The Immune System and Melanoma

Transcript

00:00 --> 00:01Funding for Yale Cancer Answers
00:01 --> 00:03is provided by Smilow Cancer
00:03 --> 00:05Hospital and AstraZeneca.
00:07 --> 00:09Welcome to Yale Cancer Answers
00:10 --> 00:12with your host Dr. Anees Chagpar.
00:12 --> 00:14Yale Cancer Answers features the latest
00:14 --> 00:16information on cancer care by
00:16 --> 00:17welcoming oncologists and specialists
00:17 --> 00:20who are on the forefront of the
00:20 --> 00:22battle to fight cancer. This week,
00:22 --> 00:23it's a conversation about Melanoma
00:23 --> 00:25with Doctor Harriet Kluger.
00:25 --> 00:27Doctor Kluger is a professor of
00:27 --> 00:28medicine and medical oncology
00:28 --> 00:30at the Yale School of Medicine
00:30 --> 00:33where Doctor Chagpar is a
00:33 --> 00:34professor of surgical oncology.
00:37 --> 00:40I thought that we would dive
00:40 --> 00:42right into the treatment of Melanoma.
00:42 --> 00:46We've talked a lot on this show
00:46 --> 00:48about Melanoma being one of the
00:48 --> 00:50most deadly skin cancers.
00:50 --> 00:53Can you talk a
00:53 --> 00:55little bit about how we have
00:55 --> 00:57traditionally treated Melanoma
00:57 --> 01:00and where things might be going?
01:00 --> 01:03Sure, when we
01:03 --> 01:05think about oncologic treatments,
01:05 --> 01:08there are three major categories.
01:08 --> 01:11You can take a cancer out with surgery,
01:11 --> 01:14you can do radiation, or you can
01:14 --> 01:16give what we call systemic therapy,
01:16 --> 01:20which is therapy that's given by mouth.
01:20 --> 01:23But I feel the vast majority of melanomas
01:23 --> 01:25are actually discovered really early on
01:25 --> 01:28when people see a changing mole
01:28 --> 01:30or a dermatologist might find
01:30 --> 01:32one on a routine skin exam.
01:32 --> 01:34Most of the melanomas are then excised,
01:34 --> 01:37in other words, taken out and
01:37 --> 01:39nothing further needs to be done,
01:39 --> 01:41and patients are simply observed.
01:41 --> 01:43Every so often patients come in
01:43 --> 01:45without ever knowing that they
01:45 --> 01:46had a Melanoma in the skin.
01:46 --> 01:49So it's a Melanoma that has
01:49 --> 01:51spread beyond the primary site.
01:51 --> 01:53Or they might have had a primary
01:53 --> 01:55Melanoma that was removed years ago,
01:55 --> 01:57but a few cells escaped and are
01:57 --> 01:59now developing into tumors in
01:59 --> 02:01other locations in the body.
02:01 --> 02:03What I do in my clinic is treat with
02:03 --> 02:05systemic therapy so things that are
02:05 --> 02:07administered by mouth or by IV
02:07 --> 02:10so they go all over the body and
02:10 --> 02:12that's what we're going to talk about
02:12 --> 02:14primarily today.
02:14 --> 02:16One of the questions that a lot of
02:16 --> 02:18patients have is when they have
02:18 --> 02:20that phenomenon of metastatic Melanoma,
02:20 --> 02:22so the Melanoma has escaped.
02:22 --> 02:24It's gone to other parts of the body
02:24 --> 02:26where surgery really can't remove the
02:26 --> 02:28Melanoma itself and where
02:28 --> 02:31you're treating with systemic therapy
02:31 --> 02:33people wonder about the prognosis
02:33 --> 02:35and whether in fact they can
02:35 --> 02:37never be quote cancer free.
02:37 --> 02:39Can you talk a little bit
02:39 --> 02:40about that?
02:40 --> 02:42When I started treating patients
02:42 --> 02:44with metastatic Melanoma in 2001,
02:44 --> 02:46if somebody had cancer
02:46 --> 02:48that had spread beyond the skin
02:48 --> 02:50and into the internal organs,
02:50 --> 02:53we would have a frank conversation
02:53 --> 02:55with the patient and say we're really sorry,
02:56 --> 02:58this is an incurable disease,
02:58 --> 02:59and on average people live
02:59 --> 03:01between 6 and 12 months.
03:01 --> 03:03You should start getting your
03:03 --> 03:06affairs in order and we will do
03:06 --> 03:08what we can and hope for the best.
03:08 --> 03:10At the time we had a chemotherapy called
03:10 --> 03:12Dacarbazine and an immunotherapy
03:12 --> 03:14called high dose interleukin two which
03:14 --> 03:16was very difficult to administer.
03:16 --> 03:18The Dacarbazine might have shrunk the
03:18 --> 03:20tumors temporarily for a few weeks,
03:20 --> 03:22and the high dose interleukin
03:22 --> 03:23two would result
03:23 --> 03:24in actual cure,
03:24 --> 03:27but in a very small percentage of patients,
03:27 --> 03:28perhaps 4 or 5%.
03:28 --> 03:30Newer therapies were then
03:30 --> 03:31developed after that,
03:31 --> 03:33and by 2005 or 2006 we were seeing
03:33 --> 03:35that the median survival was
03:35 --> 03:38actually in the order of one year.
03:38 --> 03:40At present we don't actually even
03:40 --> 03:42know what the median survival is,
03:42 --> 03:45and when a patient comes in
03:45 --> 03:47and asks what the prognosis is,
03:47 --> 03:49I say at least 50% chance that
03:49 --> 03:51we're going to have prolonged
03:51 --> 03:53survival and if prolonged,
03:53 --> 03:54disease free.
03:54 --> 03:58But I can't actually tell people if
03:58 --> 04:01the cancer is ever going to come back.
04:01 --> 04:03We do believe that we are actually
04:03 --> 04:05curing a subset of patients
04:05 --> 04:06who have metastatic Melanoma,
04:06 --> 04:08including people who've had a lot
04:08 --> 04:11of disease and disease
04:11 --> 04:14that's gone to vital organs such as the liver,
04:14 --> 04:14the lungs,
04:14 --> 04:17and the brain.
04:17 --> 04:18When you say prolonged disease free survival,
04:18 --> 04:20I'm assuming that you mean
04:20 --> 04:23more than days or weeks and maybe even
04:23 --> 04:26more than a few years. Is that right?
04:26 --> 04:28Absolutely. So when we started using
04:28 --> 04:30the first of the newer immune therapies,
04:30 --> 04:33a drug called ipilimumab
04:37 --> 04:38we still have patients who were
04:38 --> 04:41treated in those years who have never
04:41 --> 04:42required additional treatment and are
04:42 --> 04:44disease free and living their lives.
04:44 --> 04:47Now I can't say for sure that
04:47 --> 04:49it's never going to be a problem,
04:49 --> 04:51but the chances are that it's not going
04:51 --> 04:54to be a problem over a decade later.
04:54 --> 04:56So yes, we're talking about years.
04:56 --> 04:58We've talked a little
04:58 --> 05:00bit on this show about immune
05:00 --> 05:03therapy for a variety of cancers,
05:03 --> 05:05but it seems that in metastatic
05:05 --> 05:06Melanoma it really seems to
05:06 --> 05:08be incredibly effective,
05:08 --> 05:09especially when you look
05:09 --> 05:11at how far we've come
05:13 --> 05:15in 2001 telling people that
05:15 --> 05:17they had less than a year,
05:17 --> 05:19and to get their affairs in order,
05:19 --> 05:21why is it that immunotherapy seems
05:21 --> 05:24to work so well in Melanoma but may
05:24 --> 05:27not work as well in other cancers?
05:27 --> 05:29That's an excellent question.
05:29 --> 05:32Melanoma by nature tends to have
05:32 --> 05:34more mutations than many other tumors.
05:34 --> 05:37It's for the most part a
05:37 --> 05:38sun exposed malignancy.
05:38 --> 05:42So the sun will cause damage in many,
05:42 --> 05:45many genes and because of the multiple
05:45 --> 05:48mutations there are a lot of immune
05:48 --> 05:50cells that recognize these
05:50 --> 05:53cancer cells as foreign or bad and
05:53 --> 05:55with time they get exhausted and
05:55 --> 05:58these newer drugs will stimulate them.
05:58 --> 06:00But we probably have a larger
06:00 --> 06:02repertoire of immune cells in
06:02 --> 06:04Melanoma than most other cancers,
06:04 --> 06:07and that's why they respond better.
06:07 --> 06:09And I think another interesting point
06:09 --> 06:12to make is that there are
06:12 --> 06:14two other types of skin cancers.
06:14 --> 06:17There's a fairly rare skin cancer
06:17 --> 06:18called Merkel cell carcinoma,
06:18 --> 06:20which also has a fair number of
06:20 --> 06:23mutations and also some related and
06:23 --> 06:25metastatic squamous cell carcinomas and
06:25 --> 06:27also will respond very well to immunotherapy,
06:27 --> 06:30better than many other tumor types
06:30 --> 06:34where we might see response but not for many,
06:34 --> 06:36many years as we see in Melanoma.
06:37 --> 06:39But we do think it's related to
06:39 --> 06:42the tumor mutation burden or the
06:42 --> 06:45number of mutations that these cells have.
06:45 --> 06:48And so as you think about immunotherapy,
06:48 --> 06:50you mentioned that the first
06:50 --> 06:52generation of these was actually
06:52 --> 06:55brought into practice in 2005, 2006.
06:55 --> 06:57Have we developed newer forms
06:57 --> 06:59of immunotherapy since then?
06:59 --> 07:01And what's the prognosis?
07:01 --> 07:03What are some of
07:03 --> 07:05the exciting developments that
07:05 --> 07:07have happened over the more
07:07 --> 07:08recent time?
07:08 --> 07:10So there are many exciting developments,
07:10 --> 07:13the first drug Ipilimumab
07:13 --> 07:15was brought into
07:15 --> 07:18clinical trials in those years.
07:18 --> 07:20But it actually took many
07:20 --> 07:22years to achieve FDA approval.
07:22 --> 07:24It was only FDA approved for
07:24 --> 07:26metastatic Melanoma in 2011,
07:26 --> 07:28so the first Ipilimumab,
07:28 --> 07:30results in nice tumor regression,
07:30 --> 07:32in maybe 10% of
07:32 --> 07:34patient's, but the second generation drug is
07:34 --> 07:37a drug that targets a molecule called PD1,
07:37 --> 07:40which stands for programmed death one.
07:40 --> 07:42There were two that were first
07:42 --> 07:44given to patients with Melanoma.
07:44 --> 07:45Nivolumab and pembrolizumab,
07:45 --> 07:48also known as Opdivo and Keytruda.
07:48 --> 07:48Subsequently,
07:48 --> 07:50many other companies have developed
07:50 --> 07:53drugs that inhibit PD one and
07:53 --> 07:55this one seemed to be the better
07:55 --> 07:56target for the immunotherapy.
07:56 --> 07:59So when we give this to Melanoma patients,
07:59 --> 08:02instead of seeing nice responses in maybe 10
08:02 --> 08:05percent of patients we will see good
08:05 --> 08:08responses in 30 to 40% of patients,
08:08 --> 08:08and interestingly,
08:08 --> 08:10this is less toxic,
08:10 --> 08:12so the second generation was both
08:12 --> 08:14more effective and less toxic
08:14 --> 08:16than the first generation.
08:16 --> 08:19Then the question asked in around 2009,
08:19 --> 08:21when we already had a little
08:21 --> 08:24bit of experience with these PD one
08:24 --> 08:26inhibitors was what would happen
08:26 --> 08:29if we give the two drugs together.
08:29 --> 08:31So these two classes of drugs
08:31 --> 08:32target non redundant pathways
08:32 --> 08:34in the immune cell and
08:34 --> 08:36its interaction with cancer cells.
08:36 --> 08:39So if we inhibited two different
08:39 --> 08:41places in theory we will get enhanced
08:41 --> 08:43activation of our chief immune cell,
08:43 --> 08:45which is called a T cell.
08:45 --> 08:47And indeed this was the case, when we
08:47 --> 08:50give the two together in Melanoma,
08:50 --> 08:52we now see very nice responses
08:52 --> 08:54in excess of 55% of patients.
08:54 --> 08:56So the two together is better
08:56 --> 08:57than either one alone.
08:57 --> 08:59Just to clarify,
08:59 --> 09:01when you say the two together
09:01 --> 09:03you mean Ipilimumab and
09:03 --> 09:05pembrolizumab.
09:05 --> 09:07The studies have used Ipilimumab
09:07 --> 09:09and nivolumab simply because both of
09:09 --> 09:11these drugs were developed by the
09:11 --> 09:13same company. But yes, it's been
09:13 --> 09:15given with pembrolizumab as well,
09:15 --> 09:16but not Ipilimumab and
09:16 --> 09:17pembrolizumab, which both target
09:18 --> 09:19PD 1 correct. There's no point
09:19 --> 09:21in giving two drugs that inhibit
09:21 --> 09:23the same target concurrently,
09:23 --> 09:25so by that point, did we switch all
09:25 --> 09:28of our patients to dual therapy?
09:28 --> 09:29Actually no, because
09:29 --> 09:31remember, some of the patients
09:31 --> 09:32do very well with monotherapy.
09:32 --> 09:3630-40% will do well with the one drug,
09:36 --> 09:37the PD one inhibitor.
09:37 --> 09:40So we're trying very hard to select
09:40 --> 09:42those patients who are more likely
09:42 --> 09:44to respond to one drug and also
09:44 --> 09:46patients who might not be able
09:46 --> 09:48to tolerate extensive toxicity.
09:48 --> 09:50The toxicities are the main problem, it
09:51 --> 09:52depends where the patient lives,
09:52 --> 09:54how socially and economically
09:54 --> 09:55robust they are,
09:55 --> 09:56whether they're associated with
09:56 --> 09:58a health care system that can
09:58 --> 10:00support extensive toxicities,
10:00 --> 10:02but when we have patients who've got
10:02 --> 10:04aggressive disease and particularly young
10:04 --> 10:06patients with no other medical problems,
10:06 --> 10:09we do start off with the two drugs up front.
10:09 --> 10:12There are other people in the
10:12 --> 10:14Melanoma field who might start with
10:14 --> 10:17one and then add the second one if
10:17 --> 10:20the first one alone does not work.
10:20 --> 10:22So a lot of refinement of these
10:22 --> 10:24regimens still needs to be done,
10:24 --> 10:26and there are many studies looking at how
10:26 --> 10:29much to give, when to give, what sequence, etc.
10:29 --> 10:34It takes years to sort all of this out.
10:34 --> 10:37I also want to add that we now have a third
10:37 --> 10:40target that is looking very promising
10:40 --> 10:41in Melanoma,
10:41 --> 10:44there's a target called LAG-3.
10:44 --> 10:46It's an antigen that's expressed
10:46 --> 10:50on these same immune cells or T cells,
10:50 --> 10:53and when you give inhibitors of LAG-3
10:53 --> 10:55together with PD one inhibitors,
10:55 --> 10:58it does appear that it's going to be
10:58 --> 11:00better than PD one inhibitors alone.
11:00 --> 11:03The data are still very new and more
11:03 --> 11:06maturity of the data is going to be required.
11:06 --> 11:07In other words,
11:07 --> 11:09we need to follow patients for much
11:09 --> 11:11longer to make sure that it
11:11 --> 11:13actually holds up.
11:13 --> 11:15Clinical trials for that drug are
11:15 --> 11:15currently ongoing.
11:17 --> 11:19It's already in a phase three
11:19 --> 11:20study which is completed accrual
11:20 --> 11:22and the first data do suggest
11:22 --> 11:24that the two drugs are better
11:24 --> 11:26than the nivolumab alone.
11:26 --> 11:28And has anybody thought
11:28 --> 11:29about adding Ipilimumab?
11:29 --> 11:32Yes, there we again will run into
11:32 --> 11:35problems with side effects and we
11:35 --> 11:37have to be very careful when we
11:37 --> 11:40mix 3 drugs and this takes a
11:40 --> 11:42long time to work all of this out.
11:45 --> 11:48It sounds like with now the three
11:48 --> 11:50kind of tiers of immunotherapy
11:50 --> 11:52that you're talking about,
11:52 --> 11:54upwards of 55, maybe even
11:54 --> 11:57close to 65-75% of patients
11:57 --> 11:58might have prolonged
11:58 --> 12:00disease free survival.
12:00 --> 12:02We don't know yet about the 65-75%.
12:03 --> 12:05That's what we're shooting for,
12:05 --> 12:05and ultimately,
12:05 --> 12:08we're going to shoot for 100%.
12:08 --> 12:11I also want to add that this is
12:11 --> 12:14just one type of immune therapy.
12:14 --> 12:16We call it immune checkpoint inhibitors,
12:16 --> 12:19so the checkpoint refers to a negative
12:19 --> 12:21regulator of the immune cells,
12:21 --> 12:23and that's what these drugs target.
12:23 --> 12:26The various other types of cellular
12:26 --> 12:28manipulations that we can give to
12:28 --> 12:31activate the immune system against cancer,
12:31 --> 12:32but the immune checkpoint
12:32 --> 12:34inhibitors specifically refers
12:34 --> 12:36to molecules on immune cells and
12:36 --> 12:38cancer cells that have crosstalk.
12:38 --> 12:41They talk to each other and the cancer
12:41 --> 12:43cell will suppress an immune cell so
12:43 --> 12:45that it remains alive.
12:45 --> 12:48And so this is just one approach
12:48 --> 12:50to immunotherapy for cancer.
12:51 --> 12:52Well, we certainly want to
12:52 --> 12:54find out more about the other
12:54 --> 12:56approaches to immune therapy.
12:56 --> 12:58We talk a lot on this show about
12:58 --> 13:00immune checkpoint inhibitors,
13:00 --> 13:02but certainly thinking about other ways
13:02 --> 13:05that we can use and manipulate the immune
13:05 --> 13:07system to fight metastatic Melanoma
13:07 --> 13:09will be very exciting to learn about,
13:09 --> 13:12but first we're going to take a
13:12 --> 13:14short break for a medical minute,
13:14 --> 13:16so please stay tuned to learn
13:16 --> 13:18more about Melanoma with my
13:18 --> 13:19guest Doctor Harriet Kluger.
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13:40 --> 13:42The American Cancer Society
13:42 --> 13:44estimates that more than 65,000
13:44 --> 13:46Americans will be diagnosed with
13:46 --> 13:48head and neck cancer this year,
13:48 --> 13:51making up about 4% of all cancers.
13:51 --> 13:53When detected early,
13:53 --> 13:55however, head and neck cancers are
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13:57 --> 13:59Clinical trials are currently
13:59 --> 14:01underway at federally designated
14:01 --> 14:03Comprehensive cancer centers such
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14:18 --> 14:20and Neck Cancer Specialized Program
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14:23 --> 14:25address critical barriers to treatment
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14:28 --> 14:30carcinoma due to resistance to immune
14:30 --> 14:33DNA damage and targeted therapy.
14:33 --> 14:35More information is available at
14:35 --> 14:36yalecancercenter.org. You're listening
14:36 --> 14:38to Connecticut Public Radio.
14:39 --> 14:41Welcome back to Yale Cancer Answers.
14:41 --> 14:43This is doctor Anees Chagpar
14:43 --> 14:45and I'm joined tonight
14:45 --> 14:48by my guest Doctor Harriet Kluger.
14:48 --> 14:50We're talking about Melanoma and T cells
14:50 --> 14:53and Harriet right before the break we
14:53 --> 14:55were talking about these tremendous
14:55 --> 14:57advances that have happened in the
14:57 --> 14:59treatment of metastatic Melanoma.
14:59 --> 15:01For anyone who just joined us,
15:01 --> 15:04Harriet was mentioning that when
15:04 --> 15:06she started treating metastatic
15:06 --> 15:07Melanoma back in 2001,
15:07 --> 15:09prognosis wasn't great. Six months.
15:09 --> 15:1112 months, but we've now had
15:11 --> 15:14a series of immune therapies,
15:14 --> 15:16particularly with checkpoint inhibitors
15:16 --> 15:18that have really improved the disease
15:18 --> 15:20free survival now getting prolonged
15:20 --> 15:23survival in over 50% of patients.
15:23 --> 15:26But Harriet right before the break
15:26 --> 15:28you left us with this little
15:28 --> 15:31teaser that there may be other ways
15:31 --> 15:33to manipulate the immune system
15:33 --> 15:36that are now being investigated.
15:36 --> 15:39That might hold promise in metastatic melanoma.
15:39 --> 15:41Tell us more.
15:41 --> 15:42Thank you and
15:42 --> 15:43yes, absolutely.
15:43 --> 15:46We have a few teasers and that's
15:46 --> 15:48what makes this field so exciting.
15:48 --> 15:50So one of the additional classes of
15:50 --> 15:53therapies that we give is cellular therapies.
15:53 --> 15:55So for Melanoma or solid tumors we
15:55 --> 15:58know that we have these immune cells
15:58 --> 16:01that live within the tumor but
16:01 --> 16:03they keep trying to fight the tumor.
16:03 --> 16:06But at some point they get exhausted
16:06 --> 16:08and they're no longer capable
16:08 --> 16:10of getting rid of tumor cells.
16:10 --> 16:12So many years ago at the National
16:12 --> 16:14Cancer Institute doctor Rosenberg,
16:14 --> 16:16Steve Rosenberg pioneered a treatment
16:16 --> 16:18modality whereby he would resect
16:18 --> 16:20tumor and then break up all the
16:20 --> 16:21different cellular components,
16:22 --> 16:24and take the T cells that
16:24 --> 16:26originated from within the tumor
16:26 --> 16:29and grow them in a Petri dish and
16:29 --> 16:31make billions and billions of cells.
16:31 --> 16:33Then, in the meanwhile,
16:33 --> 16:35he'd bring a patient back and give them
16:35 --> 16:38high doses of chemotherapy to make space,
16:38 --> 16:40if you will, for these
16:40 --> 16:42newest cells that were growing in
16:42 --> 16:43the Petri dish and actually are
16:43 --> 16:45educated to recognize the tumor.
16:45 --> 16:47Then he would infuse those into the
16:47 --> 16:49patient after the chemotherapy and
16:49 --> 16:51after the space was made and then give
16:51 --> 16:53some growth factor called Interleukin
16:53 --> 16:55two and then cells within patients
16:55 --> 16:57would recover and go home and there
16:57 --> 16:59is a subset of patients who were actually
16:59 --> 17:01cured from this therapy as well.
17:01 --> 17:04It's similar to having a bone
17:04 --> 17:06marrow transplant you go in for
17:06 --> 17:08a one time shot for a few weeks
17:08 --> 17:10and then you go home and live your life.
17:11 --> 17:13The initial response rates at the
17:13 --> 17:15National Cancer Institute were in
17:15 --> 17:18the order of 50%, now with the immune
17:18 --> 17:19checkpoint inhibitors we're seeing
17:19 --> 17:21lower response rates simply because
17:21 --> 17:23many of the patients whose tumors
17:23 --> 17:25immune sensitive are actually cured
17:25 --> 17:27by the checkpoints that we discussed
17:27 --> 17:29in the previous session over here,
17:29 --> 17:31but still they work and we have
17:31 --> 17:34patients who are cured now from
17:34 --> 17:35the cellular therapies.
17:35 --> 17:37After they haven't responded to
17:37 --> 17:39the immune checkpoint inhibitors,
17:39 --> 17:40that gives patients
17:40 --> 17:42another option.
17:42 --> 17:44This treatment is now being
17:44 --> 17:46studied in other cancers as well.
17:46 --> 17:48Lung cancer, head neck cancer,
17:48 --> 17:49cervical cancer, and so on,
17:49 --> 17:52and responses are being seen there too.
17:52 --> 17:54In the meanwhile the field
17:54 --> 17:56has moved forward and the cellular
17:56 --> 17:58therapy is no longer only given
17:58 --> 18:00at the National Cancer Institute.
18:00 --> 18:00In fact,
18:00 --> 18:02at Yale we have a lab that
18:02 --> 18:04can manufacture these cells.
18:04 --> 18:07There are also companies that are
18:07 --> 18:08trying to commercialize this
18:08 --> 18:11modality. So you send the tumor
18:11 --> 18:14to the company, they grow the cells for you.
18:14 --> 18:16They send them back and we give
18:16 --> 18:18the treatment in the hospital.
18:18 --> 18:21So that is something that likely
18:21 --> 18:23will also be on the menu of
18:23 --> 18:25options within a year or so
18:25 --> 18:27for metastatic Melanoma and in the
18:27 --> 18:29future, for other tumor types.
18:29 --> 18:31So Harriet just picking up on
18:31 --> 18:34that when we think about
18:34 --> 18:36things like bone marrow
18:36 --> 18:37transplant or other transplants,
18:37 --> 18:39anytime we're thinking about putting
18:39 --> 18:41cells into somebody, we always
18:41 --> 18:42worry about rejection.
18:42 --> 18:45So do I have it correct that, what
18:45 --> 18:47we're actually doing in this cellular
18:47 --> 18:51therapy is taking a patients own tumor?
18:51 --> 18:53Taking finding their own T cells
18:53 --> 18:56and getting those T cells to grow
18:56 --> 18:59and replicate and giving the patient
18:59 --> 19:01back their own T cells so that
19:01 --> 19:03there's less risk of rejection?
19:03 --> 19:04Is that right?
19:04 --> 19:06That's right, there's
19:06 --> 19:08actually no risk of rejection.
19:08 --> 19:10The rejection only happens when
19:10 --> 19:12you give somebody another person's
19:12 --> 19:14immune cells, but in this case
19:14 --> 19:16we're talking about giving a
19:16 --> 19:18patient back their own cells,
19:18 --> 19:20just amplified to the tune
19:20 --> 19:23of billions of cells so that these
19:23 --> 19:25are the special cells that recognize
19:25 --> 19:28the tumor and can then work against
19:28 --> 19:31the tumor.
19:31 --> 19:34And one would think that if some
19:34 --> 19:37people think that your immune system
19:37 --> 19:40is fighting off cancer all the time,
19:40 --> 19:43and that people have
19:43 --> 19:46quote cancer floating around in them,
19:46 --> 19:48and that your immune system kind
19:48 --> 19:50of fights all of these little
19:50 --> 19:53deformed cells off so that you
19:53 --> 19:55don't actually develop a cancer,
19:55 --> 19:57if that was true,
19:57 --> 19:59then why wouldn't this therapy
19:59 --> 20:01work for everybody? Why
20:01 --> 20:03do we need the checkpoint inhibitors?
20:06 --> 20:08I think the problem is that when
20:08 --> 20:10we give the cellular therapy,
20:10 --> 20:13sometimes patients have many different
20:13 --> 20:15tumors in different locations and we already
20:15 --> 20:18know now that melanomas can metastasize.
20:18 --> 20:21So it is correct that they all start from
20:21 --> 20:24the same clone of cells within the skin,
20:24 --> 20:26then they metastasize internally and
20:26 --> 20:29you get subclones and daughter clones
20:29 --> 20:31and granddaughter clones and so on.
20:31 --> 20:33And those next generation
20:33 --> 20:35clones might have different mutations.
20:35 --> 20:38Now if we remove a tumor to generate the
20:38 --> 20:41immune cells from one location,
20:41 --> 20:43these cells might not be active against
20:43 --> 20:46the tumors in a different location,
20:46 --> 20:49so that's one reason that it might not work.
20:49 --> 20:51Other reasons for failure are
20:51 --> 20:54inability to grow the cells in the
20:54 --> 20:56lab so not every cell grows.
20:56 --> 20:58The vast majority do,
20:58 --> 21:01but there's about 10-15% that do not grow,
21:01 --> 21:03and sometimes they just don't
21:03 --> 21:05grow enough to substantial quantities
21:05 --> 21:07and it's just insufficient to overcome
21:07 --> 21:10the tumor cells that are actually there.
21:11 --> 21:14And this whole concept of
21:14 --> 21:16taking cells, sorting them out,
21:16 --> 21:18finding the T cells,
21:18 --> 21:21growing them up in a Petri dish,
21:21 --> 21:24giving them back to the patient,
21:24 --> 21:26it sounds really like a major production,
21:26 --> 21:29and so whenever we think about
21:29 --> 21:31major productions in medicine,
21:31 --> 21:34I always think about how much does that
21:34 --> 21:37cost and does insurance cover it?
21:37 --> 21:39That's an excellent question.
21:39 --> 21:41So at present it's still experimental.
21:41 --> 21:43So the company that's making the
21:43 --> 21:45cells for us in our current clinical
21:45 --> 21:47trial covers the cost of it.
21:47 --> 21:49The National Cancer Institute,
21:49 --> 21:51when they used to do it,
21:51 --> 21:52it was free, but with some it
21:52 --> 21:54was covered by the government,
21:54 --> 21:55essentially the taxpayer.
21:55 --> 21:57But you are right, it is very expensive.
21:57 --> 22:00I think we also need to keep in
22:00 --> 22:02mind that the immune checkpoint
22:02 --> 22:03inhibitors are similarly expensive.
22:03 --> 22:05And those can also cost hundreds of
22:05 --> 22:07thousands of dollars per patient.
22:07 --> 22:09So if you start adding up the
22:09 --> 22:11hundreds of thousands of dollars
22:11 --> 22:13and you compare it to maybe 200,
22:13 --> 22:15$300,000 for a one time
22:15 --> 22:16therapy such as cellular therapy,
22:16 --> 22:18it's not all that different in terms
22:18 --> 22:20of order of magnitude is actually
22:20 --> 22:23might be a little bit less expensive,
22:23 --> 22:23if anything.
22:25 --> 22:27And so getting back to the checkpoint
22:27 --> 22:29inhibitors, those are generally
22:29 --> 22:31covered by insurance now aren't they?
22:31 --> 22:33They are yes, correct.
22:33 --> 22:34Other than the experimental
22:34 --> 22:36ones, the ones that are
22:36 --> 22:39approved are covered.
22:39 --> 22:42So it sounds to me like
22:42 --> 22:44when you have a patient
22:44 --> 22:45with metastatic Melanoma,
22:45 --> 22:48your first line of therapy is the
22:48 --> 22:49immune checkpoint inhibitors.
22:49 --> 22:51If they fail, that cellular
22:51 --> 22:52therapy is another option.
22:52 --> 22:54What if they fail that?
22:55 --> 22:58So if they fail that or sometimes by choice,
22:58 --> 23:00we actually have additional
23:00 --> 23:01experimental options for patients.
23:01 --> 23:04So I had talked about the T
23:04 --> 23:07cells that recognize the tumor.
23:07 --> 23:09Those are called adaptive immune cells.
23:09 --> 23:10In other words,
23:10 --> 23:12they've adapted to the cancer.
23:12 --> 23:14They have special specific
23:14 --> 23:16qualities that recognize that we
23:16 --> 23:18also have innate immune cells.
23:18 --> 23:20Those are generalized cells that are
23:20 --> 23:22floating around in our bodies that have
23:22 --> 23:25not developed receptors that recognize
23:25 --> 23:27specific abnormalities in cancer cells.
23:27 --> 23:29Now those innate immune cells are
23:29 --> 23:32another whole army of cells that we can
23:32 --> 23:35activate in order to target the cancer,
23:35 --> 23:37and sometimes we can co-activate
23:37 --> 23:39the innate immune cells
23:39 --> 23:40and the adaptive cells,
23:40 --> 23:43so we can combine additional drugs to
23:43 --> 23:44these immune checkpoint inhibitors.
23:44 --> 23:47There are many approaches that are
23:47 --> 23:49being taken across the country.
23:49 --> 23:51One of the approaches that we're
23:51 --> 23:54doing over here is to activate a
23:54 --> 23:56group of cells called dendritic cells,
23:56 --> 23:58that actually present the
23:58 --> 24:01tumor antigen to the T cells
24:01 --> 24:04as foreign and then make them
24:04 --> 24:06become educated or adapted.
24:06 --> 24:09So if we give those two together,
24:09 --> 24:11we might have better responses than
24:11 --> 24:13using the checkpoint inhibitors alone,
24:13 --> 24:15so that's one example of an approach.
24:15 --> 24:17There are groups that are targeting a
24:17 --> 24:20subset of cells called macrophages,
24:20 --> 24:23which are also innate immune cells.
24:23 --> 24:25Then we need to think about
24:25 --> 24:27what these cells do,
24:27 --> 24:31so they secrete substances called cytokines.
24:31 --> 24:34Interleukin two, that early drug that I
24:34 --> 24:37had mentioned that was approved already
24:37 --> 24:40in the 1990s is a type of a cytokine.
24:40 --> 24:42Many companies are now developing
24:42 --> 24:42novel cytokines,
24:42 --> 24:45so either better versions of interleukin
24:45 --> 24:47two that bind to the interleukin two
24:47 --> 24:49receptors that are more important,
24:49 --> 24:52or that bind with a
24:52 --> 24:54stronger affinity to the receptors.
24:54 --> 24:56And then there are other interleukins,
24:56 --> 24:59interleukins that are made by
24:59 --> 25:01our cells. So you could have
25:01 --> 25:03Interleukin 12, interleukin 18,
25:03 --> 25:04interleukin 15,
25:04 --> 25:06all of these are being looked
25:06 --> 25:07at as drug targets,
25:07 --> 25:10and in fact there's a researcher at
25:10 --> 25:12Yale who has developed a
25:12 --> 25:15drug that is a mimic of interleukin
25:15 --> 25:1718 that doesn't get sucked up
25:17 --> 25:19by decoy proteins in the body,
25:19 --> 25:22so should be more potent and we
25:22 --> 25:24will be excited to study that in
25:24 --> 25:27the next month or two in the clinic.
25:27 --> 25:29There's a trial that's opening
25:29 --> 25:32up and we will be administering
25:32 --> 25:34that drug to patients who have not
25:34 --> 25:36responded to the immune checkpoint
25:36 --> 25:37inhibitors both with Melanoma
25:37 --> 25:39and other diseases.
25:39 --> 25:42So Harriet just to unpack a couple
25:42 --> 25:45of the concepts that you mentioned.
25:45 --> 25:47It sounds to me like
25:47 --> 25:49the activation of both the innate
25:49 --> 25:51and the adaptive immune system
25:51 --> 25:53just makes intuitive sense.
25:53 --> 25:55If you have more
25:55 --> 25:56adaptive immune cells and
25:56 --> 25:59you pair that with more cells
25:59 --> 26:01that are presenting to them the
26:01 --> 26:03antigens they need to go after,
26:03 --> 26:05it seems like that would
26:05 --> 26:07be a better approach.
26:07 --> 26:10So is that something that is routinely
26:10 --> 26:11being done or is the cellular
26:11 --> 26:13therapies that we were talking
26:13 --> 26:15about earlier really going after
26:15 --> 26:17more of those adaptive cells?
26:17 --> 26:20And wouldn't it be better if they
26:20 --> 26:22could also grow up in a Petri dish
26:22 --> 26:25of patients innate T cells as well?
26:27 --> 26:29Well, we can grow it up in a
26:29 --> 26:31Petri dish or in the body,
26:31 --> 26:32so the whole concept behind
26:32 --> 26:34giving cytokines is to grow them
26:34 --> 26:35actually in the human.
26:35 --> 26:37So we give more of the cytokines
26:37 --> 26:39and we grow up both innate
26:39 --> 26:40and the adaptive cells.
26:40 --> 26:41So these are like growth
26:41 --> 26:42factors for these cells.
26:42 --> 26:43They should make
26:43 --> 26:44them propagate.
26:44 --> 26:46So that was going to be my
26:46 --> 26:48next question is you talk
26:48 --> 26:49about all of these cytokines?
26:49 --> 26:51These interleukins with various numbers?
26:51 --> 26:54How exactly do they work?
26:54 --> 26:57It's sounds now like they just
26:57 --> 27:00stimulate the innate immune system.
27:00 --> 27:01Is that right?
27:01 --> 27:04Both innate and adaptive actually?
27:04 --> 27:05So they stimulate both.
27:05 --> 27:07So all of those different
27:07 --> 27:09numbers reflect molecules that
27:09 --> 27:11have different activities.
27:11 --> 27:15So some of them will stimulate innate cells
27:15 --> 27:17and some stimulate the adaptive cells,
27:17 --> 27:19some stimulates suppressor cells.
27:19 --> 27:21The biology is getting
27:21 --> 27:23more and more complicated.
27:23 --> 27:24Well, it's always been complicated.
27:24 --> 27:25We're just learning now
27:25 --> 27:27how complicated it is,
27:27 --> 27:28and every time we look,
27:28 --> 27:30we discover that we knew nothing.
27:31 --> 27:33And so it sounds like we're
27:33 --> 27:35almost coming full circle,
27:35 --> 27:37though, because interleukin two
27:37 --> 27:39was something that you had talked
27:39 --> 27:41about at the very outset, which
27:41 --> 27:44really wasn't terribly effective back then.
27:44 --> 27:47Why would we think that now
27:47 --> 27:49these other interleukins will
27:49 --> 27:51be more effective?
27:51 --> 27:55Now we have
27:55 --> 27:57other bullets to administer with it.
27:57 --> 28:00And we understand better how to engineer
28:00 --> 28:03them so that they can be more effective.
28:05 --> 28:07So the idea is that you would use
28:07 --> 28:08these interleukins along with cellular
28:08 --> 28:10therapy and or checkpoint inhibitors.
28:10 --> 28:13Yes, or if they're so good we might
28:13 --> 28:15be able to use them alone.
28:15 --> 28:17Time will tell when you have a new
28:17 --> 28:19drug you start studying it by itself,
28:19 --> 28:21mainly because you want to
28:21 --> 28:23look at whether it's toxic,
28:23 --> 28:25but you also look a little bit at
28:25 --> 28:27the activity so some of them might
28:27 --> 28:29end up being active on their own.
28:29 --> 28:30We will see.
28:31 --> 28:33Doctor Harriet Kluger is a professor
28:33 --> 28:35of medicine and medical oncology
28:35 --> 28:37at the Yale School of Medicine.
28:37 --> 28:39If you have questions the addresses
28:39 --> 28:41cancer answers at yale.edu and
28:41 --> 28:43past editions of the program are
28:43 --> 28:45available in audio and written
28:45 --> 28:47form at yalecancercenter.org.
28:47 --> 28:49We hope you'll join us next week to
28:49 --> 28:51learn more about the fight against
28:51 --> 28:53cancer here on Connecticut Public
28:53 --> 28:55radio funding for Yale Cancer
28:55 --> 28:57Answers is provided by Smilow
28:57 --> 29:00Cancer Hospital and AstraZeneca.

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August 1, 2021

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