Supercharged Cancer-Fighting T Cells

Transcript

00:00 --> 00:02Funding for Yale Cancer Answers is
00:02 --> 00:04provided by Smilow Cancer Hospital.
00:06 --> 00:08Welcome to Yale Cancer Answers with
00:08 --> 00:11your host Doctor Anees Chagpar.
00:11 --> 00:12Yale Cancer Answers features the
00:12 --> 00:15latest information on cancer care by
00:15 --> 00:16welcoming oncologists and specialists
00:16 --> 00:19who are on the forefront of the
00:19 --> 00:20battle to fight cancer. This week,
00:20 --> 00:23it's a conversation about increasing an
00:23 --> 00:25immune cells ability to target and kill
00:25 --> 00:28cancer cells with Doctor Sidi Chen.
00:28 --> 00:30Doctor Chen is an associate professor of
00:30 --> 00:32genetics at the Yale School of Medicine,
00:32 --> 00:34where Doctor Chagpar is a professor
00:34 --> 00:35of surgical oncology.
00:37 --> 00:39So Sidi maybe we can start off by you
00:39 --> 00:41telling us a little bit more about
00:41 --> 00:42yourself and what it is you do.
00:43 --> 00:46So I'm a scientist by training and I
00:46 --> 00:49got my PhD at the University of Chicago.
00:49 --> 00:53I studied genetics and evolution and
00:53 --> 00:57then I went to MIT studying cancer
00:57 --> 01:00biology and that's when I got motivated
01:00 --> 01:03to find future cures for cancer
01:03 --> 01:05and benefit the broader population.
01:06 --> 01:07So tell us a little bit.
01:07 --> 01:09More about your research and how
01:09 --> 01:11you're trying to cure cancer.
01:12 --> 01:14I believe currently we are in
01:14 --> 01:16a new era of cancer medicine.
01:16 --> 01:18There are a number of new
01:18 --> 01:19therapies on the horizon,
01:19 --> 01:22including cancer immunotherapy,
01:22 --> 01:24using immune checkpoints,
01:24 --> 01:26and more recently on cell and gene therapy,
01:26 --> 01:29and I think the future of medicine
01:29 --> 01:32is the use of a variety of novel
01:32 --> 01:37therapeutics for for the patients,
01:37 --> 01:39and these novel therapeutics would
01:39 --> 01:42have to be better than what we have.
01:42 --> 01:44Today, for example,
01:44 --> 01:47they have to overcome the disease
01:47 --> 01:52resistance relapse and have to have
01:52 --> 01:56better safety profiles and have more
01:56 --> 01:59balanced efficacy and toxicity ratio.
01:59 --> 02:01And I can keep going,
02:01 --> 02:03but I think for our patients
02:03 --> 02:05we need better jobs.
02:05 --> 02:07Absolutely, I couldn't agree with you
02:07 --> 02:09more tell us about your research and
02:09 --> 02:12how you hope to do all of those things.
02:12 --> 02:14I mean, certainly. I I,
02:14 --> 02:18I think that those are all lofty goals.
02:18 --> 02:19So how are you approaching this?
02:20 --> 02:23Sure, I think no man can do it all.
02:23 --> 02:25Neither can I.
02:25 --> 02:28As a geneticist, I believe the
02:28 --> 02:30true power of unbiased approach.
02:30 --> 02:33All of us have the same genetic compositions.
02:33 --> 02:36We all share the same genes in the genome.
02:36 --> 02:39Of course there are variations.
02:39 --> 02:45But my approach has been let
02:45 --> 02:48nature tell us what is the right?
02:48 --> 02:50Approach. Which means we.
02:50 --> 02:54Tend to go brawl in survey the entire
02:54 --> 02:59genome or survey full set of genetic
02:59 --> 03:01composition to see which genes.
03:01 --> 03:04If you take it out or if you
03:04 --> 03:07turn it on would help our own
03:07 --> 03:10selves fight cancer cells better.
03:10 --> 03:13And we do so by performing unbiased
03:13 --> 03:16genetic screens such as CRISPR,
03:16 --> 03:17knockout, CRISPR activation screen
03:17 --> 03:20to find the therapeutic target that
03:20 --> 03:23can overcome some of the problems.
03:23 --> 03:25I mentioned previously,
03:25 --> 03:26for example,
03:26 --> 03:29resistance to cancer killing or
03:29 --> 03:31tumor infiltration or metabolism,
03:31 --> 03:35and by doing these screens we will
03:35 --> 03:40be able to see through a big pile
03:40 --> 03:43of haystacks to find the small set
03:43 --> 03:47of needles that allow us to improve
03:47 --> 03:50the property of immune cells such
03:50 --> 03:52as T cells and thereby intense.
03:52 --> 03:56Of Therapeutic FC and reduce the toxicity.
03:56 --> 03:58Delve a little bit more into
03:58 --> 04:00the details of that CD.
04:00 --> 04:02Tell us a little bit more
04:02 --> 04:04about how you go through this
04:04 --> 04:07haystack and find these needles.
04:07 --> 04:08Defined for our audience
04:08 --> 04:10what technologies you use.
04:10 --> 04:12Not everybody might be aware
04:12 --> 04:13of what exactly crisper is
04:13 --> 04:16and how that works. Sure,
04:16 --> 04:18let me slightly switch gears.
04:18 --> 04:21CRISPR is not a technology from
04:21 --> 04:24the gecko because it's actually
04:24 --> 04:27an immune system of the bacteria.
04:27 --> 04:30But then, as the human beings
04:30 --> 04:35harness those tools, those natural.
04:35 --> 04:39Component for fun bacteria to become genetic
04:39 --> 04:43tools the beauty of CRISPR is that it can be.
04:43 --> 04:46Very easy to use and can be precisely
04:46 --> 04:49targeted and can be scalable.
04:49 --> 04:52So what we are doing is to use CRISPR to
04:53 --> 04:56manipulate the genes for the expression.
04:56 --> 05:00For example, we can take out a gene,
05:00 --> 05:05or we can turn on a gene and we can do so.
05:05 --> 05:10Thousands or 10s of thousands at a time.
05:10 --> 05:11For example,
05:11 --> 05:14if there are 20,000 genes in our genome,
05:14 --> 05:18we can turn. One at a time,
05:18 --> 05:20but we do it all together.
05:20 --> 05:25And it's like we enumerate each
05:25 --> 05:30of the haystack and see by turning
05:30 --> 05:32on each of the gene.
05:32 --> 05:34Which genes would help our own cells
05:34 --> 05:35kill cancer cell?
05:35 --> 05:35Better?
05:35 --> 05:38Because we're doing so many at
05:38 --> 05:41once and the chances we finding
05:41 --> 05:44those needles are much higher than.
05:44 --> 05:46Than using a traditional one at
05:46 --> 05:48a time approach.
05:48 --> 05:50So you you start turning on these
05:50 --> 05:53genes to figure out which ones are
05:53 --> 05:56going to help you in your fight
05:56 --> 05:58against cancer and which ones are not.
05:58 --> 06:01One would think however,
06:01 --> 06:03that still that's rather simplistic
06:03 --> 06:06in terms of fighting cancers.
06:06 --> 06:09So how do you figure out which genes
06:09 --> 06:12are particularly relevant for which
06:12 --> 06:15particular cancers or which particular?
06:15 --> 06:18Drugs, or is it the fact that you
06:18 --> 06:20know certain genes are ubiquitous
06:20 --> 06:24in terms of their effect in cancer?
06:24 --> 06:26Those are great questions.
06:26 --> 06:31There are numerous ways to look to Rome
06:31 --> 06:33and just take one of our recent study.
06:33 --> 06:36For example, we are taking triple
06:36 --> 06:39negative breast cancer cells and we
06:39 --> 06:42also take T cells as the cell from our
06:42 --> 06:45own bodies immune cells to fight them.
06:45 --> 06:48And then we turn on the genes in
06:48 --> 06:51T cells using CRISPR and then we
06:51 --> 06:54measure the ability of T cells to
06:54 --> 06:57kill and there's a becomes technical.
06:57 --> 07:00There's an essay called Degranulation
07:00 --> 07:04Assay which means we can see how fast
07:04 --> 07:07these T cell degranulate meaning how
07:07 --> 07:11fast they release the enzyme to kill
07:11 --> 07:14cancer cells and by measuring the.
07:14 --> 07:14Generation,
07:14 --> 07:17which means the T cell killing ability.
07:17 --> 07:20Uh, one gene at a time,
07:20 --> 07:24but in a massive pair of manner we can
07:24 --> 07:28exhaust the entire genome for every gene.
07:28 --> 07:33T cells and then we can.
07:33 --> 07:35Identify which genes?
07:35 --> 07:37When they're activated,
07:37 --> 07:40would enhance such an ability
07:40 --> 07:41to kill cancer cells.
07:41 --> 07:44And of course, this we.
07:44 --> 07:46Initially perform in
07:46 --> 07:48breast cancer cell killing,
07:48 --> 07:53but then when we apply to other cancer types,
07:53 --> 07:56we found this is also true
07:56 --> 07:58because the gene is universal.
07:58 --> 08:01And therefore the ability of T
08:01 --> 08:03cells to cure cancer cells is
08:03 --> 08:06controlled by the same gene,
08:06 --> 08:08no matter it's getting a breast
08:08 --> 08:09cancer cell or killing leukemia
08:09 --> 08:11cell killing myeloma cell.
08:11 --> 08:14I mean, it certainly sounds
08:14 --> 08:16incredibly interesting, but one of
08:16 --> 08:20the things that might be curious is.
08:20 --> 08:23You know you're turning on these genes
08:23 --> 08:26and and kind of using CRISPR technology
08:26 --> 08:29to activate these genes within a T cell,
08:29 --> 08:33but in a human how would
08:33 --> 08:36you activate that gene?
08:36 --> 08:40Or is there a way to turn on a
08:40 --> 08:43particular genes in an in vivo system?
08:43 --> 08:46Yeah, that's another great question.
08:46 --> 08:49A cell therapy, by definition,
08:49 --> 08:53is the usage of cells as therapeutics,
08:53 --> 08:57and for many of you you might have heard of
08:57 --> 09:01car keys or camera engine receptor T cells.
09:01 --> 09:05That's one form of cell therapy and
09:05 --> 09:07what Carti or other form of self therapy
09:07 --> 09:10does is that it takes the cells from
09:10 --> 09:12a patient or from a healthy donor,
09:12 --> 09:15and then you can perform genetic
09:15 --> 09:17engineering in those cells.
09:17 --> 09:19For example, putting cameras and
09:19 --> 09:22antigen receptors on the surface.
09:22 --> 09:25Or like what we're doing?
09:25 --> 09:27Enhance the expression or turn on
09:27 --> 09:29the expression of a particular gene,
09:29 --> 09:32and we can do it by demand by using
09:32 --> 09:37genetic engineering or vector transgenes.
09:37 --> 09:41So after we modify these genes
09:41 --> 09:43in these T cells,
09:43 --> 09:47the cells would become therapeutic
09:47 --> 09:51candidate and those are the type of
09:51 --> 09:56cells we can use to infuse back into.
09:56 --> 10:00In our case, the animals to treat the.
10:00 --> 10:02The cancer in those animal models.
10:02 --> 10:03Of course, in the clinic,
10:03 --> 10:06the proof of cell therapy,
10:06 --> 10:08where the same process happened.
10:08 --> 10:10The cells were taken out from patient.
10:10 --> 10:11The genes have been modified and
10:11 --> 10:13the cells have been reinfused
10:13 --> 10:15into the patient to treat cancer.
10:15 --> 10:17Then one would think that
10:17 --> 10:19you would have some cells.
10:19 --> 10:23The native cells that are in the
10:23 --> 10:25patient's that are not quote
10:25 --> 10:27supercharged or or modified,
10:27 --> 10:29and you'd have some cells that
10:29 --> 10:31were the more therapeutic
10:31 --> 10:34cells that had been reinfused.
10:34 --> 10:39How do you get or is there a way to
10:39 --> 10:43get patients to make their own cells?
10:43 --> 10:46Have that supercharged ability
10:46 --> 10:49so that when these cells die,
10:49 --> 10:53there isn't a continued need to have
10:53 --> 10:56an infusion of these modified cells?
10:56 --> 10:59Or is that something that isn't done?
10:59 --> 11:01A patient may not need the
11:01 --> 11:03supercharged cells in the body
11:03 --> 11:05for a very long period of time.
11:05 --> 11:09And we to some degree we haven't
11:09 --> 11:11done the clinical study yet,
11:11 --> 11:14but to some degree we believe
11:14 --> 11:17it may be important to.
11:17 --> 11:20Let the cells finish the
11:20 --> 11:22job and then be done.
11:22 --> 11:23Because we don't want
11:23 --> 11:25them to stick on forever.
11:25 --> 11:30So I think some cells may
11:30 --> 11:33be sufficient to kill the
11:33 --> 11:36cancer cells and we're talking
11:36 --> 11:38about the persistence issue,
11:38 --> 11:40which is can be very long conversation, but.
11:43 --> 11:45The ideal situation would be we
11:45 --> 11:48infuse those cells into the body.
11:48 --> 11:49The cells kill off the cancer
11:49 --> 11:51and the cancer is gone,
11:51 --> 11:53and then the cells are gone too,
11:53 --> 11:55and then the patient is back to normal.
11:55 --> 11:57So that would be ideal situation.
11:57 --> 11:59But in the real clinic this is a
11:59 --> 12:00much more complicated than that.
12:00 --> 12:04I mean, one of the things that we think
12:04 --> 12:06about is recurrences or even patients
12:06 --> 12:10who denovo are at an increased risk,
12:10 --> 12:13and so when we think about the immune system.
12:13 --> 12:15Not only does the immune system help
12:15 --> 12:18us in terms of you know, clearing
12:18 --> 12:21cancer cells or treating cancer cells,
12:21 --> 12:24and so having these supercharged cells
12:24 --> 12:27would be useful in that context,
12:27 --> 12:31but they may also be relevant in terms
12:31 --> 12:33of preventing cancers from occurring.
12:33 --> 12:38At at all, so in high risk individuals or in
12:38 --> 12:41patients who are at high risk of recurrence,
12:41 --> 12:43reducing the risk of recurrence.
12:43 --> 12:46O has this kind of therapy been
12:46 --> 12:48thought about in those two contexts?
12:49 --> 12:52All you're absolutely right.
12:52 --> 12:54In cancer treatment,
12:54 --> 12:58there are many cases of relapse or
12:58 --> 13:00resistance and therefore multiple
13:00 --> 13:03dosing is often required or beneficial,
13:03 --> 13:05and it's absolutely case by
13:05 --> 13:08case in the clinic disease by
13:08 --> 13:10disease indication by indication,
13:10 --> 13:13and I think we are still early in the
13:13 --> 13:16form of self therapy because currently
13:16 --> 13:19self therapy infusion is only given once.
13:19 --> 13:22And there have been clinical
13:22 --> 13:27trials for multiple infusions, or.
13:27 --> 13:29Use as prophylaxis,
13:29 --> 13:31but those much earlier studies
13:31 --> 13:34the approved drugs were given as a
13:34 --> 13:37single infusion for most of the time.
13:37 --> 13:39OK, well, we're going to take a
13:39 --> 13:41short break for a medical minute.
13:41 --> 13:43Please stay tuned to learn more about
13:43 --> 13:45supercharged T cells fighting cancer
13:45 --> 13:47with my guest doctor Sidi Chen.
13:48 --> 13:50Funding for Yale Cancer Answers
13:50 --> 13:52comes from Smilow Cancer Hospital
13:53 --> 13:55hosting a smilow shares cancer
13:55 --> 13:57Survivor Series June 8th and 15th.
13:57 --> 13:59Register at Yale Cancer
13:59 --> 14:00Center or email cancer.
14:00 --> 14:04Answers at yale.edu.
14:04 --> 14:06Breast cancer is one of the most common
14:06 --> 14:09cancers in women in Connecticut alone,
14:09 --> 14:11approximately 3500 women will be
14:11 --> 14:13diagnosed with breast cancer this year,
14:13 --> 14:15but there is hope,
14:15 --> 14:16thanks to earlier detection,
14:16 --> 14:18non invasive treatments and the
14:18 --> 14:20development of novel therapies
14:20 --> 14:21to fight breast cancer.
14:21 --> 14:23Women should schedule a baseline
14:23 --> 14:25mammogram beginning at age 40 or
14:25 --> 14:27earlier if they have risk factors
14:27 --> 14:29associated with the disease.
14:29 --> 14:30With screening early detection
14:30 --> 14:32and a healthy lifestyle,
14:32 --> 14:34breast cancer can be defeated.
14:34 --> 14:36Clinical trials are currently
14:36 --> 14:38underway at federally designated
14:38 --> 14:40Comprehensive cancer centers such
14:40 --> 14:42as Yale Cancer Center and Smilow
14:42 --> 14:44Cancer Hospital to make innovative
14:44 --> 14:46new treatments available to patients.
14:46 --> 14:49Digital breast tomosynthesis or 3D
14:49 --> 14:51mammography is also transforming breast
14:51 --> 14:54cancer screening by significantly
14:54 --> 14:55reducing unnecessary procedures
14:55 --> 14:58while picking up more cancers.
14:58 --> 15:01More information is available at
15:01 --> 15:02yalecancercenter.org you're listening
15:02 --> 15:04to Connecticut Public Radio.
15:05 --> 15:07Welcome back to Yale Cancer Answers.
15:07 --> 15:09This is doctor Anees Chagpar and I'm joined
15:09 --> 15:12tonight by my guest doctor Sidi Chen.
15:12 --> 15:14We're learning about his research
15:14 --> 15:16into using T cells to fight cancer
15:16 --> 15:19cells and right before the break
15:19 --> 15:23he was telling us about how you
15:23 --> 15:26could use new technology to look
15:26 --> 15:29for genes that may be particularly
15:29 --> 15:33effective in terms of getting rid of
15:33 --> 15:35cancer and then using CRISPR.
15:35 --> 15:38Technology to activate these genes
15:38 --> 15:41and potentially using it in cellular
15:41 --> 15:44therapies in patients to treat cancers.
15:44 --> 15:48You had mentioned that your work
15:48 --> 15:52right now is is using largely animal models.
15:52 --> 15:53Has this been tested in clinical
15:53 --> 15:55trials or is that something that
15:55 --> 15:57is coming down the Pike?
15:57 --> 15:58Thank you for the question,
15:58 --> 16:01and my lab is Preclinical Research lab
16:01 --> 16:05and of course my goal is to discover.
16:05 --> 16:08And. Understand the therapeutic targets
16:08 --> 16:12and pathways and how it works to
16:12 --> 16:16build the portfolio or the platform
16:16 --> 16:19for future translational studies.
16:19 --> 16:22We of course talking to different
16:22 --> 16:25translational partners or potential partners
16:25 --> 16:29to bring this further down into clinic.
16:29 --> 16:32But this is a complicated
16:32 --> 16:36process because cell therapy has.
16:36 --> 16:39Complex manufacturing and
16:39 --> 16:43complex regulatory path as well,
16:43 --> 16:46so it's not as easy as some of
16:46 --> 16:47the traditional drugs.
16:48 --> 16:50Yeah, now you had mentioned that
16:50 --> 16:52you had started your research.
16:52 --> 16:54Really looking at triple
16:54 --> 16:55negative breast cancers.
16:55 --> 16:57So do you want to tell our audience
16:57 --> 16:59a little bit about why you
16:59 --> 17:01chose triple negative as a good
17:01 --> 17:03cancer to look at to begin with?
17:05 --> 17:08Yasur Alice, you are a much better
17:08 --> 17:12expert than me on breast cancer.
17:12 --> 17:14US we believed triple negative breast
17:14 --> 17:18cancer is the type of breast cancer that
17:18 --> 17:20there is no hormone targeted therapy
17:20 --> 17:23which is very commonly used for the
17:23 --> 17:27other types such as her two positive.
17:27 --> 17:32So we believe we need to identify
17:32 --> 17:35other novel therapeutic targets or
17:35 --> 17:36therapeutic approaches to adjust
17:36 --> 17:39the unmet need for this disease.
17:40 --> 17:43Yeah, I think that's right, but I think so.
17:43 --> 17:46Certainly you know we we on this show
17:46 --> 17:48talk a lot about targeted therapies
17:48 --> 17:50and triple negative by definition
17:50 --> 17:53don't have a target as such.
17:53 --> 17:55They certainly are not responsive to
17:55 --> 17:57endocrine therapy, being ER, PR negative.
17:57 --> 18:00And they're not responsive to her too.
18:00 --> 18:03Targets given the fact that they
18:03 --> 18:06don't express that receptor either.
18:06 --> 18:08One of the interesting things about
18:08 --> 18:11triple negative breast cancer is that
18:11 --> 18:14we've found that these are potentially
18:14 --> 18:16more immunogenic in in the sense that
18:16 --> 18:19they tend to have more tea infiltrating
18:19 --> 18:22lymphocytes when when you look at them,
18:22 --> 18:25when people have looked at immunotherapies,
18:25 --> 18:27they they tend to respond
18:27 --> 18:28to immunotherapy so.
18:28 --> 18:29You know,
18:29 --> 18:32in thinking about these supercharged T cells.
18:32 --> 18:36I wonder whether part of the rationale
18:36 --> 18:40is to look at cancers that are
18:40 --> 18:43particularly prime for immune regulation.
18:43 --> 18:47Did that play into your thinking,
18:47 --> 18:48and if so,
18:48 --> 18:50will it affect which cancers
18:50 --> 18:54you look at next in terms of the
18:54 --> 18:56ability for these supercharged
18:56 --> 18:59T cells to to battle cancer?
19:00 --> 19:02Ohh yes, of course,
19:02 --> 19:04you're absolutely right,
19:04 --> 19:08the breast cancer have different subtypes,
19:08 --> 19:13and even between different patients or
19:13 --> 19:17different level of immune infiltration or
19:17 --> 19:21the tumor microenvironment is complex issues.
19:21 --> 19:24There are tumors without.
19:24 --> 19:27Any or there would be very little
19:27 --> 19:29infiltrating T cells that you cancer
19:29 --> 19:32fighting cell and on the other hand
19:32 --> 19:35there are tumors that are filled
19:35 --> 19:37with immune cells and in order
19:37 --> 19:40for T cells to kill cancer cells,
19:40 --> 19:44you need T cell to get there to
19:44 --> 19:46the right place before they can do
19:46 --> 19:50their job and therefore we are also
19:50 --> 19:52looking for a genetic components.
19:52 --> 19:55That controls the process of
19:55 --> 19:56tumor infiltration.
19:56 --> 19:57Besides cancer killing,
19:57 --> 20:00and in order to do so,
20:00 --> 20:03we are adopting a similar approach,
20:03 --> 20:06unbiased genetic screens and look
20:06 --> 20:09for the genes when you either
20:09 --> 20:12get rid of or when you turn on
20:12 --> 20:14what helped the T cells get into
20:14 --> 20:16the term micro environment,
20:16 --> 20:22and I think that property can be cancelled.
20:22 --> 20:24Specific or can be more universal
20:24 --> 20:27like and what we have been doing now
20:27 --> 20:30is use triple negative breast cancer
20:30 --> 20:33as a starter model and then identify
20:33 --> 20:35those genes to supercharge the T
20:35 --> 20:38cells and then apply those findings
20:38 --> 20:41into other disease indications
20:41 --> 20:44such as other form of breast cancer
20:44 --> 20:46or Melanoma or pancreatic cancer
20:46 --> 20:48or other cancer types.
20:49 --> 20:51So CD when you've started to
20:51 --> 20:53look at these other cancers.
20:53 --> 20:56Have you found that there's a difference
20:56 --> 21:00in terms of the response of these?
21:00 --> 21:03These supercharged T cells based on how
21:03 --> 21:06immunogenic the cancer is in other words.
21:06 --> 21:09If a cancer doesn't have a lot of tea,
21:09 --> 21:13infiltrating lymphocytes say like a luminal,
21:13 --> 21:17a breast cancer or or a cancer that
21:17 --> 21:19really doesn't evade the immune
21:19 --> 21:21system or isn't as immunogenic,
21:21 --> 21:24it is the effect different in those
21:24 --> 21:27populations in those cancers in
21:27 --> 21:29those patients than it is in cancers
21:29 --> 21:32where there are a lot of tumor
21:32 --> 21:34infiltrating lymphocytes or cancers
21:34 --> 21:36that we know are highly immunogenic.
21:37 --> 21:41Oh, thank you for the question and let
21:41 --> 21:44me declare that I'm not the clinician,
21:44 --> 21:46so therefore I cannot comment on
21:46 --> 21:48the patient side, but however,
21:48 --> 21:52based on the tumor models we use in animals.
21:52 --> 21:56There are certainly differences
21:56 --> 21:59in commonalities between
21:59 --> 22:02different disease models.
22:02 --> 22:06You you find in cases where the
22:06 --> 22:09genes regulating T cell cancer
22:09 --> 22:11killing or cancer infiltration.
22:11 --> 22:16Uh is specific for some type of cancer,
22:16 --> 22:19but also there's a set of genes that
22:19 --> 22:22are common to multiple type of cancers.
22:22 --> 22:25When we're performing these T cell
22:25 --> 22:27studies cell screening studies.
22:29 --> 22:35And so. So have you looked at whether
22:35 --> 22:39when you supercharged these T lymphocytes,
22:39 --> 22:42whether there is a difference in
22:42 --> 22:44terms of how effective they are
22:44 --> 22:46in cancer killing when they are
22:46 --> 22:49coupled with other forms of therapy,
22:49 --> 22:51say immunotherapy or chemotherapy?
22:54 --> 22:55That's a great question,
22:55 --> 22:57and that's exactly what we're trying now,
22:57 --> 23:01because as you know and.
23:01 --> 23:04Most of the late stage cancer cannot be
23:04 --> 23:08cured by a single form of therapeutics,
23:08 --> 23:11and that's why having more options
23:11 --> 23:15in more innovative therapeutics would
23:15 --> 23:20allow us to have more choices for
23:20 --> 23:24the patient to have multiple lines of
23:24 --> 23:26therapy or have different combinations.
23:26 --> 23:29And we are studying different
23:29 --> 23:31combinations in our lab,
23:31 --> 23:34including immune checkpoint,
23:34 --> 23:36antibodies and chemotherapy,
23:36 --> 23:39and cell therapy with or without
23:39 --> 23:42supercharged T cells and gene therapy.
23:42 --> 23:43So we.
23:43 --> 23:46Looking forward to see the signal
23:46 --> 23:50of 1 + 1 greater than two or at
23:50 --> 23:54least 1 + 1 greater than one.
23:54 --> 23:56In terms of therapeutic efficacy
23:56 --> 23:59and hopefully in terms of toxicity,
23:59 --> 24:021 + 1 is smaller than one,
24:02 --> 24:04or like at least not.
24:04 --> 24:08Bah, too much greater than two.
24:08 --> 24:10So this is always a hot balance.
24:11 --> 24:15So CD, have you? Have you gotten any
24:15 --> 24:19initial results on that in terms of
24:19 --> 24:22understanding what combines well with
24:22 --> 24:24supercharge T cells versus what doesn't?
24:26 --> 24:29Yeah, we're still early in the
24:29 --> 24:33game and our research is ongoing
24:33 --> 24:36and with some initial observation
24:36 --> 24:40is that if we combined it with.
24:40 --> 24:44The gene therapy, or a major base?
24:44 --> 24:46Imagine therapy because
24:46 --> 24:49like one side of my study,
24:49 --> 24:54is to heat up the immune system in the tumor.
24:54 --> 24:57Like we have an approach called
24:57 --> 25:00Multiplex activation of endogenous
25:00 --> 25:03genes as chemotherapy called Meiji.
25:03 --> 25:05And we found self therapy and
25:05 --> 25:10Meiji can be combined in order to.
25:10 --> 25:12Improve the therapeutic efficacy
25:12 --> 25:14of one another.
25:14 --> 25:16This is natural because what major
25:16 --> 25:19does is to heat up the immune system
25:19 --> 25:22so the cells get in easier and
25:22 --> 25:24recognize the cancer cell better
25:24 --> 25:27and then the software app is to
25:27 --> 25:30actually providing the T cells itself,
25:30 --> 25:31supercharged them,
25:31 --> 25:33and then let them do the job
25:33 --> 25:35to kill cancer cells.
25:35 --> 25:38So I think naturally these work together.
25:38 --> 25:39But of course there's a long way to go.
25:40 --> 25:41So how does?
25:41 --> 25:44Just take us back a little bit.
25:44 --> 25:46How does gene therapy actually
25:46 --> 25:48work in terms of the clinic?
25:48 --> 25:51I mean is that using a vector
25:51 --> 25:53that goes into your cells and
25:53 --> 25:56and kind of does its own little
25:56 --> 25:59crisper in vivo help our audience
25:59 --> 26:00to understand how that works?
26:01 --> 26:03Yeah, sure, uh, gene therapy
26:03 --> 26:06for cancer is still very early,
26:06 --> 26:10and currently there's very little.
26:10 --> 26:13Approved shocks for gene therapy for cancer.
26:16 --> 26:19Currently there are.
26:19 --> 26:22A few examples, for example,
26:22 --> 26:25are you can deliver the gene
26:25 --> 26:27therapy product systemically,
26:27 --> 26:31or you can deliver the gene therapy
26:31 --> 26:33product directly into cancer and
26:33 --> 26:35hopefully. Not just.
26:35 --> 26:39Cheat the tumor you that you injected,
26:39 --> 26:42but also create inflammatory response.
26:42 --> 26:44That's going to be systemic,
26:44 --> 26:48meaning it has an effect on
26:48 --> 26:51the distance side.
26:53 --> 26:55This sounds challenging, but not impossible,
26:55 --> 26:59because our own bodies connected
26:59 --> 27:01immune system is connected.
27:01 --> 27:04So what we've been doing and trying
27:04 --> 27:08to do is to try to use therapy to
27:10 --> 27:13activate the immune system so
27:13 --> 27:15that when it gets activated,
27:15 --> 27:18it has the ability to chase
27:18 --> 27:19down the cancer cells,
27:19 --> 27:22not just from the tumor side,
27:22 --> 27:24but also on the distant side.
27:24 --> 27:26For example, the metastasis.
27:28 --> 27:31So how exactly does gene therapy
27:31 --> 27:33activate the immune system?
27:33 --> 27:36Because so many of us have heard
27:36 --> 27:37about checkpoint inhibitors.
27:37 --> 27:40You told us a little bit
27:40 --> 27:41about cellular therapy.
27:41 --> 27:44Tell us how gene therapy kind
27:44 --> 27:47of revs up the immune system as well.
27:48 --> 27:50One of our earlier studies,
27:50 --> 27:52we used CRISPR
27:52 --> 27:55activation and again this is similar to
27:55 --> 27:58what we do for supercharging T cells,
27:58 --> 28:01but in this case we are promoting
28:01 --> 28:04the expression of antigens because
28:04 --> 28:07the cancer cells they don't want
28:07 --> 28:10to be seen by the immune system.
28:10 --> 28:12Therefore they downregulate what they
28:12 --> 28:15could downregulate the expression of
28:15 --> 28:17their own antigen on the surface.
28:17 --> 28:19What we try to do is
28:19 --> 28:21forced expression of those antigen
28:21 --> 28:24to be hyperactivated or hyper
28:24 --> 28:27Express and presented on the surface
28:27 --> 28:29and therefore we're like setting a
28:29 --> 28:32light on those cancer cells and let
28:32 --> 28:34the immune system see them better.
28:34 --> 28:37Doctor Sidi Chen is an associate professor of
28:37 --> 28:39genetics at the Yale School of Medicine.
28:39 --> 28:43If you have questions the address is
28:43 --> 28:44canceranswers@yale.edu and past editions
28:44 --> 28:47of the program are available in audio
28:47 --> 28:49and written form at Yale Cancer Center.org
28:49 --> 28:51We hope you'll join us next week
28:51 --> 28:53to learn more about the fight against
28:53 --> 28:55cancer here on Connecticut Public radio.
28:55 --> 28:57Funding for Yale Cancer Answers is
28:57 --> 29:00provided by Smilow Cancer Hospital.

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June 5, 2022

Yale Cancer Center

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