Breaking Barriers in the Future of Brain Tumor Treatment

Name: Breaking Barriers in the Future of Brain Tumor Treatment
Uploaded: 2025-04-21T14:46:07.59Z
Duration: 29 min

April 21, 2025

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00:00Funding for Yale Cancer Answers
00:02is provided by Smilow Cancer
00:04Hospital.
00:06Welcome to Yale Cancer Answers
00:08with the director of the
00:09Yale Cancer Center, doctor Eric
00:11Winer.
00:12Yale Cancer Answers features conversations
00:15with oncologists
00:16and specialists who are on
00:17the forefront of the battle
00:18to fight cancer.
00:20This week, it's a conversation
00:21about the care of patients
00:22with brain tumors with doctor
00:24James Hansen.
00:25Doctor Hansen is an associate
00:27professor of therapeutic radiology at
00:29the Yale School of Medicine.
00:31Here's doctor Winer.
00:33How did you get interested
00:34in radiation oncology?
00:37That goes back
00:39way back to when I
00:40was a kid growing up,
00:42and I was a big
00:43fan of Marvel comic books.
00:45And if anybody remembers those,
00:47all those superheroes got their
00:48powers from radiation. Spiderman
00:51was bitten by a
00:52radioactive spider.
00:53The Incredible Hulk was bombarded
00:55with gamma rays.
00:56I figured, who wouldn't want
00:58to have a career in
00:59radiation?
01:00So, unfortunately,
01:02I've been a radiation doctor
01:03for years now, and I'm
01:04here to tell you, those
01:05comics are actually fiction. I've
01:07not yet seen anybody
01:09exposed to radiation get superpowers.
01:11But I have witnessed some
01:13incredible courage in our patients.
01:15And I would say those
01:16are the real superheroes for
01:17sure.
01:18Why don't you tell us
01:19a little bit
01:20about
01:21gamma knife? What is this?
01:24It's a form of radiation.
01:26I think a lot of
01:26people know that, but they
01:28don't know much in the
01:29way of specifics and
01:31where we might use it
01:32and where we wouldn't use it.
01:35I absolutely
01:37love the Gamma Knife. I
01:38think it's a fantastic machine.
01:40I have just one
01:42problem with it, and that
01:43is its name. I wish
01:45for all the world it
01:46would not have included the
01:47word knife because that scares
01:49all of our patients. There
01:50is no knife involved. It's
01:52just a machine
01:53that is designed to give
01:54radiation
01:55extremely accurately and, specifically,
01:58extremely accurately in the brain.
02:00And when we're talking about
02:00the brain, accuracy is literally
02:03everything because we're using radiation
02:05to kill things, which is
02:06good for tumors, but not
02:08great for normal tissue cells.
02:10A gamma knife can get
02:11us to less than a
02:11tenth of a millimeter of
02:13error in our targeting.
02:14We can leave
02:15the rest of the normal
02:16brain alone.
02:17We do that with a
02:19combination of a 3D
02:20targeting box that goes on
02:21the patient's head,
02:22some complex MRI imaging, and
02:25then some very sophisticated arrangements
02:26of some actual
02:28radioactive sources that give a
02:30hundred and ninety two beams
02:31to one little tiny dot
02:32in space.
02:33And so we can position
02:34the patient so that one
02:35little dot is right where
02:37we want it. It's kinda
02:38like painting by pointillism, where
02:40you just dot dot dot
02:41dot dot to cover your
02:42target, and you leave the
02:43rest of the brain alone.
02:45We call those shots.
02:46So you can target very
02:49small tumors.
02:50The smaller, the
02:51better. We love small. Yes.
02:53And
02:54what's the largest tumor you
02:56can target with a gamma
02:57knife?
02:58There's no limit,
03:00but the larger the tumor,
03:02the greater the volume of
03:03normal brain around it that
03:05is getting hit by some
03:06degree of radiation. So we
03:07have to be a little
03:07bit careful. We've got ways
03:09that we can deal with
03:09that by adjusting our dose
03:11or maybe having the patient
03:12come back for a couple
03:13treatments instead of doing it
03:15all in one day. So
03:16there's no real limit,
03:17truthfully.
03:19But, practically, when
03:21would you stop thinking about
03:23doing gamma knife
03:24and start thinking about doing
03:25something different in terms of
03:27size?
03:28Well, it depends very much
03:30on
03:31what kind of a cancer
03:32we are dealing with, because
03:34as you know, it's an
03:35entirely new world now with
03:36targeted therapies and such.
03:38If
03:39we are worried that a
03:40cancer is spread widely throughout
03:42the brain, it's not just
03:43in the one area, then
03:45we'll need to have conversations
03:46about perhaps we might need
03:47to revert to the standard
03:49technique of the whole brain
03:50radiation.
03:52But we try to avoid
03:53that for as long as
03:54we can because we do
03:55have this gamma knife technology.
03:58And
03:58with this technology,
04:00you can give much higher
04:01doses of radiation than with
04:03standard radiation?
04:05That's basically true. Yeah. It's
04:07it comes down
04:08to the biology of radiation,
04:10and we didn't need to
04:10get too far into the
04:12woods on that. But there's
04:13a difference between giving radiation
04:15all in one big dose
04:17versus a bunch of small
04:18doses. And what the gamma
04:20knife can do, because it's
04:21so accurate,
04:22we can really hit the
04:23target hard
04:24once
04:25compared to having to treat
04:26the entire brain over multiple
04:28fractions with a tinier dose
04:29to let the brain recover.
04:31And when you do those
04:33multiple fractions, say over two
04:36weeks or even longer sometimes,
04:39the total dose has to
04:41be increased.
04:43It's
04:44a little bit of hand
04:45waving in terms of how we
04:48say which dose is equivalent
04:49to the other, and not
04:50all of us believe those
04:51equations.
04:52But theoretically, yes, we might
04:54treat in a single fraction,
04:55for example, to a dose
04:57of twenty gray,
04:58whereas the total dose of
04:59a whole brain treatment is
05:00typically
05:01thirty gray.
05:02But it's not a perfect
05:04correlation at all.
05:07And when you're treating cancer
05:09in the brain,
05:10this is both cancers that
05:12start in the brain as
05:13well as cancers that spread
05:15to the brain?
05:16That's right. It does
05:18depend very much on exactly
05:20what we are treating.
05:22By far and away, the
05:23most common
05:25tumors that we are treating
05:26are cancers that have spread
05:27to the brain, which are
05:28things that we call brain
05:29metastases.
05:30There are other forms of
05:31tumors that we treat as
05:32well that start in the
05:33brain, meningiomas,
05:35pituitary adenomas, and such.
05:37But far and away, the
05:38metastases are our number one
05:40that we treat.
05:42And
05:43metastases
05:43happen in patients who have
05:45an initial cancer
05:47and then develop a recurrence
05:49of that cancer. And sometimes
05:51it spreads to the brain.
05:53Recently, there's been talk that
05:55brain metastases seem to be
05:57increasing.
05:58Do you have thoughts about
05:59that?
06:01I think that's in large
06:03part credit to oncologists like
06:06yourself, that are getting better
06:08and better at treating disease
06:10everywhere else in the body.
06:12The brain, unfortunately,
06:14is a little bit tougher
06:15to get those medicines into.
06:17As we know, there's
06:18something called the blood brain
06:19barrier that keeps those drugs
06:20out. So while we're doing
06:22better at controlling disease outside
06:23the brain,
06:25we still need better ways
06:26to control disease in the
06:27brain. And that's getting
06:28better and better. So we're
06:31relying less and less on
06:32the whole brain radiation,
06:34more on the gamma knife
06:35as these better targeted therapies
06:36come along to help us.
06:39And there have been studies
06:40that have shown that
06:42patients actually do better when
06:43treated with gamma knife
06:45or related technologies
06:47than getting whole brain.
06:50Sure. Absolutely. The normal
06:53brain doesn't wanna get exposed
06:54to that radiation. It can
06:55have an effect on things
06:56like
06:57short term memory and
06:59just overall
07:00energy levels. So if we
07:02can avoid it, we should
07:03when we can. That's not
07:05to say that there isn't
07:06a time and a place
07:07for the whole brain radiation.
07:09It's we just have to
07:10pick and choose our battles,
07:11for sure.
07:12And
07:13when would you give whole
07:14brain radiation?
07:16So
07:17it's very much dependent on
07:18the patient and the situation.
07:21If we don't have
07:22a good targeted therapy to
07:23back us up and we
07:25have
07:26many, many spots to go
07:27after, you know, thirty, forty,
07:29fifty,
07:30then we know if we
07:31see fifty spots, there's probably
07:33another ten or twenty that
07:34we can't see, and it
07:35makes more sense for the
07:36patient
07:37to treat everything.
07:39Other types of disease, for
07:40example, small cell lung cancer
07:42is a type that tends
07:44to very commonly go to
07:45the brain, and we tend
07:46to have a lower threshold
07:47for activating that whole brain
07:49decision in that case. But
07:50even that, we're trying to
07:51back off on nowadays.
07:55I have to say as
07:56a medical oncologist
07:59taking care of mostly women
08:01with breast cancer,
08:04that the advances in radiation
08:06largely through techniques like the
08:08gamma knife, have been incredible
08:09over the years.
08:10And
08:12radiation oncologists have been able
08:14to treat
08:16more and more with
08:18really less and less toxic
08:19approaches.
08:21Yeah. And I'm particularly excited
08:23about what we're seeing with
08:24these new antibody drug conjugates
08:27like HER2 that are really
08:29helping us delay that need
08:31to activate the whole brain
08:32protocol. So we can help
08:34you
08:35target just the most important
08:36tumors, and the drugs can
08:38perhaps take care of the
08:38smaller ones, which is a
08:40big change from
08:42even just a few years
08:43ago.
08:44Yeah. Which is,
08:46of course, among the many
08:48reasons why having
08:50people participate in multidisciplinary
08:52teams is so important.
08:54Absolutely.
08:56We wouldn't have nowhere near
08:57the confidence to do what
08:58we do if we didn't
09:00know we had the backup
09:01of people like Veronica Chiang,
09:03who's one of our neurosurgeons,
09:04who can operate when we
09:06need help or operate the
09:08the laser technology when there's
09:09some radiation treatment effect that
09:10we need to fix.
09:13I always need someone to
09:14call when I say, you
09:16know, I'm this is close
09:17to needing whole brain, but
09:18can you back me up?
09:19Do you have any targeted
09:20therapy that I can argue
09:22will take care of the
09:22smaller spots, and I can
09:23just go after the
09:24important ones right now?
09:26You can't do this
09:28by any one specialty anymore.
09:30Not sure maybe you ever
09:31could, truthfully.
09:33It's absolutely the case.
09:35And what about
09:37patients who have primary brain
09:39tumors where
09:41the cancer starts in the
09:42brain? Cancers like glioblastoma
09:45and other forms of
09:47brain cancer?
09:48Are there times when you
09:49use Gamma Knife after someone
09:51has had surgery?
09:53Very rare,
09:54especially here in our own
09:56institution.
09:57For example, the
09:58glioblastomas,
09:59we tend to think
10:01because of their infiltrative nature
10:03and the larger volume that
10:05you need to cover to
10:06get all
10:07the hands of the cells
10:08that are extending,
10:09it's better to go with
10:11that longer, what we call
10:12fractionated course and in combination
10:14with the chemotherapy.
10:16The Gamma Knife for other
10:18radiosurgery techniques might come into
10:20play
10:21after that. So if later
10:22down the road there was
10:23just one little spot that
10:25came back, then I might
10:26get a call from, for
10:27example, doctor Contessa or doctor
10:29Bindra to say,
10:30do you think you
10:31could gamma knife that one
10:32little spot? I've already given
10:33what I can do from
10:34the Linac side, which is
10:35called a linear accelerator, the
10:36normal radiation.
10:38It's a fairly
10:39rare occurrence that we would
10:40do that.
10:42Yeah.
10:45I think that,
10:47you know, all of this
10:48shows that these decisions
10:50are really very, very complicated.
10:53And then what about other
10:55cancers in other parts of
10:57the body other than the
10:58brain? Do you use gamma
11:00knife in those situations too?
11:02Not the gamma knife. The
11:04gamma knife is specifically
11:05built around that head
11:07frame and such so that
11:08we can have a 3D
11:09targeting specifically
11:11in the brain. But the
11:13concept
11:13of radiosurgery,
11:15meaning giving radiation
11:17extremely accurately in one dose
11:19or a couple of
11:20doses,
11:21absolutely applies elsewhere in the
11:23body.
11:24We just call it something
11:25else. We call it stereotactic
11:27body radiotherapy,
11:29or SBRT.
11:30For example,
11:32doctor Johung tends to use
11:33this for our pancreatic cancers.
11:35Doctor Park uses this for
11:36our lung cancers.
11:38Absolutely, the field of radiation
11:40has exploded in terms
11:42of new,
11:43faster, better ways to use
11:44radiation to treat cancer. And
11:46so what is it that
11:47led to this bifurcation
11:48between Gamma Knife and stereotactic
11:52radiosurgery?
11:54Well, the concept of stereotactic
11:56radiosurgery just means we're treating
11:58something super accurately with a
12:00high dose in a few
12:01fractions.
12:03The gamma knife is entirely
12:04based on basically a brand
12:07and the use of that
12:07specific head frame. So you
12:09may have heard of things
12:10like the CyberKnife.
12:12Again, they decided to use
12:14the word knife. I think
12:15that was a mistake.
12:17So that's just
12:18a different brand?
12:20Yeah. It does not use the
12:23cobalt sources like the
12:24gamma knife does, but it's
12:25the same idea of giving
12:26radiation hyper accurately just to
12:29the problem areas.
12:30And
12:31just back to gamma knife
12:33for a second. So a
12:34a patient has a gamma
12:36knife treatment.
12:37Do they need to be
12:38in the hospital? Can they
12:39go home that same day?
12:41What are the
12:42consequences a day or two
12:44later?
12:45It's remarkably well tolerated.
12:47Almost all of our patients
12:48go home the very same
12:49day.
12:51They're a little tired for
12:52a couple days and a
12:53little sore where the frame
12:54has been attached.
12:56But other than that, it's
12:57a very well tolerated treatment.
12:58And that is a huge
12:59benefit
13:00because it's so much faster
13:01than other forms of radiation.
13:03We can get them on
13:04to the next phase of
13:05either chemotherapy
13:06or targeted therapy or clinical
13:08trial without any delay.
13:12Even beyond that, who wants
13:14to feel badly from a
13:15treatment? The
13:17easier a treatment
13:18is, the more you can
13:20think about getting it.
13:23Well, we're gonna take a
13:25very brief break. And when
13:27we come back, we'll continue
13:29talking to
13:30James Hansen, associate professor of
13:32therapeutic radiology,
13:34and we'll move on to
13:36talk about
13:37some of his own research,
13:39focused on a very different
13:41area.
13:42Support for Yale Cancer Answers
13:44comes from Smilow Cancer Hospital,
13:46where their thyroid care ablation
13:48program offers an alternative nonsurgical
13:51approach to treating symptomatic or
13:52aesthetically unappealing thyroid nodules.
13:55Smilowcancer
13:56hospital dot org.
14:00Genetic testing can be useful
14:02for people with certain types
14:03of cancer that seem to
14:04run-in their families.
14:05Genetic counseling is a process
14:07that includes collecting a detailed
14:09personal and family history,
14:11a risk assessment,
14:12and a discussion of genetic
14:14testing options.
14:15Only about five to ten
14:17percent of all cancers are
14:18inherited and genetic testing is
14:20not recommended for everyone.
14:22Individuals who have a personal
14:24and or family history that
14:25includes cancer at unusually early
14:28ages,
14:29multiple relatives on the same
14:30side of the family with
14:32the same cancer,
14:33more than one diagnosis of
14:35cancer in the same individual,
14:37rare cancers,
14:38or family history of a
14:40known altered cancer predisposing
14:42gene could be candidates for
14:43genetic testing.
14:45Resources for genetic counseling and
14:47testing are available at federally
14:49designated comprehensive cancer centers,
14:51such as Yale Cancer Center
14:53and Smilow Cancer Hospital.
14:55More information is available at
14:57yale cancer center dot org.
14:59You're listening to Connecticut Public
15:00Radio.
15:02Hello again. This is Eric
15:04Winer with Yale Cancer Answers,
15:06and I'm here again
15:08with our guest, doctor James
15:10Hansen,
15:11a radiation oncologist
15:13who focuses on
15:15gamma knife treatment
15:16in his clinical work.
15:18But beyond that, like many,
15:21many physicians,
15:23is involved in research as
15:25well,
15:26involved in research to try
15:29to make
15:30treatment better for patients in
15:32the future.
15:33Some of that research involves
15:34clinical trials. Some of it
15:36involves more basic work to
15:38try to
15:39come up
15:40with new approaches
15:43that could lead to clinical
15:45trials in the future.
15:47So I wanna talk to
15:48you about
15:50lupus related antibodies
15:52and how this might
15:55ultimately improve
15:56care for individuals who have
15:58glioblastoma.
15:59And maybe before you talk
16:02about lupus related antibodies,
16:04maybe you could just talk
16:05for
16:07a minute or two about
16:08glioblastoma
16:10and
16:11where we stand with that
16:12very difficult to treat cancer.
16:15Did you say you wanted
16:16me to talk about lupus
16:17related antibodies in cancer?
16:19That sounds a little off
16:20the norm here.
16:24It is, it's your work.
16:25Oh, how about that?
16:26Alright. Yes. Happy to talk
16:28about that.
16:29So
16:30glioblastoma
16:31is one of the most
16:32aggressive
16:33primary brain tumors that we
16:35encounter.
16:36And one of the reasons
16:38that it's so tough to
16:38beat is
16:40that it has figured out
16:41ways to sort of cloak
16:43itself so that it kind
16:44of, I like to say, it runs
16:46silent, meaning that our own
16:48immune system can't see it,
16:50can't fight it off. So
16:51we try to be
16:52aggressive with surgery and radiation
16:54and chemotherapy, but we really
16:56need backup from the immune
16:58system to get after it.
16:59And, unfortunately,
17:00the T cells and such
17:02just don't tend to find
17:03it. And that's why glioblastoma
17:05is called immunologically,
17:07quote, unquote,
17:08cold.
17:10So we figured
17:11if there was a way
17:12to heat up those tumors,
17:13maybe we could get better
17:14outcomes.
17:15And by cold, you mean
17:16that
17:18immunotherapy
17:19as we give it today
17:20doesn't seem to have any
17:22impact on glioblastomas.
17:23You got it. So all
17:24those antibody things we see
17:26advertised on TV that are
17:28really making a huge difference
17:29in other kinds of cancers,
17:31they're not touching glioblastoma.
17:33So we need a way
17:34to figure out why
17:35or how to break that
17:37cycle.
17:38So where would we
17:39look to find a hyperactive
17:41immune system?
17:43How about autoimmunity,
17:45like lupus?
17:47So in lupus,
17:49a patient's own immune system
17:50goes a little crazy and
17:52starts attacking its own cells
17:54and tissues.
17:56So we figured, well, if
17:57we could figure out what
17:58are the mechanisms
17:59driving that
18:01and just isolate a few
18:02of them, maybe we could
18:03use some of those
18:04to awaken the immune system
18:05in glioblastoma.
18:08And that's what my lab
18:09focuses on, is understanding mechanisms
18:11of autoimmunity
18:12with the goal of using
18:13them against cancer.
18:15And let me just ask
18:16you. Lupus, if I remember
18:18right, from
18:19days when I
18:21trained in internal medicine,
18:23is actually a disease that
18:24occasionally affects the brain as well?
18:26Absolutely. And patients,
18:29at times, unfortunately, get what's
18:31called lupus cerebritis,
18:34where those antibodies seem
18:36to attack the brain.
18:38That's exactly right.
18:40But how in the world
18:41are they doing that? Antibodies
18:43aren't supposed to be able
18:44to cross the blood brain
18:45barrier.
18:47Antibodies aren't even supposed to
18:48be able to penetrate
18:49into live cells. So that's
18:51a good segue. Thank you.
18:54Antibody therapy, as we know
18:56it currently, is focused on
18:58binding things
18:59on the outside of cells,
19:01things circulating in the blood
19:02or on the surface of
19:03cells.
19:04Now this is where a
19:05lot of critics might say,
19:07well, no. Some antibodies get
19:08eaten by cells.
19:10But I say that those
19:11don't count because they then
19:12get destroyed inside the cell
19:13by endosomes and lysosomes.
19:16What's remarkable
19:17about lupus antibodies we have
19:19found
19:20is that a subset of
19:21them
19:22are reactive against a patient's
19:23own DNA.
19:25And so sort of a
19:26hallmark of lupus is these
19:27anti DNA antibodies.
19:30And so they look for
19:31DNA, and they find DNA
19:34where it is
19:35concentrated. So it's kind of
19:36like
19:38if anybody who's listening has
19:39seen the movie Star Trek
19:40there is a part
19:42of that movie wherein
19:43the Enterprise is facing a
19:45cloaked
19:46bad guy ship, and they
19:47can't figure out how to
19:48find it. Until suddenly, they
19:50realize
19:51the thing has to have
19:52a tailpipe. And so they
19:53figure out a way to
19:54fire off a photon torpedo
19:56to track its exhaust back
19:58to its source.
19:59Tumor exhaust is DNA,
20:02nucleic acids, as the tumor
20:03cells are cycling and releasing
20:05them. So we thought, well,
20:06maybe these anti DNA antibodies
20:07will find tumors by tracking
20:09their exhaust back to the
20:10source. And, indeed, they do.
20:12And what's even more remarkable
20:13is when they get there,
20:15they're sticking to the nucleoside
20:16components of DNA,
20:18and then the live tumor
20:19cells and other environmental
20:21cells
20:22are pulling those nucleosides in
20:25through this thing called a
20:26nucleoside salvage pathway.
20:28And so it pulls the
20:29antibody in. And the antibody
20:31then gets into those cells,
20:32skips all the security guys.
20:34It skips the lysosomes and
20:36the endosomes, and it has
20:37free rein inside that cell.
20:39Some of them go to
20:40the nucleus.
20:41Some go to the cytoplasm.
20:44What we just found, and
20:45we just published in Science
20:46Signaling and is getting quite
20:47a lot of attention and
20:48very excited about,
20:50is that one of these
20:51antibodies, when it gets into
20:53that cytoplasm, the liquid part
20:54of the cell, not the
20:55nucleus,
20:57it's sticking to RNA,
20:58a specific type of nucleic
21:00acid.
21:01And then finally,
21:02something inside the cell called
21:04a pattern recognition receptor
21:06sees that and says,
21:08that's not supposed to be
21:10here. I don't know what's
21:11going on, but something bad
21:13has happened. And it triggers
21:14off an immune reaction. And
21:16it finally says, oh my
21:18goodness.
21:19There's a tumor here this
21:20whole time. We've been sitting
21:21amongst this. We didn't realize.
21:23And then it recruits T
21:24cells, and we do see
21:25an improved response.
21:27So we figured out a
21:28way, we believe, to use
21:29a lupus antibody that can
21:31cross the blood brain barrier,
21:33penetrate into live cells, and
21:35tumor cells and non tumor
21:36cells fire up the immune
21:38system
21:39and improve outcomes. It does
21:40it by itself.
21:41And if you throw in
21:42an immune checkpoint blockade antibody,
21:44like those classic anti PD
21:46ones,
21:47it works even better. So
21:48we're pretty thrilled by
21:50this, and we we hope
21:51that we can get this
21:52to the clinical trials as
21:53soon as we possibly can.
21:55Now if it
21:57also goes to normal cells
21:59in the brain, is there
22:01some chance it would
22:03increase the
22:04side effects from immunotherapy
22:06in those normal cells in
22:07the brain?
22:09That's the real trick. Right?
22:10Is doing this in a
22:11way that we don't cause
22:12harm.
22:13And this is where it's
22:14all about
22:16where is the antibody gonna
22:17go. And and the beauty
22:18of this, and I wish
22:20I could take credit for
22:20it. I didn't design this.
22:22This is a natural antibody,
22:23a natural lupus antibody.
22:26It will only penetrate cells
22:28in areas that are super
22:30highly concentrated
22:31in the DNA that's released
22:33by the tumor because that's
22:35its path into the cell.
22:36So when it if it
22:37finds other areas in the
22:38normal brain that are not
22:40soaked in DNA, it will
22:41not penetrate. And that's the
22:43first thing that we looked
22:44for. Where does the
22:45antibody go? And it just
22:46goes into the area of
22:47the tumor and the surrounding
22:48area, not into the normal
22:50brain.
22:51So it preferentially
22:53goes into the tumor on its own.
22:54Correct. Based on
22:57targeting
22:58the DNA. And if you
23:00follow that reasoning further
23:02in noncancer applications,
23:05these antibodies will also find
23:06areas of damage. So for
23:08example,
23:09my colleagues and my
23:11team have found as well,
23:13these antibodies will find areas
23:14of a stroke
23:15in the brain
23:16or a heart attack
23:18Because DNA is being released
23:20by the damaged cells.
23:21Exactly.
23:23So all this excitement about
23:24this antibody by itself as
23:27engaging the immune system,
23:28I think, is great.
23:30There's one more dimension to it.
23:33Wait a second. If this
23:34antibody can get into cells
23:35and it can avoid all
23:37the security,
23:38skip the lysosomes,
23:40will it carry other things
23:42with it in?
23:43And indeed,
23:44we haven't published this yet,
23:45but I mean, this
23:46is just between you and me, right?
23:47No one's listening
23:48to this. I hope, oh,
23:48wait. There's this radio.
23:50I'll still be able to
23:51say it.
23:53Absolutely. These antibodies can carry
23:55cargos in with them, whether
23:57they are nucleic acids or
23:58linked other antibodies.
24:00So we can use these
24:01antibodies to deliver things to
24:02either increase the effect on
24:04tumors or perhaps to treat
24:06heart attacks, perhaps to improve
24:08improve treatment of stroke. The
24:09sky's the limit in my
24:11opinion.
24:12So
24:14almost like what we now
24:16call drug antibody conjugates, you
24:18could
24:19theoretically link
24:21a little bit of some
24:22drug that would be toxic
24:23to the cancer to the
24:25antibody.
24:27Absolutely. In fact, that was
24:29a paper from
24:30last year, and I'm
24:31really, really glad you gave
24:32me that segue.
24:34I was in, ACS Central
24:36Science. So everyone has asked
24:38me along the way,
24:39why don't you use these
24:40antibodies to deliver
24:42drugs? And I said, well,
24:43it doesn't make sense because
24:45the whole idea of an
24:46antibody drug conjugate
24:48is it gets eaten up,
24:49and then the lysosome
24:51breaks it down, and that's
24:51how the drug gets released.
24:53What's gonna release the drug
24:55for these antibodies? They don't
24:56go to the lysosome.
24:57But finally,
24:59a great postdoc by the
25:00name of Faye Kao in
25:01my lab figured out when
25:03one of these antibodies goes
25:04zipping on into the cell,
25:06this one goes into the
25:07nucleus,
25:09something happens and it triggers
25:10a specific
25:12protease,
25:13a protein that cuts
25:14other things apart from a
25:16lysosome
25:17to chase it into the
25:18nucleus.
25:19And that's what breaks it
25:20down in the nucleus. And
25:21then we realized,
25:23if we use a linker
25:25that that protease will cut,
25:27now we can deliver things
25:28into the nucleus,
25:29and the drug will be
25:30released. And so you've heard
25:32of ADCs,
25:33antibody drug conjugates.
25:35We have now coined the
25:36phrase
25:37ANADCs
25:38for anti nuclear antibody drug
25:41conjugates. And I'm really trying
25:42to get that to stick.
25:43So, hopefully, people that are
25:44listening will use that too.
25:46Well, I mean, of course,
25:48we're gonna have to see
25:49if this works in people,
25:50but,
25:51the whole idea sounds pretty
25:53cool to me.
25:55I think so too.
25:58And so
25:59in using these
26:00lupus antibodies, is there any
26:02risk that a patient
26:04is gonna develop some symptoms
26:06of lupus?
26:07Sure. That's the first question
26:09on our minds and on
26:10everybody's mind.
26:12When it comes to an
26:13anti DNA antibody,
26:15one of the dangers we've
26:16seen associated with lupus is
26:18that they can get stuck
26:19in the kidneys, and then
26:20they can trigger an immune
26:21response against the kidney to
26:23cause this thing called
26:24lupus nephritis, just inflammation
26:27of the kidney.
26:28The good news is
26:29most of that is caused
26:30by what we call the
26:32constant regions of the antibody,
26:34the FC tail for
26:35those that know any antibody
26:36structure.
26:38And the magic of these
26:39antibodies that allows them to
26:40do their thing to bind
26:42DNA, bind RNA,
26:44penetrate
26:45cells, has nothing to do
26:46with the FC or any
26:47of their constants, all in
26:48the variable regions. So we've
26:50created what we call fragments,
26:52single chain variable fragments and
26:54such that don't have any
26:56of the dangerous lupus causing
26:57parts, but still preserve the
26:59cell penetrating activity,
27:00the delivery aspects,
27:02and the engagement of all
27:03those factors that we want
27:04to try to fight off
27:05these diseases.
27:07Well, it sounds to me
27:07like we wanna try to
27:08encourage you to do this
27:09work as quickly as you
27:11can because it sounds pretty
27:13promising.
27:14Thank you. Yeah.
27:15I can take all the
27:16encouragement I can get.
27:22The truth is
27:23that if we didn't have
27:25research, if we didn't have
27:26both
27:27research in laboratories
27:29and research in the clinic,
27:31cancer treatment wouldn't change. And
27:34what has led to really
27:35a revolution in cancer therapeutics
27:38over the last
27:39twenty,
27:40twenty five years
27:42has been all the research
27:43that has gone on, and
27:44it's really quite remarkable.
27:47No question.
27:49You know, and it's just
27:51so very important.
27:52So in our last
27:54minute or so,
27:56maybe you could,
27:58look into the future
28:00and tell us what you
28:02think are gonna be the
28:04new directions for radiation oncology
28:07in the years ahead.
28:10Yeah. So I I'm very
28:11excited about
28:13immunotherapy
28:14and the combination
28:15with radiation.
28:17And we have so much
28:18to learn about
28:20how the radiation
28:22triggers and talks to the
28:23immune system.
28:24But when we can figure
28:25that out, I think we'll
28:26have even more ways to
28:28activate
28:29those, quote, unquote, cold tumors
28:31by giving radiation to the
28:32right area at the right time.
28:33Doctor James Hansen is
28:35an associate professor of therapeutic
28:37radiology at the Yale School
28:39of Medicine.
28:40If you have questions, the
28:42address is canceranswersyale
28:43dot edu,
28:45and past editions of the
28:46program are available in audio
28:48and written form at yale
28:49cancer center dot org.
28:51We hope you'll join us
28:52next time to learn more
28:53about the fight against cancer.
28:55Funding for Yale Cancer Answers
28:57is provided by Smilow Cancer
28:59Hospital.