New Targets for Triple Negative Breast Cancer

Transcript

00:00 --> 00:03Funding for Yale Cancer Answers is
00:03 --> 00:06provided by Smilow Cancer Hospital.
00:06 --> 00:08Welcome to Yale Cancer Answers
00:08 --> 00:10with Doctor Anees Chagpar.
00:10 --> 00:11Yale Cancer Answers features the
00:11 --> 00:13latest information on cancer
00:13 --> 00:14care by welcoming oncologists and
00:14 --> 00:17specialists who are on the forefront
00:17 --> 00:18of the battle to fight cancer.
00:18 --> 00:21This week it's a conversation about
00:21 --> 00:22hematopathology and breast cancer
00:23 --> 00:24research with Doctor Samuel Katz.
00:24 --> 00:27Dr. Katz is an associate professor of
00:27 --> 00:29pathology at the Yale School of Medicine,
00:29 --> 00:31where Doctor Chagpar is a professor
00:31 --> 00:32of surgical oncology.
00:34 --> 00:35So Dr. Katz, maybe we can start off
00:35 --> 00:37by you telling us a little bit more
00:37 --> 00:39about yourself and what it is you do.
00:40 --> 00:42I'm a physician scientist
00:42 --> 00:44within the Department of Pathology.
00:44 --> 00:49I split my time where I spend 20% on
00:49 --> 00:52clinical service diagnosing blood cancers,
00:52 --> 00:53leukemias. and lymphomas.
00:53 --> 00:56But I spend the majority of my time
00:56 --> 01:00running a basic research laboratory that
01:00 --> 01:03focuses on questions of how cells die.
01:03 --> 01:05And we approach it from two
01:05 --> 01:06different standpoints.
01:06 --> 01:08By the pathway within the
01:08 --> 01:11cells that cause them to die,
01:11 --> 01:14but also by a pathway external to
01:14 --> 01:16the cells and how we can kill them.
01:16 --> 01:19Because if we can manipulate
01:19 --> 01:21the ability to kill cells,
01:21 --> 01:23that could help in many
01:23 --> 01:24different diseases like cancers.
01:28 --> 01:30Tell us a little bit more about how
01:30 --> 01:34you came to work on breast
01:34 --> 01:36cancer as a hematopathologist.
01:36 --> 01:38You mentioned that in your clinical role,
01:38 --> 01:41you really focus on blood cancers.
01:41 --> 01:43So how do you get
01:43 --> 01:45into the breast cancer world?
01:46 --> 01:48As a hematopathologist who
01:48 --> 01:51focuses on the blood and the blood system,
01:51 --> 01:54I got very interested in a
01:54 --> 01:56particular cell type called a T cell.
01:56 --> 02:00And T cells are important in our
02:00 --> 02:02immune system to attack cells that
02:02 --> 02:05have been infected with foreign agents.
02:05 --> 02:07They're able to recognize the cells
02:07 --> 02:10as being infected and kill them.
02:10 --> 02:12And people have realized that they
02:12 --> 02:15have such incredible ability to kill
02:15 --> 02:17those infected cells that perhaps we
02:17 --> 02:20can usurp that ability in order to
02:20 --> 02:23attack other cells like cancer cells.
02:24 --> 02:26And so tell us more about how this
02:26 --> 02:28kind of works in breast cancer and
02:28 --> 02:32more about your research.
02:32 --> 02:34Sure, so in breast cancer there are
02:34 --> 02:37many other types of cancers,
02:37 --> 02:40there are proteins that are on
02:40 --> 02:43the surface of the cell that are
02:43 --> 02:45not present in normal cells.
02:45 --> 02:49And so we have devised a protein that
02:49 --> 02:52we can add into the T cells called
02:52 --> 02:55a CAR or chimeric antigen receptor,
02:55 --> 02:58thus making a CAR T cell that can
02:58 --> 02:59recognize this aberrant protein
02:59 --> 03:02on the breast cancer cell and
03:02 --> 03:05direct the T cells killing ability
03:05 --> 03:07towards that breast cancer cell.
03:09 --> 03:12That sounds really fascinating.
03:12 --> 03:14So tell us more about
03:14 --> 03:15how CAR T therapy works.
03:15 --> 03:17I know some of our listeners
03:17 --> 03:18may be familiar with this,
03:18 --> 03:21but many may not be. So, you know,
03:21 --> 03:23how do you actually change these T
03:23 --> 03:25cells to make them recognize these
03:25 --> 03:28proteins on the surface of the cell?
03:28 --> 03:29Because it sounds like essentially
03:29 --> 03:31what you're doing is you're
03:31 --> 03:33taking a patient's immune system,
03:33 --> 03:34these T cells,
03:34 --> 03:36and you're kind of giving them a GPS, a
03:36 --> 03:39targeting system to say go after those cells,
03:39 --> 03:40those cancer cells,
03:40 --> 03:43but somehow you have to get
03:43 --> 03:45the GPS into those T cells.
03:45 --> 03:46How do you do that exactly?
03:47 --> 03:48Absolutely. And so there's a
03:48 --> 03:51number of ways in which to,
03:51 --> 03:54as we say, reprogram those T cells.
03:54 --> 03:58The most commonly used ones are
03:58 --> 04:00viral approaches using retroviruses
04:00 --> 04:03or lentiviruses where a piece of
04:03 --> 04:06DNA and that virus will infect the
04:06 --> 04:09cell and then integrate or become
04:09 --> 04:12part of that cells genome or DNA
04:12 --> 04:15and it will then express this new
04:15 --> 04:17protein that we've made which we
04:17 --> 04:19can discuss later called the CAR,
04:19 --> 04:22the chimeric antigen receptor.
04:22 --> 04:25Another way in which to do it,
04:25 --> 04:27which is the approach we've taken
04:27 --> 04:30and really came about because of
04:30 --> 04:32some work by a senior professor here
04:32 --> 04:34at Yale called Sherman Weissman.
04:34 --> 04:37He kind of took me under his wing
04:37 --> 04:39as a mentor in this approach where
04:39 --> 04:42instead of using DNA, he was using RNA.
04:42 --> 04:46And so we can take the T cells out
04:46 --> 04:49of the patient and what we call
04:49 --> 04:51Electroplate in order to give
04:51 --> 04:53them kind of a little shock that
04:53 --> 04:54gets the RNA into the cells.
04:54 --> 04:58And this has a very high efficiency of
04:58 --> 05:01being able to reprogram those cells
05:01 --> 05:03using the RNA in this manner.
05:03 --> 05:06But it also has a lot of other advantages,
05:06 --> 05:09chief among them being safety in that
05:09 --> 05:11when you put an RNA into a cell,
05:12 --> 05:14it doesn't change the genome of all
05:14 --> 05:16of the T cells that you're taking
05:16 --> 05:18from the patients.
05:18 --> 05:20It only makes that RNA which then
05:20 --> 05:23makes that protein and after a
05:23 --> 05:25period of time it goes away.
05:25 --> 05:27And so there's an added safety to that
05:29 --> 05:32and that also sounds like that would
05:32 --> 05:34be particularly handy once the job
05:34 --> 05:37of getting rid of this cancer is done
05:37 --> 05:39that the cells go back to normal.
05:39 --> 05:42So how long does it take for
05:42 --> 05:44that RNA to disintegrate or go away?
05:45 --> 05:48The RNA actually is very
05:48 --> 05:50short lived, but the protein it
05:50 --> 05:53makes can last a little longer and
05:53 --> 05:55it really depends on the particular
05:55 --> 05:57protein that you're making.
05:57 --> 05:59But we see it in the order
05:59 --> 06:01of about a week or so.
06:01 --> 06:04So one could envision giving this
06:04 --> 06:06therapy as a weekly type of basis
06:06 --> 06:09where you're giving the cells that
06:09 --> 06:11have been reprogrammed with RNA or
06:11 --> 06:15in newer work that's still ongoing
06:15 --> 06:17trying to actually deliver the RNA
06:17 --> 06:20into the body without having to take
06:20 --> 06:23out the T cells to reprogram them.
06:27 --> 06:30It sounds like it really is intriguing,
06:30 --> 06:33right, that you kind of give
06:33 --> 06:35these T cells a little shock,
06:35 --> 06:38give them an RNA to make a protein.
06:38 --> 06:41That protein, that CAR protein goes
06:41 --> 06:44and attacks these cancer cells in a
06:44 --> 06:46very specific way because presumably
06:46 --> 06:49this protein is found on cancer
06:49 --> 06:52cells and not on normal cells.
06:52 --> 06:55So where are we in terms of actually
06:55 --> 06:57getting this into clinical trials?
06:58 --> 07:01Yeah, so we're still in the
07:01 --> 07:03early phases I'd say of doing this.
07:03 --> 07:06There's a lot of work to be done
07:06 --> 07:09to optimize the system overall
07:11 --> 07:14and these include the things that improve
07:14 --> 07:16the ability of the T cells to kill,
07:16 --> 07:21to make sure that they don't get exhausted,
07:21 --> 07:25to make sure that again,
07:25 --> 07:26as we're saying,
07:26 --> 07:27to really make sure that it's safe.
07:27 --> 07:29We still have work to do in
07:29 --> 07:32animal models before we can get
07:32 --> 07:33it into the clinical sphere,
07:33 --> 07:35but because of the RNA approach
07:35 --> 07:36and the safety,
07:36 --> 07:39we do think it is a easier transition
07:39 --> 07:41to getting it into patients.
07:43 --> 07:45And in terms of
07:45 --> 07:47the safety and side effects,
07:47 --> 07:49can you talk a little bit
07:49 --> 07:50more about the side effects?
07:50 --> 07:52I mean I would assume that this
07:52 --> 07:56has a lot to do with whether these
07:56 --> 07:58proteins are on normal cells in any
07:58 --> 08:01capacity or whether they are really
08:01 --> 08:04100% only on cancer cells and also
08:04 --> 08:07revving up the the immune system.
08:07 --> 08:09You may think that you might get some
08:09 --> 08:12immune related side effects as these T
08:12 --> 08:14cells go about doing their business.
08:14 --> 08:17and so maybe it is best to
08:17 --> 08:19take one step back and to say where
08:19 --> 08:22the CAR T cells have been really
08:22 --> 08:24successful to date in the clinic.
08:24 --> 08:28And these have been against actually
08:28 --> 08:31targets that are on B cell malignancies
08:31 --> 08:33or leukemias and lymphomas.
08:33 --> 08:35And they're going
08:35 --> 08:38after a target called CD 19,
08:38 --> 08:41which is expressed on the surface of
08:41 --> 08:46those B cells and that really is unique to
08:46 --> 08:50those cancer cells as well as normal B cells.
08:50 --> 08:52And so when the CAR T cells are
08:52 --> 08:53introduced to those patients,
08:53 --> 08:56it does get rid of all their normal B cells,
08:56 --> 08:58but patients are fine with that.
08:58 --> 08:59You can
08:59 --> 09:02live without our B cells.
09:02 --> 09:03There are some side effects
09:03 --> 09:05that are seen with that therapy.
09:05 --> 09:08One is a called a cytokine release
09:08 --> 09:10syndrome where because you're getting so
09:10 --> 09:13much killing so quickly of the cancer,
09:13 --> 09:15it releases a lot of the cytokines
09:15 --> 09:17that leads to kind of like an
09:17 --> 09:19immune storm within the patients.
09:19 --> 09:21They feel very sick and you have to really
09:21 --> 09:24watch them carefully within the hospital.
09:24 --> 09:27And there's also been some less well
09:27 --> 09:31understood neurological disorders
09:31 --> 09:34that occur in some patients.
09:34 --> 09:36And some people have hypothesized that
09:36 --> 09:38that might be due to the fact that
09:38 --> 09:40we've learned later that there's a
09:40 --> 09:42cell type within the brain that has
09:42 --> 09:44very low expression of this target.
09:44 --> 09:47And so then that gets us back to
09:47 --> 09:50breast cancer and solid tumors where
09:50 --> 09:52there aren't as many great targets
09:52 --> 09:55that we know of that are uniquely
09:55 --> 09:59expressed on the surface of these cells.
09:59 --> 10:01The one that we're going after actually
10:01 --> 10:04turns out to be increased in more than
10:04 --> 10:06half of triple negative breast cancers
10:06 --> 10:09and its expression correlates with
10:09 --> 10:11poor prognosis within these patients.
10:11 --> 10:15There is some very low
10:15 --> 10:17expression during development,
10:17 --> 10:20but we have some reasons to believe
10:20 --> 10:23that we can kind of thread the needle
10:23 --> 10:25between this very high expression
10:25 --> 10:28on the cancer and this perhaps low
10:28 --> 10:30expression on some normal tissues.
10:31 --> 10:36Yeah, I mean I think that in general for
10:36 --> 10:42most cancer related drugs
10:42 --> 10:44it's never completely black and white.
10:44 --> 10:47Even chemotherapy we know we still use
10:47 --> 10:51and it really is designed to attack
10:51 --> 10:54rapidly growing cells and dividing cells.
10:54 --> 10:57But you still get some normal cells
10:57 --> 11:00that are also rapidly dividing
11:00 --> 11:01like your hair for example,
11:01 --> 11:05which is why many patients undergoing
11:05 --> 11:06chemotherapy lose their hair.
11:06 --> 11:08So it sounds like even if there
11:09 --> 11:11was a potential differential there,
11:11 --> 11:13it still might be really handy
11:13 --> 11:15in terms of a therapy,
11:15 --> 11:18especially if it was less toxic
11:18 --> 11:20than our standard therapies,
11:20 --> 11:23which for triple negative breast
11:23 --> 11:25cancer are primarily chemotherapy.
11:25 --> 11:27Now the other question that I have
11:27 --> 11:29for you is in triple negative
11:29 --> 11:31breast cancer in particular,
11:31 --> 11:36we've seen that there are now therapies that
11:36 --> 11:38are being used that are immunotherapies.
11:38 --> 11:41So really therapies that are
11:41 --> 11:44designed to unleash the immune system
11:44 --> 11:46especially because some of these
11:46 --> 11:49triple negative breast cancers,
11:49 --> 11:54they tend to evade the immune system.
11:54 --> 11:57So if that's the case, and this CAR
11:57 --> 12:00T therapy is really designed to
12:00 --> 12:02use the immune system,
12:02 --> 12:04is it the idea that this would
12:04 --> 12:06be paired with immunotherapies or
12:06 --> 12:09are you thinking about a different
12:09 --> 12:10way of attacking this?
12:11 --> 12:14So I think there is a potential
12:14 --> 12:17for testing the two together,
12:17 --> 12:19but it is very different in
12:19 --> 12:21the way these two different
12:21 --> 12:23classes of immunotherapies work.
12:23 --> 12:26So the ones that you're referring
12:26 --> 12:29to, so-called checkpoint inhibitors,
12:29 --> 12:35these are ones that rely on new
12:35 --> 12:37antigens that are made within
12:37 --> 12:39the cancer cell that are mutant
12:39 --> 12:42and specific to the cancer cells.
12:42 --> 12:45And they really are unique.
12:45 --> 12:47The T cells use their native,
12:47 --> 12:50their normal T cell receptors
12:50 --> 12:52to recognize those.
12:52 --> 12:54But there's a so-called break
12:54 --> 12:57mechanism that prevents the T cell
12:57 --> 13:00from killing and the immunocheckpoint
13:00 --> 13:03inhibitors take away that break, the
13:03 --> 13:05CAR that I've been talking about,
13:05 --> 13:07these CAR T cells,
13:07 --> 13:10this is a new protein that we've
13:10 --> 13:13devised by taking pieces of various
13:13 --> 13:16other parts of the T cell receptor
13:16 --> 13:19and other antigen recognition domains
13:19 --> 13:22and they recognize or we've designed
13:22 --> 13:27this one to recognize a specific
13:27 --> 13:31protein that's not mutated but wild type.
13:31 --> 13:36And this then activates the CAR T
13:36 --> 13:39cell rather than stopping the brake.
13:39 --> 13:42I'd say it's more akin to pressing
13:42 --> 13:44on the gas pedal when we have
13:44 --> 13:45that specific protein.
13:46 --> 13:48Well, we need to take a
13:48 --> 13:50short break for a medical minute,
13:50 --> 13:52but please stay tuned to learn more
13:52 --> 13:54about the role of pathology and new
13:54 --> 13:56research into a potential target for
13:56 --> 13:58metastatic triple negative breast
13:58 --> 14:01cancer with my guest, Doctor Sam Katz.
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14:12 --> 14:15evaluation, and treatment of bladder cancer.
14:15 --> 14:19Smilowcancerhospital.org.
14:19 --> 14:22The American Cancer Society estimates that
14:22 --> 14:25more than 65,000 Americans will be diagnosed
14:25 --> 14:27with head and neck cancer this year,
14:27 --> 14:31making up about 4% of all cancers
14:31 --> 14:33diagnosed. When detected early,
14:33 --> 14:35however, head and neck cancers are
14:35 --> 14:37easily treated and highly curable.
14:37 --> 14:39Clinical trials are currently
14:39 --> 14:41underway at federally designated
14:41 --> 14:43comprehensive cancer centers,
14:43 --> 14:44such as Yale Cancer Center
14:44 --> 14:46and Smilow Cancer Hospital,
14:46 --> 14:48to test innovative new treatments
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14:50 --> 14:52Yale Cancer Center was recently
14:52 --> 14:54awarded grants from the National
14:54 --> 14:56Institutes of Health to fund the Yale
14:56 --> 14:59Head and Neck Cancer Specialized
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15:06 --> 15:09carcinoma due to resistance to immune
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15:11 --> 15:14More information is available
15:14 --> 15:15at yalecancercenter.org.
15:15 --> 15:17You're listening to Connecticut Public Radio.
15:18 --> 15:21Welcome back to Yale Cancer Answers.
15:21 --> 15:23This is Doctor Anees Chagpar and
15:23 --> 15:24I'm joined tonight by my guest,
15:24 --> 15:26Doctor Samuel Katz.
15:26 --> 15:28We're talking about the role of pathology
15:28 --> 15:31and some new research into CAR T cells,
15:31 --> 15:33but now for a new indication
15:33 --> 15:34and that's really metastatic
15:34 --> 15:36triple negative breast cancer.
15:36 --> 15:36So Doctor Katz,
15:36 --> 15:38I want to go back to something you were
15:38 --> 15:40mentioning right before the break,
15:40 --> 15:43which is how traditional immunotherapies,
15:43 --> 15:45these checkpoint inhibitors which
15:45 --> 15:48we now use in triple negative breast
15:48 --> 15:51cancer really kind of get rid of
15:51 --> 15:53a break as you you phrased it in
15:53 --> 15:55terms of T cell killing, right.
15:55 --> 15:58Because we know that certain cancer
15:58 --> 16:00cells, especially triple negative
16:00 --> 16:04cancer cells, may kind of put a
16:04 --> 16:07brake on those those T cells to
16:07 --> 16:09kill off these cancer cells.
16:09 --> 16:11And so traditional immunotherapies
16:11 --> 16:15will remove that brake your car T
16:15 --> 16:18therapy is more like an accelerator
16:18 --> 16:22finding a new target on these T
16:22 --> 16:26cells to attack cancer
16:26 --> 16:28cells in a different way.
16:28 --> 16:31So kind of like putting on an accelerator.
16:31 --> 16:36My question is how do those two work
16:36 --> 16:38together or is there an interplay?
16:38 --> 16:39Thinking about, you know,
16:39 --> 16:40driving a car,
16:40 --> 16:42if you step on the gas while you're
16:42 --> 16:44still got a brake on,
16:44 --> 16:46it generally doesn't work very well.
16:46 --> 16:48Can you talk a little bit more about that?
16:48 --> 16:51Absolutely. And I think that's why,
16:51 --> 16:53as you kind of suggested,
16:53 --> 16:58the combination of this might be very useful.
16:58 --> 17:01Because while if you're just
17:01 --> 17:04releasing your foot off the brake by
17:04 --> 17:06using these checkpoint inhibitors,
17:06 --> 17:07if you don't have something driving,
17:07 --> 17:09if there isn't a mutant
17:09 --> 17:11antigen for you to go after,
17:11 --> 17:13then the car won't move forward,
17:13 --> 17:15the T cell won't kill.
17:15 --> 17:16On the other hand, like you said,
17:16 --> 17:19if the CAR T cell is engineered so that it
17:19 --> 17:22is always pressing on the gas pedal yet,
17:22 --> 17:23it might try going forward.
17:23 --> 17:25But if you have that brake
17:25 --> 17:27present at the same time,
17:27 --> 17:30then it's it won't be able to.
17:30 --> 17:32But if you can manipulate the
17:32 --> 17:34cell in ways that many people
17:34 --> 17:37are, to kind of combine the two,
17:37 --> 17:39then perhaps we could get
17:39 --> 17:42the full benefit of this.
17:42 --> 17:45I also want to bring up one other
17:45 --> 17:47thing that you had
17:47 --> 17:48mentioned before the break,
17:48 --> 17:51which is kind of getting towards
17:51 --> 17:53the difference between solid
17:53 --> 17:55tumors like triple negative breast
17:55 --> 17:58cancer and the blood tumors where
17:58 --> 18:01CAR T's have worked so well.
18:01 --> 18:03Solid tumors have remained a
18:03 --> 18:06real challenge for the CAR T field
18:06 --> 18:08to be able to work efficiently.
18:08 --> 18:11And that's because they create
18:11 --> 18:14this tumor microenvironment that
18:14 --> 18:16kind of quells the T cell,
18:16 --> 18:19some of which might be to increase the
18:19 --> 18:22brake like we've been talking about.
18:22 --> 18:24Another way is you can imagine that
18:24 --> 18:27the car won't do so well if you're
18:27 --> 18:30always pressing the gas pedal right.
18:30 --> 18:31You'll run out of gas eventually.
18:32 --> 18:34And a lot of the CAR T designs
18:34 --> 18:36in the past have this problem
18:36 --> 18:39where you're always pushing on
18:39 --> 18:41the gas even when you're not,
18:41 --> 18:42when you don't want it to,
18:42 --> 18:46when you don't have that target in sight.
18:46 --> 18:46Fortunately,
18:46 --> 18:49some work in the lab by Po Han Chen,
18:49 --> 18:51another physician scientist who's
18:51 --> 18:52been working on this problem,
18:52 --> 18:54came up with a new design towards
18:54 --> 18:56our car to make it so that it only
18:56 --> 18:58presses on the gas when we want it to.
19:00 --> 19:00That's interesting.
19:00 --> 19:03Can you tell us a bit more about that?
19:03 --> 19:05I mean, one would think that
19:05 --> 19:08if there wasn't a target,
19:08 --> 19:10but the T cells really wouldn't
19:10 --> 19:12have anything to go after and
19:12 --> 19:14so they would just be kind of
19:14 --> 19:16floating around looking for that
19:16 --> 19:17target if it should appear.
19:17 --> 19:20So how do you turn on and turn
19:20 --> 19:22off these T cells so that they
19:22 --> 19:24don't get overly active
19:24 --> 19:26and exhausted as you put it?
19:26 --> 19:29Yeah, that's a great question.
19:29 --> 19:30And I think what we have to remember
19:30 --> 19:32is when we're putting in this car,
19:32 --> 19:35this chimeric antigen receptor,
19:35 --> 19:38it's really a man made
19:38 --> 19:40Frankenstein type molecule.
19:40 --> 19:44It hasn't been engineered by nature over
19:44 --> 19:47you know millions of years of evolution.
19:47 --> 19:49It's something that we've come up with
19:49 --> 19:52and made in the lab and so therefore
19:52 --> 19:53it doesn't work necessarily perfectly.
19:53 --> 19:56We've taken snippets of different
19:56 --> 19:59proteins and put them together and a
19:59 --> 20:02normal receptor that's on the cell will
20:02 --> 20:04only single to have its downstream
20:04 --> 20:07effects when it engages its target.
20:07 --> 20:08But these
20:08 --> 20:10CARs that we've made ourselves,
20:10 --> 20:12they have a little leakiness to them,
20:12 --> 20:14many of them.
20:14 --> 20:16And that leads to
20:16 --> 20:18what we call tonic singling,
20:18 --> 20:20singling all the time or pressing
20:20 --> 20:22on that gas pedal all the time.
20:22 --> 20:25And Po Han has realized that one of
20:25 --> 20:28those domains could be optimized
20:28 --> 20:30to help reduce that issue.
20:30 --> 20:32And I think that's going to
20:32 --> 20:34be really critical for when we
20:34 --> 20:36start targeting solid tumors.
20:37 --> 20:39And so when you say optimized,
20:39 --> 20:42do you mean like it's kind of got
20:42 --> 20:46a way that it it learns when to
20:46 --> 20:48turn on and when to turn off?
20:48 --> 20:50Because presumably you want the thing to
20:50 --> 20:53to turn on when there is that target,
20:53 --> 20:55and you want it to go full speed
20:55 --> 20:57ahead and kill that target.
20:57 --> 20:58And when the target isn't there,
20:58 --> 21:00well, then you want it to conserve
21:00 --> 21:01its energy and lay low for a bit?
21:02 --> 21:06So looking at the actual structure
21:06 --> 21:10or the presumed structure of the molecule,
21:10 --> 21:13we hypothesized that they
21:13 --> 21:16might be coming together.
21:16 --> 21:18So the singling usually occurs
21:18 --> 21:20when you get more than one of
21:20 --> 21:21these CARs coming together,
21:21 --> 21:23being brought together and that's
21:23 --> 21:25what happens when it engages
21:25 --> 21:27its target on the other cells.
21:27 --> 21:30And so by changing one of those domains
21:30 --> 21:34that we thought was leading to that
21:34 --> 21:37aggregation and that baseline single,
21:37 --> 21:40we were able to decrease that baseline
21:40 --> 21:43singling and make it so that it only
21:43 --> 21:45signals when it really is being
21:45 --> 21:47brought together by the antigen on
21:47 --> 21:50the other cell and not when it's
21:50 --> 21:52existing on its own in the T cell.
21:53 --> 21:55The other question that I
21:55 --> 21:57have for you is you mentioned that one
21:57 --> 22:00of the things that makes solid tumors
22:00 --> 22:02tricky is this tumor microenvironment.
22:02 --> 22:03The fact that
22:03 --> 22:06the cancers know how to make an
22:06 --> 22:08environment around themselves that's
22:08 --> 22:10very comfortable for the cancer cells
22:10 --> 22:13to grow in and not so comfortable
22:13 --> 22:15for anything else to kill them.
22:15 --> 22:18But in thinking about CAR T
22:18 --> 22:20therapy and blood cancers,
22:20 --> 22:23you know when you think
22:23 --> 22:25about metastatic disease,
22:25 --> 22:28really there is potentially a way
22:28 --> 22:32to think about solid tumors that
22:32 --> 22:34maybe like a blood tumor in the
22:34 --> 22:36sense that when they're metastatic
22:36 --> 22:39you're really trying to get at the
22:39 --> 22:42circulating tumor cells and
22:42 --> 22:44the disease that isn't necessarily
22:44 --> 22:47in a particular solid organ.
22:47 --> 22:49Can you talk a little bit about that, is
22:50 --> 22:53CAR T therapy particularly good
22:53 --> 22:55for metastatic disease and
22:55 --> 22:58reducing the circulating tumor burden?
22:58 --> 22:59Yeah, absolutely.
22:59 --> 23:04So as I was mentioning the CD 19
23:04 --> 23:08CAR that targets B cell leukemias,
23:08 --> 23:11that one works phenomenal.
23:11 --> 23:13It doesn't have any of
23:13 --> 23:15the tonic singling that we were just
23:15 --> 23:18talking about it is a great target.
23:18 --> 23:21It's all in the bloodstream and
23:21 --> 23:23patients do very well with that.
23:23 --> 23:26Just underneath that there are so-called
23:26 --> 23:29B cell lymphomas which take up residence.
23:29 --> 23:32They form more of a mass as opposed
23:32 --> 23:34to just being circulating through
23:34 --> 23:36the bloodstream that they also can
23:36 --> 23:39use the CD 19 CAR and they do OK,
23:39 --> 23:41not as well as the leukemias
23:41 --> 23:42with that CD19 CAR,
23:42 --> 23:45but still somewhat OK and part
23:45 --> 23:48of that is probably this tumor
23:48 --> 23:50microenvironment that's created there.
23:50 --> 23:53Now one of the best reasons to use
23:53 --> 23:55the T cell to deliver these
23:55 --> 23:59CAR T cells is that the T cells seek
23:59 --> 24:00out and destroy these metastases
24:00 --> 24:02that are throughout the body.
24:03 --> 24:05There are molecules that kind of
24:05 --> 24:08tell them to look within these areas
24:08 --> 24:11and it gets them places where other
24:11 --> 24:14less smart drugs might not realize
24:14 --> 24:17how to get to or where to go.
24:17 --> 24:20And so improving CAR T cells ability
24:20 --> 24:23to find these metastases is another
24:23 --> 24:25active area of investigation.
24:25 --> 24:26In fact,
24:26 --> 24:29we have a collaboration with another
24:29 --> 24:31senior professor John Morrow in
24:31 --> 24:34determining ways of how we can improve
24:34 --> 24:36the T cells ability to traffic
24:36 --> 24:39to get to where they're going.
24:39 --> 24:41And then once they're there,
24:41 --> 24:43they have to then face this
24:43 --> 24:45kind of a barrier,
24:45 --> 24:46this impenetrable barrier that
24:46 --> 24:48the tumor kind of forms this wall.
24:49 --> 24:51And so there are other ways that
24:51 --> 24:53people are designing to equip the T
24:53 --> 24:54cells to kind of get through that
24:54 --> 24:56barrier a little better.
24:57 --> 25:00You know as you mentioned thinking
25:00 --> 25:02about metastatic sites and so
25:02 --> 25:04on and the ability for T cells
25:04 --> 25:07potentially to navigate through these
25:07 --> 25:09barriers better than other drugs.
25:09 --> 25:11It makes you think about things
25:11 --> 25:13that have been historically very
25:13 --> 25:16difficult for us to treat with
25:16 --> 25:18standard chemotherapy and that's kind
25:18 --> 25:20of getting to brain metastases and
25:20 --> 25:22getting past the blood brain barrier.
25:22 --> 25:24But earlier before the break,
25:24 --> 25:28you were talking about some neurotoxicity
25:28 --> 25:30associated with these newer therapies.
25:30 --> 25:33Can you talk a little bit
25:33 --> 25:35about whether CAR T therapy,
25:35 --> 25:37you envisage this really having a
25:37 --> 25:39role to play in in brain metastases
25:39 --> 25:42and how exactly that would work?
25:42 --> 25:46Yeah, absolutely. So interestingly enough,
25:46 --> 25:49some of those original patients that
25:49 --> 25:52had leukemias or blood lymphomas wound
25:52 --> 25:55up having disease within their brain
25:55 --> 25:57and it was found that the CAR T cells
25:57 --> 26:00were making were actually
26:00 --> 26:03fighting off the disease that was there.
26:03 --> 26:05So I think the potential is possible
26:05 --> 26:07and it's not quite understood yet
26:07 --> 26:09whether they were able to get in
26:09 --> 26:10because the blood brain barrier that
26:10 --> 26:13we talked about was disrupted a little
26:13 --> 26:15bit because the disease was already
26:15 --> 26:17there or whether the CAR T cells
26:17 --> 26:20are able to even in a completely
26:20 --> 26:22intact blood vein barrier get in.
26:22 --> 26:24But I think there's certainly is
26:24 --> 26:27the potential and there have been
26:27 --> 26:29several studies since then trying
26:29 --> 26:31to target not just hematopoietic
26:31 --> 26:33tumors that make it to the brain,
26:33 --> 26:34but also solid tumors that have
26:34 --> 26:36made it to the brain as well.
26:36 --> 26:39In addition to brain tumors themselves,
26:39 --> 26:41where there are different CARs that people
26:41 --> 26:43have been developing in order to do that.
26:43 --> 26:46And there is some evidence of some
26:46 --> 26:48efficacy still needs to be improved though.
26:49 --> 26:52Yeah, you know the, it sounds like such
26:52 --> 26:54a wonderful exciting new target,
26:54 --> 26:58but I wonder about the downsides as well.
26:58 --> 27:01So you know when we think about really
27:01 --> 27:03turning on the immune system after having
27:03 --> 27:06lived through the the COVID pandemic,
27:06 --> 27:08many of us saw that there were some
27:08 --> 27:11patients whose immune systems were turned
27:11 --> 27:14on so much that you ended up with this
27:14 --> 27:17immune storm and really that caused a
27:17 --> 27:19lot of side effects for these patients.
27:19 --> 27:23Would you expect the same kind
27:23 --> 27:25of thing with CAR T therapy?
27:25 --> 27:28I mean, it seems like it might be a
27:28 --> 27:30balance between too much and too little.
27:30 --> 27:31On the one hand,
27:31 --> 27:33you don't want your T cells to get exhausted.
27:33 --> 27:36On the other hand, you don't want them
27:36 --> 27:37working too hard either,
27:37 --> 27:39at the expense of toxicity.
27:40 --> 27:42Absolutely. And this is one of the
27:42 --> 27:45reasons why I really appreciate the
27:45 --> 27:48wisdom of Sherman Weissman in devising
27:48 --> 27:51and thinking about this RNA approach.
27:51 --> 27:54So when you give a standard CAR therapy
27:54 --> 27:58using the lentiviral type approach and DNA,
27:58 --> 28:01you really don't have any control over
28:01 --> 28:04those T cells and how much they proliferate,
28:04 --> 28:06how long they stay around for,
28:06 --> 28:08what kind of dosing you give.
28:08 --> 28:10And if a patient winds up having
28:10 --> 28:12some of these side effects,
28:12 --> 28:15there's not much you can do.
28:15 --> 28:17On the other hand,
28:17 --> 28:18for the RNA approach,
28:18 --> 28:21you can very precisely decide
28:21 --> 28:23how much you're giving and when,
28:23 --> 28:26and you can titrate that amount so
28:26 --> 28:28that you can make it less if in order
28:28 --> 28:31to not get into that territory where
28:31 --> 28:34you get those types of side effects.
28:34 --> 28:37Samuel Katz is an associate professor of
28:37 --> 28:39pathology at the Yale School of Medicine.
28:39 --> 28:41If you have questions,
28:41 --> 28:43the address is canceranswers@yale.edu,
28:43 --> 28:46and past additions of the program
28:46 --> 28:48are available in audio and written
28:48 --> 28:49form at yalecancercenter.org.
28:49 --> 28:52We hope you'll join us next time to learn
28:52 --> 28:54more about the fight against cancer.
28:54 --> 28:57Funding for Yale Cancer Answers is
28:57 --> 29:00provided by Smilow Cancer Hospital.

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New Targets for Triple Negative Breast Cancer with guest Samuel Katz May 19, 2024