NorthWest Biotherapeutics Inc (NWBO)

[Hbpainter]

with time stamps:

00:04
all right so we'll go ahead and get
00:06
started and then let everyone continue
00:08
to join
00:09
uh so good evening everyone today it is
00:11
my honor to introduce dr linda liao who
00:13
really needs no introduction but i'm
00:16
thrilled to recount her many
00:17
accomplishments for the group anyways uh
00:19
dr liao is currently professor and chair
00:21
of the department of neurosurgery at the
00:23
david geffen school of medicine at ucla
00:26
where she is the co-director of the
00:28
brain tumor center pi and director of
00:30
the nci designated brain tumor spore as
00:33
well she's had a truly remarkable career
00:36
starting with her undergraduate studies
00:37
in biochemistry and political science at
00:40
brown where as a fun fact she was named
00:42
by time magazine as one of the top 100
00:45
college students in the united states
00:47
which i didn't even know that list
00:49
existed but that's wonderful she then
00:51
ventured to warmer climates receiving
00:53
her md at sanford and a phd in
00:55
neuroscience at ucla dr liao then
00:58
completed her neurosurgical residency
01:00
and a fellowship in neurosurgical
01:01
oncology at ucla after which she joined
01:04
the faculty with a rapid acceleration in
01:07
her clinical and research pursuits she's
01:09
had continuous nh funding for her work
01:12
over the past 25 years which focuses on
01:14
translational immunotherapies for brain
01:16
tumors and biomarkers
01:19
she's very well known for pioneering
01:21
dendritic cell-based vaccines for
01:22
glioblastoma and has really helped to
01:25
launch the investigation of immune-based
01:27
therapies for glioma in our field
01:29
in a real testament to her contributions
01:31
to science she was elected to the
01:33
national academy of medicine in 2018 and
01:36
her work has resulted in over 200
01:38
peer-reviewed papers chapters and a
01:40
foundational textbook
01:42
she's on innumerable scientific
01:44
committees and boards leading our field
01:46
both nationally and internationally
01:48
she served as editor-in-chief of the
01:50
journal of neuro-oncology from 2007 to
01:52
2018. also serving first as board
01:55
director of the american board of
01:57
neurological surgery and then becoming
01:59
its first woman chair from 2019 to 2020.
02:03
during this time because of course she
02:04
was not busy enough she also received an
02:07
mba from ucla going on to become a
02:09
tenured professor of neurosurgery in
02:11
2007 and chair of the department in
02:14
2017. she's mentored dozens of medical
02:17
students residents postdocs and junior
02:19
faculty really leaving an indelible
02:21
impression on the next generation uh dr
02:24
liao represents the rare triple threat
02:26
in our field and has further been a real
02:29
trail blazer for women in neurosurgery
02:31
and neural oncology dr liao we are just
02:33
so delighted to have you here today well
02:36
thank you so much for that very kind
02:38
introduction thank you so much for
02:40
having me um
02:41
it's uh really nice to kind of see um
02:44
kind of some of the some of my old
02:46
friends at least on on the zoom name
02:48
screen and
02:50
um it's really a pleasure to be here um
02:53
so uh
02:54
today i'm just gonna i'm gonna talk
02:56
about targeting immunotherapy-induced
02:58
resistance and glioblastoma and um
03:01
what's a little bit different about this
03:03
is you know we've talked a lot about you
03:04
know resistance to treatments um and
03:08
there's certainly resistance mechanisms
03:10
chemotherapy
03:11
but uh now we're learning that
03:14
there's actually resistance that occurs
03:16
from our therapies basically our
03:18
therapies are causing these tumors
03:21
to uh create
03:23
even further uh resistance to to uh to
03:27
treatments
03:28
and um
03:29
and when i started in this field you
03:31
know almost 30 years ago i thought we
03:33
would have a cure to gbm by now
03:36
but unfortunately we don't and i think
03:38
the the complexities of this disease are
03:40
just um
03:42
uh
03:42
you know getting uh
03:44
just now getting to be better elucidated
03:47
so um
03:49
i'm gonna just uh let's see
03:51
if i can move forward
03:53
so
03:54
oh these are my disclosures
03:57
and then um so just as an introduction
03:59
uh
04:00
in terms of fda approved treatments for
04:03
glioblastoma um as we all know you know
04:06
radiation and chemotherapy is still the
04:07
standard care for this treatment
04:09
radiation has been around since the mid
04:11
70s
04:12
and um really nothing happened for about
04:15
20 years um the only treatment available
04:17
to our patients was radiation and
04:19
surgery
04:20
bcnu and ccnu was fda approved at the
04:23
time but the clinical trials really
04:25
didn't show any added efficacy uh over
04:29
radiation so for about 20 years or so
04:31
radiation was
04:32
was the treatment um um actually for
04:36
about 25 to 30 years that was kind of
04:38
the main mainstay of treatment
04:40
um you know in the late 90s uh then the
04:42
gliado wafer was approved and then as
04:45
was temozolomide and then in 2005 with
04:48
the stoop protocol the standard of care
04:50
for glioblastomas uh it became radiation
04:54
with concomitant temozolomide and and
04:57
really that's kind of been the standard
04:59
of care for the last 15 years and
05:02
there have been a few other things that
05:04
have been fda approved before the system
05:06
for recurrent jbms and then the
05:08
tumor treating fields the optune device
05:11
but other than that really nothing
05:13
has been fda approved for uh for many
05:16
decades for this disease and that's not
05:18
for lack of trying
05:20
um and
05:23
as a uh
05:26
you know uh a comparison uh in the last
05:29
five years there have been over 50 uh
05:31
cancer immunotherapy drugs approved for
05:33
glioblastoma none yet for
05:36
for other cancers but none yet for
05:37
glioblastoma and then yet for brain
05:39
cancer and and these are all the
05:41
different cancers where there are now
05:43
immunotherapeutic drugs that are
05:45
available for patients um even
05:46
pancreatic cancer i mean in some small
05:49
subsets of pancreatic cancer there are
05:52
some drugs that are fda approved for
05:54
these very small subsets of patients
05:56
um so what what is making glioblastoma
06:00
so difficult uh to treat uh in
06:05
you know particularly with uh with
06:07
standard treatments but also with
06:08
immunotherapy
06:10
um
06:11
and again it isn't for lack of trying uh
06:14
you know as as you know many uh
06:16
checkpoint inhibitors have been fda
06:18
approved for other uh cancers and there
06:21
have been several large clinical trials
06:23
of uh checkpoint inhibition for
06:25
glioblastoma and this is one of the uh
06:28
you know the initial ones uh nivolumab
06:30
versus specific patients with current
06:33
glioblastoma
06:34
we're currently a blessed german as you
06:36
can see the the two survival curves are
06:38
essentially the same
06:39
um and this was published in you know
06:42
just a little over a year ago
06:44
um and you know in uh i guess true form
06:49
we always hear about these trials from
06:50
the uh the uh pharma companies
06:52
oftentimes before they actually get
06:54
published so that trial that uh that was
06:57
published in jam on colleges checkmate
06:59
143 that was just
07:02
alone and then there's also been
07:03
checkmate
07:04
498 that's an ebola map with radiation
07:07
and then the wall back with the volume
07:09
and these are still
07:10
um
07:11
these are trials that uh you know
07:13
unfortunately have not reached their uh
07:15
primary endpoints but there are now you
07:18
know different combinations of these
07:20
types of checkpoint inhibitors with
07:21
other treatments
07:24
so um
07:26
you know and for a while you know it's
07:28
thought that perhaps you know
07:29
immunotherapy you know at least
07:31
checkpoint inhibition wasn't a you know
07:33
a viable treatment for uh for
07:35
glioblastoma
07:37
um but then you know a couple years ago
07:39
uh this paper from uh from
07:41
our group at ucla as well as you know
07:44
patrick lynn at
07:46
the brigham um
07:48
as well as some other groups that have
07:50
kind of published similar studies showed
07:52
that perhaps it's the timing of these
07:54
treatments so this is a paper that
07:57
showed that if you gave
07:59
anti-pd1 inhibition neoadjuvantly
08:01
meaning before surgery there was some
08:04
increase in survival
08:05
in these recurrent glioblastoma patients
08:08
um
08:09
and granted the numbers are very small
08:11
we're talking only about 16 patients
08:13
there's 19 patients in the other arm
08:16
there it was a statistically significant
08:18
difference um and interestingly the um
08:22
this was one of those window of
08:24
opportunity studies so we actually took
08:26
the patient's tumor samples after uh the
08:30
um
08:31
administration of neoadjuvant uh
08:35
anti-pd1 inhibitors and then looked at
08:37
uh you know uh um
08:40
immune signatures and there was an
08:41
increase in gamma interferon uh
08:44
signatures uh in the um
08:47
um in the neoadjuvant group versus those
08:50
who did not get neoadjuvant vampirism up
08:53
suggesting that
08:55
an upregulation of the interferon gamma
08:57
pathway may play a role in this
09:04
but um
09:06
at around the same time there are other
09:07
studies that came out that suggested
09:09
that um if you give pd-1 blockade in a
09:13
subprimed setting basically the t cells
09:15
are not yet primed against your antigen
09:17
you can actually induce dysfunctional
09:20
uh
09:21
pd1 positive cells and and and and
09:24
anti-pd1 resistance so actually
09:26
it's count you know basically makes uh
09:29
makes the tumor um more resistant to
09:32
immunotherapy if you actually uh give a
09:36
checkpoint inhibitor without activating
09:38
the t cells and that that's always been
09:40
a problem with glioblastomas it's
09:42
actually an immunologically cold tumor
09:44
for the most part you're not you know
09:46
many studies have shown that although
09:48
yet there are some t cells in
09:49
glioblastoma there aren't very many
09:52
and perhaps the um the results that
09:54
we're seeing with neoadjuvant treatment
09:56
of
09:57
uh of these uh tumors is that
10:01
for those patients that have t cells in
10:03
the tumor you are perhaps able to uh
10:06
induce activation or of those t cells
10:09
against the antigen
10:10
however this would suggest that if you
10:12
have a subprimed t cell
10:15
the the
10:17
use of a checkpoint inhibitor may
10:18
actually make your um tumor even more
10:20
immune resistant
10:23
um and then some work done by uh rob
10:25
prinzen in our group at ucla
10:28
what he found was that in glioblastoma
10:31
patients uh the expression of pd1 by t
10:34
cells uh in in in these tumor samples
10:38
actually uh reflect uh exhausted t cells
10:41
and this is just a study looking at
10:43
different uh markers of t cells they're
10:45
the activated t cells they're the um
10:48
um memory t cells the activation t cells
10:51
and the exhaustion t cells and in
10:53
glioblastoma patients uh both in the um
10:57
well mostly in the tumor infiltrating
11:00
cells most of those cells are are
11:04
exhausted or in that path to exhaustion
11:07
so
11:08
so the the question is well how do we uh
11:12
perhaps revive those t cells that so
11:15
that they can be tumor specific and
11:16
actually attack uh you know attack these
11:20
tumors and and really drive this to the
11:22
memory t cells which is actually what we
11:25
want um and uh patients do have memory t
11:28
cells in the periphery but these t cells
11:31
are just not getting in uh
11:34
into the tumors when they're you know
11:36
infiltrating into the tumors
11:38
um
11:39
so um
11:42
to that
11:43
regard we went back and looked at um the
11:46
basically the tumor samples from the
11:48
patients that were enrolled in this in
11:51
the neoadjuvant pd1 blockade trial
11:53
and looked at their tumor infiltrating t
11:56
cells and then comes to see well
11:58
what was found was that these patients
12:01
um you know perhaps had an increased
12:03
survival there was an increased
12:04
interferon gamma signature in these
12:07
tumor samples and then uh the the
12:10
question the next question was well
12:12
what's going on with those t cells so we
12:14
uh so from the resected tumor tissue
12:17
um
12:18
uh we isolated the cd45 cells and then
12:22
did scitov mass spectroscopy or
12:24
single cell genomic sequencing
12:27
and what uh and muscle's work was done
12:30
by uh you know rob prince and uh and his
12:32
group uh
12:33
along with uh the people
12:36
working um in uh in our labs
12:39
collectively um
12:41
and this actually was part of our spore
12:44
project um as part of our ucla brain
12:46
cancer sport but what we found was that
12:49
the um neoadjuvant anti-pd1 treatment
12:53
um
12:54
it did increase the uh
12:57
perhaps the number of t cells but these
12:59
t cells were actually
13:01
uh progenitor like exhausted t cells
13:03
they actually had exhausted t cell
13:06
markers uh
13:08
for instance in this cluster this l4
13:10
cluster here as well as these there's an
13:13
increase in t red cells which are also
13:15
immunosuppressive t cells
13:17
so
13:18
um i guess as a a feedback mechanism
13:23
that these tumors kind of uh probably
13:26
would were um expressing was
13:28
that when we treat it with these
13:30
anti-pa1 inhibitors
13:32
these teeth it actually drove these t
13:35
cells further to uh exhaustion
13:38
and that could be one mechanism for uh
13:40
for resistance because if you have t
13:42
cells that
13:44
you have a number you know small number
13:45
of t cells in the tumor perhaps you are
13:48
increasing the the activation of those t
13:51
cells but then you're actually
13:53
um over stimulating them to a point of
13:56
exhaustion that they can't really attack
13:58
the tumors
13:59
but actually the the the bigger
14:02
immunosuppressive effect of antipedin1
14:05
therapy or immunotherapy prior
14:07
um
14:09
uh to uh
14:11
t cell activation is this uh
14:13
infiltration of immunosuppressive
14:16
macrophages and myeloid cells
14:18
so
14:20
what we found was that anti-p1 treatment
14:22
in a population of patients induces
14:24
upregulation of immunosuppressive
14:26
macrophages and myeloid cells so even
14:29
though you you're getting more t cells
14:31
in and perhaps the t cells are more
14:33
activated
14:35
you know the t cells may be getting
14:36
exhausted
14:38
and then on top of that you're
14:39
recruiting this whole population of
14:43
immunosuppressive cells that are
14:45
actually coming in to
14:47
uh fight the t cells so there's really
14:49
this kind of battle going on in the
14:51
tumor
14:52
microenvironment that is actually
14:54
induced uh by applied by our treatments
14:57
and so i think
14:59
in order to really uh get effective
15:02
treatments for glioblastoma we really
15:04
need to understand what our treatments
15:07
actually cause and and the timeline for
15:09
that you know when when when the tumor
15:12
you know when certain treatments should
15:13
be given
15:14
to mitigate some of these uh
15:16
immunosuppressive responses
15:20
so how do you get more t cells into the
15:23
tumor so because that's really uh and i
15:26
still believe that is the first step the
15:28
problem with
15:29
um
15:30
and probably one of the reasons that
15:32
immune checkpoint inhibitors don't work
15:33
as a single agent for glioblastoma is
15:36
that we don't really have a lot of t
15:37
cells in the tumor
15:39
and even if they're in there they're
15:41
exhausted um so you really need to
15:43
recruit new t cells from the periphery
15:46
because um as i showed in the um in this
15:50
slide here
15:51
oops
15:54
the
15:54
glioblastoma patients do have memory t
15:57
cells and activated t cells in the
15:59
periphery but how do we get them into
16:01
the tumor
16:02
um so
16:04
uh one of the best ways to actually get
16:06
t cells into the tumor is is through
16:09
active vaccination um
16:11
and uh and this was actually um work
16:14
that i you know did as part of my you
16:16
know my my first uh koa award many many
16:19
years ago and what uh we were the first
16:22
group to find that with vaccination we
16:25
could actually get t cells to cross the
16:28
blood-brain barrier and go into brain
16:30
tumors um i didn't realize that at the
16:32
time but apparently no one else had
16:36
found this uh before this point
16:38
um and it was because at the time
16:41
it was thought that the uh the the brain
16:44
was immune uh immune privileged so that
16:46
there was no uh way to get activated t
16:50
cells or at least tumor specific t cells
16:52
to migrate from the periphery
16:54
into brain tumors or at least it's not
16:56
that that doesn't happen now of course
16:58
people know that it does uh and it
17:00
actually happens in several different
17:02
pathologies besides brain tumors um as
17:05
well but uh but now you know but now i
17:09
think we understand that there are ways
17:10
to get t cells into tumors either by
17:12
active vaccinations sometimes you know
17:15
oncolytic viruses
17:16
um do that as well as you know you could
17:19
actually just give adoptive therapy of
17:21
of car t cells or other types of t cells
17:23
directly into the tumor but the first
17:25
step needs to be getting those kind of
17:27
fresh
17:28
non-exhausted t cells into the tumor
17:31
um and then
17:32
once uh and the those initial studies
17:36
that we did using dendritic cell
17:38
vaccination for instance uh did show
17:41
that t cells got into the tumor and then
17:43
uh we did see some increased survival
17:46
uh in uh patients in the early trials um
17:50
particularly in patients with uh the
17:52
mesenchymal subtype of glioblastoma
17:55
and uh and these studies subsequently
17:57
led to other phase one phase two and and
17:59
uh and phase three uh clinical trials
18:01
which um i'm not gonna talk about
18:04
uh in this talk but what i wanted to
18:07
focus on were the resistance mechanisms
18:09
that we learned uh from from all these
18:11
studies uh over the years um so as i
18:14
mentioned you know this was a paper we
18:16
published 10 years ago
18:18
what we found was that when we used um
18:21
dendritic cell vaccination the
18:23
mesenchymal gene expression signature
18:25
was associated with the increased tumor
18:27
tumor infiltrating lymphocytes and we
18:30
often see this in you know increased
18:32
contrast enhancement after treatment
18:34
which subsequently went away on its own
18:37
and in these patients
18:39
when we were able to get the post
18:41
treatment specimens we saw um you know
18:44
this kind of large infiltration of cd8
18:47
cell t cells which you know what wasn't
18:49
uh
18:50
visible uh or we didn't see in for
18:53
instance the pro-neural subgroup of
18:55
glioblastoma patients
18:57
so this mesenchymal subtype tends to be
19:00
more
19:01
immuno-responsive you know these uh it
19:03
tends to uh
19:05
react more to immunotherapy in the sense
19:08
that you could get t cells into these
19:09
tumors
19:10
so um
19:12
we then went to look at well what kind
19:15
of you know
19:17
what can we do to make glioblastomas
19:21
more immune responsive to you know help
19:23
turn these kind of relatively cold
19:26
tumors to more hot tumors
19:28
and uh some adjuvants that could be used
19:31
are things like toe like receptors
19:34
tlr's
19:35
recognize pamps pathogen-associated
19:38
molecular patterns and it's really an uh
19:41
you know an important uh
19:43
element in the innate immune system
19:45
and there happened to be you know for
19:47
instance uh fda approved tl7
19:51
agonists uh there's a drug called uh
19:54
amico mode and recyclamod
19:57
that's been fda approved for warts um
20:00
and then tl3 agonist uh there's a drug
20:03
called poly iclc that's been used in the
20:05
past for glioblastoma and clinical
20:07
trials
20:08
it actually was negative as a single
20:11
agent
20:12
but um but i think in combination with
20:15
vaccination or with some sort of t cell
20:18
activation signal these uh tlr and
20:23
agonists could be of benefit
20:25
so we did a very a small clinical trial
20:28
to test that we looked at
20:31
um a group of patients who just got that
20:36
well that well all these patients got dc
20:38
vaccination so we looked at a group that
20:40
got dc vaccination plus placebo dc
20:43
vaccination plus poly iclc which is a
20:45
tlr3 agonist or dc vaccination plus a
20:49
mechamod
20:50
and what we found was that um
20:53
with the tlr
20:56
agonist the poly iclc there was an
20:59
increased
21:00
um uh
21:03
effector uh
21:05
effector pd1 positive t cell response so
21:08
and uh and there was also an increase uh
21:11
you know
21:12
number and and activation of uh
21:15
t cells
21:16
uh suggesting that that this particular
21:19
uh
21:21
uh adjuvant was was
21:23
driving these cells more towards
21:26
activation and less towards
21:29
the
21:30
immunosuppressive phenotype
21:33
um and we also looked at this with a
21:36
single cell sequencing again looking at
21:38
the t cell cluster
21:40
showing you know drive of these t cells
21:42
to active memory t cells
21:44
as opposed to the um
21:47
the more kind of naive
21:51
anergic t cells
21:54
and
21:56
we did uh gene expression profiling and
21:58
then
21:59
and showed that this particular group
22:01
that got treated with the poly iclc
22:04
actually both the groups that got
22:05
treated with poly iclc as well as were
22:08
recycle mod they did show some changes
22:11
in myeloid cell differentiation uh gene
22:13
expression patterns as well as
22:15
lymphocyte gene expression patterns more
22:17
so in the poly iclc group
22:20
than the um
22:21
than the recipromite group
22:24
and they that these these adjuvants
22:27
really helped to elicit a very strong
22:29
type 1 type 2 interferon response
22:32
um
22:33
and then what was even more interesting
22:35
was that uh with poly iclc actually the
22:38
patients live longer um
22:40
this particular group albeit the the
22:42
numbers are very small again um
22:45
there but it was statistically
22:47
significant uh the group that got
22:49
dendrite cell vaccination plus poly ice
22:51
celsius uh had a 50 survival rate and
22:55
now we're you know the majority of these
22:58
patients are reaching 100 months
23:00
uh and uh with
23:03
not only survival but but really um
23:06
no tumor recurrence so it does suggest
23:09
that there is some um
23:11
added benefit uh to adding these um
23:15
these adjuvants to to
23:18
t cell activation signals
23:23
and
23:24
as i mentioned i think one reason that
23:27
single agent checkpoint inhibitors
23:29
aren't working in glioblastoma
23:32
is because the t cells are not getting
23:34
in and what we do know is that uh
23:38
at least in
23:40
in our animal studies and and several
23:42
other studies is that you do need an
23:44
activation signal to get the peripheral
23:47
t cells to go into the brain tumors um
23:50
sometimes we already see uh
23:52
glioblastomas with t cells so there
23:54
probably was some activation signal that
23:56
got those cells in there but for the
23:59
most part the majority of these tumors
24:01
don't really express a lot of activated
24:03
t cells but the dendritic cell
24:05
vaccination is able to get these t cells
24:08
infiltrated into the tumor and these are
24:10
just uh schematics of of what what
24:12
happens
24:13
um if you just use the anti-pd1 antibody
24:17
alone we don't really see a
24:20
significant increase in t cells in the
24:22
tumor
24:23
if you use the dendritic cell
24:26
vaccination we do see increased
24:28
t cells into the tumor
24:31
but uh but in terms of if we combine the
24:35
two then we we see not only increase in
24:37
numbers but also the increase in uh
24:40
perhaps percentage of activation uh
24:43
signals and activated t cells um
24:49
so
24:51
so the the
24:52
thought is that uh you know again
24:56
pd when blockaded alone uh did not show
24:59
a response in our uh animal models
25:02
uh if we gave the dendritic
25:03
self-vaccination alone we did see a
25:05
response to some of the animals but it
25:08
was uh not in all of the animals
25:10
and uh part of that was because the
25:13
the percent of t cells that were
25:15
activated was relatively low
25:18
compared to when we actually used both
25:20
agents alone
25:23
however
25:25
what we also found um was that
25:29
in when we used um dendritic cell
25:32
vaccination plus pv1 inhibition
25:35
uh again you get more t cells into the
25:38
tumor but then you also get a uh a yes a
25:42
compensatory migration of these immune
25:44
suppressive cells
25:46
uh that are actually coming in from the
25:48
you know
25:49
from the periphery to try to basically
25:52
suppress that immune response that is
25:54
being activated by the activated t cells
25:57
plus checkpoint uh inhibition
26:00
um
26:01
so uh
26:02
so our uh
26:04
you know initial uh
26:06
clinical trial that we started uh as
26:08
part of our spore five years ago
26:11
was to look at
26:13
um basically
26:15
the effect of
26:17
neoadjuvant pd1 blockade with dendritic
26:20
cell vaccination this is a group of 20
26:22
patients in each arm and then uh we the
26:25
the end point this is a window of study
26:28
uh window of opportunity study so then
26:30
point was really to look at the tumor
26:31
tissue uh after the neoadjuvant blockade
26:35
and then also look at overall survival
26:37
in the group that got a
26:39
dc vaccination plus uh pd-1 blockade
26:42
versus the group that got dc vaccination
26:45
plus placebo
26:46
um and uh this this study is still
26:49
ongoing so i don't have the results of
26:51
this study yet
26:53
we actually um
26:55
after all the pre-clinical studies and
26:57
ind enabling studies who got fda
27:00
approval in november 2019
27:02
uh the trial opened in 2020 but had some
27:05
fits and starts because of covid um but
27:07
we've already enrolled 20 patients we're
27:09
halfway through so anticipate we should
27:11
have the results of that study uh you
27:13
know in the next year or two
27:16
but one thing that was interesting you
27:17
know in some of these patients um was
27:20
that just like we saw in our animal
27:22
studies we
27:24
saw an enhanced immune response
27:28
with
27:29
autologous tumor lysate and uh
27:32
and the antip one uh antibody
27:35
but uh
27:36
we we saw this uh very
27:39
actually very profound immune response
27:41
in in some of these patients very
27:43
similar to like the um
27:45
uh the side effects that you see in
27:47
people who have gotten you know cartier
27:49
therapies um so you know this is an
27:53
example of one particular patient he got
27:55
the uh autologous tumor lysate dendritic
27:57
cell vaccine plus pembro
27:59
uh as part of the trial
28:01
at the window of opportunity trial we
28:03
did surgery took out his tumor
28:05
uh
28:06
he
28:06
you know he clinically did better we
28:09
were measuring uh crp and other kind of
28:11
you know immune
28:13
or inflammatory markers that actually
28:15
went down
28:16
and then um
28:18
subsequently uh he
28:20
he had uh
28:22
injections of of his uh subsequent
28:25
injections and every time he had an
28:26
injection
28:27
these markers went up
28:29
uh to a point where um in this
28:31
particular case he was getting so much
28:34
inflammation that we had to treat him
28:35
with uh an il6 inhibitor of toaster
28:38
leucine and then eventually we were able
28:40
to control the inflammation with
28:42
bevacizumab
28:43
but
28:44
in this particular study this is
28:46
actually a patient where his post
28:50
uh you know pembroke vaccine treatment
28:52
caused so much inflammation we had to go
28:54
back in and resect some of the tumor
28:57
tissue um and what we found was uh was
29:01
actually quite interesting um so
29:04
following just neoadjuvant pd1 uh
29:07
inhibition we saw increased uh t cells
29:10
this is a cd3 t-cell marker the red dots
29:12
are t cells
29:14
um but then when we you know when he had
29:16
the vaccinations with the pembroke um
29:19
pembrolizumab he had increased t cells
29:22
and this is probably what led to some of
29:25
that inflammation that he had
29:27
that required subsequent uh debulking of
29:30
the tumor so but this this actually
29:34
probably was not the the uh
29:36
i guess the reason he had so much
29:38
inflammation
29:40
it was probably because in addition to
29:42
the t cells coming in
29:44
um he had uh after
29:47
immunotherapy there was a huge migration
29:50
of immunosuppressive myeloid and
29:52
macrophage cells
29:54
so even though we there are the red
29:56
cells the t cells getting into this
29:57
tumor there is this there are these
29:59
immunosuppressive cells that came in and
30:02
really there's this battle going on in
30:04
the brain between the tumor cells and
30:06
the t cells and then this new population
30:09
of
30:10
of myeloid cells that were actually
30:12
induced by the immunotherapy because we
30:14
don't actually see this
30:16
uh as much in people who didn't get the
30:18
neoadjuvant pd1
30:20
inhibition so um
30:24
so this is kind of uh you know what what
30:26
it looked like so this was the initial
30:28
surgery where you know the patients only
30:30
got the pd1
30:32
um antibody and uh and there was you
30:36
know some increased
30:38
uh
30:39
um
30:41
the tumor cells are in blue the the t
30:44
cells are in red and then the green
30:46
cells are the immunosuppressive
30:47
macrophages and then after the
30:50
combination treatment you could see you
30:53
do get more of the t cells which are the
30:55
the red cells but many many more of the
30:58
green cells
30:59
so
31:00
this this whole
31:02
lesion was actually being overcome by
31:04
the these green cells the green cells
31:06
the immunosuppressive macrophage has
31:08
actually outnumbered even the tumor
31:09
cells
31:10
uh and the t cells
31:13
so
31:14
um
31:15
and and this is you know this is these
31:18
green cells are fighting the the red
31:20
cells and over time it allows the blue
31:24
cells the tumor cells to outgrow this
31:26
population
31:27
so
31:28
that led to kind of our the design of
31:31
our upcoming clinical trial because i
31:34
think it's it's not going to be enough
31:36
to
31:37
just
31:38
you know what we do know is it's not
31:40
enough to just use a checkpoint
31:41
inhibitor you need to get the t cells in
31:43
so uh so that's why we combine the
31:46
activation signal the vaccine plus you
31:48
know to get the t cells in plus the
31:50
checkpoint inhibitor but then as a
31:52
result of that we get this uh
31:53
compensatory or response whereby
31:57
um immune effect that combination of
32:00
immunotherapy creates
32:01
this uh
32:03
huge influx of these myeloids um
32:06
macrophage tumor suppressor immune
32:08
suppression of cells so this next uh
32:10
trial is is really a combination of
32:14
dendritic cell vaccine plus poly iclc to
32:17
do
32:18
activate that danger signal that innate
32:20
immune response
32:22
immune checkpoint inhibition to to
32:25
really block the immune checkpoints and
32:27
then csf inhibition which actually is an
32:30
agent that blocks that those screen
32:32
cells those myeloid macrophage cells and
32:35
that's kind of the the upcoming trial
32:37
design and uh this is
32:39
you know the
32:40
the uh
32:43
the design where we're gonna try to um
32:46
add add those uh other components to
32:49
to this uh uh
32:51
current uh pd1 uh plus
32:54
um
32:55
uh dendritic cell vaccine trial
32:58
um one other thing that i think is
33:01
lacking in the field is uh
33:03
is the ability to monitor response or or
33:06
to actually have biomarkers to determine
33:09
which patients will have a response um
33:12
and one thing that we've been looking at
33:14
uh over the years is the um
33:18
i guess the use of tcr uh you know t
33:22
t-cell receptor sequencing and the old
33:26
overlap of tcr sequencing um
33:29
uh antigens you know the antigens for
33:31
which these t cells are responsive to
33:34
um to look at that overlap between the
33:37
peripheral blood and the tumor because
33:39
if if you can imagine if
33:41
the there is
33:43
the the peripheral blood has
33:46
antigen specific t cells that actually
33:49
can get into the tumor that match the
33:52
antigens within the tumor then the hope
33:54
is that there will be this kind of
33:56
perpetual
33:57
replenishing of t cells from the
33:59
periphery that could get into the tumor
34:01
and attack the tumor rather than have
34:04
relying on the infra tumor t cells which
34:07
uh as we have shown are for the most
34:09
part you know tired and exhausted and
34:11
get even more tired and exhausted when
34:13
you give people inhibition
34:15
so um so this is you know a potential
34:18
blood marker that we could uh
34:21
potentially monitor
34:22
uh over time to see if there was any
34:25
response to immunotherapy in our prior
34:28
dendritic cell vaccine trials what we
34:30
did find was that people who had a high
34:33
overlap
34:34
um pre-op and a high overlap post-op for
34:38
the most part they all have very good
34:39
responses meaning long-term survivals of
34:42
of more than five years or so and people
34:45
who had low overlap before treatment
34:48
there was a group where
34:50
they they were able to have high overlap
34:53
after treatment um some of those had had
34:56
very good responses and some
34:58
did not and we're still trying to figure
35:00
out what dictates
35:02
uh the difference between those that
35:04
respond and those that did not and then
35:07
if you're you don't have any overlap
35:09
either before or after treatment for the
35:11
most part we're not seeing the t cells
35:14
uh
35:15
you know expanding that will will
35:17
actually attack the tumor antigens in
35:19
the tumor and those tend to have poorer
35:21
survival
35:23
um
35:24
so i'm just going to spend the next you
35:26
know a few minutes just uh
35:28
talking not so much about the science or
35:31
and and the immunology um but but also
35:34
about but more so about the the clinical
35:36
trial design and uh and this is actually
35:39
the other reason i think we are we don't
35:41
have any fda approved treatments for
35:43
immunotherapy right now
35:45
um as i mentioned the there's the
35:47
science behind it because there's the i
35:50
think the need to
35:52
uh use combination immunotherapies and
35:54
combinations in the right order and the
35:56
right uh rationale
35:58
uh for using these treatments and uh and
36:01
that's certainly a big part of kind of
36:04
the um the bottleneck that that we're
36:06
having in in the field but i think
36:09
another um
36:11
a
36:12
problem with uh
36:14
with getting these these you know
36:16
treatments to patients is really the
36:17
clinical trial design and as as many of
36:20
you know um there are challenges to
36:22
randomize clinical trials uh
36:24
particularly in glioblastoma and it's so
36:26
hard to get now patients who want to be
36:29
the placebo arm of any trial uh you know
36:32
and uh and that you know becoming more
36:34
and more difficult uh you know for for
36:38
these larger phase three trials because
36:40
you know most patients would rather
36:43
go to a phase one or phase two trial
36:45
where they're actually guaranteed the
36:46
treatment even though it hasn't shown uh
36:49
efficacy in those early phase studies
36:52
so patient recruitment and retention is
36:54
difficult uh there is a lack of active
36:56
treatment you know um
36:59
the lack of an active treatment arm in
37:01
the control arm does you know
37:03
have some ethical uh issues as you can
37:06
imagine to really keep patients on these
37:08
trials when they you know that they're
37:11
only getting the placebo
37:13
um you know and glioblastomas are rare
37:15
they're it's a heterogeneous disease
37:16
compared to other cancers and the
37:18
numbers uh that we need to do these
37:21
trials are are just not there and then
37:23
given the heterogeneity and the sub
37:25
stratification
37:26
uh that you know you need to uh
37:30
have in order to show efficacy even in
37:32
small subgroups
37:34
uh that that's just incredibly difficult
37:37
and not only is there stratification of
37:39
the tumor there are also characteristics
37:42
of the host and the host response that
37:45
you know i didn't really talk about but
37:46
you know the host um
37:48
also plays a role in this heterogeneity
37:51
and then you know as i mentioned we have
37:53
of the lack of biomarkers for for
37:55
response uh to to a lot of these
37:58
treatments and then by the time you
38:00
finish a trial there's rapidly
38:02
progressing new knowledge uh that could
38:05
change the the the course of how you
38:07
evaluate um
38:09
treatment response for instance what you
38:11
know and uh a lot of the way we evaluate
38:13
treatment responses by imaging
38:15
and uh and as you know that that has
38:18
changed over time as well
38:20
um
38:21
so
38:22
there is more of a movement towards the
38:24
use of external control arms
38:26
and uh this has been you done in other
38:28
fields
38:30
outside of brain cancer and you know for
38:32
other cancers and and i think it is
38:34
gaining popularity and it's something
38:36
that i think our field really needs to
38:37
consider uh
38:39
more deeply simply because of the
38:41
problems
38:42
with you know getting uh
38:45
good data from randomized controlled
38:47
trials and keeping patients on these
38:49
trials
38:50
so um
38:51
and this is just a schematic uh that
38:54
that was uh you know that shows how some
38:57
you know some of these trials can be
38:58
designed whereby you use external data
39:01
with some propensity matching and you
39:03
know get your kind of
39:05
virtual treatment versus control arms
39:08
um
39:09
there's there's actually some guidelines
39:11
in terms of you know quality checks for
39:13
what what would serve as
39:16
kind of good data sources for uh
39:19
selection of external control arms and
39:22
many of these um you know have to do
39:24
with like for instance getting data from
39:26
large well-controlled randomized
39:28
clinical trials because the database and
39:30
the
39:31
data collection is is relatively good in
39:34
these larger kind of well-controlled
39:36
trials
39:37
you know you have to look at the
39:38
similarity of data sets some synthetic
39:40
control methods
39:42
um as well as the relevance and
39:44
reliability
39:47
and um and i'll talk to touch a little
39:49
bit about that on that a little bit
39:51
later
39:51
but um but so so with that in mind i
39:54
mean if you just look at the um for
39:57
instance the last you know seven seven
39:59
to ten years
40:01
um there have been several large
40:03
randomized control trials that have been
40:04
done for newly diagnosed glioblastoma
40:07
and many of these trials have control
40:09
arms
40:10
so
40:11
so this is the so this is the control
40:14
arm in in these studies so there's you
40:16
know in this particular study there's
40:18
411 229 it
40:21
if you add all these control patients
40:23
all these control patients got the exact
40:25
same thing they got radiation and
40:27
temozolomide the stupid protocol so
40:29
you're you know if you just look at
40:31
these controlled
40:33
patients you already have
40:35
1300 control patients who got the exact
40:38
same thing and if you look at the
40:40
control the kaplan meyer curves of these
40:42
trials
40:44
they
40:44
they absolutely overlap um so
40:48
so
40:49
you know one question is do we need to
40:51
do another
40:53
you know do we need to have control arms
40:55
for all our future clinical trials will
40:57
enroll another thousand thousands of
40:59
patients onto the control arm if we have
41:02
a robust data set
41:04
that shows pretty much the same uh
41:06
survival among all these patients who
41:08
got temozolomide and
41:10
radiation
41:12
um
41:14
and uh you know one
41:16
uh
41:17
thought was that well how uh i guess how
41:21
how rigorous is the use of uh of
41:24
external controls would
41:26
a study that a a true randomized control
41:29
study that was negative be
41:31
erroneously
41:33
um i guess
41:35
statistically tested as they or come out
41:37
as positive when we use these external
41:39
control arms so this was just an
41:42
exercise that showed um you know for
41:44
instance the um
41:46
the cell death study with rinda pippa
41:48
matt and temozolomide using that as
41:51
the experimental arm and testing that
41:54
against the all these external controls
41:56
that trial actually turned out to be
41:58
negative as you know similar to what the
42:01
con you know the controlled study showed
42:03
as did dose dense temozolomide the only
42:06
trial that actually was positive in this
42:08
comparison was actually the um the tumor
42:11
treating field study which actually was
42:13
also positive
42:14
when uh when that um when the actual uh
42:17
randomized control trial was done
42:20
um
42:22
and then you know when we think about
42:24
randomized control trials as i mentioned
42:26
there's the issue about you know having
42:29
patients on the placebo arm
42:31
um and uh and then the ability to to
42:34
really kind of you know uh
42:37
rigorously do this in a in a such a
42:40
heterogeneous population of patients
42:43
such as those who have glioblastoma
42:45
um
42:46
another consideration is that well are
42:48
these randomized control arms really um
42:52
reflective of the real world
42:55
you know population you know what we do
42:57
in the real world for our patients
43:00
and uh and one thing that uh that knows
43:03
you know in the data
43:05
you know from pulling the data from
43:07
these uh trials that have been done over
43:09
the last decade or so
43:11
the majority of these patients that were
43:13
enrolled in these trials you know up to
43:15
94 i mean 87 was the average
43:19
87 of these patients were white
43:22
um
43:23
so
43:24
we really are lacking in diversity uh in
43:28
in our you know randomized controlled
43:30
trials at uh in neuro neuro-oncology in
43:34
our academic centers
43:36
so that's something that i think we
43:38
really need to think about more deeply i
43:40
mean is
43:41
one um you know our randomized control
43:44
trials the best you know
43:46
way to test new therapeutics
43:49
even if it is scientifically
43:51
is it the best representation of what we
43:53
will actually do
43:55
um you know clinically for for our
43:57
patients because
43:58
the representation in these trials is
44:01
really not reflective of what our real
44:03
the real world is um at least not not uh
44:07
not in los angeles and new york i think
44:11
so in conclusion um you know things to
44:14
think about uh how to accelerate the
44:16
translation uh and clinical development
44:19
of nucleoblastoma therapies i i think we
44:21
need to develop better immunocompetent
44:23
animal models that better recapitulate
44:25
tumor and host heterogeneity because
44:28
heterogeneity is still a very big
44:29
problem um with uh with the studies that
44:32
we do in this for this disease
44:34
um we have to consider timing sequencing
44:37
and the role of surgical resection in
44:38
combination immunotherapies and it's not
44:42
just a matter of throwing everything
44:43
together at the same time i think there
44:45
is uh
44:47
you know
44:48
some thought that needs to be put into
44:50
how the how the immune system works with
44:53
the how the immune response works and
44:55
what you know how to time
44:57
the the combination treatments to best
44:59
fit that
45:01
we need better biomarkers of response
45:03
whether it be tumor or blood or csf
45:05
biomarkers uh oh and or and or imaging
45:08
biomarkers that could actually look look
45:11
at
45:12
response to treatment or stratify
45:14
patients that would respond to certain
45:16
treatments uh non-invasively
45:19
um and then you know
45:21
these previously large randomized
45:23
controlled trials have been done in
45:25
glioblastoma it would be good if these
45:27
uh trials uh release their data um so
45:30
that it could be mined for
45:32
uh external controlled propensity
45:35
matching
45:36
and uh and also i think um
45:39
the you know more of a movement towards
45:41
the use of external control arms for
45:43
registration on our trials or even going
45:46
on to
45:47
phase four trials uh with real world
45:50
efficacy as opposed to
45:52
having this kind of step-wise
45:54
progression from you know from very
45:56
strict randomized controlled trials that
46:00
um
46:00
you know
46:01
could get to publications and fda
46:03
approval but aren't really being used in
46:05
the real world because they're just not
46:07
either not practical or not reflective
46:10
of the population that we're serving
46:13
so with that being said um i just wanted
46:16
to end with um
46:18
kind of a an overview of our brain
46:20
cancer spore at ucla
46:23
um the theme of our overall sport is
46:25
targeting resistance and what i talked
46:28
about today was just project one it was
46:31
this project uh that's led by myself and
46:34
rob prince where we're looking at
46:36
immunotherapy resistance and and how to
46:38
target the tumor micro environment
46:41
to improve immunotherapy resistance
46:43
we also have a project led by tim klause
46:46
and dave nathanson that's looking at
46:49
resistance to chemotherapy and targeted
46:52
inhibitors
46:54
and how
46:55
actually by
46:57
giving targeted inhibitors it leads to
47:00
uh this metabolic vulnerability state
47:04
um and also uh kind of
47:07
but this vulnerability state that could
47:09
be uh i guess attacked by for instance
47:12
bclx1 inhibitors
47:15
but there are two blocks to apoptosis
47:18
and the goal really is to block both of
47:20
these signals uh when when uh when
47:23
patients are treated with these
47:24
inhibitors and then our third trial our
47:27
third project uh is a a study on rate uh
47:31
radiation resistance um this is led by
47:34
uh frank pajama
47:37
and it's really looking at you know why
47:40
radiation fails and one thought is that
47:42
it actually induces
47:44
uh this population of glioma stem cells
47:48
that actually uh then becomes you know
47:51
non-radio-sensitive and uh and there's
47:53
some you know uh interesting clinical
47:55
trials uh based on pre-clinical data
47:57
that we're starting uh with the use of
48:00
dopamine receptor antagonists and
48:02
statins for radiation resistant
48:04
tumors
48:06
so with that i just wanted to say thank
48:08
you for your time uh and uh thank you
48:12
for inviting me to to give this talk
48:15
it's really an honor to be here
48:20
hi sander
48:23
that was great
48:25
a tour de force for sure
48:27
um i'm i'm so fascinated with the the
48:31
the non-randomized clinical trial thing
48:33
um what does that mean for fda approval
48:37
if if you went that route
48:40
well um
48:42
i you know i i don't know i mean i think
48:44
the fda uh you know uh hopefully would
48:48
be more open to this you know i mean
48:51
have they been for other
48:53
cancers or is there a track record of
48:55
them allowing for that type of data and
48:58
giving cms
48:59
approval to move forward to develop
49:01
anything like that
49:03
yeah not
49:05
uh not final approval i mean i think for
49:08
there have been some conditional
49:09
approvals
49:11
um i think uh other regulatory agencies
49:14
are more open to this the european ones
49:16
the canadian ones
49:18
um fda is a little uh different in the
49:21
sense that um
49:23
they
49:25
they don't you know for those of you
49:27
who've done you know kind of submitted
49:28
things to the fda it's almost like you
49:30
submitted and if you don't hear anything
49:31
for 30 days it's good
49:33
right
49:34
um so
49:36
so you know we submitted things and you
49:38
know there wasn't a negative response
49:41
but
49:42
but i think um as far as other
49:44
treatments um
49:46
you know i i don't know off the top of
49:48
my head anything that's had you know
49:49
final approval but
49:51
but i think we're at a point at least in
49:54
glioblastomas where you know i'm not
49:57
sure how we're gonna get anything
49:58
approved if we have to do big you know
50:01
hundreds of patients randomized trials
50:04
yeah i agree
50:08
hi linda it's guy that was great thank
50:10
you
50:11
hi guy i had a quick question for you
50:13
maybe i missed this because i i i had to
50:15
be back and forth with something else
50:17
but in your in your pv1 trial that
50:19
you're running
50:20
are you i i saw that it was for you know
50:22
for for resectable recurrent tumors but
50:25
is there any sort of screen you know
50:27
because obviously there's been a bunch
50:29
of papers looking at which tumors may be
50:31
more or less pd1 sensitive and so how
50:34
are you how are you pre-screening to up
50:36
the ante on on potential
50:38
responders yeah yeah um right now we're
50:42
not pre-screening um because actually we
50:45
don't know exactly which biomarkers are
50:48
you know are are gonna be the the uh you
50:51
know the potential responders um i i
50:55
my personal opinion for for
50:57
immunotherapy in general i i do think
51:00
the um
51:02
the the mesenchymal subtype
51:05
are probably more are going to be more
51:07
immunoresponsive and they've been other
51:09
groups um you know mark gilbert and amy
51:11
humber found out as well and and i think
51:14
perhaps also the people at the mayo
51:15
clinic
51:16
but the problem is i i don't think
51:18
there's any consensus as how to test
51:22
for response you know whether it's white
51:24
imaging whether it's by immunotypistic
51:26
chemistry
51:27
sequencing you know
51:29
there's no test yet that we have
51:34
thank you
51:39
hi hi linda this is fabio very very nice
51:42
talk with you
51:45
in this issue of you know the
51:48
pd1 inhibitor when given before you have
51:52
a primed or or in a subprimed
51:57
tumor
52:01
do you have any idea when after for
52:04
example giving the dendritic cell
52:06
vaccine this tumor will be primed that
52:09
then you know will be the best timing to
52:11
add
52:13
yeah good question um in our animal
52:16
studies it's about it's about two weeks
52:19
because i mean
52:20
theoretically you want to get t cells in
52:23
so hopefully i mean if
52:26
if t cells are going in and they're at
52:27
you know and you know we we could take
52:29
them out and be sure they're antigen
52:31
specific if the t cells are in then
52:33
theoretically they should be
52:35
primed and it takes
52:37
you know it's probably about you know
52:40
two weeks in humans
52:44
but
52:45
we haven't done the study where we go in
52:47
and biopsy you know we haven't taken out
52:49
the tumor in the human to really know
52:51
that
52:55
another question what what do you think
52:57
is the ideal um
53:00
nice model for just studying
53:02
immunotherapy because one of the issues
53:04
of gl 261 for example it seems like
53:07
everything works
53:12
yeah i think that's one problem with
53:14
immunotherapy there's just no good mouse
53:16
model right um because you need a you
53:19
need an immunocompetent um
53:22
model um i mean the best
53:24
kind of models for heterogeneity are the
53:28
you know the xenograph models but they
53:29
don't have an immune system so um
53:32
so i think um
53:34
that's why we you know we rely a lot on
53:36
these you know window of opportunity
53:38
studies where we actually you know just
53:40
just test test these agents you know in
53:43
humans and take out the
53:45
you know
53:46
the tumor and and and actually
53:48
i think
53:50
we probably need to move that into the
53:51
newly diagnosed setting because you know
53:53
a lot of trials now are done in the
53:55
recurrent setting
53:57
but um
53:58
actually i think i think immune therapy
54:00
works much better in the newly diagnosed
54:02
setting before you know everybody's kind
54:04
of failed all of their treatments um and
54:08
but uh so i think one of our our next
54:10
sport trials is actually to
54:13
you know do do the the current trial but
54:15
you know with with the
54:16
newly diagnosed patients but with these
54:19
window of opportunity
54:20
types of
54:22
designs so for instance we would give
54:24
the immunotherapy um
54:26
you know uh
54:28
be before
54:30
or or after radiation and chemotherapy
54:32
and then have a you know maybe a 12-week
54:35
set point where we go into
54:37
and see what's going on
54:41
thank you so much for such a wonderful
54:43
and comprehensive talk um just a couple
54:45
questions one you know curious about
54:47
your thoughts on car t cells and sort of
54:50
the the promises and pitfalls and the
54:52
failures that we've seen you know we
54:54
know just basic of course in what you're
54:56
saying the activation is important we
54:58
seem to obviate the need for that with
55:00
these activated cars um there you know
55:03
it seems like maybe the predominant
55:04
issue is the myeloid suppressors i was
55:07
just curious if you think there's still
55:09
sort of hope hope there in that field um
55:12
as an immunotherapy and then secondly
55:14
with respect to the radiation resistance
55:16
that we seem to be
55:18
incurring
55:19
is there do you think that there's some
55:21
possibility that you know in the
55:23
recurrent setting perhaps for methylated
55:25
patients that there's a role for
55:27
overcoming that with for example you
55:29
know stereotactic radiosurgery you know
55:31
where we can overcome some of the radio
55:33
resistance is there you know any thought
55:35
at um combination therapies uh with that
55:39
yeah you know great questions um so as
55:42
far as car t therapy um yeah we actually
55:44
have you know one of our developmental
55:46
projects in our sport is actually a uh
55:48
by specific car t
55:50
um and it actually is you know it's
55:52
basically a car t to target the the
55:54
antigen target but also it um it
55:59
releases uh you know
56:01
something to target pgf beta so so
56:04
basically the the immunosuppressive
56:06
signal that occurs when you actually put
56:09
in adoptive t cells so so i think you
56:11
know
56:12
i think there are kind of innovative
56:14
ways to to design uh you know car t
56:18
cells that could hopefully
56:20
get like because what you need to do is
56:22
not just target the tumor cells you have
56:24
to fight off the other stuff that comes
56:26
with targeting yourself so i think that
56:29
hopefully you know may have some promise
56:32
it's still you know as you know it's
56:33
still not um
56:35
great for
56:37
for solid tumors you know it's shown you
56:39
know a lot of you know efficacy for for
56:41
you know blood tumors but but where
56:45
where that will be for solid tumors you
56:48
know i don't know but i think it you
56:50
know you need to move beyond just single
56:52
target
56:53
car t's if we're gonna try to tackle gpm
56:56
and then in your in response to your
56:58
answer regarding radiation um yes i
57:01
think actually as i was mentioning you
57:02
know what's the third project in our
57:04
sport um is actually uh from one of our
57:06
radiation you know oncology colleagues
57:09
and it's looking at um so so what he did
57:12
and i didn't get into this um but um
57:14
what he did was he looked at cells that
57:17
uh
57:18
actually
57:19
were
57:20
you know non-uh basically grew out
57:23
despite radiation basically we're
57:25
radiation resistant
57:27
um and if you just look at cells
57:29
themselves they should you know gpm is
57:32
pretty radiation sensitive
57:34
but then why can't you kill you know why
57:36
can't you kill him in the brain um so he
57:38
basically took took those cells and
57:41
ended this kind of screening panel to
57:43
see what what actually prevents these
57:45
cells from
57:46
transforming from a radio-sensitive cell
57:49
to a radio-resistant cell and
57:51
interestingly um the agents that came up
57:54
the most often were dopamine antagonists
57:58
um so uh
58:00
so actually uh you know we're starting a
58:03
trial of quito pain which is seroquel
58:06
for uh you know for uh for these tumors
58:10
and um
58:11
and i think
58:14
there could be a role where
58:16
for instance if you had a glioblastoma
58:18
patient who got radiation or you know
58:21
and then failed there could be a role
58:24
where you actually re-irradiate and then
58:26
give these kind of um agents like like i
58:29
said you know what one what particular
58:31
classes are the dopamine antagonists to
58:34
block that transition from the uh immuno
58:37
you know the radiation sensitive to the
58:39
radiation
58:41
uh resistant cells um because
58:44
interestingly the the use of this drug
58:46
like
58:47
the the dopamine antagonist it doesn't
58:49
work by itself you actually have to do
58:51
it with radiation at the same time which
58:54
i i think is um it's an interesting
58:56
phenomenon
58:59
interesting thank you
59:04
so if that's all the questions we'll um
59:07
maybe let dr lee i'll take a short break
59:10
and then uh the residents can stay on uh
59:12
for their meeting
59:15
okay great thanks linda appreciate it
59:19
thanks sander
59:21
let me know when you want to come to l.a
59:25
thanks very much great talk
59:27
bye
59:50
you