Improving Outcomes for Patients Undergoing CAR T-cell Therapy

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 care
00:13 --> 00:15by welcoming oncologists and
00:15 --> 00:17specialists who are on the forefront
00:17 --> 00:19of the battle to fight cancer.
00:19 --> 00:21This week it's a conversation about CAR T
00:21 --> 00:24cell therapy with Doctor Timothy Robinson.
00:24 --> 00:26Doctor Robinson is an assistant
00:26 --> 00:28professor of Therapeutic radiology
00:28 --> 00:30at the Yale School of Medicine
00:30 --> 00:30where Dr. Chagpar
00:30 --> 00:32is a professor
00:32 --> 00:33of Surgical oncology.
00:34 --> 00:35Tim, maybe we can start off by you
00:35 --> 00:37telling us a little bit more about
00:37 --> 00:38yourself and what it is you do.
00:39 --> 00:42Sure. So I am a radiation oncologist,
00:42 --> 00:45which means that I treat tumors or
00:45 --> 00:47cancers using radiation therapy
00:47 --> 00:50and I have a clinical presence,
00:50 --> 00:51so I treat patients.
00:51 --> 00:53I specialize in the treatment of hematologic
00:53 --> 00:56malignancies as well as CNS disease.
00:56 --> 00:57I also have a small lab that
00:57 --> 00:59tries to work more on the research side,
00:59 --> 01:00trying to figure out how
01:00 --> 01:00to do these things better.
01:01 --> 01:04And so tell us a little bit more
01:04 --> 01:05about what your lab is up to.
01:07 --> 01:11Sure, my lab has been working on
01:11 --> 01:13ways to try and figure out with lymphoma
01:13 --> 01:16how to make our treatments better.
01:16 --> 01:18As a radiation oncologist,
01:18 --> 01:20I think about radiation a lot.
01:20 --> 01:22Lymphomas are unique in that
01:22 --> 01:24in many cancers we use
01:24 --> 01:25radiation to treat many
01:25 --> 01:27different cancers and solid tumors,
01:27 --> 01:29but lymphomas and other so called
01:29 --> 01:31liquid tumors, so lymphoma,
01:31 --> 01:33myelomas, leukemias are actually
01:33 --> 01:36exquisitely sensitive to radiation
01:36 --> 01:39and so it's another place where
01:39 --> 01:40radiation can actually be helpful.
01:40 --> 01:42However, even though in general
01:42 --> 01:44these tumors tend to be very
01:44 --> 01:45sensitive for aggressive lymphomas
01:45 --> 01:47that have kind of blown through
01:47 --> 01:49all the conventional treatments,
01:49 --> 01:50we actually will sometimes even for
01:50 --> 01:52them see that they will actually grow
01:52 --> 01:54through radiation treatment and we don't
01:54 --> 01:55have a good understanding of why that is.
01:56 --> 01:58And so my lab is interested in
01:58 --> 02:01understanding how those tumors
02:01 --> 02:03become resistant to radiation and
02:03 --> 02:05then also how are those tumors becoming
02:05 --> 02:08resistant to some of these new and
02:08 --> 02:10these emerging therapies like cellular
02:10 --> 02:12therapies like CAR T cell therapy
02:12 --> 02:13that have really kind of
02:13 --> 02:15revolutionized our treatment of these tumors.
02:15 --> 02:17But they still don't always work
02:17 --> 02:18and we're trying to figure out
02:18 --> 02:19ways to make them work better.
02:20 --> 02:23So tell us a bit more about what
02:23 --> 02:25exactly CAR T cell therapy is.
02:25 --> 02:27I mean some of our audience may
02:27 --> 02:29have heard of it, it seems to be
02:29 --> 02:32something that is fairly novel.
02:32 --> 02:33Many of our audience may know
02:33 --> 02:36the standard surgery,
02:36 --> 02:37chemotherapy, radiation,
02:37 --> 02:40maybe even have heard about immunotherapy.
02:40 --> 02:43But CAR T cell therapy sounds
02:43 --> 02:44really new and interesting.
02:44 --> 02:46So can you tell us a bit more about
02:46 --> 02:48what it is and how it works?
02:48 --> 02:49Well, it is new and interesting,
02:49 --> 02:51you're correct.
02:51 --> 02:53So CAR T cell therapy,
02:53 --> 02:55what it stands for is chimeric
02:55 --> 02:58antigen receptor, T cell therapy.
02:58 --> 03:01So chimera meaning a mix and then
03:01 --> 03:03antigen receptor is basically what
03:03 --> 03:05they've done it's actually very cool.
03:05 --> 03:07It almost sounds
03:07 --> 03:08like science fiction.
03:08 --> 03:10So what they can do is they can take your
03:10 --> 03:12immune cells, or your T cells specifically,
03:12 --> 03:14which is why it's called CAR T cell therapy.
03:14 --> 03:16And your T cells are part of your
03:16 --> 03:17immune system that can recognize of
03:17 --> 03:19course foreign antigens, infections,
03:19 --> 03:21but also potentially, cancers.
03:21 --> 03:25And basically what you can do is
03:25 --> 03:28you can take somebody's individual T cells,
03:28 --> 03:30so let's say somebody has an aggressive,
03:30 --> 03:32you know, lymphoma that's grown
03:32 --> 03:34through all the chemotherapy treatments
03:34 --> 03:36that are kind of standard of care.
03:36 --> 03:37And they have this
03:37 --> 03:38aggressive lymphoma that's just
03:38 --> 03:40not responding for those patients.
03:40 --> 03:42CAR T cell therapy has been approved.
03:42 --> 03:44And what you can do is basically take
03:44 --> 03:46the immune cells out of that patient,
03:46 --> 03:47put them in a Petri dish,
03:47 --> 03:49genetically engineer them to go
03:49 --> 03:52after markers on those cancer cells,
03:52 --> 03:53kind of have a pep rally in
03:53 --> 03:54the Petri dish
03:54 --> 03:55get them good and revved up and
03:55 --> 03:57then inject them back into the patients.
03:57 --> 04:00And then those CAR T cells
04:00 --> 04:02they're chimera because they've now been
04:02 --> 04:04put with a specific marker to
04:04 --> 04:05kind of heat sink towards
04:05 --> 04:06the cancer cells,
04:06 --> 04:08so it's a chimera or mix
04:08 --> 04:09of your normal T cells,
04:09 --> 04:11but now kind of targeted
04:11 --> 04:12towards the cancer cells.
04:12 --> 04:14And with that approach we can actually
04:14 --> 04:16cure people who previously really
04:16 --> 04:19didn't have any curable options.
04:19 --> 04:20And really what you need is kind
04:20 --> 04:22of a specific target to go after.
04:22 --> 04:24And this has been a very exciting area
04:24 --> 04:25in cancer overall,
04:25 --> 04:27but it's been very successful
04:27 --> 04:29in pediatric leukemias but also
04:29 --> 04:30in adult lymphomas.
04:31 --> 04:33But you know when some of
04:33 --> 04:35us hear the words lymphoma,
04:35 --> 04:37we think about
04:37 --> 04:39T cell lymphomas, B cell lymphomas.
04:39 --> 04:42So if you're taking people's
04:42 --> 04:45T cells out of them
04:45 --> 04:47and they have a lymphoma,
04:47 --> 04:49especially if they have a T cell lymphoma,
04:49 --> 04:51how does that work exactly?
04:51 --> 04:53Yeah, sure. So it's a great question.
04:53 --> 04:55So the thing is that right now
04:55 --> 04:57we're still figuring this out.
04:57 --> 05:00And so right now CAR T cell therapy
05:00 --> 05:03works great for B cell lymphomas because
05:03 --> 05:06almost all B cell lymphomas and many
05:06 --> 05:08B cell leukemias over-express a very
05:08 --> 05:11specific kind of protein on their surface
05:11 --> 05:13and it happens to be called CD19 and
05:13 --> 05:15that's kind of the bullseye so to speak.
05:15 --> 05:18It's a protein that is
05:18 --> 05:19over-expressed on malignant
05:19 --> 05:21B cells or lymphoma cells,
05:21 --> 05:22but not really over-expressed on
05:22 --> 05:24any other cells in the body.
05:24 --> 05:25And that's the target that the
05:25 --> 05:27CAR T cells go after.
05:27 --> 05:28We're trying to figure out how
05:28 --> 05:31could we go after T cell lymphomas
05:31 --> 05:32which are very aggressive.
05:32 --> 05:33But as you point out,
05:33 --> 05:34those don't necessarily have
05:34 --> 05:36the same markers and we haven't
05:36 --> 05:37cracked that nut so to speak,
05:37 --> 05:38but we are trying to figure
05:38 --> 05:40out specific markers on T cell
05:40 --> 05:41lymphomas that might work as well,
05:41 --> 05:42but we haven't figured that out just yet.
05:43 --> 05:46And so if you have these T cells
05:46 --> 05:48that are going after these markers
05:48 --> 05:51on B cells for B cell lymphoma,
05:53 --> 05:57is it true that, it sounds like that's great,
05:57 --> 05:58it sounds like you're just kind
05:58 --> 06:00of getting your immune system
06:00 --> 06:04to go after these cells and kill them off,
06:04 --> 06:07some of our audience might get confused
06:07 --> 06:09between that and immunotherapy.
06:09 --> 06:13Is this a form of immunotherapy and if so,
06:13 --> 06:16does it need to be administered with
06:16 --> 06:19chemotherapy as immunotherapies do or is
06:19 --> 06:21this something that is just
06:21 --> 06:25your body being revved up and
06:25 --> 06:27those T cells having gone to the pep
06:27 --> 06:30rally in the Petri dish, as you say,
06:30 --> 06:32just going out there and doing their job?
06:33 --> 06:35Typically when we
06:35 --> 06:36give this therapy, yeah,
06:36 --> 06:39the conditioning so to speak is
06:39 --> 06:41it's not given alongside
06:41 --> 06:43cytotoxic chemotherapy or other agents.
06:43 --> 06:45It really is kind of expected to act
06:45 --> 06:48on its own and that's what they
06:48 --> 06:50call lympho depleting chemotherapy.
06:50 --> 06:52So what they will do is give you about 3
06:52 --> 06:54days typically worth of chemotherapy that
06:54 --> 06:56will kind of suppress your immune system,
06:56 --> 06:58get your T cells that are there to kind
06:58 --> 07:01of calm down and get out of the way.
07:01 --> 07:02And then two days later they go
07:02 --> 07:04ahead and inject the CAR T cells and
07:04 --> 07:05they really do kind of on their own
07:05 --> 07:07basically
07:07 --> 07:09do the job of getting rid of the cancer.
07:09 --> 07:11So on one hand it is the
07:11 --> 07:14immune system going after the cancer,
07:14 --> 07:17but on the other hand we kind of tend
07:17 --> 07:18to distinguish
07:18 --> 07:19CAR T is cellular therapies
07:19 --> 07:21because you're taking cells out,
07:21 --> 07:23you know genetic engineering
07:23 --> 07:24then putting them back in.
07:24 --> 07:26And so we tend to call those
07:26 --> 07:26cellular therapies.
07:26 --> 07:27But I mean it really is
07:27 --> 07:29splitting hairs a little bit
07:29 --> 07:30because it is still the immune system
07:30 --> 07:32being used to go after the cancer.
07:32 --> 07:36Yeah. So I mean, it sounds really cool,
07:36 --> 07:38right? And it sounds like that would be
07:38 --> 07:42something that would be the ideal.
07:42 --> 07:44Here is one of the cells in your
07:44 --> 07:47body that has gone awry and created a cancer.
07:47 --> 07:50And now all you're doing is you're kind
07:50 --> 07:53of helping your body to target
07:53 --> 07:55those cancerous cells and fight them
07:55 --> 07:58off just like they were designed to do.
07:58 --> 08:00So what's the downside?
08:00 --> 08:02I mean are there
08:02 --> 08:06side effects to CAR T cell therapy
08:06 --> 08:08and what about the financial cost?
08:09 --> 08:10Sure, these are all
08:10 --> 08:12good points and
08:14 --> 08:16first and foremost,
08:16 --> 08:18it doesn't work all the time.
08:18 --> 08:20So for patients with
08:20 --> 08:21relapse refractory aggressive lymphomas,
08:21 --> 08:23we're trying to figure out
08:23 --> 08:24ways to make it work better.
08:24 --> 08:26But for those patients
08:26 --> 08:27their cure rates are quite low.
08:27 --> 08:29With CAR T cell therapy,
08:29 --> 08:30we appear to be getting about a
08:30 --> 08:3240% durable response,
08:32 --> 08:34which you could kind of call
08:34 --> 08:35a cure for those patients.
08:35 --> 08:37And so it's not perfect.
08:37 --> 08:38It doesn't work for everybody and
08:38 --> 08:39that's what we're actually trying
08:39 --> 08:41to do is to make that better so
08:41 --> 08:41that it does cure everybody,
08:42 --> 08:44but 40 percent is a pretty good
08:44 --> 08:45number when you're talking about
08:45 --> 08:48a setting where almost
08:48 --> 08:50nothing else works well.
08:50 --> 08:52And 2nd, in terms of toxicity,
08:52 --> 08:55first of all, the biologic toxicity,
08:55 --> 08:57so one of the things that can happen
08:57 --> 08:58is that there are some
08:58 --> 09:00patients it actually is similar to
09:00 --> 09:01immune therapy in that some patients
09:01 --> 09:03will just sail right through it
09:03 --> 09:04and won't even bat an eye.
09:04 --> 09:06But then some patients can have dramatic
09:06 --> 09:09side effects or toxicities and they
09:09 --> 09:11tend to be self limited which is good.
09:11 --> 09:13And the biggest one that we worry
09:13 --> 09:15about with CAR T cell therapy is
09:15 --> 09:17this thing called cytokine release
09:17 --> 09:18syndrome or CRS and what that is,
09:19 --> 09:21we've taken these T cells and
09:21 --> 09:23thrown a PEP rally inject them in
09:23 --> 09:24and then they see a lot of
09:24 --> 09:25tumor and they get real excited.
09:25 --> 09:28Your immune system when it revs up
09:28 --> 09:30can secrete a lot of cytokines and
09:30 --> 09:32sometimes it's such a powerful kind
09:32 --> 09:34of storm of cytokines that it can
09:34 --> 09:36actually cause a severe toxicity.
09:36 --> 09:38Probably the most feared toxicity is
09:38 --> 09:41something called ICANS or this kind
09:41 --> 09:45of neurologic toxicity where it can
09:45 --> 09:48actually result in something as severe as
09:48 --> 09:49not being able to talk
09:49 --> 09:51or even being temporarily paralyzed
09:51 --> 09:52like a kind of Guillain Barre
09:52 --> 09:54type syndrome in the hospital.
09:54 --> 09:56And that happens
09:56 --> 09:57actually not infrequently,
09:57 --> 09:59it varies by the exact cellular product.
09:59 --> 10:01But I mean in some of the products
10:01 --> 10:02that can be as high as 30% rate
10:02 --> 10:04of having a toxicity so bad that
10:04 --> 10:06people can temporarily be
10:06 --> 10:08stuck in the hospital not able to
10:08 --> 10:10speak and the vast
10:10 --> 10:11majority of those are self limited
10:11 --> 10:13and go away with close monitoring.
10:13 --> 10:15But there
10:15 --> 10:17certainly is a potential
10:17 --> 10:19for real toxicity especially in
10:19 --> 10:20the acute setting chronically.
10:20 --> 10:21So far, again, we don't have
10:21 --> 10:23super long term follow up,
10:23 --> 10:26but these patients seem to do well long term.
10:26 --> 10:28It really is kind of that acute window.
10:28 --> 10:30And then lastly on the financial toxicity,
10:30 --> 10:32you know this is an expensive therapy,
10:32 --> 10:34the number that I've heard cited
10:34 --> 10:35most often because obviously
10:35 --> 10:37our healthcare systems are complex
10:37 --> 10:39and opaque and can
10:39 --> 10:41be very difficult to navigate,
10:41 --> 10:43but around $400,000 is
10:43 --> 10:45the number that I've heard.
10:45 --> 10:47Holy Dinah.
10:47 --> 10:49Yeah, holy Dinah.
10:49 --> 10:51And that's obviously
10:51 --> 10:53a very high price tag.
10:53 --> 10:55So insurance clearance is of importance.
10:55 --> 10:57I mean the good news is that insurance
10:57 --> 10:59does cover this and approve it when
10:59 --> 11:01it's appropriate and the FDA approvals
11:01 --> 11:03have kind of been moving up
11:03 --> 11:05as appropriate
11:05 --> 11:07for patients with bad disease.
11:07 --> 11:09But that's the thing
11:09 --> 11:09with cancer care these days.
11:09 --> 11:11You could do a whole segment.
11:11 --> 11:12I'm sure you've done many segments
11:12 --> 11:14on the cost of cancer care,
11:14 --> 11:15which is a rapidly moving target.
11:15 --> 11:17So you know, on the one hand you could say,
11:17 --> 11:19oh my gosh, $400,000, this is crazy,
11:19 --> 11:21how is this ever going to be a real solution?
11:21 --> 11:22We should just abandon this.
11:22 --> 11:24But I would also say that
11:24 --> 11:25technology improves over time.
11:25 --> 11:26And so NOTE Confidence: 0.95283285
11:26 --> 11:27as we get better at doing this, we
11:27 --> 11:29figure out cheaper ways to do it,
11:29 --> 11:31I think that will be a natural thing
11:31 --> 11:32that will kind of evolve over time.
11:32 --> 11:34Right now we're just excited
11:34 --> 11:35to be curing folks who before
11:36 --> 11:37we're kind of carrying a death sentence.
11:39 --> 11:42I just have to take a
11:42 --> 11:45breath at that, nearly half,
11:45 --> 11:48$1,000,000 price tag for therapy,
11:48 --> 11:50especially when you say that
11:50 --> 11:51it doesn't always work.
11:51 --> 11:56So how often does it not work and
11:56 --> 11:58what do you do then?
11:58 --> 12:00Is this something that you then repeat,
12:00 --> 12:03so multiple courses of CAR T cell therapy at,
12:03 --> 12:06you know, $400,000 a pop?
12:06 --> 12:09And if so, how many times do you do that?
12:09 --> 12:11Yeah, so to be
12:11 --> 12:12honest, I think it's important
12:12 --> 12:13to keep in mind,
12:13 --> 12:15it's easy to kind of talk about this
12:16 --> 12:17academically,
12:17 --> 12:18which is great and very important.
12:18 --> 12:20But I'll give you kind of an
12:20 --> 12:21example of a case that I saw,
12:21 --> 12:24one of the earlier cases.
12:24 --> 12:25I had a gentleman who had been referred
12:25 --> 12:27to the Cancer Center I was at where
12:27 --> 12:29I'd actually started out at
12:29 --> 12:31Moffitt Cancer Center before I came
12:31 --> 12:32to Yale who happened to do
12:32 --> 12:34some of the first CAR T therapies.
12:34 --> 12:35And so they're a big center there.
12:35 --> 12:37And anyway, this was in the early days
12:37 --> 12:41around 2018 and I had a gentleman with
12:41 --> 12:43a diffuse source B cell lymphoma that
12:43 --> 12:45had been through 6 lines of therapy.
12:45 --> 12:46And I don't know the price tags
12:46 --> 12:47of all the therapies he went through,
12:47 --> 12:49but they weren't small either.
12:49 --> 12:51Chemotherapy, rituximab,
12:51 --> 12:53he had a stem cell transplant.
12:53 --> 12:55Two rounds of radiation and his
12:55 --> 12:57cancer kept coming back,
12:59 --> 13:01and it kept on coming back to the
13:01 --> 13:03point that actually it caused his
13:03 --> 13:04leg to necrose and he actually had
13:04 --> 13:06to have an amputation
13:06 --> 13:08from the lymphoma attacking it.
13:08 --> 13:12And that's when I met him and
13:12 --> 13:14so he came to see me,
13:14 --> 13:15we did a little bit of chemo,
13:16 --> 13:19got in the car T and he actually
13:19 --> 13:21was able to survive for another
13:21 --> 13:22two years cancer free.
13:22 --> 13:24With the approach of radiation to
13:24 --> 13:26kind of get him through that danger
13:26 --> 13:27zone to temporarily control the tumor
13:27 --> 13:29and then get the CAR T cell therapy.
13:29 --> 13:32So kind of miraculous but
13:32 --> 13:34I think that
13:34 --> 13:36it's just when you're faced with these cases,
13:36 --> 13:37I mean the NOTE Confidence: 0.949198844444445
13:37 --> 13:38cold truth is that if you have a
13:38 --> 13:40really refractory disease that's life
13:40 --> 13:42threatening and if you don't fix it,
13:42 --> 13:44I mean the alternative is death.
13:47 --> 13:48and that's why we're really working
13:48 --> 13:50to try and provide potentially
13:50 --> 13:53curative options for these patients.
13:53 --> 13:55And happy to speak on that more.
13:55 --> 13:57I mean costs in the medical system is
13:57 --> 14:00a whole ball of wax and I agree it's
14:00 --> 14:02a high price tag and I think that's
14:02 --> 14:03something we'll move in the future.
14:03 --> 14:03But it's
14:03 --> 14:05a whole other topic of discussion.
14:05 --> 14:08Certainly, I mean I think
14:08 --> 14:11that CAR T therapy has its place.
14:11 --> 14:14We're going to learn more on the
14:14 --> 14:17other side of the break about
14:17 --> 14:19how it could fall short and some of
14:19 --> 14:21the work that you've been doing to
14:21 --> 14:23kind of improve outcomes in those
14:23 --> 14:25patients right after we take a
14:25 --> 14:27short break for a medical minute.
14:27 --> 14:29Please stay tuned to learn more
14:29 --> 14:31with my guest Dr. Tim Robinson.
14:31 --> 14:34Funding for Yale Cancer Answers comes
14:34 --> 14:36from Smilow Cancer Hospital where
14:36 --> 14:38their oncodermatology program treats
14:38 --> 14:40dermatologic concerns including very
14:40 --> 14:43dry skin itching and skin changes that
14:43 --> 14:45arise as side effects from chemotherapy.
14:47 --> 14:50Smilowcancerhospital.org. Genetic
14:50 --> 14:52testing can be useful for people
14:52 --> 14:53with certain types of cancer that
14:53 --> 14:55seem to run in their families.
14:55 --> 14:57Genetic counseling is a process that
14:57 --> 14:59includes collecting a detailed personal
14:59 --> 15:02and family history, a risk assessment,
15:02 --> 15:05and a discussion of genetic testing options.
15:05 --> 15:07Only about 5 to 10% of all cancers
15:07 --> 15:09are inherited, and genetic testing
15:09 --> 15:12is not recommended for everyone.
15:12 --> 15:14Individuals who have a personal and
15:14 --> 15:16or family history that includes
15:16 --> 15:18cancer at unusually early ages,
15:18 --> 15:20Multiple relatives on the same side
15:20 --> 15:23of the family with the same cancer,
15:23 --> 15:25more than one diagnosis of cancer in
15:25 --> 15:27the same individual, rare cancers,
15:27 --> 15:30or family history of a known altered
15:30 --> 15:33cancer predisposing gene could be
15:33 --> 15:35candidates for genetic testing.
15:35 --> 15:37Resources for genetic counseling and
15:37 --> 15:39testing are available at federally
15:39 --> 15:41designated comprehensive Cancer centers
15:41 --> 15:43such as Yale Cancer Center and
15:43 --> 15:44Smilow Cancer Hospital.
15:44 --> 15:47More information is available
15:47 --> 15:48at yalecancercenter.org.
15:48 --> 15:50You're listening to Connecticut Public Radio.
15:51 --> 15:53Welcome back to Yale Cancer Answers.
15:53 --> 15:55This is Dr. Anees Chagpar
15:55 --> 15:57and I'm joined tonight by my guest, Dr.
15:57 --> 15:58Tim Robinson.
15:58 --> 16:00We're talking about improving outcomes
16:00 --> 16:03for patients undergoing CAR T cell therapy.
16:03 --> 16:05And for those of you who are just joining us,
16:05 --> 16:07right before the break,
16:07 --> 16:09we were talking about this
16:09 --> 16:10fairly novel treatment,
16:10 --> 16:14cellular therapy with CAR T cells,
16:14 --> 16:17which is basically taking out your
16:17 --> 16:20own T cells, putting them into a Petri
16:20 --> 16:22dish where they have a pep rally,
16:22 --> 16:25as Tim would say, getting revved up
16:25 --> 16:29to fight against particular antigens,
16:29 --> 16:31and then they are reinjected into
16:31 --> 16:34your body where they do their magic.
16:34 --> 16:35And Tim, right before the break,
16:35 --> 16:38he told us a nice case that you had
16:38 --> 16:40seen early on in your career where
16:40 --> 16:44somebody who had failed multiple lines
16:44 --> 16:47of chemotherapy and Rituximab and
16:47 --> 16:49radiation and stem cell transplant
16:49 --> 16:54really got CAR T cell therapy and did
16:54 --> 16:56well for at least two years thereafter.
16:56 --> 17:00So certainly it has a role to play.
17:00 --> 17:03But it is not without toxicity.
17:03 --> 17:05It certainly has some biologic
17:05 --> 17:07toxicities as we talked about before
17:07 --> 17:09the break and a significant price
17:09 --> 17:12tag for those of you just joining us.
17:12 --> 17:14That price tag was estimated to
17:14 --> 17:16be roughly $400,000.
17:16 --> 17:17And so Tim,
17:17 --> 17:19the part that I want to talk
17:19 --> 17:22about in this next segment is
17:22 --> 17:24the issue that you brought up in
17:24 --> 17:27passing before the break, which is
17:27 --> 17:29it doesn't always work.
17:29 --> 17:30So tell us a bit more,
17:30 --> 17:35how often does CAR T cell therapy not work?
17:35 --> 17:36And why is that?
17:36 --> 17:39Why is it that some people may
17:39 --> 17:42have what seems to be a miraculous
17:42 --> 17:44response whereas others not so much?
17:45 --> 17:48Yeah, exactly. So that's the
17:48 --> 17:50$400,000 question.
17:50 --> 17:52What we have seen
17:52 --> 17:54is where this is being
17:54 --> 17:56actively studied by a lot of groups,
17:56 --> 17:58why do some patients respond
17:58 --> 18:00and others not respond and what
18:00 --> 18:02are the mechanisms of resistance
18:02 --> 18:04and what are the prognostic kind of
18:04 --> 18:07factors that help us understand that.
18:07 --> 18:08One of the major prognostic factors
18:08 --> 18:10that we've seen is the total amount
18:10 --> 18:12of disease that somebody has.
18:12 --> 18:13So we quantify this
18:13 --> 18:15using a term called
18:15 --> 18:17metabolic tumor burden, or
18:17 --> 18:20even just the size of the tumors.
18:20 --> 18:22And we use the term metabolic tumor burden.
18:22 --> 18:24If somebody gets a PET scan,
18:24 --> 18:26these are scans that can
18:26 --> 18:27trace the amount of metabolic
18:27 --> 18:29activity in the cancer.
18:29 --> 18:30Add that all up and we can
18:30 --> 18:32get a volume of how much disease
18:32 --> 18:33and how active it is.
18:33 --> 18:35And we have seen repeatedly and multiple
18:35 --> 18:37investigators have seen this, that
18:37 --> 18:39when you have a high burden of disease,
18:39 --> 18:42those patients don't do as well with
18:42 --> 18:44CAR T. As we learn more about this,
18:44 --> 18:45there's different mechanisms,
18:45 --> 18:48but what we think is that basically
18:48 --> 18:50there's many reasons why CAR T cells
18:50 --> 18:53can fail and I will list a few.
18:53 --> 18:53One,
18:53 --> 18:56we have seen that sometimes the target
18:56 --> 18:58they go after, the CD19 can
18:58 --> 19:00become more elusive or down regulated
19:00 --> 19:03and then that can be a way for cells
19:03 --> 19:05to kind of evade this therapy.
19:05 --> 19:07Fortunately for us the B cell lymphomas
19:07 --> 19:09tend to be fairly dependent on that.
19:09 --> 19:11So we don't think that's a
19:11 --> 19:12major source of resistance,
19:12 --> 19:13but it's theoretically
19:13 --> 19:15there and it happens in leukemia.
19:15 --> 19:17The other things that can happen,
19:18 --> 19:19the biggest issue, is just a
19:19 --> 19:20worn out immune system.
19:20 --> 19:22And what we have learned is
19:22 --> 19:23that if somebody's T cells,
19:23 --> 19:24you can take them out of their
19:24 --> 19:25body and
19:25 --> 19:26genetically engineer them to
19:26 --> 19:27put them back in.
19:27 --> 19:29But if you look at many
19:29 --> 19:31of these T cells in patients,
19:31 --> 19:33especially patients who've gone through
19:34 --> 19:36multiple rounds of chemotherapy and
19:36 --> 19:38what we've seen is that the more
19:38 --> 19:39chemotherapies that people have been
19:39 --> 19:40through before they get the CAR T,
19:40 --> 19:42the more worn out and exhausted
19:42 --> 19:44their immune system is and probably
19:44 --> 19:45the worse they do.
19:45 --> 19:47And so we think that one possibility is
19:47 --> 19:49that if somebody's immune system,
19:49 --> 19:50if their T cells,
19:50 --> 19:52they can only fight so
19:52 --> 19:53much before they become exhausted.
19:56 --> 19:58And then lastly something that my lab
19:58 --> 20:00has been interested in
20:00 --> 20:02actually really clinically is
20:02 --> 20:04what about the tumor microenvironment.
20:04 --> 20:06So again if you have a
20:06 --> 20:07very large angry tumor,
20:07 --> 20:09in a PET scan you'll see
20:09 --> 20:10what's called a necrotic lesion
20:10 --> 20:12oftentimes and we think that those are
20:12 --> 20:13areas where there's a lot of
20:13 --> 20:15those tumors are taking up a
20:15 --> 20:17ton of sugar and burning it so fast that
20:17 --> 20:19it's actually sucking up all the oxygen.
20:19 --> 20:20So there's no oxygen or there's
20:20 --> 20:22a lot of hypoxia.
20:22 --> 20:24There can be a lot
20:24 --> 20:26of lactic acid in these tumors.
20:26 --> 20:28And if you put a T cell and exposure
20:28 --> 20:31to hypoxia or acidosis,
20:31 --> 20:32they can't really function.
20:32 --> 20:34And so part of the rationale for radiation
20:34 --> 20:36where I've become interested is,
20:36 --> 20:38how do we prevent the CAR T
20:38 --> 20:40cells from not getting worn out,
20:40 --> 20:41from fighting just an enormous
20:41 --> 20:43amount of tumor where it's just
20:43 --> 20:44too much tumor to fight?
20:44 --> 20:46How can we use radiation to help
20:46 --> 20:47kind of get rid of these areas of
20:47 --> 20:49hypoxy and acidosis that are just
20:49 --> 20:50really defeating the T cells?
20:52 --> 20:54So tell us more about that. I mean
20:54 --> 20:58is the idea that maybe these people
20:58 --> 21:00should have CAR T therapy upfront before
21:00 --> 21:03they ever get chemotherapy, tell us more
21:03 --> 21:06about what your findings are showing us?
21:06 --> 21:08Yeah, sure. So I think you kind
21:08 --> 21:09of mentioned 2 viable options,
21:09 --> 21:10both of which are being pursued.
21:10 --> 21:11So I'll start with the first one,
21:11 --> 21:12which is,
21:12 --> 21:14what about getting CAR T earlier up,
21:14 --> 21:16on the docket?
21:16 --> 21:19And that's being actively explored.
21:19 --> 21:20And so you know, CAR T cell
21:20 --> 21:22therapy when it first got approved,
21:22 --> 21:23it was only for patients
21:23 --> 21:25who'd been through two prior
21:25 --> 21:26chemotherapies that didn't work.
21:26 --> 21:27So that had to be the minimum,
21:27 --> 21:29but typically they'd seen many more,
21:29 --> 21:31five or six even.
21:31 --> 21:33And that's where we got a 40% cure rate.
21:33 --> 21:36But then what we saw is that there's
21:36 --> 21:38been recently trials where after a
21:38 --> 21:41single line of chemotherapy has failed,
21:41 --> 21:42all those patients used to
21:42 --> 21:43go to something called an
21:43 --> 21:45autologous stem cell transplant.
21:45 --> 21:47And again, this is not my area
21:47 --> 21:49of expertise, but
21:49 --> 21:51actually the cost of an autologous stem
21:51 --> 21:53cell transplant from what I understand
21:53 --> 21:54is actually quite pricey as well.
21:54 --> 21:55So it may be quite comparable
21:55 --> 21:58to CAR T cell therapy.
21:58 --> 21:59And so anyway, they
21:59 --> 22:01basically would try and do that.
22:01 --> 22:02But there's randomized trials where
22:02 --> 22:04they did autologous stem cell transplant
22:04 --> 22:06versus CAR T for patients with
22:06 --> 22:08bad disease that either came back,
22:08 --> 22:11within 12 months after
22:11 --> 22:13their chemo or they just blew
22:13 --> 22:14through first line chemo altogether.
22:14 --> 22:16And they saw that CAR T therapy did a
22:16 --> 22:18much better job of getting rid of the
22:18 --> 22:20disease than the stem cell transplants.
22:20 --> 22:22So that's one thing that's been happening
22:22 --> 22:24is that we've moved from third line
22:24 --> 22:26to second line and now there's even
22:26 --> 22:28trials for patients with first line
22:28 --> 22:30treatment for high risk factors,
22:30 --> 22:30for example,
22:30 --> 22:33just patients with tumors
22:33 --> 22:35we don't expect to respond to chemo,
22:35 --> 22:37bad genomic markers, these kind of
22:37 --> 22:38double hit or triple hit lymphomas,
22:38 --> 22:39things like that.
22:39 --> 22:41There's folks who are exploring
22:41 --> 22:44introducing CAR T therapy at that line.
22:44 --> 22:45And so really what you're getting
22:45 --> 22:47is moving it further up in the process.
22:47 --> 22:49So that's kind of one option and
22:49 --> 22:50people are certainly doing that.
22:50 --> 22:52The other option is well what about radiation
22:52 --> 22:54and trying to reduce the tumor burden.
22:54 --> 22:57And so this is another possibility and
22:57 --> 23:00I certainly believe for some
23:00 --> 23:02patients that this may actually be
23:02 --> 23:04helping them out and we're trying to
23:04 --> 23:06kind of figure out ways to confirm that.
23:06 --> 23:07Right now there's many clinical
23:07 --> 23:09trials that are getting up and
23:09 --> 23:10running where that's exactly what
23:10 --> 23:12we're doing is we're taking patients
23:12 --> 23:13with large or bulky tumors
23:13 --> 23:15and we're going to use radiation
23:15 --> 23:16to basically shrink those tumors
23:16 --> 23:18down right before they get the CAR
23:18 --> 23:19T cell therapy to reduce the tumor
23:19 --> 23:21burden to get rid of those
23:22 --> 23:24acid laden and hypoxic environments
23:24 --> 23:26and really just try and give the CAR
23:26 --> 23:28T cells a better chance to fight.
23:28 --> 23:29And there's also some evidence kind
23:29 --> 23:31of which is very early stages that
23:31 --> 23:32suggests that radiation may actually
23:32 --> 23:34kind of help stimulate the immune
23:34 --> 23:36system and may actually help the CAR T
23:36 --> 23:38cells recognize these cancers better.
23:38 --> 23:40And so we're exploring all those options.
23:40 --> 23:42The other thing that
23:42 --> 23:44our audience might be thinking about,
23:44 --> 23:46especially when we talk about
23:46 --> 23:49hypoxia and hypoxic environments,
23:49 --> 23:52is the role of hyperbaric oxygen chambers.
23:52 --> 23:54I mean a lot of people have heard about
23:54 --> 23:57these hyperbaric oxygen chambers and
23:57 --> 24:00maybe asking themselves,
24:00 --> 24:03is that a role for
24:03 --> 24:06CAR T therapy to kind of fight where
24:06 --> 24:08maybe we can get more oxygen
24:08 --> 24:09into these environments.
24:09 --> 24:13Or is it more the tumor micro environment
24:13 --> 24:16itself that may or may not be influenced
24:16 --> 24:18by these hyperbaric oxygen chambers.
24:18 --> 24:20Can you kind of
24:20 --> 24:21shed some light on that?
24:24 --> 24:26So the truth is that no one's looked at that.
24:26 --> 24:28It's an interesting idea. However,
24:28 --> 24:31I suspect it would be a very bad idea.
24:31 --> 24:34The issue is that right now
24:34 --> 24:36hyperbaric oxygen, at least in the
24:36 --> 24:37radiation world where we use it,
24:37 --> 24:39is that if somebody's had radiation
24:39 --> 24:40therapy and they had to have high
24:40 --> 24:42doses of radiation with chemo,
24:42 --> 24:44and they have wound healing issues or
24:44 --> 24:45some other toxicities from radiation,
24:45 --> 24:47this is getting very high doses
24:47 --> 24:49of radiation that we don't have
24:49 --> 24:50to use as much in lymphoma.
24:50 --> 24:52But hyperbaric oxygen can be a
24:52 --> 24:54way to help with wound healing.
24:54 --> 24:56And the reason why I mention that is
24:56 --> 24:58that one of the big contraindications
24:58 --> 25:00or sources of extreme caution is
25:00 --> 25:02that if anybody has active cancer,
25:02 --> 25:04they're very wary to do hyperbaric
25:04 --> 25:05oxygen because anecdotally,
25:05 --> 25:07they've seen cases where people
25:07 --> 25:09have done hyperbaric oxygen and the
25:09 --> 25:10cancer has sprung back to life.
25:10 --> 25:11And so for example, I
25:11 --> 25:13had a patient with CAR T therapy
25:13 --> 25:14who I did radiation.
25:14 --> 25:16We got rid of this giant, very angry tumor.
25:16 --> 25:17It was ulcerating.
25:17 --> 25:19And the tumor destroyed
25:19 --> 25:20so much of the tissue around the
25:20 --> 25:22leg that you still have ulcers,
25:22 --> 25:24even though the cancer has been gone for a year.
25:24 --> 25:26And they still are being cautious
25:26 --> 25:27about doing hyperbaric oxygen
25:27 --> 25:28because they're worried that if
25:28 --> 25:29there's any cancer cells left over,
25:29 --> 25:31they will kind of bring those
25:31 --> 25:32back with the vengeance.
25:32 --> 25:33The other point I would mention
25:33 --> 25:35is that it's kind of more of a
25:35 --> 25:36technical modeling perspective,
25:36 --> 25:37but I think it's valid.
25:37 --> 25:37Is that,
25:37 --> 25:39I mean I think it's interesting
25:39 --> 25:41is that if you look at a tumor and
25:41 --> 25:43you see these hypoxic and
25:43 --> 25:46low glucose, highly acidic environments.
25:46 --> 25:48And you think, how am I going to fix that?
25:48 --> 25:51Should you increase blood flow,
25:51 --> 25:53should you
25:53 --> 25:54increase oxygen as you're mentioning?
25:54 --> 25:55And as it turns out,
25:55 --> 25:58the most effective way to normalize
25:58 --> 26:00the tumor microenvironment from a
26:00 --> 26:01metabolic perspective is actually
26:01 --> 26:04to turn the cancer cells off or
26:04 --> 26:05kill cancer cells.
26:05 --> 26:06Because the problem is,
26:06 --> 26:08that you have this kind of,
26:08 --> 26:10large number of tumor cells that are
26:10 --> 26:11sitting there going at full tilt,
26:11 --> 26:13you have this necrotic center oftentimes.
26:13 --> 26:14And if you add more oxygen,
26:14 --> 26:16all you're gonna do is
26:16 --> 26:18feed the ones on the outside just as much.
26:18 --> 26:19But then there's gonna be more to
26:19 --> 26:20spill over towards the middle and
26:20 --> 26:22there's plenty of cancer cells waiting,
26:22 --> 26:24ready to go to soak up those resources.
26:24 --> 26:26And so really from a modeling perspective,
26:26 --> 26:29and this is one of my mentors from
26:29 --> 26:31back at Duke, what they saw,
26:31 --> 26:32was that really the most effective
26:32 --> 26:34way to normalize the environment was
26:34 --> 26:36really to slow down the metabolism
26:36 --> 26:37or kill the tumor cells.
26:37 --> 26:38And that trying just to kind of
26:38 --> 26:39feed it more to normalize,
26:39 --> 26:41it really doesn't work out that way.
26:44 --> 26:46So certainly people
26:46 --> 26:49are looking at how we can do
26:49 --> 26:51CAR T cell therapy better.
26:51 --> 26:53And so what's next for
26:53 --> 26:54your lab going forward?
26:57 --> 26:58Yeah, so a few things.
26:58 --> 26:59One, I'm excited about the
26:59 --> 27:01clinical trials that are going on,
27:01 --> 27:04trying to figure out what's the best way to
27:04 --> 27:07combine radiation to make CAR T work better.
27:07 --> 27:08And the thing that I'm excited about
27:08 --> 27:10this is because it's just very pragmatic.
27:10 --> 27:11We know radiation
27:11 --> 27:12works to shrink down tumors.
27:12 --> 27:15These tumors tend to be responsive.
27:15 --> 27:17We know that can debulk tumors.
27:17 --> 27:19There's been studies showing that
27:19 --> 27:20if you do radiation before CAR T,
27:20 --> 27:22I mentioned that the total
27:22 --> 27:24amount of disease burden predicts outcome,
27:24 --> 27:26well if you look at patients
27:26 --> 27:28who get radiation, the
27:28 --> 27:30tumor burden after radiation does
27:30 --> 27:32the better job of predicting it
27:32 --> 27:34than the tumor burden beforehand.
27:34 --> 27:35So in other words we may be able to
27:35 --> 27:37kind of convert high burden of disease
27:37 --> 27:39patients to lower burden and give
27:39 --> 27:41them more favorable outcomes.
27:41 --> 27:43And I'm excited to see where
27:43 --> 27:45these different clinical trials kind
27:45 --> 27:46of end and these clinical trials
27:46 --> 27:48using radiation with smaller doses
27:48 --> 27:50to give novel ways to
27:50 --> 27:51try to wake up the immune system.
27:51 --> 27:53And so I'm very excited to see where these land.
27:55 --> 27:57And then two is more on the molecular side.
27:57 --> 27:58I haven't mentioned this too much,
27:58 --> 28:00but I actually one of the things
28:00 --> 28:02my lab studies is splicing and we think
28:02 --> 28:03that alternative splicing may actually
28:03 --> 28:06be one of the mechanisms by which
28:06 --> 28:09CAR T cell therapy actually may not work.
28:09 --> 28:10We actually think that there
28:10 --> 28:12may be alternative splicing that is
28:12 --> 28:14driving resistance in these lymphomas
28:14 --> 28:16because splicing is something that
28:16 --> 28:18occurs aberrantly
28:18 --> 28:20in many hematologic malignancies.
28:20 --> 28:24And my lab has been
28:24 --> 28:25investigating this and so hopefully
28:25 --> 28:27in the next, year or two,
28:27 --> 28:29we'll kind of hot off the press
28:29 --> 28:30we'll get that out.
28:30 --> 28:32And that's something we're actively pursuing.
28:32 --> 28:35Dr. Timothy Robinson is an assistant
28:35 --> 28:37professor of therapeutic radiology
28:37 --> 28:38at the Yale School of Medicine.
28:38 --> 28:40If you have questions, the addresses,
28:40 --> 28:42cancer Answers at yale.edu and
28:42 --> 28:45past editions of the program are
28:45 --> 28:47available in audio and written
28:47 --> 28:48form at yalecancercenter.org.
28:48 --> 28:51We hope you'll join us next week to
28:51 --> 28:53learn more about the fight against
28:53 --> 28:54cancer here on Connecticut Public Radio.
28:54 --> 28:57Funding for Yale Cancer Answers is
28:57 --> 29:00provided by Smilow Cancer Hospital.

Information

Improving Outcomes for Patients Undergoing CAR T-cell Therapy with guest Dr. Tim Robinson July 16, 2023 Yale Cancer Center visit: http://www.yalecancercenter.org email: canceranswers@yale.edu call: 203-785-4095