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The Immune System and Melanoma

August 02, 2021
  • 00:00Funding for Yale Cancer Answers
  • 00:02is provided by Smilow Cancer
  • 00:04Hospital and AstraZeneca.
  • 00:08Welcome to Yale Cancer Answers
  • 00:11with your host Dr. Anees Chagpar.
  • 00:13Yale Cancer Answers features the latest
  • 00:14information on cancer care by
  • 00:16welcoming oncologists and specialists
  • 00:18who are on the forefront of the
  • 00:20battle to fight cancer. This week,
  • 00:22it's a conversation about Melanoma
  • 00:24with Doctor Harriet Kluger.
  • 00:25Doctor Kluger is a professor of
  • 00:27medicine and medical oncology
  • 00:29at the Yale School of Medicine
  • 00:31where Doctor Chagpar is a
  • 00:33professor of surgical oncology.
  • 00:37I thought that we would dive
  • 00:40right into the treatment of Melanoma.
  • 00:43We've talked a lot on this show
  • 00:46about Melanoma being one of the
  • 00:49most deadly skin cancers.
  • 00:51Can you talk a
  • 00:53little bit about how we have
  • 00:56traditionally treated Melanoma
  • 00:58and where things might be going?
  • 01:01Sure, when we
  • 01:03think about oncologic treatments,
  • 01:05there are three major categories.
  • 01:08You can take a cancer out with surgery,
  • 01:11you can do radiation, or you can
  • 01:14give what we call systemic therapy,
  • 01:17which is therapy that's given by mouth.
  • 01:20But I feel the vast majority of melanomas
  • 01:23are actually discovered really early on
  • 01:26when people see a changing mole
  • 01:28or a dermatologist might find
  • 01:30one on a routine skin exam.
  • 01:32Most of the melanomas are then excised,
  • 01:35in other words, taken out and
  • 01:37nothing further needs to be done,
  • 01:39and patients are simply observed.
  • 01:42Every so often patients come in
  • 01:44without ever knowing that they
  • 01:45had a Melanoma in the skin.
  • 01:47So it's a Melanoma that has
  • 01:49spread beyond the primary site.
  • 01:51Or they might have had a primary
  • 01:53Melanoma that was removed years ago,
  • 01:55but a few cells escaped and are
  • 01:58now developing into tumors in
  • 01:59other locations in the body.
  • 02:01What I do in my clinic is treat with
  • 02:04systemic therapy so things that are
  • 02:06administered by mouth or by IV
  • 02:08so they go all over the body and
  • 02:10that's what we're going to talk about
  • 02:13primarily today.
  • 02:14One of the questions that a lot of
  • 02:17patients have is when they have
  • 02:18that phenomenon of metastatic Melanoma,
  • 02:20so the Melanoma has escaped.
  • 02:22It's gone to other parts of the body
  • 02:25where surgery really can't remove the
  • 02:27Melanoma itself and where
  • 02:29you're treating with systemic therapy
  • 02:31people wonder about the prognosis
  • 02:33and whether in fact they can
  • 02:36never be quote cancer free.
  • 02:37Can you talk a little bit
  • 02:40about that?
  • 02:41When I started treating patients
  • 02:43with metastatic Melanoma in 2001,
  • 02:45if somebody had cancer
  • 02:47that had spread beyond the skin
  • 02:49and into the internal organs,
  • 02:51we would have a frank conversation
  • 02:53with the patient and say we're really sorry,
  • 02:57this is an incurable disease,
  • 02:58and on average people live
  • 03:00between 6 and 12 months.
  • 03:01You should start getting your
  • 03:04affairs in order and we will do
  • 03:06what we can and hope for the best.
  • 03:08At the time we had a chemotherapy called
  • 03:10Dacarbazine and an immunotherapy
  • 03:12called high dose interleukin two which
  • 03:15was very difficult to administer.
  • 03:16The Dacarbazine might have shrunk the
  • 03:18tumors temporarily for a few weeks,
  • 03:20and the high dose interleukin
  • 03:22two would result
  • 03:23in actual cure,
  • 03:24but in a very small percentage of patients,
  • 03:27perhaps 4 or 5%.
  • 03:29Newer therapies were then
  • 03:30developed after that,
  • 03:31and by 2005 or 2006 we were seeing
  • 03:34that the median survival was
  • 03:36actually in the order of one year.
  • 03:39At present we don't actually even
  • 03:41know what the median survival is,
  • 03:43and when a patient comes in
  • 03:45and asks what the prognosis is,
  • 03:47I say at least 50% chance that
  • 03:50we're going to have prolonged
  • 03:52survival and if prolonged,
  • 03:53disease free.
  • 03:55But I can't actually tell people if
  • 03:58the cancer is ever going to come back.
  • 04:02We do believe that we are actually
  • 04:03curing a subset of patients
  • 04:05who have metastatic Melanoma,
  • 04:07including people who've had a lot
  • 04:09of disease and disease
  • 04:11that's gone to vital organs such as the liver,
  • 04:14the lungs,
  • 04:15and the brain.
  • 04:17When you say prolonged disease free survival,
  • 04:19I'm assuming that you mean
  • 04:21more than days or weeks and maybe even
  • 04:24more than a few years. Is that right?
  • 04:27Absolutely. So when we started using
  • 04:28the first of the newer immune therapies,
  • 04:31a drug called ipilimumab
  • 04:37we still have patients who were
  • 04:39treated in those years who have never
  • 04:41required additional treatment and are
  • 04:43disease free and living their lives.
  • 04:45Now I can't say for sure that
  • 04:47it's never going to be a problem,
  • 04:49but the chances are that it's not going
  • 04:52to be a problem over a decade later.
  • 04:54So yes, we're talking about years.
  • 04:57We've talked a little
  • 04:59bit on this show about immune
  • 05:01therapy for a variety of cancers,
  • 05:03but it seems that in metastatic
  • 05:05Melanoma it really seems to
  • 05:07be incredibly effective,
  • 05:08especially when you look
  • 05:10at how far we've come
  • 05:14in 2001 telling people that
  • 05:15they had less than a year,
  • 05:17and to get their affairs in order,
  • 05:20why is it that immunotherapy seems
  • 05:22to work so well in Melanoma but may
  • 05:25not work as well in other cancers?
  • 05:28That's an excellent question.
  • 05:30Melanoma by nature tends to have
  • 05:32more mutations than many other tumors.
  • 05:35It's for the most part a
  • 05:37sun exposed malignancy.
  • 05:39So the sun will cause damage in many,
  • 05:43many genes and because of the multiple
  • 05:46mutations there are a lot of immune
  • 05:49cells that recognize these
  • 05:51cancer cells as foreign or bad and
  • 05:53with time they get exhausted and
  • 05:56these newer drugs will stimulate them.
  • 05:59But we probably have a larger
  • 06:01repertoire of immune cells in
  • 06:03Melanoma than most other cancers,
  • 06:05and that's why they respond better.
  • 06:07And I think another interesting point
  • 06:10to make is that there are
  • 06:13two other types of skin cancers.
  • 06:15There's a fairly rare skin cancer
  • 06:17called Merkel cell carcinoma,
  • 06:19which also has a fair number of
  • 06:21mutations and also some related and
  • 06:23metastatic squamous cell carcinomas and
  • 06:25also will respond very well to immunotherapy,
  • 06:28better than many other tumor types
  • 06:30where we might see response but not for many,
  • 06:34many years as we see in Melanoma.
  • 06:37But we do think it's related to
  • 06:40the tumor mutation burden or the
  • 06:42number of mutations that these cells have.
  • 06:45And so as you think about immunotherapy,
  • 06:48you mentioned that the first
  • 06:51generation of these was actually
  • 06:53brought into practice in 2005, 2006.
  • 06:55Have we developed newer forms
  • 06:58of immunotherapy since then?
  • 06:59And what's the prognosis?
  • 07:01What are some of
  • 07:04the exciting developments that
  • 07:05have happened over the more
  • 07:07recent time?
  • 07:09So there are many exciting developments,
  • 07:11the first drug Ipilimumab
  • 07:13was brought into
  • 07:16clinical trials in those years.
  • 07:18But it actually took many
  • 07:20years to achieve FDA approval.
  • 07:22It was only FDA approved for
  • 07:25metastatic Melanoma in 2011,
  • 07:26so the first Ipilimumab,
  • 07:28results in nice tumor regression,
  • 07:30in maybe 10% of
  • 07:33patient's, but the second generation drug is
  • 07:35a drug that targets a molecule called PD1,
  • 07:38which stands for programmed death one.
  • 07:40There were two that were first
  • 07:42given to patients with Melanoma.
  • 07:45Nivolumab and pembrolizumab,
  • 07:46also known as Opdivo and Keytruda.
  • 07:48Subsequently,
  • 07:49many other companies have developed
  • 07:51drugs that inhibit PD one and
  • 07:53this one seemed to be the better
  • 07:55target for the immunotherapy.
  • 07:57So when we give this to Melanoma patients,
  • 08:00instead of seeing nice responses in maybe 10
  • 08:03percent of patients we will see good
  • 08:05responses in 30 to 40% of patients,
  • 08:08and interestingly,
  • 08:09this is less toxic,
  • 08:10so the second generation was both
  • 08:13more effective and less toxic
  • 08:15than the first generation.
  • 08:17Then the question asked in around 2009,
  • 08:19when we already had a little
  • 08:22bit of experience with these PD one
  • 08:24inhibitors was what would happen
  • 08:26if we give the two drugs together.
  • 08:29So these two classes of drugs
  • 08:32target non redundant pathways
  • 08:33in the immune cell and
  • 08:35its interaction with cancer cells.
  • 08:37So if we inhibited two different
  • 08:39places in theory we will get enhanced
  • 08:41activation of our chief immune cell,
  • 08:44which is called a T cell.
  • 08:45And indeed this was the case, when we
  • 08:48give the two together in Melanoma,
  • 08:50we now see very nice responses
  • 08:52in excess of 55% of patients.
  • 08:55So the two together is better
  • 08:57than either one alone.
  • 08:58Just to clarify,
  • 09:00when you say the two together
  • 09:02you mean Ipilimumab and
  • 09:04pembrolizumab.
  • 09:06The studies have used Ipilimumab
  • 09:08and nivolumab simply because both of
  • 09:10these drugs were developed by the
  • 09:12same company. But yes, it's been
  • 09:14given with pembrolizumab as well,
  • 09:15but not Ipilimumab and
  • 09:17pembrolizumab, which both target
  • 09:18PD 1 correct. There's no point
  • 09:20in giving two drugs that inhibit
  • 09:22the same target concurrently,
  • 09:23so by that point, did we switch all
  • 09:26of our patients to dual therapy?
  • 09:28Actually no, because
  • 09:29remember, some of the patients
  • 09:31do very well with monotherapy.
  • 09:3330-40% will do well with the one drug,
  • 09:36the PD one inhibitor.
  • 09:38So we're trying very hard to select
  • 09:40those patients who are more likely
  • 09:42to respond to one drug and also
  • 09:45patients who might not be able
  • 09:47to tolerate extensive toxicity.
  • 09:49The toxicities are the main problem, it
  • 09:51depends where the patient lives,
  • 09:53how socially and economically
  • 09:54robust they are,
  • 09:55whether they're associated with
  • 09:57a health care system that can
  • 09:59support extensive toxicities,
  • 10:00but when we have patients who've got
  • 10:02aggressive disease and particularly young
  • 10:04patients with no other medical problems,
  • 10:06we do start off with the two drugs up front.
  • 10:10There are other people in the
  • 10:12Melanoma field who might start with
  • 10:15one and then add the second one if
  • 10:18the first one alone does not work.
  • 10:20So a lot of refinement of these
  • 10:22regimens still needs to be done,
  • 10:24and there are many studies looking at how
  • 10:27much to give, when to give, what sequence, etc.
  • 10:30It takes years to sort all of this out.
  • 10:34I also want to add that we now have a third
  • 10:38target that is looking very promising
  • 10:41in Melanoma,
  • 10:42there's a target called LAG-3.
  • 10:44It's an antigen that's expressed
  • 10:47on these same immune cells or T cells,
  • 10:50and when you give inhibitors of LAG-3
  • 10:53together with PD one inhibitors,
  • 10:56it does appear that it's going to be
  • 10:58better than PD one inhibitors alone.
  • 11:01The data are still very new and more
  • 11:03maturity of the data is going to be required.
  • 11:06In other words,
  • 11:07we need to follow patients for much
  • 11:09longer to make sure that it
  • 11:11actually holds up.
  • 11:13Clinical trials for that drug are
  • 11:15currently ongoing.
  • 11:17It's already in a phase three
  • 11:19study which is completed accrual
  • 11:21and the first data do suggest
  • 11:23that the two drugs are better
  • 11:25than the nivolumab alone.
  • 11:27And has anybody thought
  • 11:28about adding Ipilimumab?
  • 11:30Yes, there we again will run into
  • 11:33problems with side effects and we
  • 11:35have to be very careful when we
  • 11:38mix 3 drugs and this takes a
  • 11:41long time to work all of this out.
  • 11:45It sounds like with now the three
  • 11:48kind of tiers of immunotherapy
  • 11:51that you're talking about,
  • 11:53upwards of 55, maybe even
  • 11:55close to 65-75% of patients
  • 11:57might have prolonged
  • 11:59disease free survival.
  • 12:01We don't know yet about the 65-75%.
  • 12:04That's what we're shooting for,
  • 12:05and ultimately,
  • 12:06we're going to shoot for 100%.
  • 12:08I also want to add that this is
  • 12:11just one type of immune therapy.
  • 12:14We call it immune checkpoint inhibitors,
  • 12:17so the checkpoint refers to a negative
  • 12:19regulator of the immune cells,
  • 12:21and that's what these drugs target.
  • 12:24The various other types of cellular
  • 12:27manipulations that we can give to
  • 12:29activate the immune system against cancer,
  • 12:31but the immune checkpoint
  • 12:33inhibitors specifically refers
  • 12:34to molecules on immune cells and
  • 12:37cancer cells that have crosstalk.
  • 12:39They talk to each other and the cancer
  • 12:41cell will suppress an immune cell so
  • 12:43that it remains alive.
  • 12:46And so this is just one approach
  • 12:49to immunotherapy for cancer.
  • 12:51Well, we certainly want to
  • 12:53find out more about the other
  • 12:55approaches to immune therapy.
  • 12:56We talk a lot on this show about
  • 12:59immune checkpoint inhibitors,
  • 13:00but certainly thinking about other ways
  • 13:02that we can use and manipulate the immune
  • 13:05system to fight metastatic Melanoma
  • 13:07will be very exciting to learn about,
  • 13:10but first we're going to take a
  • 13:12short break for a medical minute,
  • 13:14so please stay tuned to learn
  • 13:16more about Melanoma with my
  • 13:18guest Doctor Harriet Kluger.
  • 13:20Funding for Yale Cancer Answers
  • 13:23comes from Smilow Cancer Hospital.
  • 13:2515 care centers offer access to
  • 13:27oncologists committed to providing
  • 13:29patients with cancer and blood diseases
  • 13:31individualized, innovative care.
  • 13:33Find a Smilow Care Center near
  • 13:36you at YaleCancerCenter.org.
  • 13:40The American Cancer Society
  • 13:42estimates that more than 65,000
  • 13:45Americans will be diagnosed with
  • 13:47head and neck cancer this year,
  • 13:49making up about 4% of all cancers.
  • 13:52When detected early,
  • 13:53however, head and neck cancers are
  • 13:56easily treated and highly curable.
  • 13:58Clinical trials are currently
  • 14:00underway at federally designated
  • 14:02Comprehensive cancer centers such
  • 14:04as Yale Cancer Center and at Smilow
  • 14:06Cancer Hospital to test innovative new
  • 14:08treatments for head and neck cancers.
  • 14:11Yale Cancer Center was recently awarded
  • 14:13grants from the National Institutes
  • 14:16of Health to fund the Yale Head
  • 14:18and Neck Cancer Specialized Program
  • 14:21of Research Excellence or SPORE to
  • 14:24address critical barriers to treatment
  • 14:26of head and neck squamous cell
  • 14:28carcinoma due to resistance to immune
  • 14:31DNA damage and targeted therapy.
  • 14:33More information is available at
  • 14:35yalecancercenter.org. You're listening
  • 14:37to Connecticut Public Radio.
  • 14:39Welcome back to Yale Cancer Answers.
  • 14:42This is doctor Anees Chagpar
  • 14:43and I'm joined tonight
  • 14:46by my guest Doctor Harriet Kluger.
  • 14:48We're talking about Melanoma and T cells
  • 14:51and Harriet right before the break we
  • 14:53were talking about these tremendous
  • 14:55advances that have happened in the
  • 14:58treatment of metastatic Melanoma.
  • 15:00For anyone who just joined us,
  • 15:02Harriet was mentioning that when
  • 15:04she started treating metastatic
  • 15:06Melanoma back in 2001,
  • 15:08prognosis wasn't great. Six months.
  • 15:1012 months, but we've now had
  • 15:12a series of immune therapies,
  • 15:14particularly with checkpoint inhibitors
  • 15:16that have really improved the disease
  • 15:19free survival now getting prolonged
  • 15:21survival in over 50% of patients.
  • 15:24But Harriet right before the break
  • 15:26you left us with this little
  • 15:29teaser that there may be other ways
  • 15:32to manipulate the immune system
  • 15:34that are now being investigated.
  • 15:36That might hold promise in metastatic melanoma.
  • 15:39Tell us more.
  • 15:41Thank you and
  • 15:43yes, absolutely.
  • 15:44We have a few teasers and that's
  • 15:46what makes this field so exciting.
  • 15:48So one of the additional classes of
  • 15:51therapies that we give is cellular therapies.
  • 15:53So for Melanoma or solid tumors we
  • 15:56know that we have these immune cells
  • 15:58that live within the tumor but
  • 16:01they keep trying to fight the tumor.
  • 16:04But at some point they get exhausted
  • 16:06and they're no longer capable
  • 16:08of getting rid of tumor cells.
  • 16:11So many years ago at the National
  • 16:13Cancer Institute doctor Rosenberg,
  • 16:14Steve Rosenberg pioneered a treatment
  • 16:16modality whereby he would resect
  • 16:18tumor and then break up all the
  • 16:20different cellular components,
  • 16:22and take the T cells that
  • 16:25originated from within the tumor
  • 16:26and grow them in a Petri dish and
  • 16:29make billions and billions of cells.
  • 16:32Then, in the meanwhile,
  • 16:33he'd bring a patient back and give them
  • 16:36high doses of chemotherapy to make space,
  • 16:38if you will, for these
  • 16:40newest cells that were growing in
  • 16:42the Petri dish and actually are
  • 16:44educated to recognize the tumor.
  • 16:46Then he would infuse those into the
  • 16:48patient after the chemotherapy and
  • 16:49after the space was made and then give
  • 16:52some growth factor called Interleukin
  • 16:53two and then cells within patients
  • 16:55would recover and go home and there
  • 16:57is a subset of patients who were actually
  • 17:00cured from this therapy as well.
  • 17:02It's similar to having a bone
  • 17:04marrow transplant you go in for
  • 17:06a one time shot for a few weeks
  • 17:08and then you go home and live your life.
  • 17:11The initial response rates at the
  • 17:14National Cancer Institute were in
  • 17:15the order of 50%, now with the immune
  • 17:18checkpoint inhibitors we're seeing
  • 17:20lower response rates simply because
  • 17:21many of the patients whose tumors
  • 17:23immune sensitive are actually cured
  • 17:25by the checkpoints that we discussed
  • 17:27in the previous session over here,
  • 17:30but still they work and we have
  • 17:32patients who are cured now from
  • 17:34the cellular therapies.
  • 17:36After they haven't responded to
  • 17:38the immune checkpoint inhibitors,
  • 17:39that gives patients
  • 17:41another option.
  • 17:43This treatment is now being
  • 17:44studied in other cancers as well.
  • 17:46Lung cancer, head neck cancer,
  • 17:48cervical cancer, and so on,
  • 17:50and responses are being seen there too.
  • 17:52In the meanwhile the field
  • 17:54has moved forward and the cellular
  • 17:56therapy is no longer only given
  • 17:58at the National Cancer Institute.
  • 18:00In fact,
  • 18:01at Yale we have a lab that
  • 18:03can manufacture these cells.
  • 18:05There are also companies that are
  • 18:07trying to commercialize this
  • 18:09modality. So you send the tumor
  • 18:11to the company, they grow the cells for you.
  • 18:14They send them back and we give
  • 18:17the treatment in the hospital.
  • 18:19So that is something that likely
  • 18:21will also be on the menu of
  • 18:24options within a year or so
  • 18:26for metastatic Melanoma and in the
  • 18:28future, for other tumor types.
  • 18:30So Harriet just picking up on
  • 18:32that when we think about
  • 18:34things like bone marrow
  • 18:36transplant or other transplants,
  • 18:38anytime we're thinking about putting
  • 18:39cells into somebody, we always
  • 18:41worry about rejection.
  • 18:43So do I have it correct that, what
  • 18:45we're actually doing in this cellular
  • 18:48therapy is taking a patients own tumor?
  • 18:51Taking finding their own T cells
  • 18:53and getting those T cells to grow
  • 18:56and replicate and giving the patient
  • 18:59back their own T cells so that
  • 19:02there's less risk of rejection?
  • 19:04Is that right?
  • 19:05That's right, there's
  • 19:06actually no risk of rejection.
  • 19:08The rejection only happens when
  • 19:10you give somebody another person's
  • 19:12immune cells, but in this case
  • 19:14we're talking about giving a
  • 19:16patient back their own cells,
  • 19:18just amplified to the tune
  • 19:21of billions of cells so that these
  • 19:23are the special cells that recognize
  • 19:26the tumor and can then work against
  • 19:28the tumor.
  • 19:31And one would think that if some
  • 19:35people think that your immune system
  • 19:37is fighting off cancer all the time,
  • 19:41and that people have
  • 19:43quote cancer floating around in them,
  • 19:46and that your immune system kind
  • 19:48of fights all of these little
  • 19:51deformed cells off so that you
  • 19:53don't actually develop a cancer,
  • 19:56if that was true,
  • 19:57then why wouldn't this therapy
  • 19:59work for everybody? Why
  • 20:02do we need the checkpoint inhibitors?
  • 20:06I think the problem is that when
  • 20:09we give the cellular therapy,
  • 20:11sometimes patients have many different
  • 20:13tumors in different locations and we already
  • 20:16know now that melanomas can metastasize.
  • 20:18So it is correct that they all start from
  • 20:21the same clone of cells within the skin,
  • 20:25then they metastasize internally and
  • 20:27you get subclones and daughter clones
  • 20:29and granddaughter clones and so on.
  • 20:31And those next generation
  • 20:33clones might have different mutations.
  • 20:35Now if we remove a tumor to generate the
  • 20:38immune cells from one location,
  • 20:41these cells might not be active against
  • 20:44the tumors in a different location,
  • 20:46so that's one reason that it might not work.
  • 20:50Other reasons for failure are
  • 20:52inability to grow the cells in the
  • 20:55lab so not every cell grows.
  • 20:57The vast majority do,
  • 20:58but there's about 10-15% that do not grow,
  • 21:01and sometimes they just don't
  • 21:03grow enough to substantial quantities
  • 21:05and it's just insufficient to overcome
  • 21:08the tumor cells that are actually there.
  • 21:11And this whole concept of
  • 21:14taking cells, sorting them out,
  • 21:17finding the T cells,
  • 21:19growing them up in a Petri dish,
  • 21:22giving them back to the patient,
  • 21:24it sounds really like a major production,
  • 21:27and so whenever we think about
  • 21:29major productions in medicine,
  • 21:31I always think about how much does that
  • 21:34cost and does insurance cover it?
  • 21:37That's an excellent question.
  • 21:39So at present it's still experimental.
  • 21:42So the company that's making the
  • 21:43cells for us in our current clinical
  • 21:46trial covers the cost of it.
  • 21:48The National Cancer Institute,
  • 21:49when they used to do it,
  • 21:51it was free, but with some it
  • 21:53was covered by the government,
  • 21:55essentially the taxpayer.
  • 21:56But you are right, it is very expensive.
  • 21:58I think we also need to keep in
  • 22:00mind that the immune checkpoint
  • 22:02inhibitors are similarly expensive.
  • 22:04And those can also cost hundreds of
  • 22:06thousands of dollars per patient.
  • 22:08So if you start adding up the
  • 22:10hundreds of thousands of dollars
  • 22:11and you compare it to maybe 200,
  • 22:14$300,000 for a one time
  • 22:15therapy such as cellular therapy,
  • 22:17it's not all that different in terms
  • 22:19of order of magnitude is actually
  • 22:21might be a little bit less expensive,
  • 22:23if anything.
  • 22:25And so getting back to the checkpoint
  • 22:28inhibitors, those are generally
  • 22:29covered by insurance now aren't they?
  • 22:31They are yes, correct.
  • 22:33Other than the experimental
  • 22:35ones, the ones that are
  • 22:37approved are covered.
  • 22:39So it sounds to me like
  • 22:42when you have a patient
  • 22:44with metastatic Melanoma,
  • 22:46your first line of therapy is the
  • 22:48immune checkpoint inhibitors.
  • 22:49If they fail, that cellular
  • 22:51therapy is another option.
  • 22:53What if they fail that?
  • 22:56So if they fail that or sometimes by choice,
  • 22:59we actually have additional
  • 23:00experimental options for patients.
  • 23:02So I had talked about the T
  • 23:05cells that recognize the tumor.
  • 23:07Those are called adaptive immune cells.
  • 23:09In other words,
  • 23:11they've adapted to the cancer.
  • 23:13They have special specific
  • 23:14qualities that recognize that we
  • 23:16also have innate immune cells.
  • 23:18Those are generalized cells that are
  • 23:20floating around in our bodies that have
  • 23:23not developed receptors that recognize
  • 23:25specific abnormalities in cancer cells.
  • 23:27Now those innate immune cells are
  • 23:29another whole army of cells that we can
  • 23:33activate in order to target the cancer,
  • 23:35and sometimes we can co-activate
  • 23:38the innate immune cells
  • 23:39and the adaptive cells,
  • 23:41so we can combine additional drugs to
  • 23:43these immune checkpoint inhibitors.
  • 23:45There are many approaches that are
  • 23:47being taken across the country.
  • 23:49One of the approaches that we're
  • 23:51doing over here is to activate a
  • 23:54group of cells called dendritic cells,
  • 23:57that actually present the
  • 23:59tumor antigen to the T cells
  • 24:02as foreign and then make them
  • 24:05become educated or adapted.
  • 24:07So if we give those two together,
  • 24:09we might have better responses than
  • 24:11using the checkpoint inhibitors alone,
  • 24:13so that's one example of an approach.
  • 24:16There are groups that are targeting a
  • 24:18subset of cells called macrophages,
  • 24:20which are also innate immune cells.
  • 24:23Then we need to think about
  • 24:26what these cells do,
  • 24:28so they secrete substances called cytokines.
  • 24:32Interleukin two, that early drug that I
  • 24:35had mentioned that was approved already
  • 24:37in the 1990s is a type of a cytokine.
  • 24:40Many companies are now developing
  • 24:42novel cytokines,
  • 24:43so either better versions of interleukin
  • 24:45two that bind to the interleukin two
  • 24:48receptors that are more important,
  • 24:50or that bind with a
  • 24:52stronger affinity to the receptors.
  • 24:55And then there are other interleukins,
  • 24:57interleukins that are made by
  • 24:59our cells. So you could have
  • 25:02Interleukin 12, interleukin 18,
  • 25:04interleukin 15,
  • 25:04all of these are being looked
  • 25:07at as drug targets,
  • 25:08and in fact there's a researcher at
  • 25:11Yale who has developed a
  • 25:13drug that is a mimic of interleukin
  • 25:1618 that doesn't get sucked up
  • 25:18by decoy proteins in the body,
  • 25:20so should be more potent and we
  • 25:22will be excited to study that in
  • 25:25the next month or two in the clinic.
  • 25:28There's a trial that's opening
  • 25:30up and we will be administering
  • 25:32that drug to patients who have not
  • 25:34responded to the immune checkpoint
  • 25:36inhibitors both with Melanoma
  • 25:38and other diseases.
  • 25:40So Harriet just to unpack a couple
  • 25:42of the concepts that you mentioned.
  • 25:45It sounds to me like
  • 25:47the activation of both the innate
  • 25:49and the adaptive immune system
  • 25:51just makes intuitive sense.
  • 25:53If you have more
  • 25:55adaptive immune cells and
  • 25:57you pair that with more cells
  • 25:59that are presenting to them the
  • 26:02antigens they need to go after,
  • 26:04it seems like that would
  • 26:06be a better approach.
  • 26:07So is that something that is routinely
  • 26:10being done or is the cellular
  • 26:12therapies that we were talking
  • 26:14about earlier really going after
  • 26:16more of those adaptive cells?
  • 26:18And wouldn't it be better if they
  • 26:20could also grow up in a Petri dish
  • 26:23of patients innate T cells as well?
  • 26:27Well, we can grow it up in a
  • 26:29Petri dish or in the body,
  • 26:31so the whole concept behind
  • 26:33giving cytokines is to grow them
  • 26:34actually in the human.
  • 26:35So we give more of the cytokines
  • 26:37and we grow up both innate
  • 26:39and the adaptive cells.
  • 26:40So these are like growth
  • 26:42factors for these cells.
  • 26:43They should make
  • 26:44them propagate.
  • 26:45So that was going to be my
  • 26:47next question is you talk
  • 26:48about all of these cytokines?
  • 26:50These interleukins with various numbers?
  • 26:52How exactly do they work?
  • 26:55It's sounds now like they just
  • 26:58stimulate the innate immune system.
  • 27:00Is that right?
  • 27:02Both innate and adaptive actually?
  • 27:04So they stimulate both.
  • 27:06So all of those different
  • 27:08numbers reflect molecules that
  • 27:10have different activities.
  • 27:12So some of them will stimulate innate cells
  • 27:15and some stimulate the adaptive cells,
  • 27:17some stimulates suppressor cells.
  • 27:19The biology is getting
  • 27:21more and more complicated.
  • 27:23Well, it's always been complicated.
  • 27:25We're just learning now
  • 27:26how complicated it is,
  • 27:27and every time we look,
  • 27:28we discover that we knew nothing.
  • 27:32And so it sounds like we're
  • 27:34almost coming full circle,
  • 27:36though, because interleukin two
  • 27:37was something that you had talked
  • 27:40about at the very outset, which
  • 27:42really wasn't terribly effective back then.
  • 27:45Why would we think that now
  • 27:47these other interleukins will
  • 27:49be more effective?
  • 27:52Now we have
  • 27:55other bullets to administer with it.
  • 27:58And we understand better how to engineer
  • 28:01them so that they can be more effective.
  • 28:05So the idea is that you would use
  • 28:07these interleukins along with cellular
  • 28:09therapy and or checkpoint inhibitors.
  • 28:11Yes, or if they're so good we might
  • 28:13be able to use them alone.
  • 28:15Time will tell when you have a new
  • 28:17drug you start studying it by itself,
  • 28:20mainly because you want to
  • 28:21look at whether it's toxic,
  • 28:23but you also look a little bit at
  • 28:26the activity so some of them might
  • 28:28end up being active on their own.
  • 28:30We will see.
  • 28:32Doctor Harriet Kluger is a professor
  • 28:34of medicine and medical oncology
  • 28:36at the Yale School of Medicine.
  • 28:38If you have questions the addresses
  • 28:40cancer answers at yale.edu and
  • 28:42past editions of the program are
  • 28:44available in audio and written
  • 28:45form at yalecancercenter.org.
  • 28:47We hope you'll join us next week to
  • 28:50learn more about the fight against
  • 28:52cancer here on Connecticut Public
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  • 28:56Answers is provided by Smilow
  • 28:57Cancer Hospital and AstraZeneca.