Investigating New Targets for Triple Negative Breast Cancer

May 20, 2024

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00:00Funding for Yale Cancer Answers is
00:03provided by Smilow Cancer Hospital.
00:06Welcome to Yale Cancer Answers
00:08with Doctor Anees Chagpar.
00:10Yale Cancer Answers features the
00:12latest information on cancer
00:13care by welcoming oncologists and
00:15specialists who are on the forefront
00:17of the battle to fight cancer.
00:19This week it's a conversation about
00:21hematopathology and breast cancer
00:23research with Doctor Samuel Katz.
00:25Dr. Katz is an associate professor of
00:27pathology at the Yale School of Medicine,
00:30where Doctor Chagpar is a professor
00:32of surgical oncology.
00:34So Dr. Katz, maybe we can start off
00:36by you telling us a little bit more
00:38about yourself and what it is you do.
00:40I'm a physician scientist
00:43within the Department of Pathology.
00:45I split my time where I spend 20% on
00:49clinical service diagnosing blood cancers,
00:53leukemias, and lymphomas.
00:54But I spend the majority of my time
00:57running a basic research laboratory that
01:00focuses on questions of how cells die.
01:03And we approach it from two
01:05different standpoints.
01:07By the pathway within the
01:09cells that cause them to die,
01:12but also by a pathway external to
01:15the cells and how we can kill them.
01:17Because if we can manipulate
01:19the ability to kill cells,
01:21that could help in many
01:23different diseases like cancers.
01:29Tell us a little bit more about how
01:31you came to work on breast
01:34cancer as a hematopathologist.
01:36You mentioned that in your clinical role,
01:38you really focus on blood cancers.
01:41So how do you get
01:44into the breast cancer world?
01:46As a hematopathologist who
01:48focuses on the blood and the blood system,
01:51I got very interested in a
01:54particular cell type called a T cell.
01:57And T cells are important in our
02:00immune system to attack cells that
02:03have been infected with foreign agents.
02:05They're able to recognize the cells
02:08as being infected and kill them.
02:10And people have realized that they
02:13have such incredible ability to kill
02:16those infected cells that perhaps we
02:18can usurp that ability in order to
02:21attack other cells like cancer cells.
02:25And so tell us more about how this
02:27kind of works in breast cancer and
02:29more about your research.
02:33Sure, so in breast cancer there are
02:35many other types of cancers,
02:37there are proteins that are on
02:41the surface of the cell that are
02:44not present in normal cells.
02:46And so we have devised a protein that
02:50we can add into the T cells called
02:53a CAR or chimeric antigen receptor,
02:55thus making a CAR T cell that can
02:58recognize this aberrant protein
03:00on the breast cancer cell and
03:02direct the T cells killing ability
03:05towards that breast cancer cell.
03:09That sounds really fascinating.
03:12So tell us more about
03:14how CAR T therapy works.
03:16I know some of our listeners
03:17may be familiar with this,
03:19but many may not be. So, you know,
03:21how do you actually change these T
03:23cells to make them recognize these
03:26proteins on the surface of the cell?
03:29Because it sounds like essentially
03:30what you're doing is you're
03:31taking a patient's immune system,
03:33these T cells,
03:34and you're kind of giving them a GPS, a
03:37targeting system to say go after those cells,
03:40those cancer cells,
03:41but somehow you have to get
03:43the GPS into those T cells.
03:45How do you do that exactly?
03:47Absolutely. And so there's a
03:49number of ways in which to,
03:51as we say, reprogram those T cells.
03:55The most commonly used ones are
03:58viral approaches using retroviruses
04:00or lentiviruses where a piece of
04:04DNA and that virus will infect the
04:07cell and then integrate or become
04:10part of that cells genome or DNA
04:12and it will then express this new
04:15protein that we've made which we
04:17can discuss later called the CAR,
04:19the chimeric antigen receptor.
04:22Another way in which to do it,
04:26which is the approach we've taken
04:28and really came about because of
04:30some work by a senior professor here
04:33at Yale called Sherman Weissman.
04:34He kind of took me under his wing
04:37as a mentor in this approach where
04:40instead of using DNA, he was using RNA.
04:43And so we can take the T cells out
04:47of the patient and what we call
04:49Electroplate in order to give
04:51them kind of a little shock that
04:53gets the RNA into the cells.
04:55And this has a very high efficiency of
04:58being able to reprogram those cells
05:01using the RNA in this manner.
05:04But it also has a lot of other advantages,
05:06chief among them being safety in that
05:09when you put an RNA into a cell,
05:12it doesn't change the genome of all
05:14of the T cells that you're taking
05:17from the patients.
05:18It only makes that RNA which then
05:21makes that protein and after a
05:23period of time it goes away.
05:25And so there's an added safety to that
05:29and that also sounds like that would
05:32be particularly handy once the job
05:35of getting rid of this cancer is done
05:38that the cells go back to normal.
05:39So how long does it take for
05:42that RNA to disintegrate or go away?
05:46The RNA actually is very
05:49short lived, but the protein it
05:51makes can last a little longer and
05:53it really depends on the particular
05:55protein that you're making.
05:58But we see it in the order
06:00of about a week or so.
06:02So one could envision giving this
06:04therapy as a weekly type of basis
06:07where you're giving the cells that
06:09have been reprogrammed with RNA or
06:12in newer work that's still ongoing
06:15trying to actually deliver the RNA
06:18into the body without having to take
06:21out the T cells to reprogram them.
06:27It sounds like it really is intriguing,
06:31right, that you kind of give
06:33these T cells a little shock,
06:35give them an RNA to make a protein.
06:38That protein, that CAR protein goes
06:42and attacks these cancer cells in a
06:45very specific way because presumably
06:47this protein is found on cancer
06:50cells and not on normal cells.
06:52So where are we in terms of actually
06:55getting this into clinical trials?
06:58Yeah, so we're still in the
07:01early phases I'd say of doing this.
07:04There's a lot of work to be done
07:06to optimize the system overall
07:12and these include the things that improve
07:14the ability of the T cells to kill,
07:17to make sure that they don't get exhausted,
07:22to make sure that again,
07:25as we're saying,
07:26to really make sure that it's safe.
07:28We still have work to do in
07:30animal models before we can get
07:32it into the clinical sphere,
07:34but because of the RNA approach
07:36and the safety,
07:37we do think it is a easier transition
07:39to getting it into patients.
07:43And in terms of
07:45the safety and side effects,
07:48can you talk a little bit
07:49more about the side effects?
07:51I mean I would assume that this
07:53has a lot to do with whether these
07:56proteins are on normal cells in any
07:59capacity or whether they are really
08:02100% only on cancer cells and also
08:05revving up the the immune system.
08:07You may think that you might get some
08:10immune related side effects as these T
08:12cells go about doing their business.
08:14and so maybe it is best to
08:17take one step back and to say where
08:20the CAR T cells have been really
08:22successful to date in the clinic.
08:25And these have been against actually
08:28targets that are on B cell malignancies
08:32or leukemias and lymphomas.
08:34And they're going
08:36after a target called CD 19,
08:39which is expressed on the surface of
08:42those B cells and that really is unique to
08:46those cancer cells as well as normal B cells.
08:50And so when the CAR T cells are
08:52introduced to those patients,
08:54it does get rid of all their normal B cells,
08:56but patients are fine with that.
08:58You can
08:59live without our B cells.
09:03There are some side effects
09:04that are seen with that therapy.
09:05One is a called a cytokine release
09:09syndrome where because you're getting so
09:11much killing so quickly of the cancer,
09:13it releases a lot of the cytokines
09:15that leads to kind of like an
09:18immune storm within the patients.
09:20They feel very sick and you have to really
09:22watch them carefully within the hospital.
09:24And there's also been some less well
09:27understood neurological disorders
09:31that occur in some patients.
09:34And some people have hypothesized that
09:36that might be due to the fact that
09:39we've learned later that there's a
09:41cell type within the brain that has
09:43very low expression of this target.
09:45And so then that gets us back to
09:48breast cancer and solid tumors where
09:50there aren't as many great targets
09:53that we know of that are uniquely
09:55expressed on the surface of these cells.
09:59The one that we're going after actually
10:02turns out to be increased in more than
10:05half of triple negative breast cancers
10:07and its expression correlates with
10:09poor prognosis within these patients.
10:12There is some very low
10:15expression during development,
10:17but we have some reasons to believe
10:21that we can kind of thread the needle
10:24between this very high expression
10:26on the cancer and this perhaps low
10:29expression on some normal tissues.
10:32Yeah, I mean I think that in general for
10:37most cancer related drugs
10:42it's never completely black and white.
10:44Even chemotherapy we know we still use
10:47and it really is designed to attack
10:51rapidly growing cells and dividing cells.
10:55But you still get some normal cells
10:58that are also rapidly dividing
11:00like your hair for example,
11:02which is why many patients undergoing
11:05chemotherapy lose their hair.
11:07So it sounds like even if there
11:09was a potential differential there,
11:12it still might be really handy
11:14in terms of a therapy,
11:16especially if it was less toxic
11:19than our standard therapies,
11:21which for triple negative breast
11:24cancer are primarily chemotherapy.
11:26Now the other question that I have
11:28for you is in triple negative
11:30breast cancer in particular,
11:31we've seen that there are now therapies that
11:36are being used that are immunotherapies.
11:39So really therapies that are
11:42designed to unleash the immune system
11:44especially because some of these
11:47triple negative breast cancers,
11:49they tend to evade the immune system.
11:54So if that's the case, and this CAR
11:58T therapy is really designed to
12:01use the immune system,
12:03is it the idea that this would
12:05be paired with immunotherapies or
12:07are you thinking about a different
12:09way of attacking this?
12:12So I think there is a potential
12:15for testing the two together,
12:17but it is very different in
12:19the way these two different
12:22classes of immunotherapies work.
12:24So the ones that you're referring
12:27to, so-called checkpoint inhibitors,
12:30these are ones that rely on new
12:35antigens that are made within
12:37the cancer cell that are mutant
12:40and specific to the cancer cells.
12:42And they really are unique.
12:45The T cells use their native,
12:48their normal T cell receptors
12:51to recognize those.
12:52But there's a so-called break
12:55mechanism that prevents the T cell
12:58from killing and the immunocheckpoint
13:01inhibitors take away that break, the
13:03CAR that I've been talking about,
13:06these CAR T cells,
13:07this is a new protein that we've
13:11devised by taking pieces of various
13:14other parts of the T cell receptor
13:17and other antigen recognition domains
13:19and they recognize or we've designed
13:22this one to recognize a specific
13:28protein that's not mutated but wild type.
13:31And this then activates the CAR T
13:36cell rather than stopping the brake.
13:39I'd say it's more akin to pressing
13:42on the gas pedal when we have
13:45that specific protein.
13:46Well, we need to take a
13:48short break for a medical minute,
13:50but please stay tuned to learn more
13:53about the role of pathology and new
13:55research into a potential target for
13:57metastatic triple negative breast
13:59cancer with my guest, Doctor Sam Katz.
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15:15You're listening to Connecticut Public Radio.
15:19Welcome back to Yale Cancer Answers.
15:21This is Doctor Anees Chagpar and
15:23I'm joined tonight by my guest,
15:25Doctor Samuel Katz.
15:26We're talking about the role of pathology
15:29and some new research into CAR T cells,
15:31but now for a new indication
15:33and that's really metastatic
15:34triple negative breast cancer.
15:36So Doctor Katz,
15:37I want to go back to something you were
15:39mentioning right before the break,
15:40which is how traditional immunotherapies,
15:43these checkpoint inhibitors which
15:45we now use in triple negative breast
15:49cancer really kind of get rid of
15:51a brake as you phrased it in
15:54terms of T cell killing.
15:56Because we know that certain cancer
15:59cells, especially triple negative
16:00cancer cells, may kind of put a
16:04brake on those T cells to
16:07kill off these cancer cells.
16:09And so traditional immunotherapies
16:12will remove that brake your car T
16:16therapy is more like an accelerator
16:19finding a new target on these T
16:22cells to attack cancer
16:26cells in a different way.
16:28So kind of like putting on an accelerator.
16:32My question is how do those two work
16:36together or is there an interplay?
16:39Thinking about, you know,
16:40driving a car,
16:40if you step on the gas while you're
16:43still got a brake on,
16:44it generally doesn't work very well.
16:47Can you talk a little bit more about that?
16:49Absolutely. And I think that's why,
16:52as you kind of suggested,
16:54the combination of this might be very useful.
16:58Because while if you're just
17:02releasing your foot off the brake by
17:04using these checkpoint inhibitors,
17:06if you don't have something driving,
17:08if there isn't a mutant
17:09antigen for you to go after,
17:12then the car won't move forward,
17:13the T cell won't kill.
17:16On the other hand, like you said,
17:17if the CAR T cell is engineered so that it
17:20is always pressing on the gas pedal yet,
17:23it might try going forward.
17:24But if you have that brake
17:26present at the same time,
17:28then it's it won't be able to.
17:30But if you can manipulate the
17:32cell in ways that many people
17:35are, to kind of combine the two,
17:37then perhaps we could get
17:40the full benefit of this.
17:42I also want to bring up one other
17:46thing that you had
17:47mentioned before the break,
17:49which is kind of getting towards
17:51the difference between solid
17:53tumors like triple negative breast
17:56cancer and the blood tumors where
17:58CAR T's have worked so well.
18:01Solid tumors have remained a
18:04real challenge for the CAR T field
18:07to be able to work efficiently.
18:09And that's because they create
18:12this tumor microenvironment that
18:14kind of quells the T cell,
18:17some of which might be to increase the
18:19brake like we've been talking about.
18:22Another way is you can imagine that
18:25the car won't do so well if you're
18:28always pressing the gas pedal right.
18:30You'll run out of gas eventually.
18:32And a lot of the CAR T designs
18:34in the past have this problem
18:37where you're always pushing on
18:39the gas even when you're not,
18:42when you don't want it to,
18:43when you don't have that target in sight.
18:46Fortunately,
18:47some work in the lab by Po Han Chen,
18:50another physician scientist who's
18:51been working on this problem,
18:53came up with a new design towards
18:55our car to make it so that it only
18:57presses on the gas when we want it to.
19:00That's interesting.
19:01Can you tell us a bit more about that?
19:03I mean, one would think that
19:06if there wasn't a target,
19:08but the T cells really wouldn't
19:10have anything to go after and
19:12so they would just be kind of
19:14floating around looking for that
19:16target if it should appear.
19:18So how do you turn on and turn
19:20off these T cells so that they
19:23don't get overly active
19:25and exhausted as you put it?
19:27Yeah, that's a great question.
19:29And I think what we have to remember
19:31is when we're putting in this car,
19:33this chimeric antigen receptor,
19:35it's really a man made
19:38Frankenstein type molecule.
19:40It hasn't been engineered by nature over
19:44you know millions of years of evolution.
19:47It's something that we've come up with
19:49and made in the lab and so therefore
19:52it doesn't work necessarily perfectly.
19:54We've taken snippets of different
19:56proteins and put them together and a
19:59normal receptor that's on the cell will
20:02only single to have its downstream
20:05effects when it engages its target.
20:07But these
20:09CARs that we've made ourselves,
20:11they have a little leakiness to them,
20:13many of them.
20:14And that leads to
20:17what we call tonic singling,
20:18singling all the time or pressing
20:20on that gas pedal all the time.
20:22And Po Han has realized that one of
20:26those domains could be optimized
20:28to help reduce that issue.
20:31And I think that's going to
20:32be really critical for when we
20:35start targeting solid tumors.
20:37And so when you say optimized,
20:39do you mean like it's kind of got
20:42a way that it it learns when to
20:47turn on and when to turn off?
20:48Because presumably you want the thing to
20:51to turn on when there is that target,
20:54and you want it to go full speed
20:56ahead and kill that target.
20:57And when the target isn't there,
20:59well, then you want it to conserve
21:00its energy and lay low for a bit?
21:02So looking at the actual structure
21:06or the presumed structure of the molecule,
21:10we hypothesized that they
21:14might be coming together.
21:16So the singling usually occurs
21:18when you get more than one of
21:21these CARs coming together,
21:22being brought together and that's
21:24what happens when it engages
21:26its target on the other cells.
21:28And so by changing one of those domains
21:31that we thought was leading to that
21:35aggregation and that baseline single,
21:38we were able to decrease that baseline
21:40singling and make it so that it only
21:43signals when it really is being
21:45brought together by the antigen on
21:48the other cell and not when it's
21:50existing on its own in the T cell.
21:53The other question that I
21:55have for you is you mentioned that one
21:58of the things that makes solid tumors
22:00tricky is this tumor microenvironment.
22:02The fact that
22:04the cancers know how to make an
22:07environment around themselves that's
22:08very comfortable for the cancer cells
22:11to grow in and not so comfortable
22:13for anything else to kill them.
22:15But in thinking about CAR T
22:18therapy and blood cancers,
22:21you know when you think
22:23about metastatic disease,
22:25really there is potentially a way
22:29to think about solid tumors that
22:32maybe like a blood tumor in the
22:34sense that when they're metastatic
22:36you're really trying to get at the
22:40circulating tumor cells and
22:42the disease that isn't necessarily
22:44in a particular solid organ.
22:48Can you talk a little bit about that, is
22:51CAR T therapy particularly good
22:53for metastatic disease and
22:56reducing the circulating tumor burden?
22:59Yeah, absolutely.
23:00So as I was mentioning the CD 19
23:05CAR that targets B cell leukemias,
23:09that one works phenomenal.
23:11It doesn't have any of
23:13the tonic singling that we were just
23:16talking about it is a great target.
23:19It's all in the bloodstream and
23:21patients do very well with that.
23:24Just underneath that there are so-called
23:27B cell lymphomas which take up residence.
23:30They form more of a mass as opposed
23:32to just being circulating through
23:34the bloodstream that they also can
23:36use the CD 19 CAR and they do OK,
23:39not as well as the leukemias
23:41with that CD19 CAR,
23:43but still somewhat OK and part
23:45of that is probably this tumor
23:48microenvironment that's created there.
23:51Now one of the best reasons to use
23:54the T cell to deliver these
23:56CAR T cells is that the T cells seek
23:59out and destroy these metastases
24:01that are throughout the body.
24:03There are molecules that kind of
24:06tell them to look within these areas
24:09and it gets them places where other
24:12less smart drugs might not realize
24:14how to get to or where to go.
24:17And so improving CAR T cells ability
24:20to find these metastases is another
24:23active area of investigation.
24:26In fact,
24:27we have a collaboration with another
24:30senior professor John Morrow in
24:32determining ways of how we can improve
24:35the T cells ability to traffic
24:37to get to where they're going.
24:39And then once they're there,
24:41they have to then face this
24:44kind of a barrier,
24:45this impenetrable barrier that
24:47the tumor kind of forms this wall.
24:49And so there are other ways that
24:51people are designing to equip the T
24:53cells to kind of get through that
24:55barrier a little better.
24:58You know as you mentioned thinking
25:00about metastatic sites and so
25:02on and the ability for T cells
25:05potentially to navigate through these
25:07barriers better than other drugs.
25:09It makes you think about things
25:12that have been historically very
25:14difficult for us to treat with
25:16standard chemotherapy and that's kind
25:18of getting to brain metastases and
25:20getting past the blood brain barrier.
25:23But earlier before the break,
25:24you were talking about some neurotoxicity
25:29associated with these newer therapies.
25:31Can you talk a little bit
25:33about whether CAR T therapy,
25:35you envisage this really having a
25:37role to play in in brain metastases
25:40and how exactly that would work?
25:43Yeah, absolutely. So interestingly enough,
25:46some of those original patients that
25:50had leukemias or blood lymphomas wound
25:53up having disease within their brain
25:55and it was found that the CAR T cells
25:58were making were actually
26:01fighting off the disease that was there.
26:03So I think the potential is possible
26:05and it's not quite understood yet
26:07whether they were able to get in
26:09because the blood brain barrier that
26:11we talked about was disrupted a little
26:13bit because the disease was already
26:15there or whether the CAR T cells
26:18are able to even in a completely
26:20intact blood vein barrier get in.
26:23But I think there's certainly is
26:25the potential and there have been
26:27several studies since then trying
26:29to target not just hematopoietic
26:31tumors that make it to the brain,
26:33but also solid tumors that have
26:35made it to the brain as well.
26:36In addition to brain tumors themselves,
26:40where there are different CARs that people
26:42have been developing in order to do that.
26:43And there is some evidence of some
26:46efficacy still needs to be improved though.
26:49Yeah, you know the, it sounds like such
26:52a wonderful exciting new target,
26:55but I wonder about the downsides as well.
26:59So you know when we think about really
27:01turning on the immune system after having
27:04lived through the the COVID pandemic,
27:06many of us saw that there were some
27:09patients whose immune systems were turned
27:11on so much that you ended up with this
27:14immune storm and really that caused a
27:17lot of side effects for these patients.
27:20Would you expect the same kind
27:23of thing with CAR T therapy?
27:26I mean, it seems like it might be a
27:28balance between too much and too little.
27:30On the one hand,
27:31you don't want your T cells to get exhausted.
27:33On the other hand, you don't want them
27:36working too hard either,
27:38at the expense of toxicity.
27:40Absolutely. And this is one of the
27:43reasons why I really appreciate the
27:45wisdom of Sherman Weissman in devising
27:48and thinking about this RNA approach.
27:51So when you give a standard CAR therapy
27:55using the lentiviral type approach and DNA,
27:59you really don't have any control over
28:01those T cells and how much they proliferate,
28:04how long they stay around for,
28:07what kind of dosing you give.
28:08And if a patient winds up having
28:11some of these side effects,
28:12there's not much you can do.
28:16On the other hand,
28:17for the RNA approach,
28:19you can very precisely decide
28:21how much you're giving and when,
28:24and you can titrate that amount so
28:26that you can make it less if in order
28:29to not get into that territory where
28:32you get those types of side effects.
28:35Samuel Katz is an associate professor of
28:37pathology at the Yale School of Medicine.
28:40If you have questions,
28:42the address is canceranswers@yale.edu,
28:44and past additions of the program
28:47are available in audio and written
28:49form at yalecancercenter.org.
28:50We hope you'll join us next time to learn
28:53more about the fight against cancer.
28:54Funding for Yale Cancer Answers is
28:57provided by Smilow Cancer Hospital.