0:00
The Glasgow Neurosociety
0:04
in association with SI, or Surgical Neurology International, and SI Digital are happy to present
0:15
the abstracts and discussion of the 10th anniversary Glasgow Neurosociety meeting held in November of 2022 in Glasgow, Scotland.
0:30
Hassan Ishmael is president of the Glasgow Neurosociety at that time. He's from the Wolfson School of Medicine at the University of Glasgow in Scotland and the United Kingdom
0:45
Faculty commentators are Likith L. Akhandi, who's the consultant neurosurgeon at the Queen Elizabeth University Hospital in Glasgow
0:58
And Amy Davidson, a neurologist, also at the University of Glasgow, also at the Institute of Infection, Immunity, and Inflammation in Glasgow, Scotland.
1:11
Other Glasgow neural hosts were Alidith Middleton, Vice President of Glasgow Neural, and Attica Choudhary, another Vice President of Glasgow Neural.
1:34
This abstract is presented by Erika Major Ferrias and her colleagues from the University College of London. London, the United Kingdom. She's a postdoctoral researcher and others are involved in
1:49
different departments there.
1:53
On this study, elucidating, which is elucidating the role of regulatory T-cells and CD5 expression in human and mouse glioblastoma, using single cell RNA sequencing
2:14
I'd like to give you a short summary of the abstract, which you'll see on the screen.
2:22
Glioblastoma, we all know, is a most malignant brain tumor. It's third most common. The first is our metastases to the central nervous system, and the second is meningiomas, and those are
2:42
described as being from the meninges, and tumors arriving from the tumor cells of the central nervous system itself are glioblastoma and astrocytoma, and of those, and others, glioblastoma is the
2:58
most common, it's the most deadly All after
3:04
treatment of glioblastoma by from radiation or chemotherapy and surgery. It's somewhere between 11 and 15 months. Generally, there's some who will live a little bit longer. So Hylom and Lignon
3:18
Tumor. So these investigators were exploring whether the immune system could be used to attack the nervous system and develop some experiments to prove that.
3:36
We know that the glioblastoma grows up in an environment in the central nervous system. That's an environment that can both inhibit the tumor from growing and also has factors which can accelerate it
3:51
from growing. There are those factors in the cell itself which can do that and also factors in the environment which may do that.
4:01
From the work there, work on others, they found that the immune environment can produce substances Basically. molecular substances which would inhibit the rest of the immune system from attacking
4:14
the brain tumor.
4:17
And they were able to find an agent called RG6292
4:21
that had been used in other studies that prevents the immune system from shutting off the other parts of the immune system that would attack the brain cells.
4:36
And they used this in an experiment using animal models in mice.
4:43
So they had treated mice and untreated mice.
4:48
And what they found is in the treated mice the survivals were longer. The cells which were these cells suppressing the immune system were found to diminish in numbers and the treatment appeared to be
5:06
very
5:09
They proposed that this would be a model that could be used in humans because essentially the same system of immune suppression and support is carried on up into the human species. And so suggest
5:25
that this is a treatment that could be considered. So by manipulating the immune environment, they were able to increase the death rate of the glioblastoma cells and extend the survival of the
5:40
animals. The discussion of this work will follow. Back everyone. Our next panelist is Erica Meer-Farias, who will be presenting our very exciting work, elucidating the role of regulatory T-cells
5:42
and CD25 expression in human and
5:59
mouse glioblastoma using single cell RNA sequencing without further ado, over to you, Erika. Take the floor. Okay, hi, my name is Erica Mihia. I'm a final year medical student at King's College
6:11
London. Thank you so much for the opportunity to share some more about the work I did with the UCL Cancer Institute.
6:21
So yeah, as you can read from the title, this project focuses on glioblastoma, which is one of, which is the deadliest form of brain cancer. And so it's, it has a very poor prognosis in patients
6:37
and it has a pretty poorly understood tumor micro environment. So, you know, sort of what makes up the tumor. However, regulatory T cells, also known as T-Rex, have been found to greatly
6:51
contribute to this environment and likely are causing it to be very immunosuppressive. So to likely preventing the immune system from fighting the glioblastoma, also known as TBM Um, And this is
7:05
found to likely be through CD25 expression. So our lab has done previous experiments targeting CD25 positive T-RAGS, regulatory T-cells, using like a specific anti-CD25 monoclonal antibody. And
7:26
it's done this in mouse studies, in other cancers, so not GBM, and it's had success So this particular project focused on
7:35
mouse GBM models targeted using this monoclonal antibody. And so in the focus of this project was to use single cell RNA sequencing data to analyze the results, see what we find, and compare it to
7:51
human data sets to see if there could be a translation of the effect in the mice into human patients in the clinic And so this project did - so basically, the model integral. I'm Monica Antibody,
8:05
did successfully deplete the regulatory T cells in the mice. And this resulted in also tumor cell depletion and then increased mouse survival in the treated mice compared to control mice that weren't
8:22
treated with anything.
8:24
And so this was a very positive result
8:32
that was found And so by doing some more digging into the single cell RNA sequencing data that we had, we found that
8:38
there was a regulatory T cell signature. So like the T-Rex had a particular genetic signature. And it had several oncogenes and immunosuppressive genes in this signature. And this was translated
8:52
into what we found in
8:55
the human data sets So it had a very similar signature as well, showing that the strong monoclonal antibody effect we found in the mice does have the potential to translate into humans based on the
9:10
similarities we found between the regulatory T cells in both species.
9:15
Yeah, so this was a very positive result and this monocle antibody known as RG6292 is now currently in phase 1 clinical trials as well. And so, yeah, we hope that by, you know, sort of
9:30
harnessing these positive results we found and,
9:34
you know, the great possibility that there is of these results transing the humans. This could then, you know, provide better outcomes for this patient group with these aggressive cancers who
9:43
don't really have as many treatment options at the moment. So that's, you know, what we found what we're hoping for and yeah, it's all very exciting.
9:54
Thank you. That's really good I still, you know, trying to understand the hypothesis here. Are you trying to suppress the Tregs
10:07
so that the outcome is improved, just from a very basic point of view? Yeah, so the Tregs, Soregatory T cells, they usually down regulate the immune system, just in general. And then what we've
10:23
been found by sort of digging into the GBM tumor microenvironment is that it appears that these Tregs are using up
10:33
IL2, which is usually involved in T cell proliferation. So basically it's taking up all the IL2 and preventing T cell proliferation. And so then by targeting the Tregs and depleting them, so we
10:46
also found that this also resulted in marked T cell clonal expansion. So it does seem like if you target the Tregs, this allows other T cells to then activate, particularly in our study we found
10:59
cytotoxic CD8 T cells. to then activate and actually, you know, be able to work on the tumor, to complete the tumor cells, and then hopefully, and then as we found, increase survival. So
11:10
that's the correlation. So are we talking about T-Rex in blood or T-Rex in the tumor infiltrating T-Rex because they have two different populations? Yeah, so we, I think we focused on tumor
11:24
infiltrating T-Rex. So we were looking at like samples in the like in the brain specifically not necessarily in the like in the vessels if that makes sense. So it's the next question I'm sure you
11:34
would have been asked before is the role of steroids you know what do they do to the T-Rex and you know when you're actually treating a
11:43
patient with when you translate this into a clinical trial you have to withhold your steroids otherwise because they have a separate effect in the T-Rex but then steroids are needed for controlling
11:56
the dema so how do you overcome this problem? That's an Excellent question. So when we looked at the human data sets, we looked at two different data sets. And one of them did look at, we said
12:11
one of them did have dexamethasone treated patients and non-dexamethasone treated patients. And so we were also able to look into that a bit and see what
12:24
was happening, what it was doing to the regulatory T-cells. So we did find that, so I guess, like you said, with the dexamethasone, is it is a bit more complicated because it does cause
12:37
immunosuppression, but it's also needed for
12:41
the cerebral edema.
12:46
So it is sort of, yeah, it's just quite complex, but I mean, I guess what we found just by looking at the data is that there were less - So just for -
12:58
No, no, okay, that's a, you know, thing. But, you know, when you're doing a critical trial, would you have two arms, would you propose it? I know it's a difficult proposition, but are you
13:06
going to propose it two arms, one with steroids and one without dexamethasone? Yeah, I think that could definitely be something we'd look into. I think in the current clinical trial that's
13:15
happening right now, it's just just looking at, it's basically just looking at solid tumors and recurrent tumors just to see if it could do anything there. And, you know, see how tolerable it is,
13:25
how safe it is And I think from then on, we can then look into, you know, more finer details, like combination treatments for, you know, we should avoid this treatment with this monoclonal
13:34
antibody and that sort of thing. But it's definitely like a really great consideration. So, for one final question,
13:42
how much do we know about the crossing the blood brain barrier for the maps?
13:48
Yeah, that's also a great question So,
13:52
we found several studies that sort of support the idea monoclonal antibodies can actually cross the blood being brain barrier in pathological conditions like as in cancer. But then additionally,
14:05
there are also new techniques being looked into such as peptide shuttles. So by attaching the monoclonal antibody to a peptide, that would hopefully allow it to cross the blood brain barrier and
14:18
things like that. But yeah, I think as with most neurological conditions, that's one of the biggest issues we have is crossing the blood brain barrier But that's definitely something, you know,
14:29
another thing to look into, and to hopefully achieve more results with. And then, you know, hopefully by seeing, if we get these, you know, positive results from the patient on clinical trials,
14:39
seeing if it's horrible and safe, we could go, we could pursue that avenue as well to make sure that we can actually, you know, safely deliver the drug to patients. Thank you very much, good
14:49
work and great responses, Erica. Thank you very much I just had a really quick question if that's okay.
14:58
the opposite of what Mr Alchandi was saying there. So you're talking about kind of systemically administering a map to target a brain tumor. What's going to be the response of the rest of the body?
15:13
If you give an anti-CD-25
15:20
monoclonal, what do we think it's going to do to the kind of systemic immune system? What kind of side effects are the patients going to see? Yeah, that's a really good question. I think it's one
15:29
of those things that we see with most immunotherapies or systemic therapies. A lot of GI effects are like GI negative side effects or just general sometimes immune over activation. But I think
15:45
because what we've done is tried to
15:48
elucidate a signature that these regulatory T cells have And so I think if we're able to sort of pinpoint like a more specific signature for the T-regs in the brain and then have a look also at blood
15:59
samples, see what the T-regs and the other parts of the body look like, how they differ and see how we can sort of tailor our treatments specifically to the ones in the brain. I feel, I think that
16:11
would be good because, you know, the more it would be better to, you know, like you said, not have all these systemic effects and everything like that. But yeah, it's quite a common problem
16:19
with, you know, most immunotherapy and hopefully by further looking into the signature, we can sort of harness the signature a bit better. And could it ever be something that you think of
16:32
administering more locally? I don't know, intrinsically or directly during surgeries or, you know, is it always going to have to be something that's systemically delivered, do you think? Yeah,
16:44
that's a really good question. I'm not entirely sure the answer to that, but I think 'cause like I mentioned, like, you know, different treatment routes are being explored, you know, peptide.
16:55
and like blood brain barrier, all these things. I think that would definitely be something to explore as well, especially because in the mice, we do tend to inject it directly, but that doesn't
17:04
necessarily translate into humans. And so yeah, that's definitely something to think
17:11
about. It's not impossible though. It's not impossible. That's probably one of the delivery routes as well. So good. Interesting. Thank you very much. Great. Thank you so much for your time
17:23
Lovely, and Erica, before we let you go, any other comments or anything from your end?
17:31
Not really. Thank you for your time.
17:34
It was very nice to meet you. That question always catches people up. No, no, absolutely. And again, thank you so much for that. And that wraps up this panel report. We hope you enjoy these
17:44
presentations.
17:48
The information provided in this program is for informational purposes and is not intended for use as diagnosis or treatment of a health problem or as a substitute for consulting a licensed medical
18:04
profession
18:08
Please fill out your evaluation of this video to attain CME credit.
18:16
This recorded session is available free on snidigitalorg.
18:23
Send your questions or comments to
18:29
osmondsnidigitalorg
18:32
This program has been supported by the James I. and Carolyn R. Osman Educational Foundation, owner of SNI and SNI Digital and the Waymaster Corporation, producers of the Leading Gen Television
18:49
Series, silent majority speaks and role models and the new Medical News Network.
19:17
Thank you.
View Transcript
Listen to Podcast