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American Brain Tumor Association Webinar
Viral Therapies for Brain Tumors
>> Hello everyone and welcome to the American Brain Tumor Association webinar series. Thank you for
participating in today's free educational webinar. Today's webinar is on viral therapies for brain tumors.
It will be presented by Ian Parney M.D. Please note that all lines today are muted. If you have a
question you would like to ask, type and submit it using the question box in the control panel on the
right-hand side of your screen. Dr. Parney will answer questions at the end of the presentation.
Tomorrow you will receive an email asking you to evaluate the seminar. Please take a few minutes to
share your comments. Your feedback is important to us as we plan for future webinars. Today's webinar
is being recorded. The recording will post to the ABTA website shortly. Registered participants will
receive a webinar link in an email once the webinar is available. Let's pause for a moment so we can
begin our webinar recording.
>> The American Brain Tumor Association is pleased to welcome you back to our webinar series. Our
webinar today will discuss Viral Therapy for Brain Tumors. The webinar is sponsored by Mayo Clinic. My
name is Andrea Garces, program manager here at the American Brain Tumor Association. I am
delighted to introduce our speaker today. Ian Parney, MD, PhD. He is a neurosurgery consultant at Mayo
Clinic in Rochester Minnesota. He earned his undergraduate medical and doctorate degrees at the
University of Alberta. He completed a neurosurgery residency at the University of Alberta and
completed fellowships in neuro-oncology and brain tumor research at the University of California San
Francisco. Dr. Parney's clinical interests include brain tumor surgery, gamma knife stereotactic
radiosurgery, awake brain surgery, brain tumor vaccines and viral therapies for brain tumors. Thank you
so much for joining us, Dr. Parney. You may now begin your presentation.
>> Thank you very much. As you've heard my name is Ian Parney and I am a neurosurgeon and cancer
researcher at the Mayo Clinic here in Rochester, Minnesota. Today we are going to be talking about viral
therapies for brain tumors. I always feel a little bit of an imposter when I'm talking about viral therapies.
I've given this talk in a few different guises. There are researchers out there that have spent years trying
to get clinical trials organized for viral therapies and I know one quite prominent person who spent
about 10 years trying to get one virus into a clinical trial. I'm kind of the accidental cancer virus person in
that I've actually been involved with about four different clinical trials for viruses for brain tumors now.
Largely by being at the right place at the right time. In the course of doing that, I've come to know a fair
amount of things about virus therapy for brain tumors and that's what I'd like to review today.
>> I have some disclosures. I'm an employee at the Mayo Clinic but otherwise no relevant stocks, patent
rights or employment. I'm a consultant with a company called Agenus Inc. and I do have some clinical
trial and grant support from the National Institutes of Health, Ivy Foundation and the Brains Together
for a Cure foundation. My objective today is that I want to go over types of viral therapies for brain
tumors. And discuss a little bit about what a virotherapy means. I want to talk about strategies for using
viruses to treat cancer. I'm going to talk more specifically about a clinical trial that we have open here at
Mayo Clinic as an example of how these therapies work. It's an oncolytic measles virus study. Finally, I
want to finish with some future directions, where I think viral therapies for cancer and brain tumors may
be going in the future. Virotherapy for cancer, many of you may be thinking that's just kind of crazy.
Viruses are things that are bad and at a minimum give us the common cold and a little worse can make
us sick like the measles or mumps or things that can be absolutely terrifying like Ebola or things like that.
How could we possibly be using viruses to treat cancer? There's a few different ways that we can do
that. It really comes down to either using the virus to deliver something, a genetically engineered virus
that will deliver a new gene to a tumor that might alter that tumor’s biology, or using the virus as
something that's going to infect and kill the tumor directly. There's a few different general ways to do
that. There are things called replication-deficient viruses or viral vectors and replication competent
oncolytic viruses. These are really $10 words but really, what a replication-deficient virus means is it's
just a virus that has been modified so that it cannot divide anymore. It can infect one cell, but it cannot
divide and make more cells. These are things that are built in for the safety of the virus so you are not
going to get a virus that will escape and cause widespread injury to someone or disease like measles or
something like that. These replication-deficient viruses are usually used as vehicles to deliver something
to the tumor cells either a gene that is therapeutic in some way that might replace a gene that has been
lost in the tumor, or a gene that is something that will make the tumor cells sensitive to a drug, a pro
drug gene.
>> That's in contrast to what are called replication competent viruses, or oncolytic virus. The idea with
these is not so much to deliver a new gene to the cells, but simply to infect the tumor cells so that they
will kill those tumor cells but the virus will replicate and kill more tumor cells and propagate itself. The
added advantage is it will get more virus and there but obviously there are some risks that can be built
into that if that virus escapes and causes problems elsewhere in the body beyond the tumor. These
destroy tumor cells upon their release and then they can spread throughout the tumor. So how would
this work? You might start with something like this, a cancer-fighting virus, and say how are we going to
get this to someone with a brain tumor? Most commonly right now, this has been really just directly
injecting the virus into the tumor at surgery. In other words, making a hole in the head with a surgical
approach and injecting the virus directly into the tumor. That has been quite effective in some cases and
has led to tumor responses and has been a very promising approach. This is the general idea here is that
we would get the virus to the tumor in some way that would then allow it to do its job there and not
spread elsewhere on the body. I want to talk a little bit about gene therapy. This is about virotherapy
but the first gene therapy -- and you may have heard about these -- they are forms of viral therapies and
one of the first ways this was done for almost 20 years as an experimental treatment is something using
one of those pro-drugs, a gene that can get transferred to a tumor cell and make it sensitive to getting a
medication that wouldn’t be sensitive otherwise. You may take a glioblastoma cell sitting like this and
might give a person or a tumor in the person a replication-incompetent viral vector. This is a virus that
has been genetically modified and it will enter and infect the tumor cell, but it won't divide once it's in
there. It will just infect the cell. But when it's there it will deposit its pay load, which is a gene that has
been inserted into the virus, something called a TK gene. This is a gene that makes cells sensitive to a
medication called Ganciclovir. Normal cells in the body don't have this particular gene. Cells that have it
-- and it's a gene that comes from a different type of virus called the herpes simplex virus -- cells that
have this gene will become sensitive to ganciclovir and will then die in response to treatment with the
ganciclovir. This is something that has really gone through a lot of evaluation with brain tumor patients.
It was really one of the first gene therapy things to really become used in a clinical trial for anything. It
led ultimately to a large randomized, controlled trial of this approach that was published almost 16
years ago using this thymidine kinase gene in addition to surgical and radiation in patients with newlydiagnosed glioblastomas. What can we say about that? The general approach year was that they use
something called a retrovirus, or type of virus that they genetically engineered to have this particular
gene. Because the virus wasn't dividing on its own and they wanted to have lots of the virus there to
infect the tumor cells, what they did is use a cell that they had grown in the lab in tissue culture called
PA 317 that would produce this virus, and they would inject those cells into the walls of the resection
cavity after glioblastoma had been removed at surgery. Afterwards patients would get treated with this
medication ganciclovir for two weeks right about the same time they are getting their radiation therapy.
This was very safe. There were no SAE's linked to the gene therapy. People tolerated treatment very
well. Unfortunately I'm reminded a little bit of one of my professors of pharmacology in medical school
who said any treatment that isn't causing side effects is probably not doing much. Although this was
very safe, it was pretty ineffective. If we looked at the progression-free survival in patients with newly
diagnosed glioblastoma treated with surgery, radiation and the HSV-tk gene therapy, really not much
difference between the two groups - those who got treatment and those that didn't - and the overall
survival was not much different between the two groups. This was in an era before the standard
treatment with temozolomide. Most folks would do better than this now just with TMZ, but this was an
early study looking at a type of viral gene therapy.
>> Obviously this particular treatment has not become standard of care over this last 16 years because it
was not that effective in doing the study. But variations on this are still active and out there and people
looked at ways of how can we do this same kind of idea pro-drug, gene therapy and make this work
better? Part of the problem I think that they had in the study was delivery. I think that gene therapy and
a lot of viral therapies are like this. It's like having the perfect tool to fix your car and then throwing it at
the car. In other words, getting the virus to where you want it to be is a problem and I think the strategy
of just simply injecting a non-dividing retrovirus in particular into the tumor cavity wasn't working very
well. Those retroviruses that were used in this particular study only infect dividing cells. Obviously within
the tumor there's lots of cells that are dividing, but they are not all dividing at the same time so if they
didn't happen to be dividing when the virus was injected, they didn't get affected and the treatment
wasn't as useful. People have looked at other alternatives and said could we use a different virus
something called an adenovirus that will allow us to get higher titers and make more virus so you can
get an increased concentration, but in addition it also infects non-dividing cells, so it is more universally
effective for the tumor. About the same time that that randomized trial came out, this group had
published a study where they looked at the overall survival in a similar group of glioblastoma patients on
a non-randomized comparison of about 14 patients. The patients who had gotten the retrovirus
treatment versus the adenovirus treatment, you can see that the patients that the adenovirus treatment
had a pretty significant increase in survival between the two types of treatment. This then led to some
further studies published a few years later doing again a small randomized trial of standard treatment
which at that time was surgery and radiation. And compared to the surgery, radiation and the
adenovirus with this HSV-tk gene therapy. In this group there are still relatively small numbers but a
little bit more and there was a very highly significant increase in the survival in the patients that got the
adenovirus treatment compared to the patients that got the standard treatment. So again very
promising. Also still small study and more work was needed to be done and there was still some
technical issues about how to get the virus in there and things like that. This has kind of undergone a
few modifications over time. Now is probably most fully expressed in something called the Toca 511.
This is a different virus but it's the same general strategy. It's a replicating virus, so not just something
that is replication incompetent. It will actually divide so it will infect and kill more cells but is a
retrovirus. Instead of expressing the TK gene the other one we talked about had it has a yeast cytosine
deaminase. That's another gene that will make cells sensitive to a chemotherapy that wouldn't
otherwise be sensitive for cytosine. It has what they call a strong bystander effect which means that if
you have two cells side-by-side, one of them is infected with this virus and has this gene expression and
the other one is not. Both cells are then exposed to this drug - killing the one cell will actually still end up
killing the cell right next to it so it has a bystander effect. There are ongoing clinical trials using the Toca
511 one. There's a lot of discussion in some of the big neuro-oncology meetings right now. They are
looking at both direct injection and injection into the spinal fluid, an intrathecal injection. This is an
active area of research and something that may be coming to fruition in terms of becoming more of a
standard care down the road if the studies now hold up some of their promising early results.
>> I'm going to switch gears a little bit now. We've been talking about viral gene therapy. I want to talk
about a different approach to viral therapy for cancer and that is these oncolytic viruses. Onco being
cancer and lytic meaning licing (?) things these are viruses delivered to patients to kill tumor cells. This
may sound far-fetched and science fiction-ish but it's an idea that occurs and has been around for a long
time and it has been around for a long time because it occurs naturally, rarely, but it does occur. So I
have a reference here to a paper that was published 45 years ago. It was really the first time this was
recognized. There's a type of lymphoma that can occur most commonly in Africa called Burkitt's
lymphoma. There was this dramatic case that was published in 1971 of a young boy who had Burkitt's
lymphoma which is normally a fatal disease particularly at that time. In 1971 it was a very difficult thing
to treat. This boy who got this Burkitt's lymphoma also afterwards got a measles infection. So he had a
full-blown case of the measles. The measles got cleared by his immune system and he recovered from
that and as he recovered, the tumor disappeared as well. His tumor went away. So he had a really
dramatic response to his tumor when he had measles infecting him and the whole idea was the measles
infected a lot of different cells, but in particular it infected and killed the tumor. This was an idea -- can
we somehow exploit this potential virus to kill tumor cells in a controlled and safe manner? So this is
really using replicating viruses. These are viruses that divide. The idea here of what we want these
replicating viruses to do is that you will have a tumor cell, you will give that tumor cell - somehow
expose it to virus. The virus is going to them infect the tumor cell and within the tumor cell it will divide
like crazy until the tumor cell just cannot cope with that anymore and essentially the tumor cell
explodes. When it explodes and dies like that, that releases more virus which can then infect a bunch of
other cells, tumor cells, and also maybe, not tumor cells. So here is the rub with using these replicating
viruses. How can we think about doing this in a safe way that's going to kill the tumor cell but not kill
everything else in the body and cause widespread disease just from the virus alone. There's a lot of ways
that people have thought about how to do this and this is kind of a busy and technical slide. I will try to
walk through some of the ideas here. It basically comes down to altering the virus or choosing the virus
carefully in such a way that you can alter it so that yes it will in fact and kill tumor cells, but you can alter
it genetically so it will only infect and kill tumor cells and it cannot divide in other types of cells. Or you
could use the idea of getting an attenuated strain, a not very strong virus strain. Either naturally
occurring, that is weakened, or something that you genetically engineer so that yes it will infect and kill
tumor cells and maybe there would be the potential for some infection of other cell somewhere else
that not a really great deal of infection of other cells and your immune system might be able to mop up
the residual of that virus. In the meantime, you have gotten rid of the tumor. People have also looked at
ways to genetically engineer the virus so it will only recognize and infect tumor cells. And only infect the
cells that have that protein.
>> Finally, there are certain viruses that are described here as naturally smart oncolytic viruses. These
are viruses that for whatever reason have evolved over time so that they actually will have a specific
predilection to infect and kill tumor cells and leave normal cells unharmed. These are the general
strategies that people try to exploit to kill tumor cells and leave normal cells unharmed with a virus. Just
to go over some of that and give you some examples of that. These oncolytic viruses strategies, the
attenuated viruses, non-virulent engineered viruses. This is a bunch from the herpes simplex virus that
have been genetically engineered. They just are not as strong a virus anymore and they will kill and
infect tumor cells. They can potentially get out and kill some other things but they are weakened so that
your immune system is pretty good at dealing with them. This is a virus with its teeth removed. Here is
our virus and we will get rid of those teeth and throw them out. One way to approach the virus therapy
for cancer is just to use a slightly weakened virus and hope that your immune system is going to
eradicate whatever is left over after it finishes with the tumor. Another strategy is to use targeted
viruses or an engineered virus. A common example that many of heard of is a poliovirus. Trials have
been performed recently at Duke University. These viruses – again, the details of technically what has
been done here are not important, except to say they have been genetically altered so that they will
have a particular ability to recognize, infect and kill brain tumor cells and leave other cells unharmed. So
they have really good eyes to find the virus and in fact, this is a virus with bionic eyes that have been
man-made. The third strategy we can talk about is the viruses with a natural tumor tropism. These are
viruses that for whatever reason just naturally tend to infect and kill tumor cells and leave normal cells
unharmed. One type of virus that I've been involved with in clinical trials in the past and now is
something called reovirus. The trade name is reolysin. This is a virus that normally causes a mild cold or
upper respiratory tract infection, but it's not anything dramatic. But in a cancer cell that has some
abnormal growth factor pathways activated, the reovirus goes wild and will kill those cells. Normal cells,
there is a mild infection and your immune system clears it out, but in cancer cells the virus can be much
more effective at getting rid of those tumor cells. There's other variations on this idea. There is
something called the Newcastle disease virus that is being study at the Hebrew University in Jerusalem
which is delivered intravenously. These are naturally occurring viruses with natural eagle eyes that can
find the tumor and eradicate the tumor cells.
>> How does this look in terms of actual patients right now? To talk a little bit about that, I thought I'd
give an example from a clinical trial that we are just finishing up here at Mayo Clinic. Finishing up here at
Mayo Clinic. I would say these are all experimental. There is nothing right now that is a standard care
that you can get as a routine treatment. Any viral therapy at the moment for any type of cancer
including any type of brain tumor is going to be part of a clinical trial. What does that look like for
patients getting a clinical trial? This is a trial that I've been involved with along with Eva Galanis, she is a
medical oncologist here and I've been the neurosurgical coinvestigator on this and we have support
from the NIH for the SPORE grant. This was optimizing measles virus therapy for glioblastoma
treatment. This is kind of a case where we used an attenuated virus. This is a virus that is kind of weak
and it's actually the same strain of the virus, these are different strains of measles virus is here. It’s the
same strain of the virus that is used in making a measles vaccine. It's a replication competent virus. It is
actually genetically altered. It's not genetically altered in a way that makes it more or less effective at
killing tumor cells. It's just pretty good at killing tumor cells. We have altered it. We put in a gene that is
not normally in the virus called CEA. This is a protein that will get expressed by any cells that are
infected with the virus and it can be detected in the blood of patients. This CEA protein is normally
increased in some cancer patients with specific types of cancers, most commonly colon cancer and
things like that. It's not supposed to be elevated in patients with brain tumors, with gliomas. Although
we had one or two people that did have some baseline elevations in their CEA. Generally speaking it is
not elevated in brain tumor patients. The idea here is this was going to be a marker if our replication
competent measles virus escaped and began to cause problems outside of the brain because we would
be able to look at the CEA levels in blood over time in these patients. What we thought we might see is if
it worked exactly the way we thought than we might get a little bit of a bump in the CEA protein in the
blood of these patients but not really very much and it would then disappear as that virus was cleared.
Alternatively if we had a really significant amount of virus produced, it might get large amounts but it
should get cleared away over time. The thing we really wanted to be aware of and avoid was if we saw
this. Where we saw the virus steadily increased over time. That would really be a sign that the virus had
escaped into the body and had potential to cause problems. This was just a marker for safety as we did
the virus study of this trial.
>> This was a study for patients with adult recurrent glioblastoma. They had to be at least 18 years old.
It wasn't for patients with a newly diagnosed tumor, but with a current glioblastoma. Everybody who
was going to get enrolled in the study had to be at least a candidate for surgical resection, either a gross
total resection or a sub-total resection. It couldn't be a biopsy or no surgery at all. As with any clinical
trial, it had to have some basic normal blood tests showing everything else in the body that we would
worry about in terms of tolerating the treatment was working pretty well. We had to check the CEA
levels because they had to be normal. They are supposed to be normal in everybody with brain tumors we did have two patients that had elevated CEA levels and they were not eligible to go on with the
study. Finally, we had in the criteria that everybody had to have measurable levels of antibodies against
the virus. This was just a safety issue. We wanted to make sure if the virus did escape that people would
be able to mount a response against it. Most people in the United States have measurable levels of
measles antibodies. We've only had one or two people that were being screened for the study that were
not eligible because they didn't have the measles antibodies. We divided the study into two separate
arms. There was a Group A and a Group B. The Group A was a true phase 1 trial. You will hear about
different phases of trials - phase 1 is the earliest stage and in this case was a first in human study. It was
really just starting at a very low dose of virus in treating a few patients with that low dose and increasing
that dose a little bit and then a few more patients and so on until we established a dose that was safe to
give. In this case, we would go take up the whole tumor and then inject the measles virus into the
resection cavity or into the brain around the resection cavity. It would be one operation. We did that
and treated a number of patients and basically found that the virus was safe up to the highest dose that
we could manufacture and give to people.
>> Then we went back and said now we will do a second part of this study and this is what we're just
finishing up right now. We do two operations: the first operation was a biopsy of the tumor that had
recurred on the MRI scan. And then just stereotactically injecting through a tiny tube or catheter into
the tumor injecting the virus. And then we cut tube off and leave it in place and close everything up over
top of this. It is a small incision with a small hole and using an MRI to guide it and placing the catheter in
the tumor and injecting the virus. Then we come back five days later and do a full operation, a
craniotomy to open up and take out the tumor and the tube that we left in “en-block” which means we
take it out as one lump instead of piece-meal. Then we inject more virus around the resection cavity
again, doing this at pretty high number of viruses or concentration of viruses because it was pretty safe
to do that in the first group of patients. This study is going to ultimately be about 30 patients. We have
enrolled 28 patients so far. We just have about one or two left that are going to get enrolled into this
study. This is how that looked. Patients would have their surgery and putting the tube into the tumor
and injecting the virus and then we would check the MRI scan and look for virus and any signs of CEA
levels going up in the blood on day three. On day five we go back, we take the tumor out and the tube in
the middle of the tumor and then we inject more virus around the cavity. And we look at the MRI for
changes and follow the CEA levels to see if there's any sign of the virus escaping into the blood. We look
at a number of other things to look at the immune responses, to see if anything along that line is being
generated by our virus. I will come back to that because this idea of the immune system being a partner
for an oncolytic virus therapy like this -- this is an increasingly important concept and we will come back
to that. This slide is a little bit old. This is only the first 14 patients and we are up to twice that many
now. About 28 patients. The data is basically similar. These are pretty standard patients with recurrent
brain tumors that we are looking at. Nothing particularly unusual about them. In terms of toxicities, this
has been very well tolerated. The kinds of toxicities that we're talking about have all been grade one or
grade 2. These of all been pretty mild toxicities and the majority were grade 1. Not even 100% clear that
all of these can be related to the virus. Some of these are probably just related to the tumor and things
along those lines. The bottom line is the virus has been tolerated very well. It has been safe in addition
to non-toxicity, there's been no evidence of the virus getting out into the bloodstream or being shed.
There's been no increase in the CEA levels to go along with that and we haven't actually seen any
increase in the anti-measles antibodies. It's not like the immune system is clearing that out as you would
expect if it has gotten shed. It looked very safe.
>> One thing that I think is worth pointing out, is just the difference between patients with
glioblastomas and patients with other types of cancers, in this case of ovarian cancer. When we look at
the anti-measles antibodies in the blood of these patients, there's another trial going on at Mayo Clinic
for ovarian cancer with the same type of virus. We've drawn blood levels on all the ovarian cancer
patients as well, looking for anti-measles antibodies. What you can see is the ovarian cancer patients
have relatively normal amounts of anti-measles antibodies. Glioblastoma patients, some of them had
more normal patterns but there's a subset that really did not have very many measles antibodies. This
really seems to hold up as we look at different cancers getting treated on various trials with the measles
virus. Glioblastoma patients seem to have less anti-measles antibodies. They tend to have a little bit
more of a suppression of their immune system at baseline than patients with other cancers. So we have
to think about that as we think about treatments.
>> I'm a surgeon. I can’t go through a talk without one or two gross pictures. I apologize but, this is so
you have an idea of what I am talking about. This is the kind of tube that we have going into the tumor
that we have injected the virus in there, five days earlier, and then we take the tumor out as a big lump
including the tube sitting in it. When we do this and look for signs of virus replicating - this is now
microscopic levels of the virus and varying amounts of virus injected here – as we inject more and more
virus, we get more virus replicating within the tumor. So we are definitely seeing the virus gets out into
the tumor and divides and can have an effect on the tumor. We are beginning to see that some patients
have tumors that seem to allow the virus to divide and some patients have tumors that don't seem to
allow it to divide. We are hot on the trail of figuring out why that is. It looks like there are certain
patients with tumors where they express certain class of genes called innerferent response genes. If you
have those genes in your tumor, you may not be able to get as much of the virus dividing in your tumor
as if you don't have those genes. My lab is working very hard on trying to find some blood tests that we
could look at that will tell us in advance whether or not somebody has a tumor like that, so that we
might be able to target our treatment better in the future.
>> This trial is just finishing and we are not really able at this point to give a clear idea of what the
clinical outcome for patients in the study has been, except to say that in patients where we are seeing
the virus dividing, we are seeing some responses to the virus which is exciting. And some of the other
trials of other cancers if you go on the Mayo Clinic website, they will talk about, I believe it was a patient
with ovarian cancer who had widespread ovarian cancer metastases who got an intravenous injection of
a measles virus like this. Their tumors melted away. We are excited about this in brain tumors as well
but I think we have to wait and see how patients do going forward to get the full information. We will
think about what we're going to do in the next trial because we are just about finished with this. We
may change how we monitor these viruses and the next generation of this measles virus might have an
NIS gene and it. The only thing important about that it means we can actually detect, in this case in
mice, but actually in people if their tumors have been infected by the virus and we will have a better
idea how the virus is working in real time. I think we've optimized the dose, but we may need to do
things to address the immune response particularly the interferon response genes.
>> Here are some other trials using the next generation of these viruses in ovarian cancer, or multiple
myeloma, or prostate cancer using a type of nuclear medicine PET scan tracing. Here's an ovarian cancer
before and after. You can see the virus lighting up in their tumors. Here is the multiple myeloma patient
and similarly a prostate cancer patient. You can see the virus has lit up this tumor. We will be doing this
with brain tumor trials in the next iteration as well. This is some data using the virus in some brain tumor
models in mice, but just to point out we can see some of the virus getting out into the tumor and
causing the changes in the tumor that we see with viral infections. The cells begin to lose some of their
cell membranes and join together with them so we are seeing the kinds of things we would expect to
see with a virus infection. I still think that we are dealing with this problem. You remember the perfect
tool to fix your car that you then throw at the car? It's still a problem with this virus study. The way it's
injected is it's just injected in the tumor and I'm the guy doing that and I can tell you what I'm doing
that, I'm sitting there thinking I hope it's getting where we wanted to go. I hope it's not washing back
out into the cavity and I hope it's actually infecting the cells. I think there would be better waste to do
this. As much as I have a surgeon have no problem with surgery and I enjoy performing surgery, I like to
think I'm pretty good at it, but I think for a lot of my patients and perhaps many of you might say if I
don't have to have another brain operation, maybe that would be okay. Wouldn't it be nice to have
some way to deliver these viruses that didn't involve having to make a hole in someone's head?
>> One way we can think about doing that is to try to deliver them intravenously. They can get into the
bloodstream very well. This is an idea that is attractive, but there are some issues that we have to
address. If we can inject it into the bloodstream and it gets into the tumor and kills the tumor, that's
great. But there are some problems. There are barriers. Within the bloodstream there's a lot of proteins
and white blood cells that will just mop up the virus before it even gets to the tumor. Second, a lot of
that virus when it goes to the bloodstream it goes everywhere that the blood goes, including the liver
and spleen where the virus will often just sit there and not get out to the tumor. Finally, if you put the
virus into the bloodstream, you have to use a virus that can get out of the bloodstream. It has to get out
of the bloodstream to the tumor. There are ways that we can address these things, solutions that have
been outlined. Then we get the virus to the tumor even though we’ve delivered it intravenously. I'm
going to talk about a strategy that we are using with some brain tumors now with a virus called reovirus.
This gets back to something we published a few years ago about brain tumors and other people have
noticed this as well: If you look at glioblastomas as well as other brain tumors, it's not just tumor cells.
When you look at the tumor here itself, if you look for a certain type of white blood cell, called a
monocyte, stained brown here, you can see throughout the glioblastoma there are a lot of these brown
cells. If you look at other white blood cells, lymphocytes, there are some but not very many and they
tend to be just around the blood vessels, they’re not getting out into the rest of the tumor. We can look
at this in different ways. You have a lot of tumor cells down here, but you have a fair number of white
blood cells, most of which are these macrophage cells.
>> I work with a scientist here at Mayo Clinic named Dr. Richard Vile and we used so live next door to
each other. He is very interested in viral therapies for cancer and particularly the reovirus and he kept
hearing me give talks about all of these monocytes within the tumors so he was looking at this in some
of his studies that he is doing in reovirus where they been trying to give intravenously. They’ve found
that a lot of the reovirus would just get mopped up in the blood by these white blood cells. He had the
idea that, let’s maybe take a hitchhiking reovirus and say, we have patients that come in and everybody
has a certain number of these white blood cells in their blood. Let’s juice the system by getting more
monocytes than average by giving you a medication called GM-CSF. Then, let's give you the reovirus, and
inject it into the bloodstream. The monocytes take up that reovirus very effectively, but then the
monocytes get out and go to the tumor cell and deliver the virus to the tumor cell. This is restating the
same idea: early studies of giving intravenous reovirus – they can get virus from white blood cells, but
they couldn't find it in the plasma. If we mobilize the monocytes with this medication, and then give
patients a virus, the monocyte takes up that virus even more if people have an anti-reovirus response
beforehand. The monocytes are acting like a Trojan Horse. They release the virus at the tumor. This isn't
actually science fiction anymore. We are opening up a phase 1 study of using the reovirus in
combination with GM-CSF in pediatric brain cancer patients with refractory brain tumors. This is being
headed up by two of our pediatric oncologists, as well as myself and Dr. Vile.
>> I want to finally end up and talk about the immune system and the virus. This is an idea of taking a
dead lightbulb here, using many hands to make the light work. This reflects what happens normally with
patients with oncolytic virus approach. What I presented before is what oncolytic viruses do, you have a
tumor cell, you have viruses come in and they divide in the tumor cell, they kill the tumor cell, which
releases the virus and the infection kills tumor cells. But in fact, this is what oncolytic viruses actually do.
They come in and kill the tumor cell by dividing and lycing and that releases more virus, but that also
releases particles of dead tumor cell, which have all sorts of tumor proteins and things like that that get
taken up by immune cells, in particular, a very potent immune cell called the dendritic cell. These
dendritic cells go to the lymph nodes and present the particles of the cell that have died this way to
other white blood cells called T-cells. And these activated T-cells are going to be specific and recognize
now tumor cells, and they can go back and kill the tumor cell. In addition to just directly killing the tumor
with the virus itself, most of these oncolytic viruses to a certain degree, as an added plus, will generate
an immune response against the tumor through this indirect pathway. That's just using things as the
virus works normally.
>> The idea here is now to take our viruses a step further to do oncoviroimmunotherapy. Another $10
work. Basically to genetically alter a virus so that just allowing that process to happen by accident or
going beyond that, now we are going to try to engineer the virus to promote an immune response. We
are going to put in genes that are pro-inflammatory that will recruit and activate white blood cells.
These are some examples of genes that can do that. Or sometimes we can put genes in the virus that
will stimulate the immune system against specific tumor proteins. This is actually a cocktail of genes that
Dr. Vile and myself and others just published at the end of last year in mouse models with these
particular combinations of genes using a different type of virus that can be given intravenously. And this
generated a potent immune response against the tumor, in addition to the virus infecting and killing the
tumor itself. This is kind of like How to Train Your Dragon. Some of you may be familiar with that film.
Dr. Vile is a smart guy and he said how to train your oncolytic virus, the sequel. The idea is that you have
a wild type virus and if it gets into somebody, you get an uncontrollable disease, something fatal like
polio or smallpox. You can do what we've been doing with measles and attenuate the virus or use one
that naturally doesn't have very many sharp teeth. It's a nice cute little Dragon and maybe it has some
effects but it's not the best thing to deal with the big bad tumor. So can we rearm this virus to make it a
dragon that has some teeth. It's not as wild and awful is this and it still can be controlled, but we can
treat cancer with it by arming it with things to help get an immune response against the tumor.
>> The idea here is maybe to exploit something called immune checkpoints. You may have heard about
these and a commonly studied one now is called the PD-1, PD-L1 checkpoint. The idea behind these is
the tumors like glioblastomas will express a protein called PD-L1, and if it binds T-cells, the T-cells have a
protein called PD-1 that will bind PD-L1 and that will cause the T-cells to die. If you take an attenuated
oncolytic virus and you deliver that to the tumor, and it causes the cells to die and releases these tumor
proteins or antigens, that will activate some of the immune system and those antigens will get loaded
into dendritic cells that migrate to lymph nodes where they will activate these T-cells. The T-cells when
they get activated, now they express this PD-1 protein and when they come back towards the tumor or
metastases, they are expressing all of this PD-L1 and so the T-cells just die. They can't do their job at
getting rid of these tumor cells. Now imagine we change this, and we have generated or rearmed the
Dragon virus that will infect and kill the tumor cell, but in addition we've made our virus genetically
engineered so it will produce something that will block the PD-1 protein. Now, when you get an immune
response stimulated here, that immune response can come back here but the tumor is still producing
the things that block PD-1. So instead of these T-cells dying when they come into the tumor, they are
going to be more effective at killing the tumor. This is something that there's a lot of people working at,
trying to exploit the system to use this to help get the most effect from our oncolytic viral treatments.
>> In conclusion, I would just say that virus therapies, both replication deficient and replication
competent virus therapies, they have been safe and gliomas in phase I/II trials. But I would say that so
far, the response and patient has been modest. We are seeing things that are promising. But I'm not
sure anybody has hit it out of the park yet. I think that's probably going to change in a big way over the
next few years. With new viruses, new delivery mechanisms and marrying viral therapies with immune
therapies I think this holds a tremendous amount of promise for the future. I think we’ll stop there and
open up for questions.
>> Thank you so much, Dr. Parney. He will now take questions. If you have a question you would like to
ask please submit it using the question box in the webinar control panel on the right-hand side of your
screen. We have quite a few questions and we will try to get as many as we can. The first one is do
different kinds of brain tumors exhibit different markers that require different viruses?
>> Yes. That's an excellent question. I think the short answer is almost certainly yes. I think we are still
kind of in the early days in sorting that out. The most studies, as I am sure you know from the talk, have
been done with glioblastomas and we are kind of getting a fairly good idea about that right now. But
whether those viruses would work equally well for other types of brain tumors, ependymomas or
meningiomas or metastases or various pediatric tumors, I think that's a little bit more of an open
question. We know that all of these tumors are quite distinct and they have different molecules and
pathways that allow them to grow. I think as we get more and more experience with this, we will
probably have more and more targeted viruses - say for glioblastoma we want virus A but for others we
might want virus B.
>> Do these tumor progenitor cells also express the same protein markers that will attract the virus?
>> Yes. Another excellent question. A lot of tumors including brain tumors are made up of a population
of cells called tumor stem cells. Whether these are cells that originated from normal stem cells and then
became cancerous and formed a tumor or whether they are other cells that have become cancerous
and become a little bit more stem-like is not 100% clear. But those cells are a big part of the biology of
these tumors and we need to make sure our treatments are effective against them. So, yes. I think the
types of treatments that we outline today do seem to have affects against both the stem-like cells and
the more differentiated brain tumor cells, at least for gliomas. That's been pretty well-established for
the measles virus. For some of the other viruses, I'm not sure that's necessarily is clearly established but
there may be other things that will go along with the virus therapy like immune response that maybe
that could get activated against the stem cells.
>> There's another question about if you know when you expect to publish the results from the SCORE
trial?
>> Probably that will be a little while yet. We are almost finished with enrollment and I would anticipate
that the enrollments will be finished in the next month or two probably. We obviously have to wait for a
little while after that to see how the last few patients do with that. I would imagine it's going to be at
least a year before that's published. It may come out with some data as a meeting presentation prior to
that but I would imagine it would be at least a year before it hits print.
>> Thank you. How does the IV administration get past the blood brain barrier?
>> It may vary from virus to virus. Some viruses just naturally can get across the blood brain barrier. For
example, measles virus. If you have a really bad case of measles, one of the things that you can get with
that is encephalitis, inflammation or infection of the brain. Some viruses can naturally get across the
blood brain barrier. Other viruses may not be as effective at doing that and so for things like reovirus, if
we were relying on injecting the virus itself into the bloodstream and hoping that the naked virus could
get into the brain, it might not. That's why we've developed this hitchhiking approach where we say the
virus by itself may not get into those across the blood brain barrier, but if we can get it loaded into these
white blood cells called monocytes or macrophages, they are very effective in getting across the barrier
and they can carry the virus in. It may be different strategies for different viruses but I think it's
something we have to think about and address as we develop these treatments.
>> Thank you. In your chart where you are comparing the ovarian cancer trials and the GBM trial, do you
know if that IgG level can be dependent on whether or not you are vaccinated from measles?
>> It can be, but what we've found is the frequency of vaccination and how recent the vaccination was
seems to be pretty similar across our trials whether it's the ovarian cancer, or glioblastoma, or prostate
but the glioblastoma patients, despite having a similar vaccination history tend to have as a group more
people that have low measles antibody levels. That's why -- that's one of the reasons we think
glioblastoma patients have more suppression of their immune system. There is a whole lot of other
reasons and things we could go into about how the brain tumors suppress the immune system but that
is beyond what we're talking about today.
>> Thank you. Does immune response to the virus confer any systemic resistance to future infections
from the same or similar viruses, or is resistance limited to the brain?
>> No. If you stimulate a really effective immune response against the tumor with a virus, there is a
reasonable chance that you may also get a pretty significant response to the virus. That has implications
on how we design these studies. Would you get multiple doses of the virus? Or sometimes, we will think
about even combining different types of viruses so that you might get one virus initially and with one set
of genes. And with a different virus after that but with the same genes to stimulate the immune
response so a chase if you will.
>> Thank you. There's a few questions about viral therapy for low grade gliomas. Are they mostly the
ones that are out there for aggressive tumors or are there many for low grade gliomas as well?
>> By far the most studies that have been done for viral therapies for cancer for brain tumors have been
done in higher grade tumors. I'm not aware off-hand of anything or any large trials that have been
published in lower-grade tumors yet. But people are interested in it and it lends itself well -- some of the
lower grade tumors to these combined virus and immune therapies. Some of the more common low
grade gliomas all have a very particular mutation in a gene called IDH-1. About 90% of diffused, grade 2
gliomas will have a particular type of mutation in this IDH-1 gene. If you could make a virus with that
gene in it, so it could stimulate against that gene as well as the virus directly infecting and killing the
tumor cell, that may be very attractive and I know there's a number of groups around the country and
world that are working on exactly that.
>> The current trials, are they only for recurrent patients and not newly diagnosed?
>> Our trials that we have open for viral therapies right now at Mayo Clinic are open for recurrent
patients only. We will almost certainly be revisiting this in the future once the initial studies have shown
things are safe and we are getting some kind of useful biological response. Other places may have other
studies that are open to newly diagnosed patients. I would say the FDA has been a little bit more
resistant about doing these kind of viral studies in newly diagnosed patients just because there's a
heightened concern about the safety with a viral therapy. So they have said, take the sickest patients
first. I hope we are beginning to get beyond that now. At the moment it's been mostly just patients with
recurrent tumors.
>> Okay. There are a few questions about how people can get into the trials that you mentioned. Do you
have any suggestions for them?
>> You can contact us through the Mayo Clinic if you go through www.mayoclinic.org and go to the
brain tumor sites. There are things about, can you get an appointment and things like that, and you can
ask to get put through to the neuro-oncology study coordinator about these various viral trials to see if
you are eligible for the trials rather than coming out here if the trial wouldn’t be right for you based on
other things we could do like the surgery for example, make sure you meet the other criteria. But yes I
would be happy to field those calls and see if you would be eligible for the studies. There may be other
studies. We've been talking today about virus therapies but we also have vaccine therapies and other
immune therapies. There are other clinical trials for new chemotherapies and things like that so lots of
options.
>> Great. Thank you. I also wanted to mention on our website we have Trial Connect that is also a
service that helps you understand which of the clinical trials are available for you based on your tumor
type and treatment history. Unfortunately, that is all the time we have today for questions, but thank
you so much to all of you for joining us and thank you again, Dr. Parney, for this presentation.
>> For more information on brain tumors and to help patients and caregivers process the diagnosis,
understand a new and difficult vocabulary and access resources to help make informed decisions, call
the ABTA CareLine at 800-886-2282. Let's pause for just a moment to conclude our webinar recording.
>> We invite you all to continue to check back on our website, www.abta.org, for our ABTA library that
features experts addressing a range of brain tumor topics from treatment options and tumor types to
diets and coping with the diagnosis. Our next webinar will be on understanding and treating low grade
glioma on Tuesday, February 16 from 1 PM to 2 PM Central Standard Time. One of the most critical
questions in the fields of neuro-oncology today is how to best manage and treat low-grade glioma, a
malignant tumor of the brain. Dr. Elizabeth, professor and director of medical research, Yale School of
Public Health and attending neurosurgeon and director of stereotactic radiosurgery, has focused her
research and clinical practice on malignant tumors. As part of the ABTA educational webinar series, she
will discuss current treatment options for low grade glioma and how genetics play a role in selecting
treatment. This concludes our webinar. Thank you for joining us and please be sure to complete the
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