Skip to Main Content
All Podcasts

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.
  • 14:01 --> 14:04Support for Yale Cancer Answers comes
  • 14:04 --> 14:06from Smilow Cancer Hospital where
  • 14:06 --> 14:08their Prostate and Urologic Cancers
  • 14:08 --> 14:10program provides a multispecialty team
  • 14:10 --> 14:12dedicated to managing the diagnosis,
  • 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
  • 14:48 --> 14:50for head and neck cancers.
  • 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
  • 14:59 --> 15:01Program of Research Excellence,
  • 15:01 --> 15:01or SPORE,
  • 15:01 --> 15:03to address critical barriers to
  • 15:03 --> 15:06treatment of head and neck squamous cell
  • 15:06 --> 15:09carcinoma due to resistance to immune
  • 15:09 --> 15:11DNA damaging and targeted therapy.
  • 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.