Breakthrough Therapeutics to Tame Cancer Cells

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 --> 00:18of the battle to fight cancer.
00:18 --> 00:21This week it's a conversation about the
00:21 --> 00:22role of breakthrough therapeutics in
00:22 --> 00:24fighting cancer with Doctor Sidi Chen.
00:24 --> 00:26Doctor Chen is an associate
00:26 --> 00:28professor of genetics at the Yale
00:28 --> 00:29School of Medicine where Dr.
00:29 --> 00:32Chagpar as a professor of surgical oncology.
00:34 --> 00:36Maybe we can start off by you
00:36 --> 00:38telling us a little bit more about
00:38 --> 00:40yourself and what it is you do.
00:40 --> 00:43Yeah, sure. I'm a faculty member at Yale
00:45 --> 00:47and a professor of genetics Genetics,
00:47 --> 00:49Systems Biology Institute, and Yale Cancer Center.
00:49 --> 00:53My role in the field is trying to
00:53 --> 00:55understand the biological systems of
00:55 --> 00:58cancer and the biological systems of the
00:58 --> 01:00immune system of our cells and therefore
01:00 --> 01:02leverage immune system to fight cancer.
01:03 --> 01:07So I mean that all sounds very high tech
01:07 --> 01:10and new and novel and exciting.
01:10 --> 01:12Tell us more about
01:12 --> 01:14how exactly that works.
01:14 --> 01:15How did you get interested
01:15 --> 01:17in the field and what
01:17 --> 01:19exactly is your research doing?
01:20 --> 01:23Sure. I'll be happy to elaborate.
01:23 --> 01:27As you know, our own
01:27 --> 01:30body consists of the many,
01:30 --> 01:31many different organs.
01:31 --> 01:33And the system that protect our own organs
01:33 --> 01:36or our own health is the immune system.
01:36 --> 01:38It's our own defense system.
01:38 --> 01:41For example, if we get infected,
01:41 --> 01:45we have cells that produce antibody,
01:45 --> 01:48we have cells that clear the infection.
01:48 --> 01:50Likewise for cancer,
01:50 --> 01:54when a patient gets cancer and
01:54 --> 01:56the first reaction of the body
01:56 --> 01:58is the immune system trying to
01:58 --> 02:01distinguish which is the cancer cell,
02:01 --> 02:03which is our own healthy cells.
02:03 --> 02:05But very often our system
02:05 --> 02:07is fooled by cancer.
02:07 --> 02:08The immune system cannot recognize
02:08 --> 02:11cancer or cannot clear them and our
02:11 --> 02:13research is trying to understand
02:13 --> 02:15why is that the case and how we can
02:15 --> 02:17educate the immune system or help
02:17 --> 02:21the immune system to detect cancer
02:21 --> 02:24better and equip them with the tools
02:24 --> 02:27to fight cancer and clear cancer
02:27 --> 02:29cells and restore our own health.
02:31 --> 02:33You know that sounds a
02:33 --> 02:35lot like immunotherapy,
02:35 --> 02:36which is something that we've
02:36 --> 02:39discussed on this show previously.
02:39 --> 02:41How is your research either the
02:41 --> 02:43same or different than that?
02:43 --> 02:45I thought that immunotherapy
02:45 --> 02:46is already being used.
02:46 --> 02:49Is your work trying to extend that?
02:50 --> 02:52You're absolutely right.
02:52 --> 02:54Immunotherapy is the current
02:57 --> 02:59major therapeutic for cancer.
02:59 --> 03:01Immunotherapy involving immune
03:01 --> 03:04checkpoint blockage has been
03:04 --> 03:07approved by over 30 indications now.
03:07 --> 03:08But unfortunately immunotherapy only
03:08 --> 03:11works for a small fraction of patients,
03:11 --> 03:14about 20 to 30% overall.
03:14 --> 03:15Some cancer have a better response,
03:15 --> 03:20some cancer have literally no responses.
03:20 --> 03:23So our goal is to understand
03:23 --> 03:24why some cancers respond,
03:24 --> 03:28why some don't and then try to either
03:28 --> 03:33help the cells to improve the
03:33 --> 03:35immunotherapy response or on the other
03:35 --> 03:38hand we're thinking why don't we just
03:38 --> 03:40take the immune cells out and engineer
03:40 --> 03:43them in the lab or in the factory
03:43 --> 03:45and then give them back to the patient.
03:45 --> 03:48That's what we call cell therapy
03:48 --> 03:49or cellular immunotherapy,
03:49 --> 03:51which is another type of
03:51 --> 03:52major cancer immunotherapy.
03:52 --> 03:54So unlike immune checkpoint blockade,
03:54 --> 03:59I used to utilize a therapeutic antibody,
03:59 --> 04:01cell therapy utilizes cells
04:01 --> 04:03instead of compounds.
04:05 --> 04:07So that's very interesting and I want to
04:07 --> 04:10kind of discuss both of those angles.
04:10 --> 04:13So the first is why is it that
04:13 --> 04:15some cancers respond better
04:15 --> 04:18to immunotherapy than others?
04:18 --> 04:20We know that for example,
04:20 --> 04:23there are some cancers,
04:23 --> 04:26melanoma being one of the
04:26 --> 04:28mainstays that's very
04:28 --> 04:30receptive to immunotherapy and
04:30 --> 04:33other cancers not so much.
04:33 --> 04:35So what is it?
04:35 --> 04:38Is it something about the cancer
04:38 --> 04:41itself or is it the way that the
04:41 --> 04:43cancer evades the immune system?
04:43 --> 04:46Or is it just that the immune
04:46 --> 04:49system is better able to fight
04:49 --> 04:51cancers in particular organs?
04:51 --> 04:52Why the difference?
04:53 --> 04:55This is a billion dollar question,
04:55 --> 04:57great question. In fact,
04:57 --> 04:59the answer is very complicated.
04:59 --> 05:01I don't think I can even address
05:01 --> 05:03in half an hour or a year.
05:03 --> 05:07So the reason,
05:07 --> 05:09to put it short, cancer cells
05:09 --> 05:11can evade the immune systems and attack
05:11 --> 05:13and the immune cells sometimes
05:13 --> 05:16it's weak or enabled to find
05:16 --> 05:18cancer or eradicate cancer.
05:18 --> 05:19So in order
05:21 --> 05:23to help the immune system there are a
05:23 --> 05:26lot of different ways, for example,
05:26 --> 05:27using the monoclonal antibody to
05:27 --> 05:30hit the brake that cancer uses to
05:32 --> 05:35to put on cancer. For example PD1,
05:35 --> 05:37PDL one therapy which is well known now
05:37 --> 05:40I don't want to go too much into and
05:40 --> 05:42on the other hand it could be there's
05:42 --> 05:45not enough immune cells in the tumor
05:45 --> 05:47micro environment or there's simply
05:47 --> 05:50not enough T cells to clear the cancer.
05:50 --> 05:53So that's why cell therapy
05:53 --> 05:55provides another solution.
05:55 --> 05:58You take the cells out from the
05:58 --> 06:01patient and then you amplify them to
06:01 --> 06:03billions and billions of cells and
06:03 --> 06:05then you give it back to the patient.
06:05 --> 06:07And in addition you can equip
06:07 --> 06:09the cells because you already
06:09 --> 06:12took them out, right.
06:12 --> 06:15So now you can install things like
06:15 --> 06:18chimeric antigen receptor or CAR T that
06:18 --> 06:21can recognize specific cancer antigens
06:21 --> 06:23to distinguish cancer from the healthy
06:23 --> 06:26cells and you can amplify those cells
06:26 --> 06:28to billions and billions of them
06:28 --> 06:30and then give it back to patient.
06:30 --> 06:34So this is a solution to
06:34 --> 06:37amplify the immune system.
06:39 --> 06:41So in that case, right,
06:41 --> 06:43that seems to make sense.
06:43 --> 06:47If you have a cancer and it has
06:47 --> 06:50particular antigens on its surface and
06:50 --> 06:53it's the job of the immune system to
06:53 --> 06:56recognize things that shouldn't be there.
06:56 --> 06:58And you can take out a
06:58 --> 07:00patient's own immune cells,
07:00 --> 07:02kind of engineer them so that
07:02 --> 07:04they recognize those antigens,
07:04 --> 07:07essentially give them a targeting
07:07 --> 07:10system so that they can go after this
07:10 --> 07:13cancer and then give them back to the
07:13 --> 07:17patient in billions and billions of cells,
07:17 --> 07:19essentially giving the immune system
07:19 --> 07:22an unfair advantage over the cancer.
07:22 --> 07:24Presumably that would help
07:24 --> 07:26to wipe the cancer out.
07:26 --> 07:30So #1 is, has that been tried?
07:30 --> 07:31Does it work?
07:31 --> 07:34And #2 if it does,
07:34 --> 07:36why are we still talking about cancer?
07:36 --> 07:38Wouldn't that be the fundamental answer
07:38 --> 07:40that would kill off all cancers?
07:41 --> 07:42Those are great questions.
07:42 --> 07:47And #1, it has been approved
07:47 --> 07:49for several different diseases,
07:49 --> 07:50for example, leukemia,
07:50 --> 07:53lymphoma, and multiple myeloma.
07:53 --> 07:56And the FDA has approved six different cell
07:56 --> 07:58therapies for treating these diseases.
07:58 --> 08:02And in fact, the overall response
08:02 --> 08:05for these cell therapies are amazing.
08:05 --> 08:08And for example, in multiple myeloma,
08:08 --> 08:09the overall response rate
08:09 --> 08:12can be in the high 90% digit.
08:14 --> 08:16But the challenge is that #1 the
08:16 --> 08:19cancer still can still come back.
08:19 --> 08:21They can become resistant to cell therapy.
08:21 --> 08:25And #2 for solid tumors,
08:25 --> 08:26not leukemia, lymphoma,
08:26 --> 08:28those are what we call blood cancers.
08:28 --> 08:32Solid tumors are for example a breast cancer,
08:32 --> 08:34lung cancer, melanoma,
08:34 --> 08:36pancreatic cancer, brain cancer.
08:36 --> 08:38Those are solid tumors.
08:38 --> 08:40They are more resistant to cell
08:40 --> 08:42therapy for a number of reasons.
08:42 --> 08:43For example,
08:43 --> 08:46the cell can't get in the solid tumor,
08:46 --> 08:47the cells can get in,
08:47 --> 08:49but they fail to proliferate.
08:49 --> 08:52They can't grow because the solid
08:52 --> 08:54tumor micro environment is very
08:54 --> 08:56hostile for the immune cells or
08:56 --> 08:58the cells can get in and proliferate,
08:58 --> 09:00but then they become exhausted,
09:00 --> 09:02which means they're too tired of
09:02 --> 09:03killing so many cancer cells.
09:03 --> 09:06So there's still a lot of problems
09:06 --> 09:09hindering the success of this type
09:09 --> 09:12of cell therapy for curing cancer.
09:12 --> 09:14That's why we are trying very hard to
09:14 --> 09:17find new solutions to improve cell therapy.
09:19 --> 09:22So we don't have a magic bullet
09:22 --> 09:25although it sounds like we have
09:25 --> 09:27something very effective for the
09:27 --> 09:29the liquid tumors, the leukemias.
09:29 --> 09:33So tell us more about your work in terms
09:33 --> 09:36of how you optimize cellular therapy
09:36 --> 09:38for solid tumors because presumably when
09:38 --> 09:41most of us think about cancer we
09:41 --> 09:44tend to think about those solid tumors,
09:44 --> 09:46breast cancer, lung cancer,
09:46 --> 09:48colon cancer, prostate cancer,
09:48 --> 09:49pancreatic cancer.
09:49 --> 09:55And so it would be really nice if we had
09:55 --> 09:58a way for us to target these cancers
09:58 --> 10:02and eliminate them with high efficacy.
10:02 --> 10:04So what have you been trying and
10:04 --> 10:07how well or not has it been working?
10:09 --> 10:12Another great question in fact when
10:12 --> 10:15the cell therapy stopped working or
10:15 --> 10:18didn't even start working, the few ways
10:18 --> 10:21we can naturally think about it,
10:21 --> 10:23imagine this is a car,
10:23 --> 10:26well it is car kinematic antigen
10:26 --> 10:28receptor but pun intended.
10:28 --> 10:32So for a car, you can push the gas on you
10:32 --> 10:35can release the brake or you can
10:35 --> 10:37change the structure of the car.
10:37 --> 10:39So there's three different
10:39 --> 10:43ways to make it run faster.
10:43 --> 10:46So in order to put the gas pedal on,
10:46 --> 10:51we develop things we call a hyper
10:51 --> 10:57boost or like functional booster or
10:57 --> 11:01functional augmentation factors so that
11:01 --> 11:05we can allow the T cells to kill better,
11:05 --> 11:09become tireless and remember the cancer
11:09 --> 11:12cells, but sometimes T cells can
11:12 --> 11:15be blocked by cancer cells, right,
11:15 --> 11:18cancer cells put those brakes on and we
11:18 --> 11:21can use a thing called gene editing,
11:21 --> 11:24or CRISPR that we hear about a
11:24 --> 11:27lot to eliminate those brakes,
11:27 --> 11:30those we call cellular checkpoints
11:30 --> 11:33like PD1 but not exactly PD1.
11:33 --> 11:37So you can remove or at least
11:37 --> 11:40stampen those blocked or like the
11:40 --> 11:43hurdles the T cell has to overcome.
11:43 --> 11:46So that's another way of modifying the cells.
11:46 --> 11:47And finally
11:47 --> 11:49the newer way is that why don't we
11:49 --> 11:52make the car shape a little better,
11:52 --> 11:55so a little more smooth so they
11:55 --> 11:57can run more smoothly and that's
11:57 --> 11:59called the structural design of the
11:59 --> 12:02car to make it run more smoothly.
12:02 --> 12:04So we're doing all three different
12:04 --> 12:07approaches and we published a few pieces
12:07 --> 12:11for the the gas pedal and the brake.
12:11 --> 12:14And the recent piece of work is a
12:14 --> 12:16structural design of the car that
12:16 --> 12:19makes the car work more tirelessly
12:19 --> 12:21against cancer and avoid self
12:21 --> 12:23destruction like avoid the crashes
12:23 --> 12:25between the cars themselves.
12:27 --> 12:29So I want to dig into each of
12:29 --> 12:31those in a little bit more detail.
12:31 --> 12:34And let's start with CAR T therapy,
12:34 --> 12:36which is something that some of
12:36 --> 12:38our audience might have heard of,
12:38 --> 12:40but others might still be unaware of.
12:40 --> 12:43Can you tell us a little bit more about
12:43 --> 12:45what exactly that is and how that works?
12:46 --> 12:50Yeah, sure. To take two steps back,
12:50 --> 12:53CAR T therapy means chimeric
12:53 --> 12:56antigen receptor T cell therapy.
12:57 --> 13:01So T cells, sometimes they recognize cancer,
13:01 --> 13:03sometimes they don't.
13:03 --> 13:05And in order to make all the T
13:05 --> 13:07cells recognize the cancer
13:07 --> 13:10we want to target,
13:10 --> 13:12we install chimeric endogen
13:12 --> 13:13receptor on their surface.
13:13 --> 13:16Those are CAR for short.
13:16 --> 13:18So by putting those cars on their
13:18 --> 13:20surface then every T cell can
13:20 --> 13:21recognize those cancer cells and we
13:21 --> 13:23hope they can kill the cancer cell.
13:23 --> 13:25But sometimes they don't.
13:26 --> 13:28That's why we're doing all this,
13:28 --> 13:30the three different tricks,
13:30 --> 13:32the gas pedal,
13:32 --> 13:34hitting the brake, and changing the
13:34 --> 13:36shape in order to make them better.
13:37 --> 13:40OK, well, we're going to pick up this
13:40 --> 13:42conversation right after we take a
13:42 --> 13:44short break for a medical minute.
13:44 --> 13:46Please stay tuned to learn more
13:46 --> 13:48about breakthrough therapeutics and
13:48 --> 13:50cancer with my guest, Dr. Sidi Chen.
13:51 --> 13:53Funding for Yale Cancer Answers
13:53 --> 13:55comes from Smilow Cancer Hospital,
13:55 --> 13:57where their hematology program offers
13:57 --> 13:59diagnosis and treatment of blood cancers,
13:59 --> 14:02including lymphoma, leukemia, and myeloma.
14:02 --> 14:05More at smilowcancerhospital.org or
14:05 --> 14:08e-mail Cancer Answers at Yale dot Edu.
14:10 --> 14:12Genetic testing can be useful for
14:12 --> 14:14people with certain types of cancer
14:14 --> 14:16that seem to run in their families.
14:16 --> 14:17Genetic counseling is a process
14:17 --> 14:19that includes collecting a detailed
14:19 --> 14:21personal and family history,
14:21 --> 14:22a risk assessment,
14:22 --> 14:26and a discussion of genetic testing options.
14:26 --> 14:28Only about 5 to 10% of all cancers
14:28 --> 14:30are inherited and genetic testing
14:30 --> 14:32is not recommended for everyone.
14:32 --> 14:34Individuals who have a personal
14:34 --> 14:37and or family history that includes
14:37 --> 14:39cancer at unusually early ages,
14:39 --> 14:41multiple relatives on the same side
14:41 --> 14:43of the family with the same cancer,
14:43 --> 14:46more than one diagnosis of cancer
14:46 --> 14:47in the same individual,
14:47 --> 14:48rare cancers,
14:48 --> 14:51or family history of a known altered
14:51 --> 14:53cancer predisposing gene could be
14:53 --> 14:55candidates for genetic testing.
14:55 --> 14:57Resources for genetic counseling and
14:57 --> 14:59testing are available at federally
14:59 --> 15:01designated comprehensive cancer
15:01 --> 15:03centers such as Yale Cancer Center
15:03 --> 15:05and Smilow Cancer Hospital.
15:05 --> 15:07More information is available
15:07 --> 15:08at yalecancercenter.org.
15:08 --> 15:11You're listening to Connecticut Public Radio.
15:12 --> 15:14Welcome back to Yale Cancer Answers.
15:14 --> 15:15This is Dr. Anees Chagpar,
15:15 --> 15:18and I'm joined tonight by my guest, Dr.
15:18 --> 15:20Sidi Chen. We're talking about the
15:20 --> 15:22role of breakthrough therapeutics
15:22 --> 15:24in fighting cancer.
15:24 --> 15:25Right before the break,
15:25 --> 15:28we were talking about this concept
15:28 --> 15:31of the interplay between cancers in
15:31 --> 15:34the immune system and essentially
15:34 --> 15:36the fact that cancers try to get
15:36 --> 15:39the upper hand on the immune system
15:39 --> 15:42and do that with a number of tricks
15:42 --> 15:44that try to evade the immune system.
15:44 --> 15:46There's now been some therapeutics
15:46 --> 15:48like CAR T therapy,
15:48 --> 15:53which essentially tries to arm the T cells,
15:53 --> 15:55those fighting cells that are in
15:55 --> 15:58the immune system so that they can
15:58 --> 16:00recognize these cancers and go after them.
16:00 --> 16:02But even with that,
16:02 --> 16:04not all cellular therapeutics or
16:04 --> 16:07CAR T therapies are effective,
16:07 --> 16:10particularly for solid tumors.
16:11 --> 16:14Sidi, if I understand it correctly
16:14 --> 16:15that being the case,
16:15 --> 16:19you have 3 strategies really to
16:19 --> 16:21try to make things better,
16:21 --> 16:24give the immune system kind
16:24 --> 16:27of an upper edge on these tumor cells.
16:27 --> 16:30So the first one you talked about
16:30 --> 16:33was kind of like giving
16:33 --> 16:37the immune system a hyper boost.
16:37 --> 16:38Can you talk a little bit more
16:38 --> 16:40about what that entails?
16:40 --> 16:42I mean is that simply making more
16:42 --> 16:46of these T cells that are armed to
16:46 --> 16:48recognize the cancer cells or
16:48 --> 16:51do you try to engineer them in some
16:51 --> 16:53way to make them more effective,
16:53 --> 16:56make them be more able to
16:56 --> 16:58get into solid tumors?
16:59 --> 17:02The first strategy as we
17:04 --> 17:07term as hyper boost is with an analogy
17:07 --> 17:11to putting the gas pedal on the CAR.
17:11 --> 17:14So we're trying to engineer the car so
17:14 --> 17:17that the gas pedals are more efficient,
17:17 --> 17:19like a more fuel efficient car.
17:19 --> 17:22So as you know, T cells kill cancer
17:22 --> 17:25cells by recognizing them and then
17:25 --> 17:28produce cancer killing cytokines and
17:28 --> 17:31all trigger the cell death signal.
17:31 --> 17:37And our approach is trying to install
17:37 --> 17:41the modification to our normal T cells,
17:41 --> 17:46which often fail to kill cancer cells
17:46 --> 17:49by equipping with these T cells
17:49 --> 17:52better tools or better modifications.
17:52 --> 17:55For example, in one of the scenarios,
17:55 --> 17:59we're trying to see which of our
17:59 --> 18:01own 20,000 genes when you install
18:01 --> 18:05or overexpress on a T cell can help
18:05 --> 18:08the T cells produce more cytokines
18:08 --> 18:10to cure cancer cells.
18:10 --> 18:14And we did a scanning of the 20,000 and then
18:14 --> 18:18we found a few that are working very well.
18:18 --> 18:22This is one of the examples that we can
18:22 --> 18:26find the modification genes and hook you
18:26 --> 18:29up with the chimeric endogen receptor.
18:29 --> 18:32So now we have a substantially improved
18:32 --> 18:34CAR T cells to fight cancer cells.
18:34 --> 18:36This is approach number one.
18:37 --> 18:40So just on that, if these T
18:40 --> 18:43cells are making more cytokines,
18:43 --> 18:45could that be problematic for some patients?
18:45 --> 18:49I mean, we've just lived through the
18:49 --> 18:52COVID-19 pandemic and one of the
18:52 --> 18:55things that came up as a result of
18:55 --> 18:58that experience was that we learned
18:58 --> 19:01about things like cytokine storm.
19:01 --> 19:04So is that a possibility?
19:04 --> 19:06Is there any downside to having
19:06 --> 19:09your T cells make more cytokines?
19:10 --> 19:11Yeah, of course.
19:11 --> 19:12This is a great point.
19:12 --> 19:15In fact, one of the major cell
19:15 --> 19:18therapy drawbacks is
19:18 --> 19:19cytokine release syndrome.
19:19 --> 19:21We certainly want to avoid that.
19:21 --> 19:25So it's a balance of how much cytokine
19:25 --> 19:28you want to produce by enabling T cell
19:28 --> 19:31to produce but not overdo it so that
19:31 --> 19:34you create the unwanted side effect.
19:34 --> 19:36So we're doing a lot of work
19:36 --> 19:39trying to find the balance
19:39 --> 19:41of efficacy versus toxicity. And
19:41 --> 19:44that balance I mean is that, I don't know,
19:44 --> 19:45I'm thinking that might be
19:45 --> 19:47something that is very personal, right.
19:47 --> 19:50That depends on the individual,
19:50 --> 19:51it depends on how much
19:51 --> 19:53cancer they might have,
19:53 --> 19:55the type of cancer they might have.
19:55 --> 19:56Is that right or is that balance
19:56 --> 19:59going to be kind of a one size fits all?
19:59 --> 20:02Yes and no. There are certainly patient
20:02 --> 20:05to patient and disease to disease variations.
20:05 --> 20:07But the T cells on the other hand
20:07 --> 20:11can be modified so that they can be
20:11 --> 20:14tuned to shift towards better cancer
20:14 --> 20:16killing and not being too toxic.
20:16 --> 20:19And the other approach we're talking
20:19 --> 20:22about is modified indulgent genes
20:22 --> 20:25so they can remember cancer better,
20:25 --> 20:27so they last longer without having
20:27 --> 20:29to produce too much cytokine.
20:29 --> 20:31Yeah, So let's talk about
20:31 --> 20:33the second strategy.
20:33 --> 20:35So the second strategy you
20:35 --> 20:37talked about was kind of hitting
20:37 --> 20:40the brakes on the car.
20:40 --> 20:41Help us to understand
20:41 --> 20:43that piece a bit better.
20:43 --> 20:46As you know we have 20,000 different
20:46 --> 20:49genes and a lot of different proteins,
20:49 --> 20:52some are suppressive because nature
20:52 --> 20:54evolves so that our immune system
20:54 --> 20:57is not always on so that the
20:57 --> 20:59immune system keeps damaging the body.
20:59 --> 21:02So in order to avoid that our body and
21:02 --> 21:05billion years of evolution evolve the
21:05 --> 21:07molecule that are immunosuppressive.
21:07 --> 21:09For example, a PD1 PDL one,
21:09 --> 21:12which is one of the most famous pathway
21:12 --> 21:14and there are many others and some
21:14 --> 21:18are on the surface like PD1 PDL 1,
21:18 --> 21:19some are internal,
21:19 --> 21:22like we call this cellular checkpoint or
21:22 --> 21:25internal checkpoints and those genes hold
21:25 --> 21:30the T cells back from being too active.
21:30 --> 21:33But those genes sometimes create
21:33 --> 21:37a hurdle to block the efficacy of
21:37 --> 21:40the T cell therapy and we can use
21:40 --> 21:42gene editing to modify or dampen
21:42 --> 21:44those pathways so that we let the
21:44 --> 21:47T cell be a little more active in
21:47 --> 21:50getting an upper hand against cancer,
21:50 --> 21:51wiping them out first and then
21:51 --> 21:53we can turn it down.
21:53 --> 21:55That's the hitting the brake strategy
21:55 --> 21:58like you can release the brake and then
21:58 --> 22:00when the T cells kill the cancer cell
22:00 --> 22:02and then you can put a brake back on.
22:02 --> 22:03So those are the strategies
22:03 --> 22:04we're talking about.
22:05 --> 22:08Sidi, I can see how you can
22:08 --> 22:11combine those two initial strategies,
22:11 --> 22:14making the T cells more
22:14 --> 22:17effective in terms of releasing those
22:17 --> 22:20cytokines that hyper boost strategy
22:20 --> 22:24with this other strategy which kind
22:24 --> 22:27of dampens their brake system
22:27 --> 22:31and so you can create a kind of a
22:31 --> 22:33more effective T cell to kill cancer
22:33 --> 22:36cells but by combining those two
22:36 --> 22:39you can kind of modulate the response.
22:39 --> 22:41My question then is you know one
22:41 --> 22:43would think that would need
22:43 --> 22:45to be tempered over time.
22:45 --> 22:47So for example you might say well
22:47 --> 22:50we need to really go after and kill
22:50 --> 22:53all the cancer cells full throttle
22:53 --> 22:56initially and then we need to ease up
22:56 --> 22:58a bit and start actually using
22:58 --> 23:01that brake pedal that was there to
23:01 --> 23:04alleviate some of the side effects
23:04 --> 23:07that might come from an overabundance
23:07 --> 23:11of cytokines or T cell response.
23:11 --> 23:14So how do you do that with
23:14 --> 23:15cellular therapeutics?
23:15 --> 23:18My understanding of how cellular
23:18 --> 23:22therapies work and granted my
23:22 --> 23:24understanding is very pedestrian, is
23:24 --> 23:27really that you take these cells out,
23:27 --> 23:28you genetically engineer them and
23:28 --> 23:31you give them back to the patient.
23:31 --> 23:34So is there a need to tailor this
23:34 --> 23:38over time to kind of give patients
23:38 --> 23:41different sets of T cells with
23:41 --> 23:43different either hyper boost or
23:43 --> 23:46brake pedal capacity over time?
23:46 --> 23:48This is another excellent question.
23:48 --> 23:51In fact, by taking the T cells out,
23:51 --> 23:53there are a lot of ways
23:53 --> 23:54you can engineer them.
23:54 --> 23:57So you can change the brake,
23:57 --> 23:58put the gas pedal on,
23:58 --> 24:00and in addition you can change the structure.
24:00 --> 24:03You can also put in control elements
24:03 --> 24:05so that you can wipe them out when
24:05 --> 24:07you no longer need them. For example,
24:07 --> 24:10if you put a queue switch in the T cells,
24:10 --> 24:12let them do the job,
24:12 --> 24:14and when the CAR T clear the cancer,
24:14 --> 24:16you no longer need so much CAR
24:16 --> 24:18T that could be problematic.
24:18 --> 24:22Later on you can give the
24:22 --> 24:24patient a small molecule
24:24 --> 24:27that can turn on the Q switch so
24:27 --> 24:29to eliminate the T cells later on.
24:29 --> 24:31Those are some of the strategies
24:31 --> 24:35and in addition we now create a
24:35 --> 24:38new strategy by protein design
24:38 --> 24:40by fusing a small piece of tail
24:41 --> 24:43to the T cell so that they are
24:45 --> 24:47more long lasting,
24:47 --> 24:49they persist for longer.
24:49 --> 24:51So those are the several different
24:51 --> 24:54strategies we can utilize to make the
24:54 --> 24:57T cell more sophisticated in order
24:57 --> 24:59for us to utilize the T cell to
24:59 --> 25:01treat cancer better without
25:01 --> 25:03doing too much damage to the body,
25:04 --> 25:07so that changing the structure
25:07 --> 25:08to make them last longer.
25:08 --> 25:10That sounds like that third strategy that
25:10 --> 25:12you were talking about redesigning the car,
25:12 --> 25:16is that right? Absolutely.
25:16 --> 25:19And so again, I can see how many
25:19 --> 25:21of these are complementary, right?
25:21 --> 25:24You want the T cells to last longer
25:24 --> 25:26and to maintain their memory.
25:26 --> 25:28Presumably that could even have an
25:28 --> 25:31impact in terms of reducing recurrence.
25:31 --> 25:33So, you know, maybe the T cells
25:33 --> 25:35wipe out your initial cancer,
25:35 --> 25:38but you'll always have this
25:38 --> 25:39residual risk of recurrence.
25:39 --> 25:42And so if the T cells retain some memory
25:42 --> 25:45and if enough of them are still around,
25:45 --> 25:47then presumably they can monitor
25:47 --> 25:50the situation and get rid of cancer
25:50 --> 25:53cells early before they even become
25:53 --> 25:56a cancer recurrence down the line.
25:56 --> 25:58On the other hand,
25:58 --> 26:01I do like the idea of the kill switch
26:01 --> 26:03because we want to make sure that
26:03 --> 26:05we're not having an overabundance
26:05 --> 26:08of this cellular activity that
26:08 --> 26:10could cause other side effects.
26:10 --> 26:13So how do you kind of engineer
26:13 --> 26:15this delicate balance?
26:15 --> 26:17It's almost like a Symphony where
26:17 --> 26:19you need certain parts of the
26:19 --> 26:22orchestra playing at certain levels
26:22 --> 26:24in certain times and not in others.
26:26 --> 26:27That's a nice analogy.
26:27 --> 26:31I like symphonies too and the
26:31 --> 26:34balance between the persistence and
26:34 --> 26:37the durability is absolutely the
26:37 --> 26:41the goal for solid tumors.
26:41 --> 26:43The problem is that they don't last
26:43 --> 26:45long enough and or at least last
26:45 --> 26:47long enough in the tumor environment.
26:47 --> 26:50So by a new strategy we now
26:50 --> 26:53call the protein fusion tail,
26:53 --> 26:55we allow the T cell to be more
26:55 --> 26:57memory like which means they
26:57 --> 27:00can remember the cancer cells or
27:00 --> 27:02cancer cells antigen for longer.
27:02 --> 27:04And by doing so,
27:04 --> 27:07we enable the T cell therapy
27:07 --> 27:09to have more durable effect,
27:09 --> 27:11suppress the cancer growth for longer,
27:11 --> 27:16preventing the relapse and
27:16 --> 27:19therefore prolonged survival benefit.
27:19 --> 27:21So those are the strategies
27:21 --> 27:23we're testing right now.
27:24 --> 27:26In terms of testing these strategies,
27:26 --> 27:29have these been taken into the clinic?
27:29 --> 27:31Do we have human data on
27:31 --> 27:33whether or not these work?
27:33 --> 27:35Is this something that patients
27:35 --> 27:37can go in and talk to their doctor
27:37 --> 27:39about today or when do you think
27:39 --> 27:41that might be the situation?
27:41 --> 27:45For now, the FDA has approved 6 cell therapy
27:45 --> 27:48products for the patients
27:48 --> 27:50within those indications,
27:50 --> 27:53the doctor will see if they fit the
27:53 --> 27:56criteria to receive those therapies.
27:56 --> 27:58But unfortunately for solid tumors,
27:58 --> 28:01no cell therapy has been approved
28:01 --> 28:06yet by the FDA and there are many,
28:06 --> 28:08many clinical trials ongoing over
28:08 --> 28:111000 cell therapy clinical trials now
28:11 --> 28:15and the patient can see if they are
28:15 --> 28:17right for enrollment of the clinical trials.
28:17 --> 28:20In the newer strategy we're talking
28:20 --> 28:23about of course the goal is
28:23 --> 28:25to balance efficacy to safety
28:25 --> 28:28and hopefully this can become the
28:28 --> 28:30clinical product in the future.
28:30 --> 28:32But as of now they're not
28:32 --> 28:33approved products yet.
28:33 --> 28:36Doctor Sidi Chen is an associate professor of
28:36 --> 28:38genetics at the Yale School of Medicine.
28:38 --> 28:41If you have questions, the address
28:41 --> 28:43is Cancer Answers at Yale dot Edu,
28:43 --> 28:45and past editions of the program
28:45 --> 28:47are available 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

Breakthrough Therapeutics to Tame Cancer Cells with guests Dr. Sidi Chen September 17, 2023 Yale Cancer Center visit: http://www.yalecancercenter.org email: canceranswers@yale.edu call: 203-785-4095