create a version of
20:11violating that was completely
20:12impervious to the decoy receptor,
20:14but was still able to engage with
20:17highlighting receptor on until and
20:19what we found in mouse models with cancer.
20:21This is a very close collaboration
20:23with Marcus Bosenberg in the Center
20:25for precision cancer modeling.
20:27Is that just like in patients
20:29natural wild type Interleukin 18?
20:30That's the blue survival curve
20:32here was entirely ineffective.
20:33It had no ability to slow
20:35tumor growth or cure mice.
20:37Where's the decoy resistant variant?
20:38Had single agent activity that could
20:40clear two well established tumors from
20:42the door to these mice with activity
20:44that was commensurate in fact a bit
20:46better than checkpoint immunotherapy.
20:48And of course,
20:49it synergized which equity mean therapy.
20:51We describe these findings in that
20:53recent publication in nature.
20:54Earlier this summer.
20:55Next slide, please.
20:57Now, obviously we're tremendously
20:59excited about the potential
21:00impact of the decor Resistant
21:02Valley Team D R18 in the clinic,
21:04and we particularly want to
21:05test it out here at Yale.
21:07We have such a leading phase one unit
21:09and an experience with set of kind
21:12of new therapies instead of that.
21:14And I recently started a company
21:16called Simcha Therapeutics.
21:17We've raised over $25,000,000 to advance
21:19this molecule that was developed
21:20here at Yale into clinical trials,
21:22and I'm excited to say that there
21:25will be dosing the first patient
21:27in the first half of next year.
21:29Next slide, please.
21:32So finally I want to tell you about
21:34some emerging research in my lab.
21:36We're missing a slide,
21:37so I'll just briefly mention it.
21:39Here we go,
21:40which is that one more forward,
21:42which is that we're not just
21:44interested in making pharmacologic
21:45tools drugs against the immune system,
21:47but we're also really interested in
21:49developing technologies in profiling
21:51the drugs that are naturally
21:52produced by the immune system.
21:53That is to say,
21:55antibodies in one thing that's
21:56becoming increasingly clear is that
21:58immunotherapy doesn't just affect T cells,
22:00but it also seems to be able to affect.
22:03Other branch of the immune system.
22:05B cells,
22:05and he moral immunity,
22:07and we hypothesize that that
22:08many cancer patients,
22:09particularly those true with immunotherapy,
22:11may be making protective anti
22:13cancer antibodies or antibodies
22:14that activate the immune system
22:15and we want to learn from these
22:18clinical trials of nature.
22:19Seeing what drugs patients made
22:20and potentially get ideas for new
22:22drug targets and potentially even
22:24new therapies from these patients
22:26and so that end we've developed
22:28this technology called Reprap index
22:29approach to management profiling
22:30that we've used to discover new
22:32auto antibody targets.
22:33We've profiled extensively in
22:35autoimmune diseases like this
22:37one here shown called ape said,
22:39but we're also now applying it
22:41together with samples from the
22:43various spores that we have here
22:45at Yale of patients treated with
22:48immunotherapy in monitored longitudinally.
22:51So yeah,
22:51thank you for your attention.
22:55And thank you, that's it's amazing science.
22:58It's my pleasure to introduce Grace Chan.
23:00She's a relatively recent recruited.
23:02Yeah, who's using really fascinating
23:04work on circular RNAs and could lead to a
23:08potential new target for immune modulation.
23:11Grace please go ahead.
23:15Hi everybody, I'm excited to great.
23:17Excited to tell you about my research
23:20program so we know that cells need
23:23to be able to recognize pathogenic
23:25RNA's to prevent infection but
23:27also recognize their own self our
23:30days to prevent autoimmunity.
23:31And so my research program
23:33has two main questions.
23:35One we're trying to understand where the
23:37molecular mechanisms for maintaining this
23:39vital balance and recognition of self,
23:42nonself and then also how can we capitalize
23:45on this distinction to develop new?
23:48Cancer therapies. And so we had.
23:52Discovered that you carry out excels,
23:54have a way to distinguish between
23:57foreign circular RNAs and self
23:59circular maze or circular RNAs.
24:02Are this newly discovered class of
24:04endogenous RNAs that are abundant
24:06and ubiquitous in eukaryotes?
24:08And so, with this distinction between
24:11foreign and sell circular RNAs,
24:13we hypothesize that we could
24:15engineer foreign circular RNA's
24:17to be a potent vaccine agg event.
24:20And if you go to the next slide, please.
24:24We found that if we deliver born circular
24:27RNAs into mice and then challenged
24:30with cancer b16 Melanoma cells,
24:33we were able to protect the mice against
24:36those subsequent sort of initiation of
24:39the tumor as well as growth of the tumor,
24:42and we're excited to work with
24:45the Center for precision cancer
24:47modeling to continue to investigate
24:50one of the scope and effects of the
24:53circular RNAs as a cancer vaccine.
24:56Next please.
24:57Another area of my program is to
25:00understand what are the features of
25:02the circular RNA that allows a cell to
25:06distinguish between self and foreign,
25:08and we identify the specific
25:10RNA modification called N 6,
25:12methyl adenosine or M6 say.
25:14So we saw that self circular RNAs
25:17associated with these enzymes that
25:19recognize M6A or interact with M6A,
25:22whereas these foreign circular
25:23armies did not,
25:25and so we thought we could target the.
25:28An enzyme that installs this
25:32modifications next please.
25:34Next slide,
25:36please.
25:37And we saw that and breast cancer
25:40epithelial cells type 3 interferons
25:42were specifically upregulated when
25:45M6A modification is decreased,
25:47whereas type one interference are
25:50not changed and so next please.
25:54My program has been interested in both
25:57uncovering the molecular mechanism
25:59for how RNA modification controls
26:02an immune response as well as to
26:05understand if there are targets along
26:07that pathway that we can identify two
26:10to specifically target cancer cells.
26:12Thank you.
26:21Great, thank you.
26:23I I I I don't think the next
26:26speaker needs any introduction.
26:28Doctor Who Saki has become world famous
26:31was before but now really very well
26:34known for all her work in COVID-19.
26:37She's an outstanding immunologist and also
26:39has a research interest in cancer also Kiko,
26:43please, please go ahead.
26:46Thank you Mario.
26:47I'm delighted to be here.
26:49So today I'm just going to start
26:51with this principle guiding
26:53effective cancer immunotherapy.
26:55And I'm borrowing a page from Doctor
26:58IRA Mehlman's cancer immunity cycle
27:00book as any anyone on this call
27:03probably has seen this but essentially
27:05just wanted to highlight that there
27:08are steps in immune surveillance
27:10and clearance of cancer that is not
27:14working very well and that's Why.
27:16People develop cancer and some of
27:18them are treatable with checkpoint
27:21inhibitors while others are not.
27:23So my laboratory has started to
27:26really examine these fundamental
27:28issues relating to all those stages of
27:31recognition and clearance of cancer.
27:33So the immune surveillance begins by
27:36dendritic cells within the cancer.
27:39Carrying the The Antigen to the
27:41draining lymph node and that stimulates
27:44T cells that are specific to cancer
27:47antigens and those T cells can
27:50divide and become effector cells.
27:52They will migrate back to the site
27:55of cancer to infiltrate into that
27:57issue and that allows for T cells to
28:00recognize cancer cells through specific
28:03antigen and clearance of the cancer.
28:06Using cytotoxic mechanisms and of course,
28:09checkpoint inhibitors can.
28:10Really engage in in this whole cycle
28:13by allowing the effector function of
28:16T cells to occur more more robustly.
28:20Next slide, please.
28:21So we began to sort of try to
28:24understand why this immunity cycle
28:27doesn't work in most cases,
28:30and one of the issues that we
28:33tackled recently,
28:34which was this paper that
28:36published earlier this year,
28:38we discovered that the.
28:40Lymphatics that are draining the brain,
28:43which is the monagea lymphatics.
28:46Do not do not drain that issue as well
28:49as other lymphatics found in the skin.
28:52For example an by increasing the
28:55drainage through the meningeal
28:57lymphatics by introducing into the
28:59CSF or veg of see we can actually
29:02increase the immune surveillance
29:04and better priming for glioblastoma
29:06and also other brain meds and so
29:10this is so it's driven us to in new
29:14technology we call in faxes where.
29:16Doctor Alan Ring and I are
29:18collaborating to make a better sort
29:21of more specific agent that can
29:23stimulate the meningeal lymphatics
29:25to increase immune surveillance
29:27in clearance of cancer.
29:29Next please.
29:32Next please.
29:33The other key issue is the antigen,
29:37so in addition to the mutation
29:39load that accumulates in cancer,
29:42there's also this other type of
29:44antigen that we're focusing on,
29:46which is the endogenous retrovirus
29:49which Anderson at Nosiness.
29:50Retroviruses are occupy 8% of our genome,
29:53and many of them have coding capacity,
29:57and many are mostly silenced
29:59after developmental stage.
30:00Early developmental stage,
30:02but can be reactivated during
30:04oncogenesis and so we're targeting
30:06and what first identifying what
30:08kinds of endogenous retroviruses
30:09or reactivated in some cancers and
30:12targeting this using a new tool
30:15that we created called Earth map.
30:17And this is also an ongoing collaboration
30:21with Marcus Bosenberg's group as well
30:24as Grace Chen to look at these or of
30:28dysregulation in cancer tissues next please.
30:31So once these thank you,
30:33once these energies are
30:35recognized by T cells,
30:36diesel still have to migrate
30:38back into the tumor tissue to
30:40perform its cytolytic function.
30:42And what we're trying to do is to
30:45encourage this process by stimulating
30:47the local micro environment using
30:49short RNA that stimulates free guy,
30:52which we call stem Blue Barney SLR.
30:54This is a collaboration with
30:56an appliance group here,
30:58and we've just formed a new
31:01company called rig immune.
31:02Which is really inoculation of
31:04this LR into the tumor to stimulate
31:07not only T cell migration,
31:09but also priming of tumor specific
31:12T cell and possibly Rick Kumanan
31:14clearance of this these tumors,
31:17and finally,
31:17in order for the checkpoint
31:20inhibitors to work in,
31:21you know privileged organs like
31:23the brain we are allowing those
31:26antibodies such as anti PD L1 to
31:28come into that issue using a BBB
31:31access technology we developed.
31:33We call synaxis an.
31:35It allows the baby to transient
31:37Lee open to enable any kind of
31:40macromolecules to come into the
31:43brain for transition time period
31:45for a better access.
31:47An better clearance of glioblastoma
31:49so I'll end there. Thank you.
31:54OK, cool, thank you.
31:56It's really outstanding science so it's
31:58my pleasure to introduce our moment.
32:00He's as you know, the vice president.
32:03Cancer immunology for Genentech.
32:04Professor of biochemistry
32:05and biophysics at UCSF,
32:06but formerly before all of those was
32:09actually ahead of cell biology here at Yale.
32:12Higher first of all, let me thank you
32:14for agreeing to provide some comments.
32:17We just like to ask you to to give you.
32:20Give us briefly your thoughts
32:22about challenges and opportunities
32:23in Immuno Oncology.
32:24Highlight those that you think might be
32:27might benefit from collaborations with.
32:29With academics for example.
32:32Thanks Mario Dan Hyder. All my
32:34friends who there is been alluded to.
32:37I do have multiple connections to deal.
32:39In fact, we've spent probably well
32:42more than half of my adult life there,
32:45so I left back in 2007.
32:47Really for the purpose of trying
32:49to accelerate this field,
32:51feeling that what was really needed
32:53in the first instance was the
32:55production of experimental agents
32:57that we could get into patients and
33:00sample what is actually happening.
33:02As a consequence of therapy,
33:04in order to understand it.
33:06As I think I often find myself
33:08saying the only model for human
33:10cancer is human cancer in the end,
33:13and it's not to say that you
33:15can't learn many,
33:16many critical things from mice,
33:18but if you actually want to reduce
33:20to practice what it is you're
33:22trying to do in the laboratory,
33:24you need access not only to patients,
33:26but to experimental drugs that
33:28you can actually perform.
33:29These types of critical studies in patients.
33:31And it turns out that that's a very
33:34difficult thing to do in academia.
33:36And moving to a biotech company.
33:38Large one is genetic really
33:40provided that opportunity.
33:41So that's something that the companies
33:43do well and I think one reason I
33:46chose or took the opportunity to
33:49move to Genetec as opposed to other
33:51places was be cause it is a very
33:54highly researched based place.
33:56In other words,
33:57we are as serious I think as you are,
34:00or I was well also faculty member in
34:03pushing the field of basic research.
34:06Particularly in this area, as as anyone.
34:11Part of that was to try and breakdown.
34:17With biomarker studies understanding
34:18what the various steps in cancer had
34:21to be overcome in order to generate
34:23a productive immune response,
34:25and Akiko is kindly already referred to this.
34:29But again, the main reason was really
34:32the production of agents that that we
34:35could use to study these various steps
34:37and so called cancer immunity cycle.
34:40Now, OK, we've done that.
34:42We have a variety of agents in the clinic
34:45and they're starting to study them.
34:48These range from the checkpoint
34:50inhibitors such as the PD one,
34:52blockers that Roy Herbst is
34:54already brought to your attention
34:57and everybody already knows.
34:59Second generation checkpoint inhibitors.
35:00The one that we have advanced
35:03in something called Tigit.
35:05We seem to be performing quite
35:07well in the clinic thus far
35:09in a variety of indications,
35:10but I think more importantly,
35:12the next major goal is going to
35:14be to address those patients.
35:16As Akiko was saying,
35:17that do not exhibit much in the way
35:20of response to checkpoint inhibitors.
35:21In order to do this,
35:23you need to have a holistic view of
35:25various steps and potential rate limiting
35:27steps that impede the progress of an
35:30immune response in a cancer patient.
35:32The one that I think we find.
35:34Most daunting at the moment.
35:36Certainly the most common is found
35:39here between steps 5 and step 6,
35:41which is the egress or.
35:45Tumor reactive T cells.
35:48Or other cells from the blood
35:50got into the tumor because most
35:52tumors are not just sitting there
35:55waiting to receive these cells,
35:57but rather are invested by a highly
36:00immunosuppressive and physical blockade
36:01in the form of the Peri Tumoral Strama,
36:04which basically Christy
36:05cells and inactivates them.
36:07So I think one of the major scientific
36:09challenges we have is to how to
36:12overcome that stromal barrier,
36:14and by doing so,
36:15we feel we can probably unlock.
36:18The benefits of even just first
36:21generation checkpoint inhibitors to
36:23as many as 50% more cancer patients
36:25than are currently being addressed
36:27with just checkpoint inhibitors alone
36:29or in combination with chemotherapy
36:31or other types of targeted therapy.
36:33Now this is where the partnership
36:36comes in because.
36:38To add a company,
36:40we don't have a medical school
36:43or a hospital and less.
36:45Happened to be in a John Le Carre novel
36:49which didn't workout too well for them.
36:52But traditional relationship
36:55between companies and academic
36:56institutions is to fill that gap.
36:59In other words,
37:00when trials are run of new
37:02investigational agents,
37:03they run at hospitals.
37:04To a first approximation,
37:06those hospitals are in academic centers,
37:08but that's again a really one way
37:11relationship that allows you to
37:13generate some important clinical data
37:15on the Efficacy and safety of a new agent,
37:18but doesn't really allow
37:20anybody to learn very much.
37:22That can only be done by having
37:25a joint enterprise that is still
37:27as committed to pushing forward
37:30and understanding the science that
37:32underlies all of these events.
37:34And do that in partnership.
37:36Where where on the company size
37:39early on the genetic side we can
37:42bring to bear many assays and
37:44resources and insights that we've
37:47gotten from our experience by
37:49treating thousands and thousands of
37:51cancer patients with these agents,
37:54together with the rare an insightful
37:57cyantific insight that one can find
37:59at a top academic institution,
38:01and they all certainly for us.
38:04Is it's always at the top of the
38:07list and not only because of
38:10my own filial loyalty,
38:12but simply be cause the focus on
38:14immunology and how that interfaces
38:17with human biology at Yale has
38:19really emerged over the last 10
38:22years or so is really being quite.
38:26Quite inspiring and I also find
38:28it much more easy to deal with the
38:31culture and the commitment of the
38:33faculty and the administration to
38:35actually advancing these types of studies.
38:37Then I find in many of our other
38:40partner institutions where often
38:41unfortunately one finds a variety
38:43of roadblocks.
38:44So I think you know,
38:46Yale provides a really good substrate to
38:49actually get these kinds of studies done.
38:52What's needed is to get together on
38:55the types of samples that are needed,
38:57what types of analytics are required,
38:59and then in the matter of any good
39:02collaboration each party brings to the
39:04table what that party is best at doing.
39:07And in our Case No.
39:08We believe we have a lot of science to offer,
39:12not just support and funding,
39:14and in your case certainly got
39:16more than just patients to offer.
39:18There is a enormous amount of as I said,
39:21scientific expertise and insight that.
39:23Will turn out to be critical.
39:25I think to solving these various problems.
39:28So with that I think I probably
39:31end my remarks and continue
39:33on to the next next element.
39:37Alright, thank you very much and
39:38thank you for the kind words.
39:40Let me please invite all the panelists
39:42to turn on their microphones in their
39:45in their videos and I want to remind
39:47all the attendees to please submit your
39:50questions through the chat feature.
39:53I might I might just start.
39:55I see a couple of questions,
39:56but I might just start with just a
39:58challenging question to the panelists
40:00and any. Body can take this.
40:02What do you think we've,
40:04you know, as you know,
40:05the problem in the clinic is that
40:08a subset respond to anti PD one
40:10and PDL one few combinations.
40:13The majority of patients don't
40:14respond obviously although
40:15we've made enormous progress.
40:17What do you think we've learned from
40:20mechanisms of response to anti PD
40:22one or video one that would drive?
40:27Future targets future development.
40:33Maybe I'll start with that one if that's OK,
40:36Miro and I'll let others jump in.
40:38So I think you know it's been a bit
40:42frustrating on those fronts in that.
40:45Mechanisms of resistance
40:46have been determined,
40:47one of which is loss of MH C Class
40:51one or reduction of MH C Class one
40:55through a variety of mechanisms.
40:58You know there are some.
40:59You know reasons why that you'd think
41:02that might not result in an resistance,
41:04because natural killer cells might
41:06be able to kill those tumors
41:08without that inhibitory signal.
41:10I'd like to highlight for those of
41:12you haven't followed Aaron rings,
41:14I'll 18 story that this is one of the
41:16few therapies that's actually effective
41:18on both class one proficient in class,
41:21one deficient tumors,
41:22but that's still a pretty
41:24small minority of cases.
41:25I think there are also issues with.
41:28Low mutation burden.
41:29Lack of antigenicity.
41:30I think I referred to T cell trafficking
41:32as well and the reasons why T cells
41:35traffic and actually I would say
41:37that as a pathologist we don't know
41:39if T cells were there and then left.
41:42We typically get one snapshot
41:44and we you know,
41:45we know that they're not there when we look,
41:48but I think there's a number of things
41:50that we just simply don't understand
41:52about how anti cancer immunity happens
41:54even to the level of our the till
41:57are the cells that are in the tumor.
42:00Actually what's responding
42:00to PD one blockade?
42:02Or is it?
42:03Something outside of that,
42:04and those are pretty basic questions.
42:06I think that's where yell could help
42:08others workout how these things work.
42:10So I think the mechanisms of resistance
42:13are still need quite a bit of work.
42:17If you do any of you think that there's a,
42:20how would we approach those low mutation
42:22tumors that the tumors that have load
42:25the mutation burdens may be endogenous?
42:26Retrovirus would be a target,
42:28but are there other targets?
42:30Or will we eventually need to
42:32isolate out rare specific T cells
42:34and clone out the T cell receptors?
42:36What do you think are the
42:38approaches to address those?
42:39Those types of tumors?
42:41Akiko, maybe I can ask you to address that,
42:43since you are the world
42:44expert on an 8 immunology.
42:46Oh, thank you, yeah,
42:48so that's the issue that you know.
42:50First there has to be some sort of
42:53antigen that T cells can recognize
42:55unless we go into the NK type of therapy
42:58that Aaron might want to comment later.
43:00But but you know what?
43:02We are kind of not looking at is
43:05really the endogenous retrovirus.
43:07Sodium in the cancer,
43:09and whether those are many,
43:11are coding capable sequences
43:12that are dysregulated and up
43:14regulated and expressed in cancer,
43:16and so right now what we're
43:18trying to do is to elude the
43:21peptides from the MHC of cancers.
43:23Different cancer cells.
43:24Jeff issues.
43:25You and I are actually collaborating
43:27on this project so we can actually
43:30identify if there are peptides that
43:32are derived from herbs that can
43:34become target of T cell recognition.
43:37And can we? Take advantage of that.
43:40And methods to upregulate those antigens?
43:42I guess you're also working on it
43:44at this time. Yes, Marcus.
43:49I'm going to take a question from
43:52the audience intermittently,
43:53as we're addressing these questions.
43:54One was are there treatments coming
43:56along for for glioblastomas? Now?
43:58I'm not a glioblastoma expert, but akiko.
44:00I'll just turn that over to you
44:02because I think your research
44:04address is perhaps one of the
44:06bigger problems in glioblastoma.
44:08Right, so glioblastoma,
44:10unlike other non non brain tumors,
44:13have an extra layer of challenge,
44:15which is the there's very little
44:19immunosurveillance that's occurring
44:21in the brain due to a limited
44:24drainage by the meningeal lymphatics.
44:27And the fact that you know,
44:29you know priming T cells and T cells are
44:32not migrating into the tissue either.
44:34So one of the ways in which we're trying
44:37to overcome this is to increase immune
44:40surveillance by injecting veg FCI.
44:42Referred to that in my slide and
44:44we're calling it lymph axis and
44:47essentially to increase the drainage.
44:49An stimulation of T cells against you
44:51manage and in the draining lymph node.
44:54And once that happens, these diesels
44:56can migrate back into the brain.
44:59And tackle the CIMA.
45:00Ran it.
45:01It obviously works well with
45:03checkpoint inhibitors as well,
45:04so and we're also collaborating with
45:07Aaron's lab to make a better reagent
45:09that can more specifically stimulate
45:12visit for three to be able to do this
45:15efficiently without any side effects.
45:17So that's one possible way that
45:19we're trying to tackle this issue.
45:22That's excellent Roy maybe.
45:23Yeah, I was wondering if you
45:25could address the brain tumors
45:26for also that maybe that could be
45:28a project in this war actually,
45:30but but other other approaches not
45:32only within immunology but also to
45:34mention that there other Yale engage
45:35sessions with other approaches
45:36to glioblastoma is also right.
45:38Well, there is this
45:39more group and they are studying
45:41that and I think he goes.
45:43Approach would be a good one,
45:45but I did want to mention Mario was
45:46the need to personalize immunotherapy
45:48and I think we're right on the
45:50precipice of doing that in a place like
45:53yellow should be able to do that so.
45:55We already heard that you know,
45:57if you don't have MHT one or you don't
45:59have the adaptive immune response,
46:01and that's being shown for 456 years now.
46:03But what do you do if you have a cold tumor?
46:06If you have a tumor that doesn't have HD one,
46:08no capability had a paper on that.
46:10It's about 5% of lung cancers,
46:12so I'd like to propose that you
46:14know what we need to do is we need
46:16to dissect tumors out, you know.
46:18And just like we would profile
46:19a tumor in genetically,
46:20we need to profile the immune
46:22microenvironment and these cold tumors.
46:23These tumors that might not be driven.
46:26PDL one or perhaps ticket is involved
46:27as we heard tomorrow we need to start
46:30thinking about the right combinations,
46:31but you know the biggest problem
46:33is we're just flying blind and
46:35the clinical world will do. That.
46:37Will go on for years if not stopped.
46:39You know just combining different
46:41drugs and using them,
46:42but I think you know right now
46:44it's a perfect time and you and
46:46I have talked about this.
46:47It's very complicated in refractory setting.
46:49Someone gets chemo immunotherapy
46:50and then refractory.
46:51There could be thousands of different
46:53mechanisms put in the frontline
46:54setting primary resistance and
46:56we know that with Ateez Alisme,
46:57Abbott Pembrolizumab.
46:58Half the patients about will respond
47:00when you have the high PD L1 Group,
47:02the other half don't.
47:02I would suggest that the group to
47:04look for some of the mechanisms
47:05we've heard about today.
47:06I can't wait to get my hands on Aaron's drug,
47:09you know,
47:09and look at that and things like that.
47:12You know, maybe I can ask her to comment,
47:15because obviously that's a major.
47:17You know you. You need to know what
47:19the mechanisms of resistance are in
47:21Biomarkers for development of your drugs.
47:23So how do you approach that internally?
47:25And also in collaboration
47:26with academic institutions?
47:28I think you know the the problem
47:31of resistance has even a
47:33darker aspect to it,
47:34which is we don't really,
47:36truly understand the mechanism of
47:39why things work when they work.
47:42Someone's were diluted to this,
47:44but our understanding of how
47:46these checkpoint inhibitors work.
47:47Even Witcher vision Lee
47:49was framed by off bias,
47:51all based in the series of assumptions as
47:54reversing this process of T cell exhaustion,
47:57thereby acting in the tumor
47:59to reactivate T cells,
48:00either certainly is not the whole story.
48:03In fact, maybe only marginally
48:05true in some patients.
48:06So if in fact the PD one PD,
48:10L1 or Tigit Axis along
48:12with simulate 4C28 Axis.
48:14Full works in lymphoid tissues to
48:16expand the T cell compartment.
48:18Then that means we have the entire
48:20mechanism of how PD one blockade works.
48:23Not quite right if not incorrect.
48:25If that's the case,
48:27it's very difficult to know how
48:29to improve upon that or how to
48:31understand resistance mechanisms.
48:33If you don't really know the mechanism
48:35of immune mechanism that Modulated
48:37as a consequence of your drug.
48:39So I think it's important to.
48:43You know,
48:44even just as a basic science project,
48:47be sure that we really understand
48:49that all of the predictions associated
48:51with a presumed mechanism of action
48:54are actually correct before we
48:56can really understand resistance,
48:58you know.
48:59That said,
49:00there's certain aspects of
49:02resistance that are that are
49:04finding increasingly important.
49:06We've invested very heavily
49:08in tumor antigens,
49:10particularly mutant knew antigens as well as.
49:16Endogenous elements that Akiko is setting.
49:19Chloe Arbiser line elements and
49:21transposable elements as potential antigens,
49:23'cause they certainly a
49:25great antigens in mice,
49:27but we find that you know the context
49:30of our vaccine programs you see as
49:33significant debilitating amount of MSE loss.
49:36Sometimes it's a hard loss which
49:39means loss of heterozygosity
49:41for particular MA serial.
49:42Other times it means soft loss which is
49:46just simply transcriptional repression.
49:48And you need to workout computational
49:50workflows so that you could
49:52actually examine patients on a
49:53patient by patient basis to find
49:55out not only what the range of
49:57antigens are that they're making,
49:58so that you can design an appropri.
50:01Vaccine in fact,
50:02that was that that's your goal.
50:05Or design an appropriate
50:06type of cell therapy,
50:08but also to know how that
50:11patient is reacting,
50:12whether the patient responds or
50:14doesn't respond at the genetic level
50:17in the tumor in terms of whether
50:20transcriptional patterns are different
50:21that now create a resistance environment,
50:24perhaps by losing irrelevant MSE molecule.
50:27Or again bye bye genetic loss,
50:30which is something that the tumors do.
50:32Unfortunately very very well and has been
50:35a real problem even be targeted therapies.
50:38So you know,
50:39again,
50:39I think this type of work can really only
50:42be done on a patient by patient basis,
50:45and it's not something if we use
50:47clinical sites just to run trials.
50:49And if you use us just to give
50:52you drugs to run clinical trials,
50:54that's not going to work.
50:56That's not new advanced the field.
50:58I think there really does need to be.
51:02An interface which is developing
51:04but really needs to be.
51:07Advanced around the science,
51:08even forgetting about the clinical
51:10development issues for the moment,
51:12but just, you know,
51:13really concentrated on the
51:14science that that is controlling
51:16response and lack of response,
51:18either as primary resistance
51:20or acquired resistance.
51:23Thank you, I mean, you know.
51:24Obviously I followed your work
51:26about the way PD one worked and
51:28the effects on CD 28 signaling,
51:30and there's been a lot of data about
51:32the need for new for it's the early
51:34stem cells that are generating the
51:35anti tumor response and not the
51:38terminally differentiated cells.
51:39There's a lot of data out there that
51:41makes the whole mechanism of how anti
51:43PD one works relatively confusing,
51:44but I just want to address maybe
51:46a couple of issues 'cause we have
51:48some expertise on the panel,
51:50one based on errands,
51:51work on our 18 and again going back to Akiko.
51:54And maybe grace on on innate immunity.
51:57How do you?
51:57How do you view the in patients
52:00who lose class one and and maybe
52:02don't have a lot of T cells?
52:04How do you think that we can Co opt
52:07innate immunity to treat those patients?
52:09Let me just start with them because
52:11I think he has some interesting
52:13data with I'll 18 and it may be
52:16good at Grayson Akiko and see what
52:18their thoughts are about this.
52:22And this is obviously a
52:23topic that here at Yale,
52:25we have a really keen an intense interest.
52:28You know from some of the initial
52:30observations that that loss of
52:31beta 2 micro Glenn was for current
52:33theme of patients who acquired
52:36secondary resistance immunotherapy.
52:37So Marcus and I have been working on
52:40this problem looking for preclinical
52:41agents that could that could treat
52:44mouse tumors where we have deleted
52:46MHT class one or take tumors that
52:48naturally have loss of other components
52:50of antigen presentation like tapasin.
52:53As well and then we see you know,
52:55as you may expect, that you know me loud.
52:58Immunological dogma is that NK cells
53:00should recognize these cells that have
53:03lost image C Class one this marker itself.
53:05But we know that the truthfully NK cells,
53:08particularly the tumor micro environment,
53:09become rapidly energic or exhausted,
53:11depending on what terminology want to use.
53:13This is work by David Relay and others.
53:16And so it is clear preclinically that we can
53:19reinvigorate some of those NK cell response.
53:21But we started kind therapies.
53:23Others have started to use.
53:25Agents against NK cell receptors,
53:27like agonists of the NK G2D.
53:29That's like sort of as best you could say,
53:31TC are equivalent and NK cells or inhibiting
53:34key receptors like the anti NK G2A.
53:36That's the Mona Lisa map drug.
53:38It actually has some activity when
53:40combined with monoclonal antibodies.
53:41I think one thing that is underexplored,
53:43but it's going to be a major challenge
53:46in harnessing NK cell activity,
53:48particularly against these tumors.
53:49Last class one is a lot of these
53:52preclinical models and work guilty of
53:54it here at Yale are not amino edited.
53:56So in the same way that tumors become
53:58amino edited against T cells they can
54:01become Immuno edited against NK cells.
54:03In loss of self antigens is
54:04not enough to drive killing.
54:06Sorry.
54:06Lots of markers himself like image C
54:08Class one is not enough to drive killing.
54:11You need you need other signals.
54:13NK,
54:13activator signals antagonist signals in
54:15tumor cells appear to edit those out.
54:17For a great example of that has been
54:19seen in lymphoma where we know that
54:21that you know class one loss is common.
54:24But what usually Co occurs almost.
54:26Always is loss of CD 2,
54:28which is an important molecule
54:29that drives NK cell killing,
54:31and so I think really we need to think
54:33about how can we do more than just
54:36this inhibit or activate NK cells.
54:38But how do we really direct the
54:40tumor engagement?
54:41I think there's some really exciting
54:42programs like the dragon fight programs,
54:44monoclonal antibodies.
54:45Of course we're good at that and something
54:48that we really keenly have our eye on,
54:50something that Marcus and I are
54:51working on at the Center for
54:53precision cancer modeling.
54:56And Grace, What do you think about your rig?
54:59I agonist or that would they be
55:02able to address this issue?
55:03Yeah, I think these are really important
55:06questions and highlights the point
55:08that I read brought up about coupling
55:10the basic science with the translation
55:12all aspects right because we think
55:15that there are potentially new types
55:17of science that's happening within
55:19different types of immune cells,
55:21either in response to new antigens
55:23or under normal conditions,
55:24and that would be important to understand.
55:27Or how we can then address in disease states.
55:31So, for example, there's pulmonary
55:33evidence that RNA modifications,
55:35and specifically the N 6 methyl
55:37adenosine that I mentioned.
55:39The levels are different in, you know,
55:42cancer situations versus healthy
55:44situations and that they change in
55:47different types of immune cells.
55:49So given that Arnie modifications is
55:51like an epic transcriptomic regulator,
55:54it controls all sorts of different
55:56aspects and within a cell.
55:59M6A has been shown to control
56:01the transcript stability as well
56:04as its cellular localization,
56:06as well as its ability to be translated.
56:09So we have data showing that
56:12depending on the level of M6A,
56:15the Genomic Architecture is different,
56:17and the Genomic confirmation then
56:19affects the types of transcripts
56:22that are being produced,
56:24and subsequently the proteins that
56:26could be expressed from those
56:28transcripts and stuff we can identify.
56:31Key aspects that are differentially
56:34changing between cancer states or
56:36healthy States and or the different
56:39types of immune cells in a cancer state.
56:42Potentially,
56:42we have new targets to then go after
56:45in sort of difficult situations.
56:49Let me let akiko in an Marcus comment
56:51'cause I you know this is an area that's
56:54become a substantial interest to us,
56:56including the myeloid component.
56:57So maybe you can comment a little
56:59bit on that. Akiko and Marcus.
57:03Thank you so since the NK issue is so
57:06nicely covered by air and I'm just going
57:09to sort of mention another thing that it's
57:13fundamental to immuno oncology Ann yet
57:16really hasn't garnered enough attention,
57:18which is the sort of immunosuppressive state.
57:22Of tumor burden and this I learned kind of,
57:25you know, through experiment.
57:26So the rest of my lab does antiviral
57:30immunity, and so we've been looking
57:32at what happens to antiviral immunity
57:34in mice that are bearing tumors an
57:37they are really immuno suppressed.
57:39They cannot generate diesel immunity.
57:41In case else you know their
57:44dendritic cells are wacky.
57:45So I think before we can even start thinking
57:49about how to improve immune oncology.
57:52We have to deal with this impact
57:53of tumor burden and what it's
57:55doing to the immune system.
57:57I don't think we understand that very well.
57:59Or maybe I'm just being ignorant
58:01of those facts,
58:02but I feel like that's something
58:03that we need to deal with no matter
58:05what the immunotherapy is going
58:07to be in order to really elicit
58:09a robust immunity against tumors.
58:13Marcus, if you could comment,
58:14yeah, that's excellent.
58:15Sure, yeah. I think it's really interesting.
58:17IRA also had kind of touched on
58:19this to talking about how I mean
58:221 version of MHT class losses,
58:23sort of by allelic beta,
58:25two microglobulin loss and everything is gone
58:27and you expect NK cells perhaps to hit those,
58:30but it's probably more subtle than that.
58:32Frequently have specific MHT class,
58:33one alleles or even specific
58:35antigens that are really important.
58:36Antigens that are lost and it's really hard
58:39to know how that happens along the way,
58:41but I think one of the things
58:43that's been surprising too.
58:45I think many immuno oncology field.
58:47Is the demonstration by a lot of different
58:49approaches that interferon gamma
58:51reception or interferon reception and
58:53tumor cells is really critical for being
58:55able to be killed by the immune system?
58:57And it seems that one of the principle
59:00things that that does is upregulate
59:01MHC class one in the tumor cells
59:04so the transcriptional regulation
59:05of MFC class one in tumor cells is
59:08really really important and some of
59:10the approaches that people have been
59:11referring to with innate immunity and
59:14even things like cytosolic nucleic
59:15acid sensing like Regai agonism.
59:17And things like that were in our hands.
59:20Irv reactivation is great at Reactivating.
59:23You know interferon secretion
59:25and sometimes type.
59:26One interferon can substitute for
59:28Interferon Gamma at least an upregulation
59:31of MFC Class 1 SI think things that
59:34are locally going to be inducing the T
59:37cell tumor cell interaction in that fashion.
59:40An override whatever local
59:42immunosuppressive effects that are
59:43there will really be critical.
59:45I think one of the difficulties
59:48that we've had.
59:49In studying.
59:50The tumor microenvironment is that
59:52it's been very difficult.
59:53For instance, I mean T regs have
59:55a very well established role,
59:57but other aspects, like whatever
59:59versions one will call different MD.
01:00:00Yes,
01:00:01sees things like that,
01:00:02so myeloid derived factors that
01:00:04can be suppressive than tumor
01:00:05environment or hard to entirely
01:00:07get rid of in most contexts.
01:00:09And you can't really study
01:00:10them adequately in human.
01:00:12So I think their roles an exactly what
01:00:14they're doing has been harder to determine,
01:00:16but.
01:00:18I'd refer back to some comments about the
01:00:21personalized immunotherapy and how you know,
01:00:23with these explant assays you can
01:00:25actually do these things and we can
01:00:28keep tumors alive for over a month
01:00:30with all the sto kiamat re preserved
01:00:33and one could reconstitute tumors
01:00:34to take out my load components.
01:00:37So I think I'm very enthusiastic about
01:00:39this approach to actually evaluate
01:00:41how different cell types contribute
01:00:43to localized immune suppression,
01:00:44which hopefully will lead
01:00:46to mechanistic advances,
01:00:47an understanding.
01:00:49Let me just ask you one more question
01:00:51before I want to turn out back to Iran.
01:00:54Ask him a couple of questions but
01:00:56the do you think that there's a role
01:00:58for purely non T cell dependent
01:01:00mechanisms in cancer treatment?
01:01:02Do you think that we could without
01:01:04getting any T cell response,
01:01:06activate NK cells, myeloid cells,
01:01:08macrophages in a sufficient way
01:01:10or modulate their function that
01:01:11you could see significant anti
01:01:13tumor activity in the clinic?
01:01:16I think you know there's a couple examples,
01:01:19so at the NK approaches, ankhar,
01:01:21NK and things like that, I think that
01:01:23it is likely to be possible to do that.
01:01:28Other things that, for instance,
01:01:30one of our researchers here at Yale Allies,
01:01:32who is looking at using Carty with
01:01:35myeloid cells, like with basophils,
01:01:36another Excel types,
01:01:37and that this approach might be
01:01:39something that would be really,
01:01:40really could work well,
01:01:42and that's oppressive pathways.
01:01:43Might not actually work as well
01:01:44against a non T cell because that's
01:01:47typically how the suppression
01:01:48would be expected to work.
01:01:50I think there's still some work
01:01:51to be done in those areas,
01:01:53but you know I I'm open to the
01:01:56possibility that other things
01:01:57can work and I think it's worth.
01:01:59Pursuing it based on the preliminary
01:02:01data that you're seeing in those areas.
01:02:03So I am enthusiastic about that.
01:02:07Interesting, so I just want to ask
01:02:08you a question you you know you lead
01:02:11development in a company and I wonder you
01:02:13know that when you look at combinations,
01:02:15all the combinations that we've done.
01:02:17One is not overwhelmed by the by the
01:02:19level of activity that's been observed.
01:02:22Maybe it's because we don't
01:02:23have the right biomarkers.
01:02:24Have you taken home any any lessons
01:02:26from the the three that seemed to
01:02:28have worked CTA for chemotherapy
01:02:30and vege perceptor Inhibitors,
01:02:32which seem to be the ones that
01:02:34are sort of at the forefront now,
01:02:36notwithstanding the early Dec
01:02:37with digit but but but those?
01:02:39Those seem to have sort of
01:02:41moved to the front,
01:02:42which are not the ones that other than
01:02:45CTA four chemotherapy and the veg F
01:02:47Receptor Inhibitors would have been.
01:02:49The top ones on my list 10 years ago.
01:02:53No, you're actually right.
01:02:55Mario. I mean when we decided
01:02:58to go into using chemotherapy.
01:03:02Theoretical pieces for that was not well,
01:03:04Gee, maybe some of them if they're not.
01:03:08Therefore, blade,
01:03:09if you can choose those properties,
01:03:11maybe they'll cause some type of information
01:03:13or immunogenic cell death that will
01:03:15somehow synergized with immunotherapy.
01:03:16I think that's turned out not to be the case.
01:03:20That my guess is now.
01:03:22No looking having book
01:03:25for epitope spreading and.
01:03:28Expansion of TC Arts Fonality and stuff.
01:03:30In lot of these patients.
01:03:32I just think that's an additive
01:03:34effect that you get a certain amount
01:03:37of tumor debulking associated
01:03:39with chemotherapy that then allows
01:03:41the immunotherapy to do what it's
01:03:43going to do almost separately.
01:03:45So I think that the idea that at
01:03:49least most conventional chemo.
01:03:51Immunotherapy combinations are synergistic.
01:03:53That's that's still waiting for
01:03:56good evidence that case of.
01:04:00Antagonist is an interesting
01:04:02one where I think that is.
01:04:04That's one of the examples where I
01:04:07think we really need to look into that.
01:04:11From a mechanistic POV in HTC for example,
01:04:14the that particular combination is really
01:04:17quite effective from surprisingly so,
01:04:19especially considering
01:04:19that in renal it's not.
01:04:22So what's with that?
01:04:23Because both of the system app on
01:04:27it by itself is supposed to have.
01:04:30Activity and in both of those indications,
01:04:32so I take that to suggest that it's not
01:04:36necessarily an additive phenomenon there,
01:04:38but there's something that specific
01:04:40that's going on in ACC that is
01:04:43being addressed by the definition,
01:04:46which could actually have to do
01:04:48with myeloid cell suppression or
01:04:50overcoming mile itself suppressions,
01:04:52and certainly by Jeff is one way that
01:04:55one can use to turn off dendritic cell
01:04:58activity and antigen presentation,
01:05:00so perhaps.
01:05:01That's slowing down what aspect
01:05:03of the problem.
01:05:04So there again, is just a plea for saying,
01:05:07You know,
01:05:08we need to look into that from
01:05:10mechanistic point of view,
01:05:12better than we have thus far.
01:05:16In terms of no future combinations. My.
01:05:24What I keep trying to push is
01:05:26to take a mechanistic approach,
01:05:28look at the tumors and figure
01:05:30out what what's wrong with them.
01:05:32What is the rate limiting step here?
01:05:34What is the rate limiting step
01:05:35there and then try and pick apart
01:05:38mechanisms associated with them,
01:05:39and I think it markets are just saying and
01:05:42I think it increasing number of cases.
01:05:44It does look like the myeloid
01:05:46compartment is playing a.
01:05:48Important, but as yet poorly understood,
01:05:50role in a lot of this,
01:05:52and I think it's it's more than
01:05:55high time to go back and look more
01:05:58seriously at the myeloid compartment.
01:06:01The whole field of so-called mileage
01:06:03derived suppressor cells that I think is,
01:06:05is still very very sketchy in
01:06:07terms of the precision with which
01:06:10those cells are described.
01:06:11What they do and who they
01:06:13are and how to modulate them.
01:06:15So I think we have to kind
01:06:18of back off in some way,
01:06:20at least as scientists and understand
01:06:22the basic immunology and cell
01:06:24biology before really designing
01:06:25and knowing precisely what agents
01:06:27to bring forward in the interim.
01:06:29Obviously we don't as.
01:06:31Conditions don't want to wait
01:06:32around for the basic scientists
01:06:34to figure it all out for us,
01:06:36assuming that they'll even do that.
01:06:39But agents are coming out all the time
01:06:41and I think crafting combinations of them,
01:06:45which I find in companies,
01:06:47is often akin to just throwing
01:06:50spaghetti against the wall.
01:06:52Still has to be.
01:06:55In a fashion that has some some
01:06:57logic associated with that,
01:06:59and I think that's that's a struggle
01:07:01in both of our communities to
01:07:03just keep people from doing stuff
01:07:06because it can be done and instead
01:07:08spending your time and effort and
01:07:11the commitment of patients to doing
01:07:13those things that have the best
01:07:15chance of working based on the
01:07:17science as we currently understand it.
01:07:21Thanks, Alright,
01:07:22I'm glad you mentioned mileage,
01:07:23so you're interested.
01:07:24Also were very interested.
01:07:25I think Marcus is prioritizing.
01:07:26That is one of the areas of
01:07:28research for the El Senor de
01:07:30mean onkologie and we have.
01:07:31You know, we can't bring everybody
01:07:33onto the phone conversation.
01:07:34We have a lot of expertise
01:07:36here in immunobiology,
01:07:36in that area that that again we
01:07:38just can't fit everybody into
01:07:40one hour and a half session.
01:07:41So I just want to maybe just turn
01:07:43to Roy for a second before you go
01:07:46back to more of the basic science.
01:07:48Well, there's a question
01:07:49about rare tumor initiatives,
01:07:50so I wanted to ask you 2 questions.
01:07:52What do we do here about
01:07:54rare tumors and what?
01:07:55What are the efforts that we have?
01:07:57And the other question that
01:07:58I have for you is, you know.
01:08:00Now, now that you've heard all this way,
01:08:02where?
01:08:02Where do you think the field
01:08:04is headed in lung cancer?
01:08:05For Immunobiology and even on Koleji.
01:08:08Well, the second question is a
01:08:10lot easier for me to answer than
01:08:12the first rare tumors we send
01:08:14them to Pat Larusso in phase one.
01:08:16So we know where we're growing.
01:08:18You know, the yell when I row is the
01:08:21director of the deputy director of science.
01:08:23You know we're seeing a couple
01:08:25of 1000 patients now.
01:08:26We have about eight 9000 a year
01:08:28and we have a large number of
01:08:30care centers 15 around the state,
01:08:32so we are seeing you know,
01:08:34like sarcoma is an issue.
01:08:36You know we see enough of those now
01:08:38that we probably need to form more
01:08:40full fledged order that area and
01:08:42certainly even more rare tumors.
01:08:44You know, skin tumors you know
01:08:45you see some of those, right?
01:08:47Merkel cell tumor approved.
01:08:49You know agents so as this happens,
01:08:52we're getting to do more and more of
01:08:54that where we're at the point now.
01:08:56We're probably going to have to
01:08:58set up a unknown tumor clinic or
01:09:00something for the everything else,
01:09:02'cause we're seeing more and more of that.
01:09:05And we are moving towards a tumor agnostic,
01:09:07you know,
01:09:08sort of treatment with some of these agents.
01:09:10You know,
01:09:11the Pember Lizum app was just
01:09:13approved based on AT MB,
01:09:14so I think with more advanced Genomic
01:09:16profiling and immune profiling.
01:09:18I think that might be one way to deal
01:09:20or deal with the more we are tumors.
01:09:22As far as lung cancer.
01:09:24No,
01:09:24I've been doing this now for almost 25 years,
01:09:27certainly in the area of targeted therapy.
01:09:29I think we've done.
01:09:31We're doing what we need to do.
01:09:33I remember when we first with
01:09:35John Mendelsohn started to look
01:09:36at EGFR inhibitors.
01:09:38We treated everyone we saw a 10% response.
01:09:40We were thrilled drugs became approved.
01:09:42It was seven years before the
01:09:44EGFR mutation was developed,
01:09:45and then once that happened, of course.
01:09:48Still not a home run.
01:09:49'cause of resistance.
01:09:50But then we started to treat
01:09:52patients in the frontline setting.
01:09:54And now just recently there are
01:09:56data now in the agement setting
01:09:57with some of these agents where
01:09:59perhaps they'll be more potent or.
01:10:01Early on, before resistance develops,
01:10:02I think we're at a point in
01:10:04lung cancer immunotherapy.
01:10:05We have to take a deep breath,
01:10:07and it's hard because Iris said,
01:10:09it's very hard for a company or
01:10:10group not to just add on and
01:10:13start to build combinations.
01:10:14Who would have thought chemotherapy
01:10:15combinations would have worked?
01:10:16In fact, no.
01:10:17I led the trial of a Tesla might
01:10:19as a single agent.
01:10:21I was offered the combo.
01:10:22I didn't want it.
01:10:23I talked to a few people here leaping.
01:10:26I didn't think chemotherapy
01:10:27would be the reason.
01:10:28And I totally agree with IRA,
01:10:30I think it's an additive approach.
01:10:32They're not.
01:10:32They're not antagonistic, but but still.
01:10:34The thing that bothers me is in lung cancer.
01:10:37We those are the agents,
01:10:39you know, see TLA four.
01:10:40A little bit vague, Jeff,
01:10:42you know their number of Axl Mer TK.
01:10:44We have some with Carla Rothlin.
01:10:46We have some some expertise there.
01:10:48I think some of these approaches
01:10:50that we heard from Aaron,
01:10:52you know, 50% of lung cancers,
01:10:54maybe 60% when the ping and David rim
01:10:56and Kurt look at them have no tail.
01:10:59So so, so there's clearly a need to.
01:11:02Personalized this therapy and I
01:11:03think the next step really has to be,
01:11:06and I know I was actually going
01:11:08to ask you a question, Mario,
01:11:10why don't we do more of this?
01:11:12Why five years now after chemo immunotherapy?
01:11:15I mean, do we not know what's going on?
01:11:18What's the sweet spot?
01:11:19Went to work when patients
01:11:20become have primary resistance,
01:11:22we need to obtain more samples
01:11:24and it's very hard because those
01:11:26studies are very in labor intensive.
01:11:28Specially now in this covid area.
01:11:30Or we just want to survive.
01:11:32But we need samples, we need biopsies.
01:11:34We need to take him to our labs pressing.
01:11:36Pressing has to be quick,
01:11:38but you know I reset the best model
01:11:40sort of human and all the animal models
01:11:42we've mentioned are fraught with issues.
01:11:44So I would say right now.
01:11:46Lung cancer. It's amazing.
01:11:47You know you know therapy.
01:11:48I just got the.
01:11:50Five year results now with
01:11:52with drugs 30% survival in an
01:11:54untreated metastatic lung cancer,
01:11:55no PDL 1 high but you know PDL 1 low.
01:11:59It's a lot different and many patients
01:12:01don't benefit klemen they want what
01:12:03they see in the commercials and many
01:12:05patients have acquired resistance.
01:12:07This field is perfect for the alliance
01:12:09between industry and academia to
01:12:11you know of course you've got to
01:12:13do the big phase three trials.
01:12:15I would do that too if I was in the company,
01:12:19but we've got it in.
01:12:21Have a few studies.
01:12:22That are really focusing on the mechanism
01:12:24and either taking the new drugs and
01:12:26like you know with Aaron's drug,
01:12:27you know the first trials will have to
01:12:29be just to show some activity in safety,
01:12:32but then they have to move forward
01:12:34with liepins drug, the cyclic 15.
01:12:35There have been responses in the phase one.
01:12:38But are there enough well that
01:12:39time will tell,
01:12:40but now it's time to develop an assay.
01:12:42So what we've been able to do here at
01:12:44Yale in partnership is we early on got
01:12:47David Rimm working closely with next.
01:12:49You're one of the companies that
01:12:50John will tell you was developed
01:12:52here and it's taken a few years
01:12:53to develop a good bioassay.
01:12:55But now we can start to treat patients
01:12:57based on the biomarker because
01:12:58science is going to prevail otherwise.
01:13:00No,
01:13:00it it's going to be random and there's just,
01:13:03you know,
01:13:03you and I talk about this all the time
01:13:06in the Hall and we now and I see each other.
01:13:09Occasionally now,
01:13:09'cause we're all locked in their offices,
01:13:11but every once in awhile
01:13:12we bump into each other.
01:13:13That's going to be the key thing.
01:13:15How do we figure out resistance
01:13:16and be proactive about
01:13:17it?
01:13:19Yeah, by the way,
01:13:20I was wondering once we told you
01:13:22not to bother with chemotherapy,
01:13:23and I think that just reflects how
01:13:25humbling it is to where you are.
01:13:27The biggest influence bending and
01:13:28mad at you for awhile.
01:13:30Yeah yeah, yeah, the so we.
01:13:31You know it's the biology is very
01:13:33complex and one of the reasons
01:13:35why I started that question is
01:13:37that when I look at CTA four I can
01:13:39think of 10 different reasons why
01:13:40it might make anti PD one better.
01:13:42But in any individual patient I
01:13:44can't tell which of those mechanisms
01:13:45might be active for chemotherapy.
01:13:47I mean you could do be doing
01:13:4910 different things.
01:13:50I think the exploration of email
01:13:52object is really important and
01:13:54that's why I like this focus on
01:13:55really going back to the tumor,
01:13:57immunobiology and actually to
01:13:58thank Charlie for his commitment
01:14:00to recruiting people who who are
01:14:02focusing on that area because I
01:14:04think as we build our strength and
01:14:05continue to build our strength in that
01:14:07area and were very strong already,
01:14:09we may actually get the answer
01:14:11to some of these questions.
01:14:12So let me just ask one question
01:14:14here that I can answer because
01:14:16I don't know is you know the
01:14:18there was a question related to
01:14:20nano particles in an Atom.
01:14:21Articles fit in into the world of of baby no.
01:14:25Biology and Immuno Oncology
01:14:27or any of you in the capable
01:14:30of addressing that question.
01:14:32I'm not.
01:14:35I can take a stab at it.
01:14:38I don't know it entirely,
01:14:40but I do know I think John is also
01:14:43put some comments in the the chat
01:14:46for attendees to look at as well.
01:14:49So Mark Salzman's been a central player
01:14:52in the Nanoparticle area at Yale,
01:14:54and more broadly for a very long time,
01:14:57and I believe with Mike Gerardi
01:14:59is also recently started.
01:15:01A company called stratify that also
01:15:03is likely interested in using.
01:15:05Anna particle based approaches
01:15:06to enhance immunotherapy's.
01:15:07So there certainly are efforts
01:15:09along those lines and it's not just
01:15:11mark that are additional people
01:15:12at Yahoo are doing these things.
01:15:14All the platforms tend to be quite
01:15:16different and I think if one
01:15:18actually follows up and looks at
01:15:20Akiko's paper related to the rig
01:15:22immune with Anna pile and we help
01:15:24with some of those studies.
01:15:25But looking at EPS copal affects
01:15:27for nanoparticles I think part of
01:15:29the difficulty has been getting
01:15:31trafficking to tumors are not like
01:15:33T cells which seem to be really
01:15:34good at finding tumors.
01:15:36Nanoparticles have a harder time
01:15:38and tend to end up in macrophages,
01:15:40so a lot of those efforts tended
01:15:42to be intratumoral and then trying
01:15:44to see these so-called abscopal
01:15:46effects or distant effects for
01:15:48intratumoral agents is one of the
01:15:50challenges that frequently happens,
01:15:51and again at the center position,
01:15:54counseling were particularly well set
01:15:55up to help those folks evaluate whether
01:15:57they're seeing these abscopal affects,
01:15:59but that's kind of,
01:16:01I think,
01:16:02a broader scope across yell as to
01:16:04what's happening.
01:16:06I think Mario is in the.
01:16:09In the back scene area,
01:16:11not a particles have been in use
01:16:14and are increasingly being in use.
01:16:17It certainly the RNA vaccine
01:16:19we're developing with buying tech.
01:16:21Is it basically an added
01:16:23particle based approach,
01:16:25as is the cold vaccine that
01:16:28they're developing as well as.
01:16:31Maderna there are a number of.
01:16:36Ways of using them?
01:16:37I think the first incarnation was
01:16:39to try and use that particles.
01:16:41That's kind of surrogate or artificial
01:16:43antigen presenting cells so far that
01:16:45hasn't really worked out that well
01:16:47because Antigen presenting cells
01:16:49are more than simply inert surface.
01:16:51Is that present antigens.
01:16:52They actually act and perform a complex
01:16:55POD to do with the T cells and B
01:16:58cells that they are presenting too,
01:17:00but using them as delivery vehicles for
01:17:02RNA has actually worked out pretty well,
01:17:05but it also turns out.
01:17:07Surprisingly,
01:17:07when they work well,
01:17:09they can also be quite toxic,
01:17:12and I think a lot of the adverse
01:17:15events associated with either the
01:17:17cancer vaccines over the covid
01:17:19vaccines can be attributed as much
01:17:22to the data particle themselves and
01:17:25its ability to trigger inflammasome
01:17:27responses as the RNA another adjutants
01:17:31that data particles contain.
01:17:33I've worked with Mark and with
01:17:35Tarek Fahmi and I actually get
01:17:38a princely sum every month for
01:17:40being on the patent that controls
01:17:42these princely sum I think gets me
01:17:45coffee at the corner coffee store.
01:17:49But nevertheless, you know,
01:17:50I think they're very interesting platforms,
01:17:53but they haven't really been put
01:17:55into into play it in a way that's
01:17:58that really establishes what
01:17:59the future is going to be.
01:18:01That's not to say they shouldn't be studied.
01:18:04One thing it hasn't come up that in
01:18:07this context I'd like to make bring
01:18:09up for the group's consideration
01:18:11is actually self therapy.
01:18:13When we think of cell therapy,
01:18:15we think of car T cells, which I think are.
01:18:19It can be extraordinarily effective
01:18:21in heme onc setting, certain of them,
01:18:24but thus far less so in solid tumor settings,
01:18:27and it's probably wide variety
01:18:29of reasons for that.
01:18:31We have only ourselves recently
01:18:33started getting into this area.
01:18:35I'm not sure what Yale's
01:18:38involvement has been,
01:18:40but I do think despite my reluctance
01:18:45to embrace cartis in our own shop,
01:18:48I do think that.
01:18:52Cells engineered cells are the
01:18:54nanoparticles of the future in terms
01:18:57of being able to engineer and design
01:19:00them in ways that will allow them
01:19:02not only to be therapeutic agents,
01:19:05but also per say,
01:19:06but also delivers of therapeutic
01:19:09agents such that you can.
01:19:12Get them to use.
01:19:14Make use of their of the cells
01:19:16ability to find out where it
01:19:19is you would like it to go.
01:19:22Get to that spot and then turn it
01:19:24on to generate other activities,
01:19:27possibly even the release and
01:19:29secretion of Biotherapeutics,
01:19:30which would change entirely business
01:19:32of how we make drugs and the patients.
01:19:35So I think this is this is an area that.
01:19:41I find personally very exciting.
01:19:43We are investing heavily in.
01:19:47Looking at how to do I
01:19:50PSC technology perhaps?
01:19:52Diane sender at the Yelton can help push
01:19:55this forward collaboratively because this
01:19:57is just again at the very beginning, but.
01:20:00But this is a place right?
01:20:03I do see a very remarkable future.
01:20:07Thank you for making it.
01:20:08As a matter of fact, we we do have
01:20:11a large clinical Carty program.
01:20:13We've we've done a great deal of work
01:20:15with til cells actually actually sending.
01:20:17This sells out and infusing them here
01:20:19so we have a very well oiled machine
01:20:21for administering self therapy.
01:20:23We've also done some cell generation
01:20:24of our own and there's a huge amount
01:20:27of work in Immunobiology looking at
01:20:29targets within T cells that could
01:20:31be used as intellectual property
01:20:33for T cell Engineering.
01:20:35So there is a nascent program here in in.
01:20:38In some areas, in some well developed.
01:20:42Well developed in other areas and
01:20:44we are very interested in that.
01:20:46And I mean we only have
01:20:48about, I think 10 more minutes
01:20:50and I just want to spend a few
01:20:52minutes on an area that I think is
01:20:55a particular strength here at Dale,
01:20:57which is the animal modeling
01:20:58and how important it is towards
01:21:00Immunooncology and Marcus.
01:21:01And perhaps you might make
01:21:03some comments again,
01:21:04because you just mentioned
01:21:05some of the resource,
01:21:07but there's a huge number of resources
01:21:09related to animal modeling and how it
01:21:11fits in with with testing.
01:21:13Well, this has been a tough crowd
01:21:15for traditional animal model I.
01:21:17No IRA's point of view and respected
01:21:20an remember seeing him at the
01:21:22back of a city workshop that I
01:21:24organized on animal modeling in IO.
01:21:26I view that as a compliment even
01:21:29if it wasn't intended to be one.
01:21:32But what I would say is our lab
01:21:34has developed a number of immuno
01:21:36genic syngeneic lines that are
01:21:38used widely including by Pharma.
01:21:40These Yale University mouse, Melanoma,
01:21:42Yum and Yum are lines that enable
01:21:44people to see responses to checkpoints.
01:21:47And sort of tune your system so you
01:21:49can see either additive or synergistic
01:21:51effects by adding a second agent.
01:21:54Obviously that's harder to tell
01:21:55whether that will happen in humans,
01:21:57in which humans that will happen.
01:21:59But to get some kind of enthusiasm
01:22:01or not for your agent certainly
01:22:04has been used on those purposes.
01:22:06One of the things I'd like to
01:22:08focus on is there's a recent nature
01:22:10biotechnology paper by Nick Joshis lab,
01:22:13so Joshi and it uses a very
01:22:15controlled way of antigen delivery.
01:22:17Digital model antigens from LCMV.
01:22:18Both class one and Class 2,
01:22:20but it allows for modeling of
01:22:23immune related adverse events in
01:22:24ways that we haven't really been
01:22:26able to do to this point in time,
01:22:29so you can specifically turn antigens on,
01:22:31either in the context of a cancer
01:22:33elsewhere or even without that,
01:22:35and look at immune checkpoint
01:22:37inhibitor induced.
01:22:39IR A's that I think that has
01:22:42been a big lack in this area.
01:22:44There was recently an NCI
01:22:46meeting related to that.
01:22:48Also sort of suggesting the same Katie
01:22:50Palitti who was had been at yell out
01:22:53for about 10 years as well as very
01:22:55active and lung cancer modeling.
01:22:57So I do agree that we have great strengths.
01:23:01Yeah I would again for this
01:23:03particular group as well.
01:23:04As for I think these other groups
01:23:06that are developing these patients
01:23:08arrive explant models including.
01:23:10The National Cancer Institute in
01:23:12Amsterdam and Daniella Talmon and Tom
01:23:14Schumacher the big challenge in this
01:23:16area has been A to keep things alive,
01:23:18and I've mentioned that we can do that.
01:23:20But also what the readouts are that
01:23:23correspond to responses in human patients.
01:23:25I think there's all sorts of biology
01:23:27you can do in those systems,
01:23:29but there's obviously a lot of
01:23:31interest in personalized therapy.
01:23:32To see how those responses are,
01:23:34and they haven't published yet,
01:23:35it will be interesting to see when people do.
01:23:38Right now, it seems to be elicited cytokines.
01:23:41Of certain profiles that seem
01:23:42to be the best answer,
01:23:44but I think there's more work
01:23:46to be done on those areas,
01:23:48but I would agree,
01:23:49and the other thing that Yale
01:23:50has an advantage is for these
01:23:52different syngenetic models.
01:23:53We've developed many crisper derived
01:23:55genetic mutants like beta two microglia
01:23:57knockout so forth that make it easy
01:23:59for Pharma to come in and just
01:24:01establish an SRA to look at class one.
01:24:03Deficient models of a variety of types
01:24:05that can be responsive to mu agent,
01:24:08so it's kind of a broader swath of
01:24:10and that's all centered really through
01:24:12the center precision cancer modeling.
01:24:14Nearly all of that except for next stuff.
01:24:16Could you just mention briefly the
01:24:18humanized mouse models and with what
01:24:20they will might be, so that was a
01:24:23fairly large mistake on my part.
01:24:25So Richard Flavelle is probably developed.
01:24:27You know, the I would argue amongst the
01:24:30most advanced humanized mouse models.
01:24:32These so called Mr G mice which have
01:24:35not kins of human cytokines for various
01:24:38cytokines that are really important for.
01:24:41Full development and re engraftment
01:24:43of different components of
01:24:44the hematopoetic system,
01:24:45and I think the real strength with the Mr.
01:24:49G model is that it in graphs various
01:24:52components of the myeloid derivatives
01:24:54much better than most other models
01:24:56have up to this point in time.
01:24:59So there's two papers of note
01:25:01related to that,
01:25:02so one is related to modeling multiple
01:25:05human multiple myeloma and mice,
01:25:07which was done with MoD adopt
01:25:09carp a couple years back.
01:25:11And they would Stephanie Hellena
01:25:13they've modeled MD's AML,
01:25:15engraftment into these models.
01:25:17The difficulty with a lot of these
01:25:19models has been that to actually
01:25:22test whether agents work on them,
01:25:24they've been very,
01:25:24very good to show that you can re in
01:25:27Grafton get these different things to
01:25:29work and you can look at additional
01:25:31genetic changes that happen in those models,
01:25:34but the remaining challenges to
01:25:35use these to then say how is,
01:25:37say an immune checkpoint or a new
01:25:40therapy going to help in that context.
01:25:42But the other issue until more
01:25:44recently was that Regenerx on had
01:25:46participated in the generation
01:25:47of those models which made.
01:25:49A little bit complex to work with other
01:25:51companies and outside of Richard's lab,
01:25:53but I think that's at least
01:25:55possibly being solved,
01:25:56and I wouldn't view that as
01:25:57an impediment now.
01:26:01OK, I'm going to ask one more question.
01:26:03I don't see a whole lot of the questions
01:26:06from the chat before I turn it back
01:26:08over to Charlie for closing comments.
01:26:11One challenging question,
01:26:12you know every day I read a
01:26:14new paper about another T cell
01:26:16checkpoint inhibitor and you know,
01:26:18I I probably can't count on,
01:26:20you know 100 hands and fingers and toes.
01:26:22How many things actually block T cell
01:26:24function in the tumor microenvironment?
01:26:26Or peripherally,
01:26:27how does one know which those are
01:26:29the critical non redundant targets?
01:26:31For therapy.
01:26:39How do you
01:26:40know well? I mean, I just have
01:26:43how OK I'll give you a hug.
01:26:45You approach it.
01:26:46How do you approach it?
01:26:47Because I you know. I mean,
01:26:49I can list 15 in the back of my head.
01:26:52I don't know how to decide is it.
01:26:54Is it true that they're all important?
01:26:56It's just an individual patients?
01:26:57Or are they are some of them
01:26:59redundant or in the same pathway?
01:27:01Or is biology not important that
01:27:02some of this biology is just not
01:27:04important in cancer but may be
01:27:05important in other settings like
01:27:07infectious disease or something else?
01:27:10I'm. I mean, how do you know is
01:27:14I think it's all tide up with the
01:27:17beginning theme of this whole meeting,
01:27:19which is you have to understand
01:27:22mechanism and understand the science so.
01:27:25Back and how long ago.
01:27:2710 years ago when these things
01:27:29were first being laid out.
01:27:30I remember you know,
01:27:32constructing a diagram with the
01:27:34negative and positive regulators
01:27:35that were known at the time and
01:27:37which one should we look out,
01:27:39which was which one should we look at?
01:27:42And I think a lot of investigators and
01:27:45companies went off just to look at them
01:27:48all without really understanding what
01:27:50the relative contributions of them were.
01:27:52We decided to look at one which was tigit.
01:27:55And you know,
01:27:56that emerged as a consequence of perhaps
01:27:59we're deluding ourselves into this,
01:28:01but that emerged as a consequence
01:28:04of increased understanding as
01:28:05to how it is that PD one works.
01:28:08So if the current hypothesis is
01:28:10that PD one blockade causes an
01:28:12increase in the number of this self
01:28:14renewing stem light compartment.
01:28:16That generates effector T cells.
01:28:19Then what else is there?
01:28:24If you're trying to add to that and forget
01:28:27about the reversal of exhaustion business,
01:28:29if you do that,
01:28:30it turns out that the only other
01:28:32negative regulator that's expressed
01:28:34on the SCM compartment engine,
01:28:36and so if that and it also turns out
01:28:38that we haven't published this yet,
01:28:41that PD one is actually
01:28:43what regulates CD 226.
01:28:45Enzymatically and tigit with a regular C226.
01:28:48Only by competing for like end.
01:28:51OK so that means that there's
01:28:54a close Functional Association.
01:28:55And so if you want to enhance
01:28:58the function then you have to
01:29:01go after both of those things.
01:29:04Assuming you correct with respect to
01:29:06understanding what is the target cell
01:29:09type that that that you're dealing with.
01:29:12No interesting if you look
01:29:14at the exhausted cells.
01:29:16There's lots of digit on them,
01:29:18but there's no CD 226,
01:29:20so unless you know there's another
01:29:22element of the mechanism that we missing,
01:29:25which is entirely possible.
01:29:28Blockade in exhaust itself can't be
01:29:32expected to reactivate its client.
01:29:35A positive rate costimulatory
01:29:37molecule that's a costimulatory
01:29:38molecule isn't even there.
01:29:41So you know those types of considerations.
01:29:43I think you know one really
01:29:44needs to think them through,
01:29:46not just believe what's in the literature,
01:29:48but set up your own systems,
01:29:50often in mice to figure out.
01:29:52And in fact,
01:29:53if if your hypothesis holds any water.
01:29:55'cause these are big decisions you make
01:29:57you enter into a development program.
01:29:59Whether you doing it in an academ.
01:30:01Lab or industrial lab.
01:30:03You know it takes 2 years at least
01:30:05to select the best antibody and then
01:30:07to grow it up and then you know,
01:30:10put it in patients you're out.
01:30:12You know,
01:30:12with a huge investment of money
01:30:14and time at least five years before
01:30:16you know anything.
01:30:18Yeah, we're actually gonna validating
01:30:19some of those targets with some of
01:30:21the resources that we have here.
01:30:22Thank you. Alright,
01:30:23it's always been a vexing question.
01:30:24I could talk to you all all day.
01:30:26Actually, it's my favorite thing to do,
01:30:28but I think at this point I
01:30:29want to turn it over back over
01:30:31to Charlie for closing remarks,
01:30:32and I want to thank all the
01:30:34participants for all their comments.
01:30:36Charlie, please go
01:30:37ahead. Thank you and I just want to
01:30:40thank all of our panelists for superb
01:30:43discussion and obviously think IRA for
01:30:45taking the time out to join us today.
01:30:48You know, as you've heard,
01:30:50we've had great advances,
01:30:52probably unprecedented advances in io,
01:30:54but clearly the next generation is
01:30:56going to require innovation at a
01:30:58level that builds on terrific science.
01:31:01Outstanding science moves into the clinic,
01:31:03and I'm I'm so proud of the fact
01:31:06that everyone of our panelists.
01:31:08Is innovating in that space and
01:31:11many others who we said they
01:31:13couldn't include in the forum.
01:31:15In fact 1.0. I'll mention a city Chen,
01:31:18one of our leading investigators who
01:31:21company being launched tomorrow,
01:31:22evolve immune therapeutics.
01:31:24Looking at the T cell targeting space.
01:31:26Just one of the many things that
01:31:29are our investigators are leading.
01:31:31You know,
01:31:32I want to thank all the attendees
01:31:35for joining us today and again
01:31:37want to emphasize this should be
01:31:40the beginning of the conversation.
01:31:42Please reach out to us.
01:31:44We will be following up with you because
01:31:47we want to build more collaborations,
01:31:50more conversations.
01:31:50And finally want to thank Kathy Lynch
01:31:54and her team for organizing this and
01:31:57remind all of you that we actually
01:31:59have two more forms of cancer engage
01:32:02on November 5th or novel cancer
01:32:05therapeutics and delivery system.
01:32:06And then on December 9th,
01:32:08defining mechanisms and biomarkers
01:32:10of sensitivity and resistance to
01:32:12answer Anti cancer treatments.
01:32:14So really key topics beyond IO that
01:32:16our investigators are leading.
01:32:18So again thank all of you.
01:32:20Mario, thank you for your leadership.
01:32:23Any final. Large meal.
01:32:25No, I want to thank you Charlie.
01:32:27Thanks to all the panelists,
01:32:29all the people who participated today.
01:32:30Please contact us.
01:32:31We are very interested in
01:32:33developing collaborations.
01:32:33We have an enormous wealth of talent here.
01:32:35Hope will be working
01:32:36with you in the future.
01:32:38Thank you again.