NorthWest Biotherapeutics Inc (NWBO)

[Hbpainter]

Dodgy Transcript of Linda Liau's Talk:

https://youtu.be/Yyihecx6gDo

ll right so we'll go ahead and get
started and then let everyone continue
to join
uh so good evening everyone today it is
my honor to introduce dr linda liao who
really needs no introduction but i'm
thrilled to recount her many
accomplishments for the group anyways uh
dr liao is currently professor and chair
of the department of neurosurgery at the
david geffen school of medicine at ucla
where she is the co-director of the
brain tumor center pi and director of
the nci designated brain tumor spore as
well she's had a truly remarkable career
starting with her undergraduate studies
in biochemistry and political science at
brown where as a fun fact she was named
by time magazine as one of the top 100
college students in the united states
which i didn't even know that list
existed but that's wonderful she then
ventured to warmer climates receiving
her md at sanford and a phd in
neuroscience at ucla dr liao then
completed her neurosurgical residency
and a fellowship in neurosurgical
oncology at ucla after which she joined
the faculty with a rapid acceleration in
her clinical and research pursuits she's
had continuous nh funding for her work
over the past 25 years which focuses on
translational immunotherapies for brain
tumors and biomarkers
she's very well known for pioneering
dendritic cell-based vaccines for
glioblastoma and has really helped to
launch the investigation of immune-based
therapies for glioma in our field
in a real testament to her contributions
to science she was elected to the
national academy of medicine in 2018 and
her work has resulted in over 200
peer-reviewed papers chapters and a
foundational textbook
she's on innumerable scientific
committees and boards leading our field
both nationally and internationally
she served as editor-in-chief of the
journal of neuro-oncology from 2007 to
2018. also serving first as board
director of the american board of
neurological surgery and then becoming
its first woman chair from 2019 to 2020.
during this time because of course she
was not busy enough she also received an
mba from ucla going on to become a
tenured professor of neurosurgery in
2007 and chair of the department in
2017. she's mentored dozens of medical
students residents postdocs and junior
faculty really leaving an indelible
impression on the next generation uh dr
liao represents the rare triple threat
in our field and has further been a real
trail blazer for women in neurosurgery
and neural oncology dr liao we are just
so delighted to have you here today well
thank you so much for that very kind
introduction thank you so much for
having me um
it's uh really nice to kind of see um
kind of some of the some of my old
friends at least on on the zoom name
screen and
um it's really a pleasure to be here um
so uh
today i'm just gonna i'm gonna talk
about targeting immunotherapy-induced
resistance and glioblastoma and um
what's a little bit different about this
is you know we've talked a lot about you
know resistance to treatments um and
there's certainly resistance mechanisms
chemotherapy
but uh now we're learning that
there's actually resistance that occurs
from our therapies basically our
therapies are causing these tumors
to uh create
even further uh resistance to to uh to
treatments
and um
and when i started in this field you
know almost 30 years ago i thought we
would have a cure to gbm by now
but unfortunately we don't and i think
the the complexities of this disease are
just um
uh
you know getting uh
just now getting to be better elucidated
so um
i'm gonna just uh let's see
if i can move forward
so
oh these are my disclosures
and then um so just as an introduction
uh
in terms of fda approved treatments for
glioblastoma um as we all know you know
radiation and chemotherapy is still the
standard care for this treatment
radiation has been around since the mid
70s
and um really nothing happened for about
20 years um the only treatment available
to our patients was radiation and
surgery
bcnu and ccnu was fda approved at the
time but the clinical trials really
didn't show any added efficacy uh over
radiation so for about 20 years or so
radiation was
was the treatment um um actually for
about 25 to 30 years that was kind of
the main mainstay of treatment
um you know in the late 90s uh then the
gliado wafer was approved and then as
was temozolomide and then in 2005 with
the stoop protocol the standard of care
for glioblastomas uh it became radiation
with concomitant temozolomide and and
really that's kind of been the standard
of care for the last 15 years and
there have been a few other things that
have been fda approved before the system
for recurrent jbms and then the
tumor treating fields the optune device
but other than that really nothing
has been fda approved for uh for many
decades for this disease and that's not
for lack of trying
um and
as a uh
you know uh a comparison uh in the last
five years there have been over 50 uh
cancer immunotherapy drugs approved for
glioblastoma none yet for
for other cancers but none yet for
glioblastoma and then yet for brain
cancer and and these are all the
different cancers where there are now
immunotherapeutic drugs that are
available for patients um even
pancreatic cancer i mean in some small
subsets of pancreatic cancer there are
some drugs that are fda approved for
these very small subsets of patients
um so what what is making glioblastoma
so difficult uh to treat uh in
you know particularly with uh with
standard treatments but also with
immunotherapy
um
and again it isn't for lack of trying uh
you know as as you know many uh
checkpoint inhibitors have been fda
approved for other uh cancers and there
have been several large clinical trials
of uh checkpoint inhibition for
glioblastoma and this is one of the uh
you know the initial ones uh nivolumab
versus specific patients with current
glioblastoma
we're currently a blessed german as you
can see the the two survival curves are
essentially the same
um and this was published in you know
just a little over a year ago
um and you know in uh i guess true form
we always hear about these trials from
the uh the uh pharma companies
oftentimes before they actually get
published so that trial that uh that was
published in jam on colleges checkmate
143 that was just
alone and then there's also been
checkmate
498 that's an ebola map with radiation
and then the wall back with the volume
and these are still
um
these are trials that uh you know
unfortunately have not reached their uh
primary endpoints but there are now you
know different combinations of these
types of checkpoint inhibitors with
other treatments
so um
you know and for a while you know it's
thought that perhaps you know
immunotherapy you know at least
checkpoint inhibition wasn't a you know
a viable treatment for uh for
glioblastoma
um but then you know a couple years ago
uh this paper from uh from
our group at ucla as well as you know
patrick lynn at
the brigham um
as well as some other groups that have
kind of published similar studies showed
that perhaps it's the timing of these
treatments so this is a paper that
showed that if you gave
anti-pd1 inhibition neoadjuvantly
meaning before surgery there was some
increase in survival
in these recurrent glioblastoma patients
um
and granted the numbers are very small
we're talking only about 16 patients
there's 19 patients in the other arm
there it was a statistically significant
difference um and interestingly the um
this was one of those window of
opportunity studies so we actually took
the patient's tumor samples after uh the
um
administration of neoadjuvant uh
anti-pd1 inhibitors and then looked at
uh you know uh um
immune signatures and there was an
increase in gamma interferon uh
signatures uh in the um
um in the neoadjuvant group versus those
who did not get neoadjuvant vampirism up
suggesting that
an upregulation of the interferon gamma
pathway may play a role in this
but um
at around the same time there are other
studies that came out that suggested
that um if you give pd-1 blockade in a
subprimed setting basically the t cells
are not yet primed against your antigen
you can actually induce dysfunctional
uh
pd1 positive cells and and and and
anti-pd1 resistance so actually
it's count you know basically makes uh
makes the tumor um more resistant to
immunotherapy if you actually uh give a
checkpoint inhibitor without activating
the t cells and that that's always been
a problem with glioblastomas it's
actually an immunologically cold tumor
for the most part you're not you know
many studies have shown that although
yet there are some t cells in
glioblastoma there aren't very many
and perhaps the um the results that
we're seeing with neoadjuvant treatment
of
uh of these uh tumors is that
for those patients that have t cells in
the tumor you are perhaps able to uh
induce activation or of those t cells
against the antigen
however this would suggest that if you
have a subprimed t cell
the the
use of a checkpoint inhibitor may
actually make your um tumor even more
immune resistant
um and then some work done by uh rob
prinzen in our group at ucla
what he found was that in glioblastoma
patients uh the expression of pd1 by t
cells uh in in in these tumor samples
actually uh reflect uh exhausted t cells
and this is just a study looking at
different uh markers of t cells they're
the activated t cells they're the um
um memory t cells the activation t cells
and the exhaustion t cells and in
glioblastoma patients uh both in the um
well mostly in the tumor infiltrating
cells most of those cells are are
exhausted or in that path to exhaustion
so
so the the question is well how do we uh
perhaps revive those t cells that so
that they can be tumor specific and
actually attack uh you know attack these
tumors and and really drive this to the
memory t cells which is actually what we
want um and uh patients do have memory t
cells in the periphery but these t cells
are just not getting in uh
into the tumors when they're you know
infiltrating into the tumors
um
so um
to that
regard we went back and looked at um the
basically the tumor samples from the
patients that were enrolled in this in
the neoadjuvant pd1 blockade trial
and looked at their tumor infiltrating t
cells and then comes to see well
what was found was that these patients
um you know perhaps had an increased
survival there was an increased
interferon gamma signature in these
tumor samples and then uh the the
question the next question was well
what's going on with those t cells so we
uh so from the resected tumor tissue
um
uh we isolated the cd45 cells and then
did scitov mass spectroscopy or
single cell genomic sequencing
and what uh and muscle's work was done
by uh you know rob prince and uh and his
group uh
along with uh the people
working um in uh in our labs
collectively um
and this actually was part of our spore
project um as part of our ucla brain
cancer sport but what we found was that
the um neoadjuvant anti-pd1 treatment
um
it did increase the uh
perhaps the number of t cells but these
t cells were actually
uh progenitor like exhausted t cells
they actually had exhausted t cell
markers uh
for instance in this cluster this l4
cluster here as well as these there's an
increase in t red cells which are also
immunosuppressive t cells
so
um i guess as a a feedback mechanism
that these tumors kind of uh probably
would were um expressing was
that when we treat it with these
anti-pa1 inhibitors
these teeth it actually drove these t
cells further to uh exhaustion
and that could be one mechanism for uh
for resistance because if you have t
cells that
you have a number you know small number
of t cells in the tumor perhaps you are
increasing the the activation of those t
cells but then you're actually
um over stimulating them to a point of
exhaustion that they can't really attack
the tumors
but actually the the the bigger
immunosuppressive effect of antipedin1
therapy or immunotherapy prior
um
uh to uh
t cell activation is this uh
infiltration of immunosuppressive
macrophages and myeloid cells
so
what we found was that anti-p1 treatment
in a population of patients induces
upregulation of immunosuppressive
macrophages and myeloid cells so even
though you you're getting more t cells
in and perhaps the t cells are more
activated
you know the t cells may be getting
exhausted
and then on top of that you're
recruiting this whole population of
immunosuppressive cells that are
actually coming in to
uh fight the t cells so there's really
this kind of battle going on in the
tumor
microenvironment that is actually
induced uh by applied by our treatments
and so i think
in order to really uh get effective
treatments for glioblastoma we really
need to understand what our treatments
actually cause and and the timeline for
that you know when when when the tumor
you know when certain treatments should
be given
to mitigate some of these uh
immunosuppressive responses
so how do you get more t cells into the
tumor so because that's really uh and i
still believe that is the first step the
problem with
um
and probably one of the reasons that
immune checkpoint inhibitors don't work
as a single agent for glioblastoma is
that we don't really have a lot of t
cells in the tumor
and even if they're in there they're
exhausted um so you really need to
recruit new t cells from the periphery
because um as i showed in the um in this
slide here
oops
the
glioblastoma patients do have memory t
cells and activated t cells in the
periphery but how do we get them into
the tumor
um so
uh one of the best ways to actually get
t cells into the tumor is is through
active vaccination um
and uh and this was actually um work
that i you know did as part of my you
know my my first uh koa award many many
years ago and what uh we were the first
group to find that with vaccination we
could actually get t cells to cross the
blood-brain barrier and go into brain
tumors um i didn't realize that at the
time but apparently no one else had
found this uh before this point
um and it was because at the time
it was thought that the uh the the brain
was immune uh immune privileged so that
there was no uh way to get activated t
cells or at least tumor specific t cells
to migrate from the periphery
into brain tumors or at least it's not
that that doesn't happen now of course
people know that it does uh and it
actually happens in several different
pathologies besides brain tumors um as
well but uh but now you know but now i
think we understand that there are ways
to get t cells into tumors either by
active vaccinations sometimes you know
oncolytic viruses
um do that as well as you know you could
actually just give adoptive therapy of
of car t cells or other types of t cells
directly into the tumor but the first
step needs to be getting those kind of
fresh
non-exhausted t cells into the tumor
um and then
once uh and the those initial studies
that we did using dendritic cell
vaccination for instance uh did show
that t cells got into the tumor and then
uh we did see some increased survival
uh in uh patients in the early trials um
particularly in patients with uh the
mesenchymal subtype of glioblastoma
and uh and these studies subsequently
led to other phase one phase two and and
uh and phase three uh clinical trials
which um i'm not gonna talk about
uh in this talk but what i wanted to
focus on were the resistance mechanisms
that we learned uh from from all these
studies uh over the years um so as i
mentioned you know this was a paper we
published 10 years ago
what we found was that when we used um
dendritic cell vaccination the
mesenchymal gene expression signature
was associated with the increased tumor
tumor infiltrating lymphocytes and we
often see this in you know increased
contrast enhancement after treatment
which subsequently went away on its own
and in these patients
when we were able to get the post
treatment specimens we saw um you know
this kind of large infiltration of cd8
cell t cells which you know what wasn't
uh
visible uh or we didn't see in for
instance the pro-neural subgroup of
glioblastoma patients
so this mesenchymal subtype tends to be
more
immuno-responsive you know these uh it
tends to uh
react more to immunotherapy in the sense
that you could get t cells into these
tumors
so um
we then went to look at well what kind
of you know
what can we do to make glioblastomas
more immune responsive to you know help
turn these kind of relatively cold
tumors to more hot tumors
and uh some adjuvants that could be used
are things like toe like receptors
tlr's
recognize pamps pathogen-associated
molecular patterns and it's really an uh
you know an important uh
element in the innate immune system
and there happened to be you know for
instance uh fda approved tl7
agonists uh there's a drug called uh
amico mode and recyclamod
that's been fda approved for warts um
and then tl3 agonist uh there's a drug
called poly iclc that's been used in the
past for glioblastoma and clinical
trials
it actually was negative as a single
agent
but um but i think in combination with
vaccination or with some sort of t cell
activation signal these uh tlr and
agonists could be of benefit
so we did a very a small clinical trial
to test that we looked at
um a group of patients who just got that
well that well all these patients got dc
vaccination so we looked at a group that
got dc vaccination plus placebo dc
vaccination plus poly iclc which is a
tlr3 agonist or dc vaccination plus a
mechamod
and what we found was that um
with the tlr
agonist the poly iclc there was an
increased
um uh
effector uh
effector pd1 positive t cell response so
and uh and there was also an increase uh
you know
number and and activation of uh
t cells
uh suggesting that that this particular
uh
uh adjuvant was was
driving these cells more towards
activation and less towards
the
immunosuppressive phenotype
um and we also looked at this with a
single cell sequencing again looking at
the t cell cluster
showing you know drive of these t cells
to active memory t cells
as opposed to the um
the more kind of naive
anergic t cells
and
we did uh gene expression profiling and
then
and showed that this particular group
that got treated with the poly iclc
actually both the groups that got
treated with poly iclc as well as were
recycle mod they did show some changes
in myeloid cell differentiation uh gene
expression patterns as well as
lymphocyte gene expression patterns more
so in the poly iclc group
than the um
than the recipromite group
and they that these these adjuvants
really helped to elicit a very strong
type 1 type 2 interferon response
um
and then what was even more interesting
was that uh with poly iclc actually the
patients live longer um
this particular group albeit the the
numbers are very small again um
there but it was statistically
significant uh the group that got
dendrite cell vaccination plus poly ice
celsius uh had a 50 survival rate and
now we're you know the majority of these
patients are reaching 100 months
uh and uh with
not only survival but but really um
no tumor recurrence so it does suggest
that there is some um
added benefit uh to adding these um
these adjuvants to to
t cell activation signals
and
as i mentioned i think one reason that
single agent checkpoint inhibitors
aren't working in glioblastoma
is because the t cells are not getting
in and what we do know is that uh
at least in
in our animal studies and and several
other studies is that you do need an
activation signal to get the peripheral
t cells to go into the brain tumors um
sometimes we already see uh
glioblastomas with t cells so there
probably was some activation signal that
got those cells in there but for the
most part the majority of these tumors
don't really express a lot of activated
t cells but the dendritic cell
vaccination is able to get these t cells
infiltrated into the tumor and these are
just uh schematics of of what what
happens
um if you just use the anti-pd1 antibody
alone we don't really see a
significant increase in t cells in the
tumor
if you use the dendritic cell
vaccination we do see increased
t cells into the tumor
but uh but in terms of if we combine the
two then we we see not only increase in
numbers but also the increase in uh
perhaps percentage of activation uh
signals and activated t cells um
so
so the the
thought is that uh you know again
pd when blockaded alone uh did not show
a response in our uh animal models
uh if we gave the dendritic
self-vaccination alone we did see a
response to some of the animals but it
was uh not in all of the animals
and uh part of that was because the
the percent of t cells that were
activated was relatively low
compared to when we actually used both
agents alone
however
what we also found um was that
in when we used um dendritic cell
vaccination plus pv1 inhibition
uh again you get more t cells into the
tumor but then you also get a uh a yes a
compensatory migration of these immune
suppressive cells
uh that are actually coming in from the
you know
from the periphery to try to basically
suppress that immune response that is
being activated by the activated t cells
plus checkpoint uh inhibition
um
so uh
so our uh
you know initial uh
clinical trial that we started uh as
part of our spore five years ago
was to look at
um basically
the effect of
neoadjuvant pd1 blockade with dendritic
cell vaccination this is a group of 20
patients in each arm and then uh we the
the end point this is a window of study
uh window of opportunity study so then
point was really to look at the tumor
tissue uh after the neoadjuvant blockade
and then also look at overall survival
in the group that got a
dc vaccination plus uh pd-1 blockade
versus the group that got dc vaccination
plus placebo
um and uh this this study is still
ongoing so i don't have the results of
this study yet
we actually um
after all the pre-clinical studies and
ind enabling studies who got fda
approval in november 2019
uh the trial opened in 2020 but had some
fits and starts because of covid um but
we've already enrolled 20 patients we're
halfway through so anticipate we should
have the results of that study uh you
know in the next year or two
but one thing that was interesting you
know in some of these patients um was
that just like we saw in our animal
studies we
saw an enhanced immune response
with
autologous tumor lysate and uh
and the antip one uh antibody
but uh
we we saw this uh very
actually very profound immune response
in in some of these patients very
similar to like the um
uh the side effects that you see in
people who have gotten you know cartier
therapies um so you know this is an
example of one particular patient he got
the uh autologous tumor lysate dendritic
cell vaccine plus pembro
uh as part of the trial
at the window of opportunity trial we
did surgery took out his tumor
uh
he
you know he clinically did better we
were measuring uh crp and other kind of
you know immune
or inflammatory markers that actually
went down
and then um
subsequently uh he
he had uh
injections of of his uh subsequent
injections and every time he had an
injection
these markers went up
uh to a point where um in this
particular case he was getting so much
inflammation that we had to treat him
with uh an il6 inhibitor of toaster
leucine and then eventually we were able
to control the inflammation with
bevacizumab
but
in this particular study this is
actually a patient where his post
uh you know pembroke vaccine treatment
caused so much inflammation we had to go
back in and resect some of the tumor
tissue um and what we found was uh was
actually quite interesting um so
following just neoadjuvant pd1 uh
inhibition we saw increased uh t cells
this is a cd3 t-cell marker the red dots
are t cells
um but then when we you know when he had
the vaccinations with the pembroke um
pembrolizumab he had increased t cells
and this is probably what led to some of
that inflammation that he had
that required subsequent uh debulking of
the tumor so but this this actually
probably was not the the uh
i guess the reason he had so much
inflammation
it was probably because in addition to
the t cells coming in
um he had uh after
immunotherapy there was a huge migration
of immunosuppressive myeloid and
macrophage cells
so even though we there are the red
cells the t cells getting into this
tumor there is this there are these
immunosuppressive cells that came in and
really there's this battle going on in
the brain between the tumor cells and
the t cells and then this new population
of
of myeloid cells that were actually
induced by the immunotherapy because we
don't actually see this
uh as much in people who didn't get the
neoadjuvant pd1
inhibition so um
so this is kind of uh you know what what
it looked like so this was the initial
surgery where you know the patients only
got the pd1
um antibody and uh and there was you
know some increased
uh
um
the tumor cells are in blue the the t
cells are in red and then the green
cells are the immunosuppressive
macrophages and then after the
combination treatment you could see you
do get more of the t cells which are the
the red cells but many many more of the
green cells
so
this this whole
lesion was actually being overcome by
the these green cells the green cells
the immunosuppressive macrophage has
actually outnumbered even the tumor
cells
uh and the t cells
so
um
and and this is you know this is these
green cells are fighting the the red
cells and over time it allows the blue
cells the tumor cells to outgrow this
population
so
that led to kind of our the design of
our upcoming clinical trial because i
think it's it's not going to be enough
to
just
you know what we do know is it's not
enough to just use a checkpoint
inhibitor you need to get the t cells in
so uh so that's why we combine the
activation signal the vaccine plus you
know to get the t cells in plus the
checkpoint inhibitor but then as a
result of that we get this uh
compensatory or response whereby
um immune effect that combination of
immunotherapy creates
this uh
huge influx of these myeloids um
macrophage tumor suppressor immune
suppression of cells so this next uh
trial is is really a combination of
dendritic cell vaccine plus poly iclc to
do
activate that danger signal that innate
immune response
immune checkpoint inhibition to to
really block the immune checkpoints and
then csf inhibition which actually is an
agent that blocks that those screen
cells those myeloid macrophage cells and
that's kind of the the upcoming trial
design and uh this is
you know the
the uh
the design where we're gonna try to um
add add those uh other components to
to this uh uh
current uh pd1 uh plus
um
uh dendritic cell vaccine trial
um one other thing that i think is
lacking in the field is uh
is the ability to monitor response or or
to actually have biomarkers to determine
which patients will have a response um
and one thing that we've been looking at
uh over the years is the um
i guess the use of tcr uh you know t
t-cell receptor sequencing and the old
overlap of tcr sequencing um
uh antigens you know the antigens for
which these t cells are responsive to
um to look at that overlap between the
peripheral blood and the tumor because
if if you can imagine if
the there is
the the peripheral blood has
antigen specific t cells that actually
can get into the tumor that match the
antigens within the tumor then the hope
is that there will be this kind of
perpetual
replenishing of t cells from the
periphery that could get into the tumor
and attack the tumor rather than have
relying on the infra tumor t cells which
uh as we have shown are for the most
part you know tired and exhausted and
get even more tired and exhausted when
you give people inhibition
so um so this is you know a potential
blood marker that we could uh
potentially monitor
uh over time to see if there was any
response to immunotherapy in our prior
dendritic cell vaccine trials what we
did find was that people who had a high
overlap
um pre-op and a high overlap post-op for
the most part they all have very good
responses meaning long-term survivals of
of more than five years or so and people
who had low overlap before treatment
there was a group where
they they were able to have high overlap
after treatment um some of those had had
very good responses and some
did not and we're still trying to figure
out what dictates
uh the difference between those that
respond and those that did not and then
if you're you don't have any overlap
either before or after treatment for the
most part we're not seeing the t cells
uh
you know expanding that will will
actually attack the tumor antigens in
the tumor and those tend to have poorer
survival
um
so i'm just going to spend the next you
know a few minutes just uh
talking not so much about the science or
and and the immunology um but but also
about but more so about the the clinical
trial design and uh and this is actually
the other reason i think we are we don't
have any fda approved treatments for
immunotherapy right now
um as i mentioned the there's the
science behind it because there's the i
think the need to
uh use combination immunotherapies and
combinations in the right order and the
right uh rationale
uh for using these treatments and uh and
that's certainly a big part of kind of
the um the bottleneck that that we're
having in in the field but i think
another um
a
problem with uh
with getting these these you know
treatments to patients is really the
clinical trial design and as as many of
you know um there are challenges to
randomize clinical trials uh
particularly in glioblastoma and it's so
hard to get now patients who want to be
the placebo arm of any trial uh you know
and uh and that you know becoming more
and more difficult uh you know for for
these larger phase three trials because
you know most patients would rather
go to a phase one or phase two trial
where they're actually guaranteed the
treatment even though it hasn't shown uh
efficacy in those early phase studies
so patient recruitment and retention is
difficult uh there is a lack of active
treatment you know um
the lack of an active treatment arm in
the control arm does you know
have some ethical uh issues as you can
imagine to really keep patients on these
trials when they you know that they're
only getting the placebo
um you know and glioblastomas are rare
they're it's a heterogeneous disease
compared to other cancers and the
numbers uh that we need to do these
trials are are just not there and then
given the heterogeneity and the sub
stratification
uh that you know you need to uh
have in order to show efficacy even in
small subgroups
uh that that's just incredibly difficult
and not only is there stratification of
the tumor there are also characteristics
of the host and the host response that
you know i didn't really talk about but
you know the host um
also plays a role in this heterogeneity
and then you know as i mentioned we have
of the lack of biomarkers for for
response uh to to a lot of these
treatments and then by the time you
finish a trial there's rapidly
progressing new knowledge uh that could
change the the the course of how you
evaluate um
treatment response for instance what you
know and uh a lot of the way we evaluate
treatment responses by imaging
and uh and as you know that that has
changed over time as well
um
so
there is more of a movement towards the
use of external control arms
and uh this has been you done in other
fields
outside of brain cancer and you know for
other cancers and and i think it is
gaining popularity and it's something
that i think our field really needs to
consider uh
more deeply simply because of the
problems
with you know getting uh
good data from randomized controlled
trials and keeping patients on these
trials
so um
and this is just a schematic uh that
that was uh you know that shows how some
you know some of these trials can be
designed whereby you use external data
with some propensity matching and you
know get your kind of
virtual treatment versus control arms
um
there's there's actually some guidelines
in terms of you know quality checks for
what what would serve as
kind of good data sources for uh
selection of external control arms and
many of these um you know have to do
with like for instance getting data from
large well-controlled randomized
clinical trials because the database and
the
data collection is is relatively good in
these larger kind of well-controlled
trials
you know you have to look at the
similarity of data sets some synthetic
control methods
um as well as the relevance and
reliability
and um and i'll talk to touch a little
bit about that on that a little bit
later
but um but so so with that in mind i
mean if you just look at the um for
instance the last you know seven seven
to ten years
um there have been several large
randomized control trials that have been
done for newly diagnosed glioblastoma
and many of these trials have control
arms
so
so this is the so this is the control
arm in in these studies so there's you
know in this particular study there's
411 229 it
if you add all these control patients
all these control patients got the exact
same thing they got radiation and
temozolomide the stupid protocol so
you're you know if you just look at
these controlled
patients you already have
1300 control patients who got the exact
same thing and if you look at the
control the kaplan meyer curves of these
trials
they
they absolutely overlap um so
so
you know one question is do we need to
do another
you know do we need to have control arms
for all our future clinical trials will
enroll another thousand thousands of
patients onto the control arm if we have
a robust data set
that shows pretty much the same uh
survival among all these patients who
got temozolomide and
radiation
um
and uh you know one
uh
thought was that well how uh i guess how
how rigorous is the use of uh of
external controls would
a study that a a true randomized control
study that was negative be
erroneously
um i guess
statistically tested as they or come out
as positive when we use these external
control arms so this was just an
exercise that showed um you know for
instance the um
the cell death study with rinda pippa
matt and temozolomide using that as
the experimental arm and testing that
against the all these external controls
that trial actually turned out to be
negative as you know similar to what the
con you know the controlled study showed
as did dose dense temozolomide the only
trial that actually was positive in this
comparison was actually the um the tumor
treating field study which actually was
also positive
when uh when that um when the actual uh
randomized control trial was done
um
and then you know when we think about
randomized control trials as i mentioned
there's the issue about you know having
patients on the placebo arm
um and uh and then the ability to to
really kind of you know uh
rigorously do this in a in a such a
heterogeneous population of patients
such as those who have glioblastoma
um
another consideration is that well are
these randomized control arms really um
reflective of the real world
you know population you know what we do
in the real world for our patients
and uh and one thing that uh that knows
you know in the data
you know from pulling the data from
these uh trials that have been done over
the last decade or so
the majority of these patients that were
enrolled in these trials you know up to
94 i mean 87 was the average
87 of these patients were white
um
so
we really are lacking in diversity uh in
in our you know randomized controlled
trials at uh in neuro neuro-oncology in
our academic centers
so that's something that i think we
really need to think about more deeply i
mean is
one um you know our randomized control
trials the best you know
way to test new therapeutics
even if it is scientifically
is it the best representation of what we
will actually do
um you know clinically for for our
patients because
the representation in these trials is
really not reflective of what our real
the real world is um at least not not uh
not in los angeles and new york i think
so in conclusion um you know things to
think about uh how to accelerate the
translation uh and clinical development
of nucleoblastoma therapies i i think we
need to develop better immunocompetent
animal models that better recapitulate
tumor and host heterogeneity because
heterogeneity is still a very big
problem um with uh with the studies that
we do in this for this disease
um we have to consider timing sequencing
and the role of surgical resection in
combination immunotherapies and it's not
just a matter of throwing everything
together at the same time i think there
is uh
you know
some thought that needs to be put into
how the how the immune system works with
the how the immune response works and
what you know how to time
the the combination treatments to best
fit that
we need better biomarkers of response
whether it be tumor or blood or csf
biomarkers uh oh and or and or imaging
biomarkers that could actually look look
at
response to treatment or stratify
patients that would respond to certain
treatments uh non-invasively
um and then you know
these previously large randomized
controlled trials have been done in
glioblastoma it would be good if these
uh trials uh release their data um so
that it could be mined for
uh external controlled propensity
matching
and uh and also i think um
the you know more of a movement towards
the use of external control arms for
registration on our trials or even going
on to
phase four trials uh with real world
efficacy as opposed to
having this kind of step-wise
progression from you know from very
strict randomized controlled trials that
um
you know
could get to publications and fda
approval but aren't really being used in
the real world because they're just not
either not practical or not reflective
of the population that we're serving
so with that being said um i just wanted
to end with um
kind of a an overview of our brain
cancer spore at ucla
um the theme of our overall sport is
targeting resistance and what i talked
about today was just project one it was
this project uh that's led by myself and
rob prince where we're looking at
immunotherapy resistance and and how to
target the tumor micro environment
to improve immunotherapy resistance
we also have a project led by tim klause
and dave nathanson that's looking at
resistance to chemotherapy and targeted
inhibitors
and how
actually by
giving targeted inhibitors it leads to
uh this metabolic vulnerability state
um and also uh kind of
but this vulnerability state that could
be uh i guess attacked by for instance
bclx1 inhibitors
but there are two blocks to apoptosis
and the goal really is to block both of
these signals uh when when uh when
patients are treated with these
inhibitors and then our third trial our
third project uh is a a study on rate uh
radiation resistance um this is led by
uh frank pajama
and it's really looking at you know why
radiation fails and one thought is that
it actually induces
uh this population of glioma stem cells
that actually uh then becomes you know
non-radio-sensitive and uh and there's
some you know uh interesting clinical
trials uh based on pre-clinical data
that we're starting uh with the use of
dopamine receptor antagonists and
statins for radiation resistant
tumors
so with that i just wanted to say thank
you for your time uh and uh thank you
for inviting me to to give this talk
it's really an honor to be here
hi sander
that was great
a tour de force for sure
um i'm i'm so fascinated with the the
the non-randomized clinical trial thing
um what does that mean for fda approval
if if you went that route
well um
i you know i i don't know i mean i think
the fda uh you know uh hopefully would
be more open to this you know i mean
have they been for other
cancers or is there a track record of
them allowing for that type of data and
giving cms
approval to move forward to develop
anything like that
yeah not
uh not final approval i mean i think for
there have been some conditional
approvals
um i think uh other regulatory agencies
are more open to this the european ones
the canadian ones
um fda is a little uh different in the
sense that um
they
they don't you know for those of you
who've done you know kind of submitted
things to the fda it's almost like you
submitted and if you don't hear anything
for 30 days it's good
right
um so
so you know we submitted things and you
know there wasn't a negative response
but
but i think um as far as other
treatments um
you know i i don't know off the top of
my head anything that's had you know
final approval but
but i think we're at a point at least in
glioblastomas where you know i'm not
sure how we're gonna get anything
approved if we have to do big you know
hundreds of patients randomized trials
yeah i agree
hi linda it's guy that was great thank
you
hi guy i had a quick question for you
maybe i missed this because i i i had to
be back and forth with something else
but in your in your pv1 trial that
you're running
are you i i saw that it was for you know
for for resectable recurrent tumors but
is there any sort of screen you know
because obviously there's been a bunch
of papers looking at which tumors may be
more or less pd1 sensitive and so how
are you how are you pre-screening to up
the ante on on potential
responders yeah yeah um right now we're
not pre-screening um because actually we
don't know exactly which biomarkers are
you know are are gonna be the the uh you
know the potential responders um i i
my personal opinion for for
immunotherapy in general i i do think
the um
the the mesenchymal subtype
are probably more are going to be more
immunoresponsive and they've been other
groups um you know mark gilbert and amy
humber found out as well and and i think
perhaps also the people at the mayo
clinic
but the problem is i i don't think
there's any consensus as how to test
for response you know whether it's white
imaging whether it's by immunotypistic
chemistry
sequencing you know
there's no test yet that we have
thank you
hi hi linda this is fabio very very nice
talk with you
in this issue of you know the
pd1 inhibitor when given before you have
a primed or or in a subprimed
tumor
do you have any idea when after for
example giving the dendritic cell
vaccine this tumor will be primed that
then you know will be the best timing to
add
yeah good question um in our animal
studies it's about it's about two weeks
because i mean
theoretically you want to get t cells in
so hopefully i mean if
if t cells are going in and they're at
you know and you know we we could take
them out and be sure they're antigen
specific if the t cells are in then
theoretically they should be
primed and it takes
you know it's probably about you know
two weeks in humans
but
we haven't done the study where we go in
and biopsy you know we haven't taken out
the tumor in the human to really know
that
another question what what do you think
is the ideal um
nice model for just studying
immunotherapy because one of the issues
of gl 261 for example it seems like
everything works
yeah i think that's one problem with
immunotherapy there's just no good mouse
model right um because you need a you
need an immunocompetent um
model um i mean the best
kind of models for heterogeneity are the
you know the xenograph models but they
don't have an immune system so um
so i think um
that's why we you know we rely a lot on
these you know window of opportunity
studies where we actually you know just
just test test these agents you know in
humans and take out the
you know
the tumor and and and actually
i think
we probably need to move that into the
newly diagnosed setting because you know
a lot of trials now are done in the
recurrent setting
but um
actually i think i think immune therapy
works much better in the newly diagnosed
setting before you know everybody's kind
of failed all of their treatments um and
but uh so i think one of our our next
sport trials is actually to
you know do do the the current trial but
you know with with the
newly diagnosed patients but with these
window of opportunity
types of
designs so for instance we would give
the immunotherapy um
you know uh
be before
or or after radiation and chemotherapy
and then have a you know maybe a 12-week
set point where we go into
and see what's going on
thank you so much for such a wonderful
and comprehensive talk um just a couple
questions one you know curious about
your thoughts on car t cells and sort of
the the promises and pitfalls and the
failures that we've seen you know we
know just basic of course in what you're
saying the activation is important we
seem to obviate the need for that with
these activated cars um there you know
it seems like maybe the predominant
issue is the myeloid suppressors i was
just curious if you think there's still
sort of hope hope there in that field um
as an immunotherapy and then secondly
with respect to the radiation resistance
that we seem to be
incurring
is there do you think that there's some
possibility that you know in the
recurrent setting perhaps for methylated
patients that there's a role for
overcoming that with for example you
know stereotactic radiosurgery you know
where we can overcome some of the radio
resistance is there you know any thought
at um combination therapies uh with that
yeah you know great questions um so as
far as car t therapy um yeah we actually
have you know one of our developmental
projects in our sport is actually a uh
by specific car t
um and it actually is you know it's
basically a car t to target the the
antigen target but also it um it
releases uh you know
something to target pgf beta so so
basically the the immunosuppressive
signal that occurs when you actually put
in adoptive t cells so so i think you
know
i think there are kind of innovative
ways to to design uh you know car t
cells that could hopefully
get like because what you need to do is
not just target the tumor cells you have
to fight off the other stuff that comes
with targeting yourself so i think that
hopefully you know may have some promise
it's still you know as you know it's
still not um
great for
for solid tumors you know it's shown you
know a lot of you know efficacy for for
you know blood tumors but but where
where that will be for solid tumors you
know i don't know but i think it you
know you need to move beyond just single
target
car t's if we're gonna try to tackle gpm
and then in your in response to your
answer regarding radiation um yes i
think actually as i was mentioning you
know what's the third project in our
sport um is actually uh from one of our
radiation you know oncology colleagues
and it's looking at um so so what he did
and i didn't get into this um but um
what he did was he looked at cells that
uh
actually
were
you know non-uh basically grew out
despite radiation basically we're
radiation resistant
um and if you just look at cells
themselves they should you know gpm is
pretty radiation sensitive
but then why can't you kill you know why
can't you kill him in the brain um so he
basically took took those cells and
ended this kind of screening panel to
see what what actually prevents these
cells from
transforming from a radio-sensitive cell
to a radio-resistant cell and
interestingly um the agents that came up
the most often were dopamine antagonists
um so uh
so actually uh you know we're starting a
trial of quito pain which is seroquel
for uh you know for uh for these tumors
and um
and i think
there could be a role where
for instance if you had a glioblastoma
patient who got radiation or you know
and then failed there could be a role
where you actually re-irradiate and then
give these kind of um agents like like i
said you know what one what particular
classes are the dopamine antagonists to
block that transition from the uh immuno
you know the radiation sensitive to the
radiation
uh resistant cells um because
interestingly the the use of this drug
like
the the dopamine antagonist it doesn't
work by itself you actually have to do
it with radiation at the same time which
i i think is um it's an interesting
phenomenon
interesting thank you
so if that's all the questions we'll um
maybe let dr lee i'll take a short break
and then uh the residents can stay on uh
for their meeting
okay great thanks linda appreciate it
thanks sander
let me know when you want to come to l.a
thanks very much great talk
bye
you