Immuno-Oncology

October 26, 2020

Information

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.