March 27, 2025 • 48 mins
“The most effective therapies for solid tumors are also the most toxic — and we need to fix that,” says Dr. John Connolly, chief scientific officer of the Parker Institute for Cancer Immunotherapy. In this episode of the Vanguards of Health Care podcast, Connolly tells Bloomberg Intelligence pharmaceutical analyst Sam Fazeli why managing toxicity is the key to unlocking CAR-T’s potential in solid tumors. They explore the rise of in vivo cell therapies, evolving views on the tumor microenvironment and why foundational cancer vaccines may shape the future of all immunotherapy. Connolly also shares the clinical trials he’s watching closely, the ones that could flip the script on cancer care.
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Episode Transcript
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Speaker 1 (00:19):
Hello, everybody.
Speaker 2 (00:20):
Welcome to another episode of Bloomberg Intelligence Vanguards of Healthcare podcast,
where we speak with the leaders at the forefront of
change in the healthcare industry. My name is Sam Fazzelli
and I'm a pharma analyst at Bloomberg Intelligence, the in
house research arm of Bloomberg. I'm delighted to welcome doctor
John Connolly, chief Scientific Officer of the Parker Institute for
(00:43):
Cancer Immunotherapy otherwise known as PISCY. Johnny is one of
the most energetic and dedicated people I know in this field.
He's been CSO of PISCY for the past five years
or so, giving him a very broad overarching view of
the space. The treatment for cancer has evolved leaps and
(01:03):
bounds in the past decade and a half, with the
major contribution coming from immunotherapy, which is focused on using
treatments which alert the immune system to the presence of
malignant cells and attempt to activate them against the cancer hen.
Speaker 1 (01:19):
Trying to clear it.
Speaker 2 (01:20):
And the promise is that once you've done this, the
immune memory should kick in and protect you from a
return of the cancer.
Speaker 1 (01:29):
The hope, I mean, that's where everybody's trying to get
to In the end, right.
Speaker 2 (01:32):
The whole field was kicked off by the success of
a drug that does just that year, VOI or epilimum
ab in melanoma. This was swiftly followed by the demonstration
of even better efficacy from drugs do target the PD one.
That's another what's called the checkpoint on immune cells, on
the killer T cells. So you block that and it
(01:52):
unleashes their firepower on the cancer cells. Right, T cells,
those are the ones that are targeted here, and they
are the main play in this conversation.
Speaker 1 (02:01):
What we get to that So, and of course one
of the best.
Speaker 2 (02:04):
Examples of what I said leaps and bounds is the
death rate from melanoma has plummeted in countries where these
drugs are available and people can afford them. So, without
further ado, I'm going to ask John to tell us
a little bit.
Speaker 1 (02:18):
About his journey of how he ended up.
Speaker 2 (02:20):
At piss and what keeps him ticking at the very
high speed.
Speaker 1 (02:25):
That he does.
Speaker 3 (02:27):
Thanks Sam, Thank you very much. It's a real pleasure.
Speaker 4 (02:29):
And honor to be here on the Bloomberg ban Guards podcast.
I'm a huge fan of you and the podcast itself,
so it's a dream to talk to you here. So
my background is as an imminologist and a human imminologist.
So I trained with Jacques Bontreau and team developing cancer vaccines,
and my back the position was a Baylor building that out,
(02:50):
and while I was there, we had extended this really
focusing on clinical trials in melanoma and breast cancer and
a number of different spaces and diving deep into cell
biology and cellular therapy. And this is this really led
to the development a lot of our imun monitoring technologies
and expanding this out and building infrastructure programs and our
(03:11):
how to monitor clinical trials, and so it's really where
we really started getting into into that space. And Jaka
of course had a and still has a real industrial
bent background in biotech and etroche and sharing plow prior
to that, and was very much encouraging that kind of
entrepreneurial spirit. So it was it was really quite wonderful.
(03:31):
And prior to that, I had trained with Mike Fanger
at Dartmouth. Mike had started, along with Paul Geyer, that
small company called Metarex that that started the you know,
worked on Ippu Luma MAB and built that out, and
of course was acquired by BMS, and so it really
was it's kind of in my blood to translate many
of these early ideas that we had in the lab
into the clinic really really quickly and then move those
(03:55):
into biotechs and so that they could really get out
there to all the all patients. About twenty ten, I
ended up really it turned out that that infrastructure and
training program that we were working on really expanded to
extend throughout the Baylor Healthcare system, looking deeply at immune
phenotyping on multiple clinical trials. And I think that caught
the eye of one of the advisors to the Prime
(04:16):
Minister of Singapore who wanted to build a program like
that out, a guy named Felipe Kilski who had stepped
down as a head of the past year Institute. And
so I met with Philippe, and I met with the
people in Singapore about building a national program out there,
and so I moved out to Singapore to build that
program out and which still exists.
Speaker 3 (04:35):
It's in each of the.
Speaker 4 (04:36):
Clinical trial centers there in Singapore, and worked with ASTAR,
their government agency, to really put that together. And that
was a great, great run, and again that kept the
lab going, kept that entrepreneurial spirit moving and we started
pushing this forward. In one of our clinical trials that
we had done, this was a phase two trial in
nasophar and geal carcinoma, again keeping that self therapy event
(04:58):
using virus specific T cells. Turned into a company called
Testa Therapeutics, and you know, Tesso had expanded and the
results kept coming in. It looked really good, and we
expanded to a global pivotal phase three trial, the largest
T cell therapy trial for cancer. You know, so five countries,
three hundred and thirty patients, multiple sites, centralized cell therapy manufacturing.
(05:18):
So we took care of a lot of the hurdles
that are out there in the industry, and I think
we've experienced some of those challenges. And unfortunately that Phase
three didn't turn out the way we wanted it to.
And you know, during that time, we collaborated with the
Parker and Supercancer Amminotherapy and this was it. I worked
with Jeff Bluestone and Fred Ramsdell there, and they were
really interested in the scope and scale and the number
(05:40):
of samples that we had that were coming out of
the clinical trial. You know, given my background and immune monitoring,
imman phenotyping. We spent a lot of time in really
detailed analysis of looking at mechanisms of action and resistance
to the cell therapy, and so.
Speaker 3 (05:54):
We collaborated with them.
Speaker 4 (05:54):
We were the first cell therapy collaborating, only the second
industrial collaborator with the Parker Institute. And so that started
that step in going to San Francisco, talking a lot
about how we design our analysis, diving deep, giving sample
access to people from some of our biobanks, and working
with the teams at Parker to get things done. That
began that relationship. And then Jeff started a company called
(06:17):
Sonoma Therapeutics Do a car. It's a car t rag
company that's doing very well, and stepped away from the Institute.
Speaker 3 (06:24):
And at that time he and Fred left and.
Speaker 4 (06:28):
So I talk to them and they asked me if
I wanted to come in and take that kind of
analysis and work that we were doing to the Parker Institute.
Speaker 3 (06:36):
And so that began my journey in twenty twenty.
Speaker 2 (06:38):
Right, So John, actually, I think the natural next question
for me is for you to tell us a little
bit about what is Parker Institute and how.
Speaker 1 (06:46):
Does it function?
Speaker 3 (06:48):
So thanks Sam.
Speaker 4 (06:49):
So the PISCE is a five oh one C three charity.
It's a nonprofit and so we primarily give grants and
give funding out to fourteen different centers around the US
and so these are really groups of investigators that are
sill of the top people in the US that are
focused on immino oncology. And these are really given as
gifts to the universities, to the resource centers. And what
(07:12):
we'd like to do is we want to kind of
break down the barriers between the different universities, create an
institute where information is shared readily between the different groups
that they can work together and they can fund collaborative projects.
And so if you become a center, the money comes
in as a gift and we're really betting on people,
not on projects. So a lot of this are around
big programs that the centers want to build together and
(07:35):
we really have a line of sight to our core mission,
which is all cancer scurable disease. And so by funding
this Blue Sky research and the efforts that are there,
we want them to fund early stage clinical trials that
can then translate those into the clinic. And this is
really where some of the biotech work happens, and that
is we start moving some of these If there's a
mechanism of resistance that's been identified, we want to move
(07:57):
these into identify the technology that can address that, and
then move these into say biotechs that can take them
into the clinic. Underproject Management, we have a venture philanthropy
arm fully within the within the nonprofit that can fund
those companies and move those forward and lead rounds and
push it, push it out there, and so it continues.
(08:17):
We've expanded it from four centers you know, to the
fourteen that I mentioned and really captured a huge, huge
number of investigators. I heard recently we had touched We're
funded up to nine hundred and fifty investigators when.
Speaker 3 (08:29):
You look at it.
Speaker 4 (08:29):
So it's a real, real, huge commitment by Sean Parker,
who's really the brains and the firepower behind this entire effort.
Speaker 1 (08:39):
That's great.
Speaker 2 (08:40):
I mean, look, I mean all of all the things
that you guys do, and I don't know how you managed.
Speaker 1 (08:45):
To keep it all.
Speaker 2 (08:46):
Of course, there's a team here, but I want to
give John a plug himself too. There's a very nice
podcast that they've started doing, which I enjoy every time
I listened to, and you cannot come off it without
learning something.
Speaker 1 (08:58):
And that's called from bench to fireside.
Speaker 2 (09:01):
And you know, and I listened to sometimes twice or
three times because there's so much information.
Speaker 1 (09:06):
Packed in there.
Speaker 2 (09:07):
I need to you know, I start taking notes. So
thank you for that. That takes some organization.
Speaker 1 (09:12):
Now, without further ado, I thought, what we'll do.
Speaker 2 (09:15):
I think I've said that twice. Now we have to
be careful not to keep saying that. And let's go
to the meat of the conversation. I'm going to start
with you talked.
Speaker 1 (09:22):
About engineered T cells or engineer immune cells.
Speaker 2 (09:25):
Let's talk about cartes and the aim months conversation, in
every segment we talk about one of these mechanisms of
action for one of the better phrase. We're going to
try and see if we can get John to tell
us how the world's going to change. You know today cartes,
which are the engineered T cells.
Speaker 1 (09:43):
So you take the T cells.
Speaker 2 (09:44):
Out of the patients, those are the immune killer cells,
engineer them in the lab, and then give it back
to the patient. Hopefully they can make it and the
T cells are alive, et cetera, et cetera several weeks
or depending on the product.
Speaker 1 (10:00):
To the patients and then they go in and do
their job, which is fine. The tumor you hope and
kill it.
Speaker 2 (10:06):
Now, there are several, I mean, and they are amazing
efficacy when they work. There are patients who've been alive
for years now having had a cardi therapy, which is
the whole point, right, So let's talk about these carties.
Speaker 1 (10:19):
We know what the limitations are. Maybe you want to
just reel them off as we talk and then tell
us where you think the big innovation's coming or two
or three. I mean, I don't know if you can
pinpoint one, but you know what I'm trying to get to.
Speaker 2 (10:34):
How do we make these number one more easily given
to patients and number two expanded out into not just
where the most of the efficacy seems to be today,
which is in blood cancers versus solid tumors.
Speaker 3 (10:47):
Well, Sam, thanks very much.
Speaker 4 (10:49):
I think I told you before my self professed cell therapist,
I'm not going to back away from it.
Speaker 3 (10:54):
But there are challenges in the field. But I want
to actually start with one of the big successes.
Speaker 4 (10:58):
If you look right now, I think it was maybe
two three weeks ago there was an announcement from Baylor
College of Medicine from the CGT unit. There about an
eighteen year follow up on a Gen one car T.
This is a GD two car TI in neuroblastoma, and
the patients eighteen years follow up there in a lethal disease.
(11:19):
That original clinical trial had three of nine complete responses
in a solid tumor. Right, this is back eighteen years ago.
So we knew early on that there was a possibility,
even with first generation car TIE, that we could get
something if we had the right targets and the right
conditions and trial design and you know, everything that went
into that wonderful carte. That same binder has gone on
(11:40):
to treat pediatrically omas and other things with great success.
So it does tell you that one of the targets
and finding good targets is one of the most important
things in the car T space. So I'm tremendously excited
about the potential for car TE therapy, even given the
challenges of access and price and deficacy. I think it's
one of the one of the biggest biggest challenges that
(12:02):
we've seen I think has been originally is the ability
of these cells to function in the.
Speaker 3 (12:07):
Tumor micro environment.
Speaker 4 (12:08):
You know, we I think the fields really have spent
a lot of time looking at that tumor micro environment,
studying carefully and asking how you can overcome some of
the challenges of the metabolic micro environment, a huge, huge issue.
Speaker 3 (12:20):
Many of these solid tumors.
Speaker 4 (12:21):
Are just completely depleted from glucose, which of course is
essential for functioning T cells, high lactic acid production, trip
to fink, catabolism, you know, I dentiity and catabolism, all
of these real huge problems that are going on there.
And so what we've done is use the tools of
synthetic biology to begin to design around these challenges. And
(12:42):
we've I think with the advent and you know, as anything,
technology really pushes science forward, and with the application of
CRISPERD based technology and screening, we've been able to identify
a huge number of key nodes that we can modulate
to improve survival in the tourmur micro environment. And so
this is again identifying mechanisms of resistance and then building
(13:02):
around that the other of these wound healing signatures, things
like TGF beta driven signatures. Overcoming those is a big
challenge and has been, and we've got we now have
solutions for that. And then finally and probably in humans.
Most importantly is the master coordinator of all of this suppression,
which are these myloid components which seem to be particularly
important in humans or even over our model systems like mice,
(13:26):
and so overcoming those challenges has been has been a big,
big move. So both the academic labs and biotechs have had.
Speaker 3 (13:32):
Their solutions for each of them.
Speaker 4 (13:34):
What we found is that some of the most and
then taken those into the clinic and some of the
most innovative have begun to see efficacy in solid tumors.
So the downside is is what we even in these
early clinical trials is that this efficacy.
Speaker 3 (13:50):
Seems to be intimately linked with toxicity.
Speaker 4 (13:52):
And so this is really the modern challenge now is
what we've got is the more effective the drug is
at killing the tumor we're seeing is it's inducing systemic
myloid activation. So that's the characteristic of the toxicity we're seeing.
It reads out as things like hlh I cans central
nervous system inflammation, and so what we're focused on now
(14:13):
is how do you decouple that mechanism of equacy and
toxicity so you can begin to see the excellent anti
tumor activity but not have to completely back off and have.
Speaker 3 (14:23):
This dose limiting toxicity that's associated with it.
Speaker 4 (14:26):
And so what that entails, at least from the academic side,
we're being to see is how do you uncouple the
communication between the engineered car tee and this myloid component
that's there as a sentinel to look for tissue damage.
And so this is where we're seeing the next generation
of therapies. I can tell you that people that are
thinking about this and companies that are thinking about it
that are starting to see really nice efficacy. And I
(14:48):
can point out some of the many companies, but one
in arsenal Bio early clinical trials going in there with
their RCC seem to be able to decouple some of
that toxicity and efficacy.
Speaker 1 (15:00):
Thank you, John.
Speaker 2 (15:01):
So just just thinking about this, you know, breaking down
all the elements. I'm assuming therefore, that you believe in
terms of the time to.
Speaker 1 (15:09):
Getting the product back to the patient or whatever it's called.
Needle to needle, vein to vein, brain to vein. I mean,
I've heard all coins of versions of this that's coming down.
Speaker 2 (15:18):
Accessibility and affordability are different things, and there are carts
that are being manufactured that seem to have lower side
effect profile because.
Speaker 1 (15:28):
Of the way that they expand in the patient, et cetera.
But in terms of so let me just make sure
I've understood here, you are optimistic.
Speaker 2 (15:37):
That within the next three four five years we will
see more successes in solid tumor cartings, and that the
main step than three Okay, that the main step that
has to also be taken there is to work out
the way to manage the side effect profile.
Speaker 4 (15:53):
So that for that three year target, absolutely it's going
to be the side effect profiles have to be and
the toxicity profiles have to be managed. And I think
this is where a lot of companies that are doing
and academic labs really that are doing innovative car tee
in early stage signifying clinical trials. This is what they've
been thinking about and how they've been doing it. They're
creating much more on target effect, but that on target
(16:15):
effect on tumor effect really, and that's highly specific for
the anti tumor activity. It's not completely disengaging the rest
of the immune system. I think it may be that
when we talk about the five and seven year cartes,
in five seven years from now, cartes, this is where
we're going to begin to re engage the rest of
the immune system, where we start to say, how can
(16:37):
we bring in this sort of second order immunological response,
things like recruitment of dendrit excels, recruitment of NK and
KT cell components. But at this point it's very much
focused on limiting the TALX profile and keeping that on
tumor effect there. Now you mentioned access and price and
things like that, these are all still challenges. I think
in the solid tumor car T space, what we're really
(16:58):
looking for is efficacy, and then we can begin to
ask how can you know, parallel technological development improve things
like access, price, and yeah, exactly and and and you know, affordability.
Speaker 1 (17:13):
Got it. Thank you for that.
Speaker 2 (17:14):
Now, just very quickly before we move on from cartes
in vivo versus engineered x vivo carties and of course
this week asked Elka did the deal for with the
Belgian company for a lentiviral in vivo.
Speaker 1 (17:26):
Do you want to just talk us through.
Speaker 2 (17:27):
The opportunities and the challenges of in vivo engineering.
Speaker 4 (17:32):
Yeah, I think that the this is huge promise in
vivo engineering. So I am incredibly bullish on the development
of in vivo engineering, particularly for low hanging fruit like
I don't want to call it lowla hanging fruit, but
like multiple my aluma, like the ESCO biodeal as deal
you're referring to, so he malignancies. I think you know,
cartes are their massive successes in this space. So we're
(17:55):
really really excited about that. But where did they go next?
How can we address access issues and how can we
address things like the challenges associated with late stage patients
getting car TE and this is things like lympho depletion
conditioning regiments that are required for conventional car T therapy.
This is very, very difficult for patients with extensive disease
(18:16):
to actually manage and handle.
Speaker 3 (18:17):
It also limits who can do a cart therapy.
Speaker 4 (18:20):
It really limits it to academic medical centers that have
the capability to manage that limpha depletion regimen. And so
with in vivo carte, particularly things like the pseudotype engineer
at lentiviruses that you heard from Escobio, but also some
of the lipid nanoparticle work that's out there. I'm really
excited about the ability to just simply deliver this to
use the lymph nodes in the natural system, as you know,
(18:43):
the incubators to generate these car tes. This is another
one of those examples. And I think it's something you
see with a lot of the academic scientists is they
spend a lot of time kind of engineering things that
replicate how the normal immune system functions. You know, if
you have a virus infection, it was somewhere around sixty
eighty percent of circulating cells in the in the context
(19:05):
of a blood based flavy virus infection, are specific for
the virus in a matter of you know, three or
four days. That's a huge output. And we can never
replicate that, you know, in an incubator. It's just not possible.
So the ability to capture all of those known unknowns
that come with normal lymphnobiology is a huge benefit.
Speaker 3 (19:27):
So I'm excited it.
Speaker 4 (19:28):
Actually, it may be from an industry standpoint, I think
it may be slowing down the atologous carte space because
people are kind of a bit of a weight and
see in the in the vivo car tee where they're
really we have a lot of hope there, and that's fine.
Speaker 3 (19:41):
You know, I have a lot of hope there as well.
What I do say, though, is you.
Speaker 4 (19:45):
Know I talk to you guys about the challenges associated
with tumor micro environments in solid tumor, this might be
a bit difficult to put highly engineered circuits that are
both sensing and can adapt to the tumor micro environment
of a solid tumor into something as.
Speaker 3 (20:00):
Small as a pseudotype enginer Lenty.
Speaker 4 (20:01):
I'm fairly certain we could do this for hemallignancies, but
it might be difficult in the solid tumor space.
Speaker 3 (20:06):
But again, we love challenges.
Speaker 1 (20:09):
Right, I see, I get your point.
Speaker 2 (20:10):
In terms of the number of transgenes that you need
to get in, there is.
Speaker 1 (20:14):
There an advantage.
Speaker 2 (20:15):
I'm assuming Lenty versus AAV the issue is still the same.
Speaker 4 (20:19):
Right, Yeah, it's it's still the same, although there's packaging
differences there of course. But I think one of the
big challenges associated with your vector selection in this space
is that the body when you're putting even a lipid
nanoparticle in which is you know, lipids in case nu
clic acid to your immune system. That's exactly why you
have macrophages to see things like that. That's why you
(20:40):
have hepatocites and rearticular ethereal cells and all of these
things are built to really clear these.
Speaker 3 (20:47):
And so I think this is it's a big specific target.
Speaker 1 (20:51):
So John, let's go to the natural next step. You've
obviously kind.
Speaker 2 (20:56):
Of I don't think you actually did that declared an.
Speaker 1 (21:00):
I'm not going to say it. You're not biased because
I know you also do quite a lot of work
in the T cell redirection space, right, So do you
want to just took us through that.
Speaker 2 (21:10):
I mean there's folks who do Carti companies do Carti
say that's the future. Folks who do the bispecifics and
try specifics that try and get to bind the T
cells to drag them into.
Speaker 1 (21:21):
The tumor cloaked or uncloaked or whatever. That's the There
was other folks who say, but this is the way
to do it.
Speaker 2 (21:28):
And of course they each have their own you know,
one is a supposedly one and doone. The other one
is a is a regular type of therapy that you'd
have to keep giving.
Speaker 1 (21:37):
Do you want to talk us through what.
Speaker 2 (21:38):
The status is today and where you see that space
in four or five years, where do we expect to
get major change?
Speaker 3 (21:45):
Yeah, I am, I'm enthusiastic.
Speaker 4 (21:46):
I think about this space but I do want to
say that as died in the Wall cell therapiest like,
the cells are the autonomous agents of change in the
immune system, so they're really bringing the programming to the
to the site itself. They can adapt to that micro environment,
and so we can learn a lot from just studying
what the key interactions are in the context of say
a car T therapy or a till therapy. But it
(22:09):
doesn't mean we're a good protein engineer. Can't sit there
and begin to design that and engage in vibo using
biologics some of those same programs with the existing till
populations that are already there.
Speaker 3 (22:21):
So in the.
Speaker 4 (22:21):
Context of cancer, I'm hugely enthusiastic about multi specific engagers
and engaging say T cells, but it's not just T cells,
you know that. I was really encouraged yesterday by some
of the drand bio deal with the macrophage engages decked
in one by CD twenty depleted simply because it engages
a new cell type in this case of macrophage that
(22:43):
doesn't necessarily initiate a lot of that cytokine release when
it's engaging. So I think that this idea of bringing
in multiple cell types. We're going to see more and
more of this. So of course with Dragonfly and other companies,
we've seen multi specific biologics engaging in K cells, but
there are receptors that are shared betwe many of these cells,
and so being able to figure out which cells you
(23:03):
want to target in the context of cancer, the tumor
cells or the suppressive myloid cells or you know, the
fibroblasts that are in the tumor itself. Coming up with
targets that can hit each of these components, and developing
biologics that can bring in particular cell types to take
them out, I think is the next step.
Speaker 3 (23:20):
That we're moving forward to. So multi cell.
Speaker 4 (23:22):
Type engagement, not just T cells, but multiple cell types
engaging anti tumor. The other is a much more nuanced thing,
which is you know you don't I think first generation
TCR engagers. These these are really potent molecules and so
you're always dealing with a lot of toxicity associated with them,
and so those are really hitting the tumor but engaging
(23:43):
these very strong T cell responses. So what we've seen
is a d tuning of many of these receptors so
that they're not so potent on the tumor, they don't
initiate this massive anti tumor response, but inten instead depend
on the avidity of.
Speaker 3 (23:57):
The CD three interaction on the surface.
Speaker 4 (23:58):
So it's not just this massive highffinity interaction, it's kind
of a more avid surface. And then finally, I think
again studying how tills function, how good car tes function,
we've begun to look at multiple receptors, so engaging not
just the CD three domain, but the CD two engager,
so you can actually give some costimulation alongside of some
(24:20):
of that anti tumor effect. So in doing so, you
you've decoded how cell therapy works when it works well,
and developing next generation biologics that hit those receptors in time.
Speaker 2 (24:30):
So let me let me just pick up on a
point you made earlier with regards to multiple cell type
be directly yes, in the same product. Is that what
you're thinking, same activity or just a mix of like
two or three one targeting in K one targeting t
SALE one target work.
Speaker 4 (24:46):
Yeah, So there's there's a couple of different approaches you
can do there, and we've seen so you've seen multi
specific engagers that will engage two different receptors, things like
n case all activating receptors GD two D, KG two
D as well as CD three. These the others are
things like CD two which are also expressed on NK
cells plus T cells. So that's the other kind of
approach where you look for activating receptors that are shared
(25:09):
between cell types, and that's that's.
Speaker 3 (25:11):
How you're engaging, engaging those the receptors themselves, and.
Speaker 1 (25:14):
Doesn't that then just multiply your risk of toxicity.
Speaker 3 (25:18):
Well, the receptors are there for a reason, you know,
so they you know.
Speaker 4 (25:22):
I think what it does is depending on Again, you
can detune this depending on the level of engagement and
the biology downstream that receptor. So it's not just a
CD three response that's kind of blowing out a lot
of cytocons. It's really engaging things like fagastic receptors on
those cells that can begin to you know, actually attack
(25:42):
the tumor cells. So it's not necessarily increase toxicity just
because they're hitting multiple cell types. You know, one thing
that I think we have to understand is anytime we
engage CD three, we're engaging multiple cell types because the
first thing you're making is you know, chemicons that are
calling in secondary cells and those chemicons and interfering gamma
is one of the big at primers there is for macrophages,
and of course AL twelve is priming the nksell response.
(26:06):
All of this is downstream because you're engaging not a
sell but a system if you want to affect a
durable anti gum response.
Speaker 2 (26:13):
One of the tough things to figure out is when
you look at the plethora of things that folks are trying.
You know, we just talked about that with the armored
car ties for instance, with the Nile fifteen in it. Oh,
we've seen some of the I mean I remember a
couple of years ago we saw the TGIF beta domin negative.
So all of them designed to try and get you
more efficacy in the solid tumor space. It's just very
(26:34):
hard to know if you were an investor in these
kind of things, where would you put your bet?
Speaker 1 (26:40):
Do you have to bet on everything? And I hope
some of them workout? What are the some obvious areas
you would focus on?
Speaker 4 (26:47):
Well, I think as an investor, I think I'd step
back a little bit and just just ask the next question.
So when you're you know, it's it's kind of picks
up on our last conversation, which is you're really you know,
what is it you're trying to achieve have the end
goal result in mind. So if you're trying to achieve
a durable anti tumor immune response, then that is I
(27:07):
don't mean to be too academic about this, but that's
an emergent property of a system. It's a multi cell
event that you're engaging, and so you're trying to do
many things in time to get there.
Speaker 3 (27:18):
So you're trying to destroy the target cell.
Speaker 4 (27:21):
But you're also trying to engage epitope spreading so that
you're hitting other targets to prevent the escape of the
immune system.
Speaker 3 (27:27):
And so the tumor itself has a say in the matter.
Speaker 4 (27:30):
So it's a conversation between the immune system and the tumor.
So simply blocking TJBATA is a good example. So coming
with a dominant negative TJF beta receptor on a car te,
which we've done in our clinical trials with Baylor and
the team there at CGT, is a really good idea.
You know, the cells in vitro work much better in
our mouse systems. They work really good but when you
(27:53):
actually look at that tumor micro environment, what you find
is those cells. Because you're completely blocking the ta jet
beta signature, there's a there's a feedback loop from the
tj beta receptor that prevents the secretion of tjeft beta.
Speaker 3 (28:06):
So what you can actually see is that because the
T cells.
Speaker 4 (28:09):
Can't feel TJF beta at all anymore, they begin to
produce some tjet beta and so what you see is
the tissue around them is actually feeling more TJF beta,
you know, than it would otherwise because it's you know,
it's local. So you've got to understand that conversation between
the immune system and the and the beyond just sort
of a target product profile the it's an actual system
(28:31):
that you're trying to engage, right.
Speaker 1 (28:32):
That's interesting.
Speaker 2 (28:33):
So last word on these two things that involve the
T cells. You've got the car TIS and you have
T celler redirection. And the two camps. I mean some
of the larger companies that don't have camps. They're in
both Johnson and Johnson being the obvious one in multiple
my Looma. If you thought forward, do you still see
them coexisting? Do they serve different patient types?
Speaker 4 (28:53):
Yeah, I think that there's a reality when it comes
to things like the cell therapy that this is. This
is a first foray in I think anybody there's a
drug developer would tell you that it's just a lot
easier to create a biologic.
Speaker 3 (29:04):
It just makes a huge amount of sense.
Speaker 4 (29:06):
So if you can capture the same level of efficacy
and durability of response, you'll want to move to a
biologic that can be mass produced and isn't fully atologous.
So I love the idea of working the biology out
in early stages in the cell therapy space, getting a
deep understanding of that, and then asking can we move
this to another system that's a lot easier to deliver?
Speaker 1 (29:26):
Right?
Speaker 2 (29:26):
So would that tells me if I again read between
the lines that if you can solve for all the
different things that you need to solve for when it
comes to redirection, redirections is a more desired way forward
than engineer T cells.
Speaker 3 (29:43):
Yeah.
Speaker 4 (29:43):
I again keep in mind what you want to achieve.
If your goal is really reaching everyone, then that's right
now with the current infrastructure that we have, it just
makes more sense to move to a biologic. So with
all the caveats, great news is we have a lot
of experience with biologic so we know things like ada
responses and things that could be challenges that we don't
generally see otherwise.
Speaker 2 (30:03):
Now, John, the next topic I have here is four
C and four D tumor metabolism, tumor micro environment, which
of course are intertwined. So just help us contextualize this
because you did do that a little bit earlier.
Speaker 1 (30:17):
On the tumor is an organ, right Is that fair
to say it's got its own little biology right for sure?
Speaker 3 (30:24):
Yeah, that's right.
Speaker 2 (30:25):
And it's not the normal place that a t sell
or immune system is supposed to be working.
Speaker 1 (30:31):
So just took us through what the challenges there are.
And we always keep hearing car T cells and T cells. Yes,
sure you can block this and improve that, but you
can't get them into the tumor.
Speaker 2 (30:41):
And that becomes the kind of big barrier, it's literally,
So do you want to talk us through where we
are on that and how you see this evolving?
Speaker 1 (30:50):
And do you see a future where, again with the.
Speaker 2 (30:54):
Outlock of three to five years, that we'll be able
to solve some of these issues By opening the door
to the tube, we're letting itselves in and to do
their job.
Speaker 3 (31:02):
Yeah, thanks Sam.
Speaker 4 (31:03):
This is you know, actually, I think that the immune
system certainly doesn't know that it's a tumor. You know,
it just thinks it's a happily growing part of you,
as they say. But it's also it is hugely metabolically
just regulated relatives to the rest of the tissue. And
the way that your immune system really it's your body
deals with this is it initiates a wound healing program
(31:23):
in many of these tissues. And this is this is
kind of the myloid environment that comes in and one
of the most important parts about healing a wound is
shutting off the inflammatory damage that's happening there. And this
is where these TJ beta axis comes in. I'll tend
the dentisye media suppression. All of these things are key
points to healing a simple scratch, for instance, that you
have and so that's the kind of signature that you
(31:45):
see in many of these solid tumors.
Speaker 3 (31:47):
You know, I was struck yesterday.
Speaker 4 (31:49):
I was at a meeting where I was reminded we
was looking at pancreatic cancer and it was a tissue
section and it highly multiplexed imaging, spatial analysis were almost
no tumor cells in that image.
Speaker 3 (32:02):
Almost all of it was this fibris.
Speaker 4 (32:05):
Tissue and stromal cells that were being called in by
the tumor in this massive TGF beta driven I eleven
driven tissue wound repair that was happening. And there were
t cells there, but they were locked in. They were
in this state that were completely surrounded by fiber stisue
and I think that's a common image that we see
in things like obviously pancreatic cancer, but also in things
(32:27):
like prostate cancer and other very very difficult cancers. So
the tumor is coordinating through the metabolic condition that it's
in as well as some of the growth factors this
incredible wound tailing signature around that. So I think the
first step is really try to understand what those are,
so it's not just targeting the tumor cell itself but
all the cells that are being called in around it.
(32:48):
So the key I touched on some of the key
axis one.
Speaker 3 (32:50):
Is the availability of glucose.
Speaker 4 (32:53):
So I could point to some wonderful work on a
Crystal Makos group at Stanford, but I think others have
been thinking about this as well. To improve car te
by actually transducing in glucose transporters, so they can actually
compete on a molecule by molecule basis with the tumor
for the uptake of glucose in that low micro environment,
and they see improved function there. And there are others
that are manipulating through crisper screens that identifying key regulatory
(33:18):
nodes in ammino acid biology, in epigenetic remodeling that allow
the car TI to function within that tumor micro environment.
So I do think that we can engineer our way
around many of these issues, but we really have to
better understand them, and so getting deeper into the immunem
metabolism I think is essential.
Speaker 3 (33:35):
You also said that there's sort of immune.
Speaker 4 (33:36):
Suppressive aspect of this because it's a wound healing signature
that's really there.
Speaker 3 (33:41):
I think it's a good way to think about it.
Speaker 4 (33:43):
It's in many tumors, these are coordinated with each other,
so that you know, the hypoxic micro environment is calling
in macrophages, these are being polarized a particular way. They're
responding to the tumor, but they're responding to other cells
that are around them. I think this is you know,
this may be an area, and I'm enthusiastic about this
where we have to actually take a much more aggressive
approach here. The key is to change the conversation between
(34:05):
the immune system and the tumor. So when I hit
the tumor with interfer on gamma through a car tee
for instance, or TCRT or an engager, I don't want
it to respond by upregulating PDL one. I wanted to
respond by you know, secreting aisle two at me or
something like that. And so I'm really enthusiastic about labs
that are starting to look at combinations of cell therapy
(34:26):
and tumor specific gene therapy where you're going in there
with oncotrophic viruses. You know, these are sort of first
generation akalytic viruses and aren't that lytic, but can actually
still get into tumor as well and actually change the
genetic circuits within the tumor to help them create positive
feedback loops, change that tumor micro environment, and really potentiate
(34:46):
the immune response you're trying to generate.
Speaker 1 (34:48):
That's a John.
Speaker 2 (34:49):
As you were talking, it dawned on me that one
of the problems that we face, you know, when you
told me about that tumor that pretty much had hardly
any tumor cells in it.
Speaker 1 (34:58):
A lot of these new th therapies, this is the
history of drug development in oncology. You tend to go
for third line or fourth line patients who.
Speaker 2 (35:07):
Probably have these enormously fibrootic tumors that aren't going to
respond to anything apart from you know, a laser for
you know, So, how do we break that issue? I
mean a lot of folks are going now more and
more accepting to go into the new adjuvant space, But
is the regulatory system Are we ready to be able
to actually test things where you have the much higher
(35:30):
probability of gaining access And then related to that, the
biology of a very early tumor, a few cells beginning
to form a metastasis, How sure are we because that
by definition, how do you know where they are?
Speaker 1 (35:45):
How do you study them? How do you solve for that?
Speaker 2 (35:48):
The fact that what you see is the tumor that
you can see, and the ones that you want to
get rid of are the ones that are going to
cause you trouble further down the road, especially with their
new adjuvant or adjuvancy.
Speaker 4 (35:58):
Yeah, absolutely so, this has been the universal problem in
all academic clinical trials. I think everybody for my entire
thirty years of doing this has talked about if we
could only move this to earlier stage before the immune
system is so racked by both the therapy but as
well as the cancer itself. And there is absolutely truth
in that. The response we know this if you you know,
(36:20):
it's the number one correlate when we look at a
correlative success and disease non progression on clinical trials is
the extent of metastasis, like the volume of disease that
you have. If you have less disease, you're just going
to do much better and you respond well. So there
is a systemic change that really does impact the immune
system heavily. So I think trial design is one of
(36:42):
the biggest things out there.
Speaker 3 (36:44):
I think it's almost tried to say that.
Speaker 4 (36:45):
Everyone everyone knows that if you design the right trial
and you hit something and say the relapse setting or
even in a NEO aadgunt setting where you can actually
come in and have minimal residual disease and monitor that, I'm.
Speaker 3 (36:58):
Loving some of those clinical trials.
Speaker 4 (37:00):
The downside is I think a lot of this is
left to therapies that have much much lower toxicity, you know,
like a vaccine or this is sort of the you know,
this is where this is actually happening, because you do
have to balance the risk rewards profile in that setting.
But I do really think that, you know, there's a
space here to do clinical trials, particularly if you start
looking at rare diseases. So there are universal suppressive things
(37:23):
that happen in things like rare sarcomas that are also
true in lung cancer. You know, I mentioned TJF beta
and egfr signaling and some of the metabolism issues that
you and I just talked about, these are true in
rare cancers too, So it may be an opportunity for
people to kind of step into that space early on
where there aren't really other therapies that you're heavily competing with,
and there aren't other options for some of these patients
(37:44):
to try to test therapies there. And I can tell
you that that community would be incredibly grateful.
Speaker 3 (37:49):
It's really tough.
Speaker 1 (37:51):
Yew.
Speaker 2 (37:51):
The next kind of again two related topics. That two
are antigens and cancer vaccines. So maybe you know, I mean,
do you believe there's a I think there was a
talk of about a year ago year in Africa a
renaissance of cancer vaccines. I mean they were they were
the first attempts that folks made at trying to kick
the immune system into action by vaccinating. Everybody knows what
(38:15):
vaccine is, right, So do you want to talk us
through where we are today in the cancer vaccine world
and where you think the success is going to come from?
Speaker 1 (38:23):
You just mentioned not so.
Speaker 2 (38:25):
Lytic on politic viruses approaches, We of course here on
a daily basis about the MR and a individual neotherapy,
new antigen therapy, et cetera.
Speaker 1 (38:38):
How do you think this is going to shape up
in the next four to five years?
Speaker 4 (38:41):
So I think I'm excited by it because you know,
we've cancer vaccines, as you mentioned, Sam, they've been out
there for a long time, neo antigen vaccines, tumor antigen vaccines,
and they've taken many forms. You know, they've taken viral forms.
Speaker 3 (38:55):
We've seen this with things like.
Speaker 4 (38:57):
Newcastle disease virus modified and others in the dendritic cell
space I mentioned before, where highly immunis stimulatory cells loaded
and readministered, but also peptide vaccines have been around for
quite a while. I think that there's some technological advances
that have really pushed this forward.
Speaker 3 (39:14):
I think the.
Speaker 4 (39:15):
Obvious one is this is a product of covid is
the RNA based vaccines, you know, with immunis stimulatory backbones,
where we're able to actually stimulate an immune response, but
also come up with a scale delivery platform in the
lipid nanoparticle to actually begin to build those responses out.
And so this has obviously caught the eye of the
big players in this field, with BioNTech, gene Tech vaccine
(39:38):
memorials on Kettering and those trials as well. Of course
the Mark Maderna trial that we're all eagerly awaiting but
looked looked.
Speaker 3 (39:44):
Really interesting in a mononoma space.
Speaker 4 (39:47):
But also I think, you know, we recently had a
nice paper out of Yale and our PISCE site at
Dana Farber in the renal cell carcinoma space showing some
really promising survival data with the vaccine. So I'm really
encouraged by where this is going, particularly because we're moving
away from what the NIH could fund, which is small
clinical trials where you always ended up with the same result.
(40:09):
It looked promising you know, we had some if you
could initiate a big potent response in an imenogenetic tumor,
you saw a beautiful response in the clinic. But if
you couldn't initiate that response or you couldn't maintain it,
then you saw progressions. So we're always left with this
seventeen to twenty percent efficacy that looked really promising. We
could never get funded for the next big thing and
could never get enough interest. Now you're talking about definitive trials,
(40:34):
whether it's the final vaccine or not, with mRNA based
therapies in well designed studies that you can actually look at.
Speaker 3 (40:42):
So I'm encouraged by the outcome.
Speaker 4 (40:44):
I think the entire field is going to pivot to
a large degree based on how those large scale trials
play out.
Speaker 1 (40:50):
Yeah.
Speaker 2 (40:50):
Well we're both going to AACR, so hopefully we'll see
some new developments there. I'm aware of a couple of
interesting data sets that are going to come out, looking
forward to seeing those.
Speaker 1 (41:01):
So in general, let me summarize here again.
Speaker 2 (41:03):
You are optimistic about how kinds of vaccines are evolving,
and specifically the RNA. Let's hope that they hit I
mean they're doing the right, trials, Right, that's for.
Speaker 4 (41:13):
Sure, That's all we can really ask for at this point,
you know, Sam take a step further though, when it
comes to vaccines again, I think that when we see
efficacy in a hurt car T trial or something like that,
we see a patient that responds. None of this response
is because the tumor. You know, tumors can downregulate and
they're highly heterogeneous. The long term, durable response that you're
(41:36):
looking for, as we talked about, really requires initiation or
the rest of the immune sytem, which you really get
get it going. And this is probably true you know,
for radiation and many other things too. It's about creating
an anti tumor immune response that sees multiple epitopes, that
engages things like gamba delta T cells, that has an
answer presenting cell. And the reason we say this is
(41:56):
that the big correlates are things like tertiary lymph node
structures that are formed around the tumor and they're really
the sites of epitope spreading and priming against other tumor intigens.
And once you can catch that fire, this is really
where you see this feed forward response. So you know,
I don't want to say everything is a vaccine, but
that's really what you're trying to accomplish with CAR therapy,
TCL engagers, all of it. So because of that, I think,
(42:19):
even if you know you can make the argument and
this is a trial for the future that we need
to do is first thing you want to do when
it comes to something like sequencing, and this may be
something that Memorials start doing because they have all the data,
is get a neo engine profile of every tumor that
comes through the door, all of them, and start with
a very safe vaccine, very low toxicity, easy, and that
becomes the foundation for immunotherapy that happens afterwards.
Speaker 3 (42:41):
It's not about the epicy of vaccine.
Speaker 4 (42:43):
It's about setting up the efficacy of every other immintotherapy
checkpoint blockade, CAR T therapy, TCR engagers that you're going
to receive downstream for that solid tumor. So I cross
my fingers for the large scale trials, mostly because I
see the future of foundational vaccines really as forming that
that basis for all immunotherapy.
Speaker 5 (43:03):
Right now, obligatory question of PD one version by specifics
sure or PD one veg of by specific in a
year's time, will we still be excited because it's definitely
called people's imagination.
Speaker 1 (43:15):
How do you feel.
Speaker 4 (43:17):
I'm a fan, so I'm a fan. So I think
there's there was a lot of skepticism out there.
Speaker 3 (43:21):
I don't know if you were skeptical, but I.
Speaker 1 (43:23):
Think I think I've come.
Speaker 2 (43:25):
I've got over the idea that it's not just about vegion, sure,
but it's about the bispecific action there you go, yeah,
and that you can get a different outcome if you
have the molecules together. And I've also got to understand
that that Jeff, is a I mean a suppressive, it's
a checkpoint almost.
Speaker 4 (43:42):
Yeah, it's a it's part of a wound healing signature. Right,
this is it you need to grow blood vessels and
it's it's part. It's a key molecule within that that
tumor wound healing signature that we talked about. I think
that you know, one one key point with this and
and they you know, the Summit group actually made this
right away, but I don't know that it really caught
on as well, which is that really what you're doing?
(44:02):
You know, the tumor cells that are there in the
immune systems there. We talk a lot about micro environments
within the tumor, right, But we don't really think what
that means. You know, the tumor doesn't care what the
concentration of vegef is in your toe or at the
tip of your nose. It's the only that really matters
is the concentration that's local right within that tumor micro environment.
And with this PDL one vedgeff does, it creates a
(44:23):
massive trap right where you want it and completely depletes
the vedgeff that's there, as opposed to systemic depletion. So
I think that this is this concept of microvine is
being captured by the Summit molecule, and it's one that's
caught fire. Now we've started to think about local concentrations
and not systemic suppression.
Speaker 2 (44:40):
Now, I was going to ask you about the environment
for science in the US, et cetera, but I think
we leave that because that's another podcast. But I do
want to hear from you if you have one or
two or three clinical trials which you're excited for seeing
the result of, not necessarily that you know it's going
to be positive, because if you did, we should all
(45:01):
come on investing you.
Speaker 3 (45:02):
Yeah, right, what a the off top of you, I've
got a couple.
Speaker 4 (45:07):
So one, of course, I think is the Mark Maderna
trial because I think it's the right trial, and I'm
not super thrilled about the construct that went in and
and even some of the approaches for neo antigen, but
the fact is just a fact. I think the field
is going to the vaccine field is going to pivot
on that that the results of that clinical trial to
a large degree. I mean, the true believers will keep going,
(45:28):
but it has the potential to really light a match
under under these studies. The same is actually true I
think for the BioNTech gene Tech trial as well, simply
because these are you know, there's a huge need in
the in the cancer space.
Speaker 1 (45:40):
And there you're referring to the new antigend.
Speaker 2 (45:42):
Yeah then yeah, sorry, the edge of the trials the
management and then correctal cancer.
Speaker 4 (45:48):
Correct cancer exactly. So really excited by by the results
of those, simply because you'll rarely do you see an
entire field of you know, thirty plus years of research
pivot on a single important trial that we've all been
waiting for.
Speaker 3 (46:01):
So I'm excited by that.
Speaker 4 (46:02):
And then you know, I mentioned arsenal bio earlier This
is an example of I think one of the most
advanced car te therapies that's out there. It's really a
test for what synthetic biology can do in cell therapy.
I haven't seen a more complex but also more well
thought out.
Speaker 3 (46:18):
And executed car tee.
Speaker 4 (46:20):
If you know the results of that RCC trial at Arsenal,
as it goes out, I think is again going to
it's going to change the field.
Speaker 3 (46:27):
So if the try and I have no knowledge how
it's going.
Speaker 4 (46:30):
So if it goes one way, it's going to be fantastic.
If it goes another we should probably look back and
ask maybe we should be.
Speaker 3 (46:35):
Thinking a little bit more about vivo CARTI brilliant.
Speaker 1 (46:37):
Thank you very much. John. This has been great.
Speaker 2 (46:39):
It's been at a very high pace and I did
We did touch a lot of things that I'm hoping
that this is going to be one of those podcasts
that a lot of people have to listen to twice.
Thanks the amount of information we talked about. But I
appreciate your time as always, your depth of knowledge, and
I look forward to seeing you at AACR.
Speaker 4 (46:59):
Thanks Sam, Thank you very much. This has been great.
Hello, everybody.
Speaker 2 (00:20):
Welcome to another episode of Bloomberg Intelligence Vanguards of Healthcare podcast,
where we speak with the leaders at the forefront of
change in the healthcare industry. My name is Sam Fazzelli
and I'm a pharma analyst at Bloomberg Intelligence, the in
house research arm of Bloomberg. I'm delighted to welcome doctor
John Connolly, chief Scientific Officer of the Parker Institute for
(00:43):
Cancer Immunotherapy otherwise known as PISCY. Johnny is one of
the most energetic and dedicated people I know in this field.
He's been CSO of PISCY for the past five years
or so, giving him a very broad overarching view of
the space. The treatment for cancer has evolved leaps and
(01:03):
bounds in the past decade and a half, with the
major contribution coming from immunotherapy, which is focused on using
treatments which alert the immune system to the presence of
malignant cells and attempt to activate them against the cancer hen.
Speaker 1 (01:19):
Trying to clear it.
Speaker 2 (01:20):
And the promise is that once you've done this, the
immune memory should kick in and protect you from a
return of the cancer.
Speaker 1 (01:29):
The hope, I mean, that's where everybody's trying to get
to In the end, right.
Speaker 2 (01:32):
The whole field was kicked off by the success of
a drug that does just that year, VOI or epilimum
ab in melanoma. This was swiftly followed by the demonstration
of even better efficacy from drugs do target the PD one.
That's another what's called the checkpoint on immune cells, on
the killer T cells. So you block that and it
(01:52):
unleashes their firepower on the cancer cells. Right, T cells,
those are the ones that are targeted here, and they
are the main play in this conversation.
Speaker 1 (02:01):
What we get to that So, and of course one
of the best.
Speaker 2 (02:04):
Examples of what I said leaps and bounds is the
death rate from melanoma has plummeted in countries where these
drugs are available and people can afford them. So, without
further ado, I'm going to ask John to tell us
a little bit.
Speaker 1 (02:18):
About his journey of how he ended up.
Speaker 2 (02:20):
At piss and what keeps him ticking at the very
high speed.
Speaker 1 (02:25):
That he does.
Speaker 3 (02:27):
Thanks Sam, Thank you very much. It's a real pleasure.
Speaker 4 (02:29):
And honor to be here on the Bloomberg ban Guards podcast.
I'm a huge fan of you and the podcast itself,
so it's a dream to talk to you here. So
my background is as an imminologist and a human imminologist.
So I trained with Jacques Bontreau and team developing cancer vaccines,
and my back the position was a Baylor building that out,
(02:50):
and while I was there, we had extended this really
focusing on clinical trials in melanoma and breast cancer and
a number of different spaces and diving deep into cell
biology and cellular therapy. And this is this really led
to the development a lot of our imun monitoring technologies
and expanding this out and building infrastructure programs and our
(03:11):
how to monitor clinical trials, and so it's really where
we really started getting into into that space. And Jaka
of course had a and still has a real industrial
bent background in biotech and etroche and sharing plow prior
to that, and was very much encouraging that kind of
entrepreneurial spirit. So it was it was really quite wonderful.
(03:31):
And prior to that, I had trained with Mike Fanger
at Dartmouth. Mike had started, along with Paul Geyer, that
small company called Metarex that that started the you know,
worked on Ippu Luma MAB and built that out, and
of course was acquired by BMS, and so it really
was it's kind of in my blood to translate many
of these early ideas that we had in the lab
into the clinic really really quickly and then move those
(03:55):
into biotechs and so that they could really get out
there to all the all patients. About twenty ten, I
ended up really it turned out that that infrastructure and
training program that we were working on really expanded to
extend throughout the Baylor Healthcare system, looking deeply at immune
phenotyping on multiple clinical trials. And I think that caught
the eye of one of the advisors to the Prime
(04:16):
Minister of Singapore who wanted to build a program like
that out, a guy named Felipe Kilski who had stepped
down as a head of the past year Institute. And
so I met with Philippe, and I met with the
people in Singapore about building a national program out there,
and so I moved out to Singapore to build that
program out and which still exists.
Speaker 3 (04:35):
It's in each of the.
Speaker 4 (04:36):
Clinical trial centers there in Singapore, and worked with ASTAR,
their government agency, to really put that together. And that
was a great, great run, and again that kept the
lab going, kept that entrepreneurial spirit moving and we started
pushing this forward. In one of our clinical trials that
we had done, this was a phase two trial in
nasophar and geal carcinoma, again keeping that self therapy event
(04:58):
using virus specific T cells. Turned into a company called
Testa Therapeutics, and you know, Tesso had expanded and the
results kept coming in. It looked really good, and we
expanded to a global pivotal phase three trial, the largest
T cell therapy trial for cancer. You know, so five countries,
three hundred and thirty patients, multiple sites, centralized cell therapy manufacturing.
(05:18):
So we took care of a lot of the hurdles
that are out there in the industry, and I think
we've experienced some of those challenges. And unfortunately that Phase
three didn't turn out the way we wanted it to.
And you know, during that time, we collaborated with the
Parker and Supercancer Amminotherapy and this was it. I worked
with Jeff Bluestone and Fred Ramsdell there, and they were
really interested in the scope and scale and the number
(05:40):
of samples that we had that were coming out of
the clinical trial. You know, given my background and immune monitoring,
imman phenotyping. We spent a lot of time in really
detailed analysis of looking at mechanisms of action and resistance
to the cell therapy, and so.
Speaker 3 (05:54):
We collaborated with them.
Speaker 4 (05:54):
We were the first cell therapy collaborating, only the second
industrial collaborator with the Parker Institute. And so that started
that step in going to San Francisco, talking a lot
about how we design our analysis, diving deep, giving sample
access to people from some of our biobanks, and working
with the teams at Parker to get things done. That
began that relationship. And then Jeff started a company called
(06:17):
Sonoma Therapeutics Do a car. It's a car t rag
company that's doing very well, and stepped away from the Institute.
Speaker 3 (06:24):
And at that time he and Fred left and.
Speaker 4 (06:28):
So I talk to them and they asked me if
I wanted to come in and take that kind of
analysis and work that we were doing to the Parker Institute.
Speaker 3 (06:36):
And so that began my journey in twenty twenty.
Speaker 2 (06:38):
Right, So John, actually, I think the natural next question
for me is for you to tell us a little
bit about what is Parker Institute and how.
Speaker 1 (06:46):
Does it function?
Speaker 3 (06:48):
So thanks Sam.
Speaker 4 (06:49):
So the PISCE is a five oh one C three charity.
It's a nonprofit and so we primarily give grants and
give funding out to fourteen different centers around the US
and so these are really groups of investigators that are
sill of the top people in the US that are
focused on immino oncology. And these are really given as
gifts to the universities, to the resource centers. And what
(07:12):
we'd like to do is we want to kind of
break down the barriers between the different universities, create an
institute where information is shared readily between the different groups
that they can work together and they can fund collaborative projects.
And so if you become a center, the money comes
in as a gift and we're really betting on people,
not on projects. So a lot of this are around
big programs that the centers want to build together and
(07:35):
we really have a line of sight to our core mission,
which is all cancer scurable disease. And so by funding
this Blue Sky research and the efforts that are there,
we want them to fund early stage clinical trials that
can then translate those into the clinic. And this is
really where some of the biotech work happens, and that
is we start moving some of these If there's a
mechanism of resistance that's been identified, we want to move
(07:57):
these into identify the technology that can address that, and
then move these into say biotechs that can take them
into the clinic. Underproject Management, we have a venture philanthropy
arm fully within the within the nonprofit that can fund
those companies and move those forward and lead rounds and
push it, push it out there, and so it continues.
(08:17):
We've expanded it from four centers you know, to the
fourteen that I mentioned and really captured a huge, huge
number of investigators. I heard recently we had touched We're
funded up to nine hundred and fifty investigators when.
Speaker 3 (08:29):
You look at it.
Speaker 4 (08:29):
So it's a real, real, huge commitment by Sean Parker,
who's really the brains and the firepower behind this entire effort.
Speaker 1 (08:39):
That's great.
Speaker 2 (08:40):
I mean, look, I mean all of all the things
that you guys do, and I don't know how you managed.
Speaker 1 (08:45):
To keep it all.
Speaker 2 (08:46):
Of course, there's a team here, but I want to
give John a plug himself too. There's a very nice
podcast that they've started doing, which I enjoy every time
I listened to, and you cannot come off it without
learning something.
Speaker 1 (08:58):
And that's called from bench to fireside.
Speaker 2 (09:01):
And you know, and I listened to sometimes twice or
three times because there's so much information.
Speaker 1 (09:06):
Packed in there.
Speaker 2 (09:07):
I need to you know, I start taking notes. So
thank you for that. That takes some organization.
Speaker 1 (09:12):
Now, without further ado, I thought, what we'll do.
Speaker 2 (09:15):
I think I've said that twice. Now we have to
be careful not to keep saying that. And let's go
to the meat of the conversation. I'm going to start
with you talked.
Speaker 1 (09:22):
About engineered T cells or engineer immune cells.
Speaker 2 (09:25):
Let's talk about cartes and the aim months conversation, in
every segment we talk about one of these mechanisms of
action for one of the better phrase. We're going to
try and see if we can get John to tell
us how the world's going to change. You know today cartes,
which are the engineered T cells.
Speaker 1 (09:43):
So you take the T cells.
Speaker 2 (09:44):
Out of the patients, those are the immune killer cells,
engineer them in the lab, and then give it back
to the patient. Hopefully they can make it and the
T cells are alive, et cetera, et cetera several weeks
or depending on the product.
Speaker 1 (10:00):
To the patients and then they go in and do
their job, which is fine. The tumor you hope and
kill it.
Speaker 2 (10:06):
Now, there are several, I mean, and they are amazing
efficacy when they work. There are patients who've been alive
for years now having had a cardi therapy, which is
the whole point, right, So let's talk about these carties.
Speaker 1 (10:19):
We know what the limitations are. Maybe you want to
just reel them off as we talk and then tell
us where you think the big innovation's coming or two
or three. I mean, I don't know if you can
pinpoint one, but you know what I'm trying to get to.
Speaker 2 (10:34):
How do we make these number one more easily given
to patients and number two expanded out into not just
where the most of the efficacy seems to be today,
which is in blood cancers versus solid tumors.
Speaker 3 (10:47):
Well, Sam, thanks very much.
Speaker 4 (10:49):
I think I told you before my self professed cell therapist,
I'm not going to back away from it.
Speaker 3 (10:54):
But there are challenges in the field. But I want
to actually start with one of the big successes.
Speaker 4 (10:58):
If you look right now, I think it was maybe
two three weeks ago there was an announcement from Baylor
College of Medicine from the CGT unit. There about an
eighteen year follow up on a Gen one car T.
This is a GD two car TI in neuroblastoma, and
the patients eighteen years follow up there in a lethal disease.
(11:19):
That original clinical trial had three of nine complete responses
in a solid tumor. Right, this is back eighteen years ago.
So we knew early on that there was a possibility,
even with first generation car TIE, that we could get
something if we had the right targets and the right
conditions and trial design and you know, everything that went
into that wonderful carte. That same binder has gone on
(11:40):
to treat pediatrically omas and other things with great success.
So it does tell you that one of the targets
and finding good targets is one of the most important
things in the car T space. So I'm tremendously excited
about the potential for car TE therapy, even given the
challenges of access and price and deficacy. I think it's
one of the one of the biggest biggest challenges that
(12:02):
we've seen I think has been originally is the ability
of these cells to function in the.
Speaker 3 (12:07):
Tumor micro environment.
Speaker 4 (12:08):
You know, we I think the fields really have spent
a lot of time looking at that tumor micro environment,
studying carefully and asking how you can overcome some of
the challenges of the metabolic micro environment, a huge, huge issue.
Speaker 3 (12:20):
Many of these solid tumors.
Speaker 4 (12:21):
Are just completely depleted from glucose, which of course is
essential for functioning T cells, high lactic acid production, trip
to fink, catabolism, you know, I dentiity and catabolism, all
of these real huge problems that are going on there.
And so what we've done is use the tools of
synthetic biology to begin to design around these challenges. And
(12:42):
we've I think with the advent and you know, as anything,
technology really pushes science forward, and with the application of
CRISPERD based technology and screening, we've been able to identify
a huge number of key nodes that we can modulate
to improve survival in the tourmur micro environment. And so
this is again identifying mechanisms of resistance and then building
(13:02):
around that the other of these wound healing signatures, things
like TGF beta driven signatures. Overcoming those is a big
challenge and has been, and we've got we now have
solutions for that. And then finally and probably in humans.
Most importantly is the master coordinator of all of this suppression,
which are these myloid components which seem to be particularly
important in humans or even over our model systems like mice,
(13:26):
and so overcoming those challenges has been has been a big,
big move. So both the academic labs and biotechs have had.
Speaker 3 (13:32):
Their solutions for each of them.
Speaker 4 (13:34):
What we found is that some of the most and
then taken those into the clinic and some of the
most innovative have begun to see efficacy in solid tumors.
So the downside is is what we even in these
early clinical trials is that this efficacy.
Speaker 3 (13:50):
Seems to be intimately linked with toxicity.
Speaker 4 (13:52):
And so this is really the modern challenge now is
what we've got is the more effective the drug is
at killing the tumor we're seeing is it's inducing systemic
myloid activation. So that's the characteristic of the toxicity we're seeing.
It reads out as things like hlh I cans central
nervous system inflammation, and so what we're focused on now
(14:13):
is how do you decouple that mechanism of equacy and
toxicity so you can begin to see the excellent anti
tumor activity but not have to completely back off and have.
Speaker 3 (14:23):
This dose limiting toxicity that's associated with it.
Speaker 4 (14:26):
And so what that entails, at least from the academic side,
we're being to see is how do you uncouple the
communication between the engineered car tee and this myloid component
that's there as a sentinel to look for tissue damage.
And so this is where we're seeing the next generation
of therapies. I can tell you that people that are
thinking about this and companies that are thinking about it
that are starting to see really nice efficacy. And I
(14:48):
can point out some of the many companies, but one
in arsenal Bio early clinical trials going in there with
their RCC seem to be able to decouple some of
that toxicity and efficacy.
Speaker 1 (15:00):
Thank you, John.
Speaker 2 (15:01):
So just just thinking about this, you know, breaking down
all the elements. I'm assuming therefore, that you believe in
terms of the time to.
Speaker 1 (15:09):
Getting the product back to the patient or whatever it's called.
Needle to needle, vein to vein, brain to vein. I mean,
I've heard all coins of versions of this that's coming down.
Speaker 2 (15:18):
Accessibility and affordability are different things, and there are carts
that are being manufactured that seem to have lower side
effect profile because.
Speaker 1 (15:28):
Of the way that they expand in the patient, et cetera.
But in terms of so let me just make sure
I've understood here, you are optimistic.
Speaker 2 (15:37):
That within the next three four five years we will
see more successes in solid tumor cartings, and that the
main step than three Okay, that the main step that
has to also be taken there is to work out
the way to manage the side effect profile.
Speaker 4 (15:53):
So that for that three year target, absolutely it's going
to be the side effect profiles have to be and
the toxicity profiles have to be managed. And I think
this is where a lot of companies that are doing
and academic labs really that are doing innovative car tee
in early stage signifying clinical trials. This is what they've
been thinking about and how they've been doing it. They're
creating much more on target effect, but that on target
(16:15):
effect on tumor effect really, and that's highly specific for
the anti tumor activity. It's not completely disengaging the rest
of the immune system. I think it may be that
when we talk about the five and seven year cartes,
in five seven years from now, cartes, this is where
we're going to begin to re engage the rest of
the immune system, where we start to say, how can
(16:37):
we bring in this sort of second order immunological response,
things like recruitment of dendrit excels, recruitment of NK and
KT cell components. But at this point it's very much
focused on limiting the TALX profile and keeping that on
tumor effect there. Now you mentioned access and price and
things like that, these are all still challenges. I think
in the solid tumor car T space, what we're really
(16:58):
looking for is efficacy, and then we can begin to
ask how can you know, parallel technological development improve things
like access, price, and yeah, exactly and and and you know, affordability.
Speaker 1 (17:13):
Got it. Thank you for that.
Speaker 2 (17:14):
Now, just very quickly before we move on from cartes
in vivo versus engineered x vivo carties and of course
this week asked Elka did the deal for with the
Belgian company for a lentiviral in vivo.
Speaker 1 (17:26):
Do you want to just talk us through.
Speaker 2 (17:27):
The opportunities and the challenges of in vivo engineering.
Speaker 4 (17:32):
Yeah, I think that the this is huge promise in
vivo engineering. So I am incredibly bullish on the development
of in vivo engineering, particularly for low hanging fruit like
I don't want to call it lowla hanging fruit, but
like multiple my aluma, like the ESCO biodeal as deal
you're referring to, so he malignancies. I think you know,
cartes are their massive successes in this space. So we're
(17:55):
really really excited about that. But where did they go next?
How can we address access issues and how can we
address things like the challenges associated with late stage patients
getting car TE and this is things like lympho depletion
conditioning regiments that are required for conventional car T therapy.
This is very, very difficult for patients with extensive disease
(18:16):
to actually manage and handle.
Speaker 3 (18:17):
It also limits who can do a cart therapy.
Speaker 4 (18:20):
It really limits it to academic medical centers that have
the capability to manage that limpha depletion regimen. And so
with in vivo carte, particularly things like the pseudotype engineer
at lentiviruses that you heard from Escobio, but also some
of the lipid nanoparticle work that's out there. I'm really
excited about the ability to just simply deliver this to
use the lymph nodes in the natural system, as you know,
(18:43):
the incubators to generate these car tes. This is another
one of those examples. And I think it's something you
see with a lot of the academic scientists is they
spend a lot of time kind of engineering things that
replicate how the normal immune system functions. You know, if
you have a virus infection, it was somewhere around sixty
eighty percent of circulating cells in the in the context
(19:05):
of a blood based flavy virus infection, are specific for
the virus in a matter of you know, three or
four days. That's a huge output. And we can never
replicate that, you know, in an incubator. It's just not possible.
So the ability to capture all of those known unknowns
that come with normal lymphnobiology is a huge benefit.
Speaker 3 (19:27):
So I'm excited it.
Speaker 4 (19:28):
Actually, it may be from an industry standpoint, I think
it may be slowing down the atologous carte space because
people are kind of a bit of a weight and
see in the in the vivo car tee where they're
really we have a lot of hope there, and that's fine.
Speaker 3 (19:41):
You know, I have a lot of hope there as well.
What I do say, though, is you.
Speaker 4 (19:45):
Know I talk to you guys about the challenges associated
with tumor micro environments in solid tumor, this might be
a bit difficult to put highly engineered circuits that are
both sensing and can adapt to the tumor micro environment
of a solid tumor into something as.
Speaker 3 (20:00):
Small as a pseudotype enginer Lenty.
Speaker 4 (20:01):
I'm fairly certain we could do this for hemallignancies, but
it might be difficult in the solid tumor space.
Speaker 3 (20:06):
But again, we love challenges.
Speaker 1 (20:09):
Right, I see, I get your point.
Speaker 2 (20:10):
In terms of the number of transgenes that you need
to get in, there is.
Speaker 1 (20:14):
There an advantage.
Speaker 2 (20:15):
I'm assuming Lenty versus AAV the issue is still the same.
Speaker 4 (20:19):
Right, Yeah, it's it's still the same, although there's packaging
differences there of course. But I think one of the
big challenges associated with your vector selection in this space
is that the body when you're putting even a lipid
nanoparticle in which is you know, lipids in case nu
clic acid to your immune system. That's exactly why you
have macrophages to see things like that. That's why you
(20:40):
have hepatocites and rearticular ethereal cells and all of these
things are built to really clear these.
Speaker 3 (20:47):
And so I think this is it's a big specific target.
Speaker 1 (20:51):
So John, let's go to the natural next step. You've
obviously kind.
Speaker 2 (20:56):
Of I don't think you actually did that declared an.
Speaker 1 (21:00):
I'm not going to say it. You're not biased because
I know you also do quite a lot of work
in the T cell redirection space, right, So do you
want to just took us through that.
Speaker 2 (21:10):
I mean there's folks who do Carti companies do Carti
say that's the future. Folks who do the bispecifics and
try specifics that try and get to bind the T
cells to drag them into.
Speaker 1 (21:21):
The tumor cloaked or uncloaked or whatever. That's the There
was other folks who say, but this is the way
to do it.
Speaker 2 (21:28):
And of course they each have their own you know,
one is a supposedly one and doone. The other one
is a is a regular type of therapy that you'd
have to keep giving.
Speaker 1 (21:37):
Do you want to talk us through what.
Speaker 2 (21:38):
The status is today and where you see that space
in four or five years, where do we expect to
get major change?
Speaker 3 (21:45):
Yeah, I am, I'm enthusiastic.
Speaker 4 (21:46):
I think about this space but I do want to
say that as died in the Wall cell therapiest like,
the cells are the autonomous agents of change in the
immune system, so they're really bringing the programming to the
to the site itself. They can adapt to that micro environment,
and so we can learn a lot from just studying
what the key interactions are in the context of say
a car T therapy or a till therapy. But it
(22:09):
doesn't mean we're a good protein engineer. Can't sit there
and begin to design that and engage in vibo using
biologics some of those same programs with the existing till
populations that are already there.
Speaker 3 (22:21):
So in the.
Speaker 4 (22:21):
Context of cancer, I'm hugely enthusiastic about multi specific engagers
and engaging say T cells, but it's not just T cells,
you know that. I was really encouraged yesterday by some
of the drand bio deal with the macrophage engages decked
in one by CD twenty depleted simply because it engages
a new cell type in this case of macrophage that
(22:43):
doesn't necessarily initiate a lot of that cytokine release when
it's engaging. So I think that this idea of bringing
in multiple cell types. We're going to see more and
more of this. So of course with Dragonfly and other companies,
we've seen multi specific biologics engaging in K cells, but
there are receptors that are shared betwe many of these cells,
and so being able to figure out which cells you
(23:03):
want to target in the context of cancer, the tumor
cells or the suppressive myloid cells or you know, the
fibroblasts that are in the tumor itself. Coming up with
targets that can hit each of these components, and developing
biologics that can bring in particular cell types to take
them out, I think is the next step.
Speaker 3 (23:20):
That we're moving forward to. So multi cell.
Speaker 4 (23:22):
Type engagement, not just T cells, but multiple cell types
engaging anti tumor. The other is a much more nuanced thing,
which is you know you don't I think first generation
TCR engagers. These these are really potent molecules and so
you're always dealing with a lot of toxicity associated with them,
and so those are really hitting the tumor but engaging
(23:43):
these very strong T cell responses. So what we've seen
is a d tuning of many of these receptors so
that they're not so potent on the tumor, they don't
initiate this massive anti tumor response, but inten instead depend
on the avidity of.
Speaker 3 (23:57):
The CD three interaction on the surface.
Speaker 4 (23:58):
So it's not just this massive highffinity interaction, it's kind
of a more avid surface. And then finally, I think
again studying how tills function, how good car tes function,
we've begun to look at multiple receptors, so engaging not
just the CD three domain, but the CD two engager,
so you can actually give some costimulation alongside of some
(24:20):
of that anti tumor effect. So in doing so, you
you've decoded how cell therapy works when it works well,
and developing next generation biologics that hit those receptors in time.
Speaker 2 (24:30):
So let me let me just pick up on a
point you made earlier with regards to multiple cell type
be directly yes, in the same product. Is that what
you're thinking, same activity or just a mix of like
two or three one targeting in K one targeting t
SALE one target work.
Speaker 4 (24:46):
Yeah, So there's there's a couple of different approaches you
can do there, and we've seen so you've seen multi
specific engagers that will engage two different receptors, things like
n case all activating receptors GD two D, KG two
D as well as CD three. These the others are
things like CD two which are also expressed on NK
cells plus T cells. So that's the other kind of
approach where you look for activating receptors that are shared
(25:09):
between cell types, and that's that's.
Speaker 3 (25:11):
How you're engaging, engaging those the receptors themselves, and.
Speaker 1 (25:14):
Doesn't that then just multiply your risk of toxicity.
Speaker 3 (25:18):
Well, the receptors are there for a reason, you know,
so they you know.
Speaker 4 (25:22):
I think what it does is depending on Again, you
can detune this depending on the level of engagement and
the biology downstream that receptor. So it's not just a
CD three response that's kind of blowing out a lot
of cytocons. It's really engaging things like fagastic receptors on
those cells that can begin to you know, actually attack
(25:42):
the tumor cells. So it's not necessarily increase toxicity just
because they're hitting multiple cell types. You know, one thing
that I think we have to understand is anytime we
engage CD three, we're engaging multiple cell types because the
first thing you're making is you know, chemicons that are
calling in secondary cells and those chemicons and interfering gamma
is one of the big at primers there is for macrophages,
and of course AL twelve is priming the nksell response.
(26:06):
All of this is downstream because you're engaging not a
sell but a system if you want to affect a
durable anti gum response.
Speaker 2 (26:13):
One of the tough things to figure out is when
you look at the plethora of things that folks are trying.
You know, we just talked about that with the armored
car ties for instance, with the Nile fifteen in it. Oh,
we've seen some of the I mean I remember a
couple of years ago we saw the TGIF beta domin negative.
So all of them designed to try and get you
more efficacy in the solid tumor space. It's just very
(26:34):
hard to know if you were an investor in these
kind of things, where would you put your bet?
Speaker 1 (26:40):
Do you have to bet on everything? And I hope
some of them workout? What are the some obvious areas
you would focus on?
Speaker 4 (26:47):
Well, I think as an investor, I think I'd step
back a little bit and just just ask the next question.
So when you're you know, it's it's kind of picks
up on our last conversation, which is you're really you know,
what is it you're trying to achieve have the end
goal result in mind. So if you're trying to achieve
a durable anti tumor immune response, then that is I
(27:07):
don't mean to be too academic about this, but that's
an emergent property of a system. It's a multi cell
event that you're engaging, and so you're trying to do
many things in time to get there.
Speaker 3 (27:18):
So you're trying to destroy the target cell.
Speaker 4 (27:21):
But you're also trying to engage epitope spreading so that
you're hitting other targets to prevent the escape of the
immune system.
Speaker 3 (27:27):
And so the tumor itself has a say in the matter.
Speaker 4 (27:30):
So it's a conversation between the immune system and the tumor.
So simply blocking TJBATA is a good example. So coming
with a dominant negative TJF beta receptor on a car te,
which we've done in our clinical trials with Baylor and
the team there at CGT, is a really good idea.
You know, the cells in vitro work much better in
our mouse systems. They work really good but when you
(27:53):
actually look at that tumor micro environment, what you find
is those cells. Because you're completely blocking the ta jet
beta signature, there's a there's a feedback loop from the
tj beta receptor that prevents the secretion of tjeft beta.
Speaker 3 (28:06):
So what you can actually see is that because the
T cells.
Speaker 4 (28:09):
Can't feel TJF beta at all anymore, they begin to
produce some tjet beta and so what you see is
the tissue around them is actually feeling more TJF beta,
you know, than it would otherwise because it's you know,
it's local. So you've got to understand that conversation between
the immune system and the and the beyond just sort
of a target product profile the it's an actual system
(28:31):
that you're trying to engage, right.
Speaker 1 (28:32):
That's interesting.
Speaker 2 (28:33):
So last word on these two things that involve the
T cells. You've got the car TIS and you have
T celler redirection. And the two camps. I mean some
of the larger companies that don't have camps. They're in
both Johnson and Johnson being the obvious one in multiple
my Looma. If you thought forward, do you still see
them coexisting? Do they serve different patient types?
Speaker 4 (28:53):
Yeah, I think that there's a reality when it comes
to things like the cell therapy that this is. This
is a first foray in I think anybody there's a
drug developer would tell you that it's just a lot
easier to create a biologic.
Speaker 3 (29:04):
It just makes a huge amount of sense.
Speaker 4 (29:06):
So if you can capture the same level of efficacy
and durability of response, you'll want to move to a
biologic that can be mass produced and isn't fully atologous.
So I love the idea of working the biology out
in early stages in the cell therapy space, getting a
deep understanding of that, and then asking can we move
this to another system that's a lot easier to deliver?
Speaker 1 (29:26):
Right?
Speaker 2 (29:26):
So would that tells me if I again read between
the lines that if you can solve for all the
different things that you need to solve for when it
comes to redirection, redirections is a more desired way forward
than engineer T cells.
Speaker 3 (29:43):
Yeah.
Speaker 4 (29:43):
I again keep in mind what you want to achieve.
If your goal is really reaching everyone, then that's right
now with the current infrastructure that we have, it just
makes more sense to move to a biologic. So with
all the caveats, great news is we have a lot
of experience with biologic so we know things like ada
responses and things that could be challenges that we don't
generally see otherwise.
Speaker 2 (30:03):
Now, John, the next topic I have here is four
C and four D tumor metabolism, tumor micro environment, which
of course are intertwined. So just help us contextualize this
because you did do that a little bit earlier.
Speaker 1 (30:17):
On the tumor is an organ, right Is that fair
to say it's got its own little biology right for sure?
Speaker 3 (30:24):
Yeah, that's right.
Speaker 2 (30:25):
And it's not the normal place that a t sell
or immune system is supposed to be working.
Speaker 1 (30:31):
So just took us through what the challenges there are.
And we always keep hearing car T cells and T cells. Yes,
sure you can block this and improve that, but you
can't get them into the tumor.
Speaker 2 (30:41):
And that becomes the kind of big barrier, it's literally,
So do you want to talk us through where we
are on that and how you see this evolving?
Speaker 1 (30:50):
And do you see a future where, again with the.
Speaker 2 (30:54):
Outlock of three to five years, that we'll be able
to solve some of these issues By opening the door
to the tube, we're letting itselves in and to do
their job.
Speaker 3 (31:02):
Yeah, thanks Sam.
Speaker 4 (31:03):
This is you know, actually, I think that the immune
system certainly doesn't know that it's a tumor. You know,
it just thinks it's a happily growing part of you,
as they say. But it's also it is hugely metabolically
just regulated relatives to the rest of the tissue. And
the way that your immune system really it's your body
deals with this is it initiates a wound healing program
(31:23):
in many of these tissues. And this is this is
kind of the myloid environment that comes in and one
of the most important parts about healing a wound is
shutting off the inflammatory damage that's happening there. And this
is where these TJ beta axis comes in. I'll tend
the dentisye media suppression. All of these things are key
points to healing a simple scratch, for instance, that you
have and so that's the kind of signature that you
(31:45):
see in many of these solid tumors.
Speaker 3 (31:47):
You know, I was struck yesterday.
Speaker 4 (31:49):
I was at a meeting where I was reminded we
was looking at pancreatic cancer and it was a tissue
section and it highly multiplexed imaging, spatial analysis were almost
no tumor cells in that image.
Speaker 3 (32:02):
Almost all of it was this fibris.
Speaker 4 (32:05):
Tissue and stromal cells that were being called in by
the tumor in this massive TGF beta driven I eleven
driven tissue wound repair that was happening. And there were
t cells there, but they were locked in. They were
in this state that were completely surrounded by fiber stisue
and I think that's a common image that we see
in things like obviously pancreatic cancer, but also in things
(32:27):
like prostate cancer and other very very difficult cancers. So
the tumor is coordinating through the metabolic condition that it's
in as well as some of the growth factors this
incredible wound tailing signature around that. So I think the
first step is really try to understand what those are,
so it's not just targeting the tumor cell itself but
all the cells that are being called in around it.
(32:48):
So the key I touched on some of the key
axis one.
Speaker 3 (32:50):
Is the availability of glucose.
Speaker 4 (32:53):
So I could point to some wonderful work on a
Crystal Makos group at Stanford, but I think others have
been thinking about this as well. To improve car te
by actually transducing in glucose transporters, so they can actually
compete on a molecule by molecule basis with the tumor
for the uptake of glucose in that low micro environment,
and they see improved function there. And there are others
that are manipulating through crisper screens that identifying key regulatory
(33:18):
nodes in ammino acid biology, in epigenetic remodeling that allow
the car TI to function within that tumor micro environment.
So I do think that we can engineer our way
around many of these issues, but we really have to
better understand them, and so getting deeper into the immunem
metabolism I think is essential.
Speaker 3 (33:35):
You also said that there's sort of immune.
Speaker 4 (33:36):
Suppressive aspect of this because it's a wound healing signature
that's really there.
Speaker 3 (33:41):
I think it's a good way to think about it.
Speaker 4 (33:43):
It's in many tumors, these are coordinated with each other,
so that you know, the hypoxic micro environment is calling
in macrophages, these are being polarized a particular way. They're
responding to the tumor, but they're responding to other cells
that are around them. I think this is you know,
this may be an area, and I'm enthusiastic about this
where we have to actually take a much more aggressive
approach here. The key is to change the conversation between
(34:05):
the immune system and the tumor. So when I hit
the tumor with interfer on gamma through a car tee
for instance, or TCRT or an engager, I don't want
it to respond by upregulating PDL one. I wanted to
respond by you know, secreting aisle two at me or
something like that. And so I'm really enthusiastic about labs
that are starting to look at combinations of cell therapy
(34:26):
and tumor specific gene therapy where you're going in there
with oncotrophic viruses. You know, these are sort of first
generation akalytic viruses and aren't that lytic, but can actually
still get into tumor as well and actually change the
genetic circuits within the tumor to help them create positive
feedback loops, change that tumor micro environment, and really potentiate
(34:46):
the immune response you're trying to generate.
Speaker 1 (34:48):
That's a John.
Speaker 2 (34:49):
As you were talking, it dawned on me that one
of the problems that we face, you know, when you
told me about that tumor that pretty much had hardly
any tumor cells in it.
Speaker 1 (34:58):
A lot of these new th therapies, this is the
history of drug development in oncology. You tend to go
for third line or fourth line patients who.
Speaker 2 (35:07):
Probably have these enormously fibrootic tumors that aren't going to
respond to anything apart from you know, a laser for
you know, So, how do we break that issue? I
mean a lot of folks are going now more and
more accepting to go into the new adjuvant space, But
is the regulatory system Are we ready to be able
to actually test things where you have the much higher
(35:30):
probability of gaining access And then related to that, the
biology of a very early tumor, a few cells beginning
to form a metastasis, How sure are we because that
by definition, how do you know where they are?
Speaker 1 (35:45):
How do you study them? How do you solve for that?
Speaker 2 (35:48):
The fact that what you see is the tumor that
you can see, and the ones that you want to
get rid of are the ones that are going to
cause you trouble further down the road, especially with their
new adjuvant or adjuvancy.
Speaker 4 (35:58):
Yeah, absolutely so, this has been the universal problem in
all academic clinical trials. I think everybody for my entire
thirty years of doing this has talked about if we
could only move this to earlier stage before the immune
system is so racked by both the therapy but as
well as the cancer itself. And there is absolutely truth
in that. The response we know this if you you know,
(36:20):
it's the number one correlate when we look at a
correlative success and disease non progression on clinical trials is
the extent of metastasis, like the volume of disease that
you have. If you have less disease, you're just going
to do much better and you respond well. So there
is a systemic change that really does impact the immune
system heavily. So I think trial design is one of
(36:42):
the biggest things out there.
Speaker 3 (36:44):
I think it's almost tried to say that.
Speaker 4 (36:45):
Everyone everyone knows that if you design the right trial
and you hit something and say the relapse setting or
even in a NEO aadgunt setting where you can actually
come in and have minimal residual disease and monitor that, I'm.
Speaker 3 (36:58):
Loving some of those clinical trials.
Speaker 4 (37:00):
The downside is I think a lot of this is
left to therapies that have much much lower toxicity, you know,
like a vaccine or this is sort of the you know,
this is where this is actually happening, because you do
have to balance the risk rewards profile in that setting.
But I do really think that, you know, there's a
space here to do clinical trials, particularly if you start
looking at rare diseases. So there are universal suppressive things
(37:23):
that happen in things like rare sarcomas that are also
true in lung cancer. You know, I mentioned TJF beta
and egfr signaling and some of the metabolism issues that
you and I just talked about, these are true in
rare cancers too, So it may be an opportunity for
people to kind of step into that space early on
where there aren't really other therapies that you're heavily competing with,
and there aren't other options for some of these patients
(37:44):
to try to test therapies there. And I can tell
you that that community would be incredibly grateful.
Speaker 3 (37:49):
It's really tough.
Speaker 1 (37:51):
Yew.
Speaker 2 (37:51):
The next kind of again two related topics. That two
are antigens and cancer vaccines. So maybe you know, I mean,
do you believe there's a I think there was a
talk of about a year ago year in Africa a
renaissance of cancer vaccines. I mean they were they were
the first attempts that folks made at trying to kick
the immune system into action by vaccinating. Everybody knows what
(38:15):
vaccine is, right, So do you want to talk us
through where we are today in the cancer vaccine world
and where you think the success is going to come from?
Speaker 1 (38:23):
You just mentioned not so.
Speaker 2 (38:25):
Lytic on politic viruses approaches, We of course here on
a daily basis about the MR and a individual neotherapy,
new antigen therapy, et cetera.
Speaker 1 (38:38):
How do you think this is going to shape up
in the next four to five years?
Speaker 4 (38:41):
So I think I'm excited by it because you know,
we've cancer vaccines, as you mentioned, Sam, they've been out
there for a long time, neo antigen vaccines, tumor antigen vaccines,
and they've taken many forms. You know, they've taken viral forms.
Speaker 3 (38:55):
We've seen this with things like.
Speaker 4 (38:57):
Newcastle disease virus modified and others in the dendritic cell
space I mentioned before, where highly immunis stimulatory cells loaded
and readministered, but also peptide vaccines have been around for
quite a while. I think that there's some technological advances
that have really pushed this forward.
Speaker 3 (39:14):
I think the.
Speaker 4 (39:15):
Obvious one is this is a product of covid is
the RNA based vaccines, you know, with immunis stimulatory backbones,
where we're able to actually stimulate an immune response, but
also come up with a scale delivery platform in the
lipid nanoparticle to actually begin to build those responses out.
And so this has obviously caught the eye of the
big players in this field, with BioNTech, gene Tech vaccine
(39:38):
memorials on Kettering and those trials as well. Of course
the Mark Maderna trial that we're all eagerly awaiting but
looked looked.
Speaker 3 (39:44):
Really interesting in a mononoma space.
Speaker 4 (39:47):
But also I think, you know, we recently had a
nice paper out of Yale and our PISCE site at
Dana Farber in the renal cell carcinoma space showing some
really promising survival data with the vaccine. So I'm really
encouraged by where this is going, particularly because we're moving
away from what the NIH could fund, which is small
clinical trials where you always ended up with the same result.
(40:09):
It looked promising you know, we had some if you
could initiate a big potent response in an imenogenetic tumor,
you saw a beautiful response in the clinic. But if
you couldn't initiate that response or you couldn't maintain it,
then you saw progressions. So we're always left with this
seventeen to twenty percent efficacy that looked really promising. We
could never get funded for the next big thing and
could never get enough interest. Now you're talking about definitive trials,
(40:34):
whether it's the final vaccine or not, with mRNA based
therapies in well designed studies that you can actually look at.
Speaker 3 (40:42):
So I'm encouraged by the outcome.
Speaker 4 (40:44):
I think the entire field is going to pivot to
a large degree based on how those large scale trials
play out.
Speaker 1 (40:50):
Yeah.
Speaker 2 (40:50):
Well we're both going to AACR, so hopefully we'll see
some new developments there. I'm aware of a couple of
interesting data sets that are going to come out, looking
forward to seeing those.
Speaker 1 (41:01):
So in general, let me summarize here again.
Speaker 2 (41:03):
You are optimistic about how kinds of vaccines are evolving,
and specifically the RNA. Let's hope that they hit I
mean they're doing the right, trials, Right, that's for.
Speaker 4 (41:13):
Sure, That's all we can really ask for at this point,
you know, Sam take a step further though, when it
comes to vaccines again, I think that when we see
efficacy in a hurt car T trial or something like that,
we see a patient that responds. None of this response
is because the tumor. You know, tumors can downregulate and
they're highly heterogeneous. The long term, durable response that you're
(41:36):
looking for, as we talked about, really requires initiation or
the rest of the immune sytem, which you really get
get it going. And this is probably true you know,
for radiation and many other things too. It's about creating
an anti tumor immune response that sees multiple epitopes, that
engages things like gamba delta T cells, that has an
answer presenting cell. And the reason we say this is
(41:56):
that the big correlates are things like tertiary lymph node
structures that are formed around the tumor and they're really
the sites of epitope spreading and priming against other tumor intigens.
And once you can catch that fire, this is really
where you see this feed forward response. So you know,
I don't want to say everything is a vaccine, but
that's really what you're trying to accomplish with CAR therapy,
TCL engagers, all of it. So because of that, I think,
(42:19):
even if you know you can make the argument and
this is a trial for the future that we need
to do is first thing you want to do when
it comes to something like sequencing, and this may be
something that Memorials start doing because they have all the data,
is get a neo engine profile of every tumor that
comes through the door, all of them, and start with
a very safe vaccine, very low toxicity, easy, and that
becomes the foundation for immunotherapy that happens afterwards.
Speaker 3 (42:41):
It's not about the epicy of vaccine.
Speaker 4 (42:43):
It's about setting up the efficacy of every other immintotherapy
checkpoint blockade, CAR T therapy, TCR engagers that you're going
to receive downstream for that solid tumor. So I cross
my fingers for the large scale trials, mostly because I
see the future of foundational vaccines really as forming that
that basis for all immunotherapy.
Speaker 5 (43:03):
Right now, obligatory question of PD one version by specifics
sure or PD one veg of by specific in a
year's time, will we still be excited because it's definitely
called people's imagination.
Speaker 1 (43:15):
How do you feel.
Speaker 4 (43:17):
I'm a fan, so I'm a fan. So I think
there's there was a lot of skepticism out there.
Speaker 3 (43:21):
I don't know if you were skeptical, but I.
Speaker 1 (43:23):
Think I think I've come.
Speaker 2 (43:25):
I've got over the idea that it's not just about vegion, sure,
but it's about the bispecific action there you go, yeah,
and that you can get a different outcome if you
have the molecules together. And I've also got to understand
that that Jeff, is a I mean a suppressive, it's
a checkpoint almost.
Speaker 4 (43:42):
Yeah, it's a it's part of a wound healing signature. Right,
this is it you need to grow blood vessels and
it's it's part. It's a key molecule within that that
tumor wound healing signature that we talked about. I think
that you know, one one key point with this and
and they you know, the Summit group actually made this
right away, but I don't know that it really caught
on as well, which is that really what you're doing?
(44:02):
You know, the tumor cells that are there in the
immune systems there. We talk a lot about micro environments
within the tumor, right, But we don't really think what
that means. You know, the tumor doesn't care what the
concentration of vegef is in your toe or at the
tip of your nose. It's the only that really matters
is the concentration that's local right within that tumor micro environment.
And with this PDL one vedgeff does, it creates a
(44:23):
massive trap right where you want it and completely depletes
the vedgeff that's there, as opposed to systemic depletion. So
I think that this is this concept of microvine is
being captured by the Summit molecule, and it's one that's
caught fire. Now we've started to think about local concentrations
and not systemic suppression.
Speaker 2 (44:40):
Now, I was going to ask you about the environment
for science in the US, et cetera, but I think
we leave that because that's another podcast. But I do
want to hear from you if you have one or
two or three clinical trials which you're excited for seeing
the result of, not necessarily that you know it's going
to be positive, because if you did, we should all
(45:01):
come on investing you.
Speaker 3 (45:02):
Yeah, right, what a the off top of you, I've
got a couple.
Speaker 4 (45:07):
So one, of course, I think is the Mark Maderna
trial because I think it's the right trial, and I'm
not super thrilled about the construct that went in and
and even some of the approaches for neo antigen, but
the fact is just a fact. I think the field
is going to the vaccine field is going to pivot
on that that the results of that clinical trial to
a large degree. I mean, the true believers will keep going,
(45:28):
but it has the potential to really light a match
under under these studies. The same is actually true I
think for the BioNTech gene Tech trial as well, simply
because these are you know, there's a huge need in
the in the cancer space.
Speaker 1 (45:40):
And there you're referring to the new antigend.
Speaker 2 (45:42):
Yeah then yeah, sorry, the edge of the trials the
management and then correctal cancer.
Speaker 4 (45:48):
Correct cancer exactly. So really excited by by the results
of those, simply because you'll rarely do you see an
entire field of you know, thirty plus years of research
pivot on a single important trial that we've all been
waiting for.
Speaker 3 (46:01):
So I'm excited by that.
Speaker 4 (46:02):
And then you know, I mentioned arsenal bio earlier This
is an example of I think one of the most
advanced car te therapies that's out there. It's really a
test for what synthetic biology can do in cell therapy.
I haven't seen a more complex but also more well
thought out.
Speaker 3 (46:18):
And executed car tee.
Speaker 4 (46:20):
If you know the results of that RCC trial at Arsenal,
as it goes out, I think is again going to
it's going to change the field.
Speaker 3 (46:27):
So if the try and I have no knowledge how
it's going.
Speaker 4 (46:30):
So if it goes one way, it's going to be fantastic.
If it goes another we should probably look back and
ask maybe we should be.
Speaker 3 (46:35):
Thinking a little bit more about vivo CARTI brilliant.
Speaker 1 (46:37):
Thank you very much. John. This has been great.
Speaker 2 (46:39):
It's been at a very high pace and I did
We did touch a lot of things that I'm hoping
that this is going to be one of those podcasts
that a lot of people have to listen to twice.
Thanks the amount of information we talked about. But I
appreciate your time as always, your depth of knowledge, and
I look forward to seeing you at AACR.
Speaker 4 (46:59):
Thanks Sam, Thank you very much. This has been great.
Host
Jonathan Palmer
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