Melanoma Awareness Month

May 15, 2020

Information

May 17, 2020

Yale Cancer Center

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00:00Support for Yale Cancer Answers comes from AstraZeneca,
00:04the Beyond Pink campaign aims to empower metastatic breast cancer patients and their loved ones to learn more about their diagnosis and make informed decisions.
00:14Learn more at lifebeyondpink.com.
00:18Welcome to Yale Cancer Answers with your host
00:21Doctor Anees Chagpar.
00:22Yale Cancer Answers features the latest information on cancer care by welcoming oncologists and specialists who are on the forefront of the battle to fight cancer. This week
00:32it's a conversation about Melanoma research with doctor Jeffrey Ishizuka.
00:36Doctor Ishizuka is an Assistant Professor of Medical Oncology at Yale School of Medicine,
00:41where Doctor Chagpar is a Professor of Surgical Oncology.
00:46Jeff, maybe we could start off by you telling us a little bit about yourself and what you do.
00:51I'm a physician-scientist and that means that I spend part of my time treating cancer patients and part of my time in the lab looking
01:00for new treatments for those patients.
01:02And so tell us a little bit more about the kinds of patients that you treat and the kinds of research that you do.
01:09I see Melanoma patients and I'm an immunologist
01:12by training. And that means I study ways to
01:16make the patient's immune system work better,
01:19to attack the cancer.
01:22Tell us more about that, we've talked on the show a little bit about immunotherapy and so on,
01:27but tell us a little bit more about the broad spectrum of immunotherapy.
01:32How exactly does it work and then the role that it plays in Melanoma.
01:36There are a couple of types of immunotherapy.
01:38And for a long time we knew that the immune system had the potential to control cancer,
01:43but I'd say the two big advances that are more recent are on the one hand,
01:47CAR T cells. And those are cells that are taken out of the patients body and reprogrammed to go back in and attack the tumor, and immune checkpoint
01:55blockade. And these are drugs that cut the brakes on the immune system.
01:58Those brakes stop the immune system from attacking the cancer.
02:02And when you get rid of them,
02:04the cancer is vulnerable to immune attack.
02:09Tell us about which of these you work on, and
02:12how exactly they work in Melanoma.
02:16In Melanoma, immune checkpoint blockade has really been one of the biggest developments
02:22really in the last, well maybe ever in the disease.
02:27And I think Melanoma was the first disease where
02:31these drugs were developed and remains one of the ones where they work the best.
02:39Can you talk about this immune checkpoint blockade.
02:42Is there more than one molecule that needs to be blocked?
02:45How does that work? Why does the immune system have brakes to begin with?
02:49These are great questions and they're really at the forefront of the field right now,
02:54so there are certainly at least a few molecules that are important.
02:58And all of the ones we learned about first are on the surface of T cells,
03:02which we know are one of the important cells for controlling cancer.
03:07There are a number of molecules that target
03:10PD-L1 and that's a major inhibitory pathway in the T cells,
03:13and also molecules that target CTL A4,
03:15which is another inhibitory pathway in T cells.
03:18And what we learned is when you block either one of these and sometimes if you block them both together it works even better.
03:25The T cells can get supercharged to attack the cancer.
03:28Why is it that
03:30they have breaks to begin with?
03:32The immune system is supposed to be able to identify foreign stuff in our bodies and get rid of it.
03:39So why doesn't that work in cancer?
03:42Why is it that we need to take off these brakes?
03:45Why do they have breaks to begin with?
03:48This is the foundational question of immunology,
03:52the distinction between self and nonself.
03:55All cells need to be able to get rid of foreign things just as you said,
03:59but at the same time
04:01they need to have mechanisms to avoid attacking the normal cells in the body that are healthy and so
04:10why is it that the immune system thinks that these cancer cells are normal?
04:16I think it's really because cancer cells arise from normal cells as normal cells become dysregulated as they acquire genetic errors called mutations.
04:27And eventually you develop cancer.
04:29And because the cancer cell arises from a backdrop of normal cells,
04:34doing normal cell things, the immune system has to find specific signals of damage or mutations that
04:41look abnormal in order to recognize cancer.
04:43So you're telling me that normally it won't do that?
04:48Some tumors are recognized by the immune system and the immune system can actually get rid of them,
04:54and other aren't. And really what we're trying to understand and at the heart of the field is how can we take tumors that are not well recognized by
05:03the immune system and turn them into tumors that the immune system can see and destroy?
05:07And so it seems to me that if you take that problem just at its face,
05:11there are two ways of doing that.
05:13One is to make the tumor look more abnormal so that the immune system
05:19realizes, I need to attack it and get rid of it without actually revving up the immune system or getting rid of the
05:28brakes and the other is to supercharge the immune system as you put it to make it more sensitive to recognizing what might be abnormal.
05:37Yeah, that's right, and I think people are working at both sides of that problem.
05:42We and others in the lab, are thinking of strategies both to make tumors put out signs for the immune system, saying,
05:49come get me and also looking for new ways to charge the immune system to be more aggressive against cancer.
05:56Tell us more about the first,
05:58because I think that we've heard a little bit about checkpoint inhibitors,
06:05but we really haven't heard a lot about the work that's going on to have tumor cells put out those signs that
06:11say, come get me. And it seems to me that might be a way to allow the immune system without getting supercharged to eat up or
06:22get rid of these cancer cells,
06:25because one of the problems,
06:27as you point out, of having a supercharged immune system is that it can then attack its own cells.
06:35Yeah, that's a great point and
06:38we've been thinking, and others as well,
06:43that it comes down to tricking the tumor cell into making inflammatory signals,
06:49tricking it into making kind of an antiviral response that recruits anti tumor immune cells into the micro environment,
06:56and I think
06:57you can go about that by infecting the tumor with a virus or making it think it's infected with a virus or triggering certain danger signals in the micro environment
07:07directly around the tumor.
07:11Tell us more about that work, is that actually something that's being done?
07:16Is it in clinical practice?
07:19How do we do that?
07:21There are a number of clinical trials now using stimulators of viral pathways that look like DNA or RNA,
07:30things that viruses make and that ourselves have dedicated sensors in order to detect,
07:37and I think none of them has proven to be the Magic bullet for cancer yet.
07:42But there are still some technical hurdles to workout.
07:47And I think we're getting there though.
07:50Why has that not proven to be as successful as supercharging the immune system?
07:56I think one of the challenges is that cancer in many cases can spread to many locations,
08:03and when you think about triggering an inflammatory response in the tumor bed,
08:09you're really thinking about triggering it,
08:12not just at one site,
08:14but at many sites all at once,
08:16and so finding ways to send drugs
08:19to all of the different sites that cancer occupies in the body is one of the major challenges to getting this approach to work.
08:26The other approach then is the one that is the mainstay of immunotherapy,
08:34which is to quote supercharge the immune system to get rid of the blocks.
08:39I always think of it like Harry Potters invisibility cloak,
08:43right. The tumor has kind of made itself invisible to the immune system,
08:48and it's getting rid of that that cloak and getting the immune system to recognize it and to go after it and two,
08:57to be quote supercharged now.
09:00You mentioned two molecules, in particular CTL A4 and PDL1, tell us a little bit about the differences between the two.
09:10I mean we have drugs that will block either pathway.
09:14How do you figure out which one to use?
09:18Tell us more about that interplay.
09:21I think we still don't fully understand the mechanism of either drug and either pathway.
09:29And people have done a lot of good work,
09:32in fact, the Nobel Prize was awarded a few years back for some of that work,
09:36but I wouldn't say that we completely understand which,
09:39even sometimes which cells are being targeted,
09:42but certainly which pathways within the cell are being activated.
09:45So a lot of how we figured this out has been empirically.
09:48We've done clinical trials with different drugs or different combinations of drugs,
09:52and we've seen what's been effective for patients,
09:55and the hope is going forward that as we learn more about the immune system,
09:59and as we learn more about the tumor that we will be able to do better
10:04and even predict the next set of these drugs that could be usefully combined.
10:10So tell us more about the differences between CTLA for an PDL1.
10:14I get the fact that we've discovered these kind of fortuitously and empirically and have just made drugs that affect each of these pathways,
10:24and seeing that they work.
10:26But we must know more about these actual molecules.
10:30Yeah, they both play an inhibitory role in T cells.
10:34I think it's broadly thought
10:37that one of them plays more of a role in T cells initially getting primed against the tumor,
10:43but maybe plays more of a role in lymph nodes then generating the T cells that are capable of responding whereas the other one,
10:52that speedy one may play more of a role in activating the T cells that are already primed against the tumor that already have the capacity to attack the tumor.
11:01And I'm going to steer clear of the term of exhaustion because there are a lot of debates about whether T cells
11:08are actually exhausted or not,
11:10but there's this idea that T cells can, after seeing a lot of tumor antigen stop responding very well that they can become dysfunctional and so one
11:21of the things that PDL1 blockade does,
11:27is to make the T cells that have become dysfunctional more functional.
11:32And so if these two pathways then are complementary,
11:36one being more so for priming T cells and one being more so for T cells that are already primed,
11:42has there been any work looking into either concurrent therapy or sequential therapy of different immuno therapies that might work better than either in isolation?
11:54There has, and in Melanoma combining two drugs,
11:57one that targets CTL A4.
11:58and one that targets PDL1 seems to be better than using either drug alone and potentially better than using them both in sequence,
12:08although the latter is a less clear conclusion.
12:17And one of the exciting things in this field has been seeing the slew of approvals for immuno therapies in different cancer types in Melanoma.
12:28Certainly it's become standard of care in the frontline for most patients and it's being explored in basically every stage of care of the disease other than for disease that
12:39can just be removed and surgically cut out in the early stages and really beyond Melanoma,
12:45it spread throughout many many solid tumor types and it's being tried in almost any tumor type you can think of.
12:54And so two questions. First question is one of the things you mentioned earlier as being one of the
13:00downfalls of some therapies is that it can't always get to all of the cells where the tumors may be hiding.
13:08Does immunotherapy have that problem in terms of getting to the T cells and activating them or supercharging them?
13:17Or is that concept, this may not work if there's a tumor,
13:22for example in the brain?
13:24Because this drug can't cross the blood brain barrier?
13:28Or does it affect T cells wherever they are?
13:32We know that we can get effects certainly in the brain.
13:38So you can see effects of these drugs in what are thought of usually as sites of the body that are hard to get to or immune privilege sites but
13:51I guess what I don't know for sure,
13:53it's hard to say is whether there is a problem activating immune cells somewhere in the body.
13:59That is to say, whether we're getting these drugs as effectively as possible to all the immune cells that might be able to be mobilize against the tumor.
14:07We're going to learn a lot more about Melanoma immunotherapy right after we take a short break for a medical minute.
14:15Please stay tuned to learn more about this research with my guest doctor Jeffrey Ishizuka. Support for Yale Cancer Answers comes from AstraZeneca.
14:23Providing important treatment options for patients with different types of lung,
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14:32More information at astrazeneca-us.com.
14:36This is a medical minute about breast cancer,
14:38the most common cancer in women. In Connecticut alone,
14:42approximately 3000 women will be diagnosed with breast cancer this year,
14:46but thanks to earlier detection,
14:49noninvasive treatments, an novel therapies,
14:51there are more options for patients to fight breast cancer than ever before.
14:56Women should schedule a baseline mammogram beginning at age 40 or earlier if they have risk factors associated with breast cancer.
15:04Digital breast tomosynthesis or 3D mammography is transforming breast screening by significantly
15:11reducing unnecessary procedures while picking up more cancers and eliminating some of the fear and anxiety
15:18many women experience. More information is available at yalecancercenter.org.
15:23You're listening to Connecticut public radio.
15:27Welcome back to Yale Cancer Answers.
15:29This is doctor Anees Chagpar andnI'm joined tonight by my guest doctor Jeffrey Ishizuka.
15:35We're talking about Melanoma research and in particular we're talking about immunotherapy.
15:41Jeff, right before the break we were talking a little bit about immunotherapy in terms of,
15:47really getting the immune system to attack cancer cells,
15:52which it may not recognize because as you put it,
15:55these cancer cells come from normal cells and that
15:58may not be as foreign looking to the immune system to really trigger it and we talked a little bit about two separate pathways,
16:08CTL A4 and PDL1 and the fact that we now have drugs,
16:12this explosion of drugs in immunotherapy targeting these two pathways and how this really has become the mainstay of therapy,
16:21particularly for cancers like Melanoma.
16:24I had a few questions to kind of follow up on that.
16:28The first is, tell us a little bit about the side effects.
16:32We think about
16:35chemotherapy, and you know, traditionally,
16:40chemotherapy was therapy that kills off cancer cells and was really thought to be therapy that switches off
16:47rapidly dividing cells and so people ended up losing hair and maybe getting sick because it effects your GI lining,
16:55which are rapidly turning over cells.
16:58Do you get the same kind of thing in immunotherapy,
17:01or are there other side effects that are the results of
17:06kind of supercharging this immune system and getting the immune system to attack healthy cells?
17:12So I think that's it exactly.
17:14Many of the side effects that you get from immunotherapy are actually side effects of supercharging the immune system,
17:20so the immune system can accidentally attack different areas of the body.
17:24Some of the things we see are inflammation in the lungs,
17:27inflammation in the GI system we see inflammation of the endocrine system,
17:32and when we first started seeing these side effects,
17:34there wasn't a good sense of how you treat them,
17:37how you manage them, or even how you monitor.
17:40We didn't really know what to look for.
17:42But I will say that as experience with these agents has progressed,
17:46we've gotten better at detecting these side effects as they occur,
17:50and managing them, usually using immunosuppressives and one of the questions that comes up when you start saying,
17:56well, you're using drugs to charge the immune system and at the same time to shut down the immune system,
18:02is that going to be is going to be bad for the patients.
18:06Are they going to have that outcomes and the data isn't really completely mature on this yet,
18:11but it certainly appears from the early data that
18:14you can safely give these immunosuppressives and that you don't at least don't clearly make their responses against the cancer
18:22worse.
18:26That's really interesting. Why would that be the case? I can imagine that when we think about people who are immunosuppressed,
18:32people who for example have HIV or other things that turn off their immune system,
18:38they are more at risk of developing cancer,
18:41and I guess for the same reason that you talked about before the break,
18:45which is your immune system,
18:47unbeknownst to you, might be getting rid of little cancers that you don't know you have because it recognizes them and it gets rid of them,
18:56and so if you are immuno compromised you're at increased risk of getting cancer,
19:02and that's the whole point of
19:04supercharging the immune system to get rid of these cancers.
19:11Why is it that giving people an immunosuppresant at the same time as an immuno supercharger doesn't seem to affect the cancer in a bad way?
19:22A couple of potential thoughts here.
19:25The first one is that I want to be careful we don't know for sure that it doesn't affect the
19:32response to therapy in a negative way.
19:35I think what we can say is that
19:37at first blush, patients who needed immunosuppressives because they had these bad immune effects and got them didn't do obviously worse,
19:45at least in the early studies
19:46then patients who didn't need them in the first place and that actually could be a kind of selection bias issue where the patients who needed the immunosuppressives
19:55actually were having the strongest immune responses to begin with,
19:59and so I think we have to do some careful experiments in a controlled setting to see whether it was really true that the immunosuppressives weren't having any effect there.
20:08And I think that's probably the main thing that I would think about for that issue.
20:15The other question that I have is, these autoimmune side effects,
20:21the side effects of people's immune system now attacking their own normal cells,
20:26are those permanent? Are
20:29they forever or are they short lived? I mean when you get chemotherapy and you lose your hair,
20:38your hair will grow back.
20:39Is it the same with immunotherapy that this is a short term thing?
20:45Or when your immune system attacks your lungs,
20:47now you've got pulmonary fibrosis forever?
20:51I think it depends on the type of immune side effect that we're talking about.
20:56I think many of them,
20:57if they're controlled with immunosuppressives,
21:00and if you take the patient off of the immunotherapy, will actually go away.
21:04So we see this in a lot of cases,
21:06inflammation in the colon, or inflammation in the lungs.
21:10I think the case in which this isn't necessarily true is when the immune system attacks the cell type
21:17that produces hormones in the body and destroys all of that cell type because in that case you may not really know what's going on until the cell type
21:26is gone, and after that there's really no bringing it back.
21:30So in most cases we actually have been able to give hormone replacement.
21:37It's extremely bad if it's not detected,
21:40but in a lot of cases it can be solved by giving a pill a day.
21:45When you talk about hormones,
21:47are you talking about thyroid are you talking about ovaries, what hormones are we talking about?
21:54Yeah, so thyroid is one that you certainly see,
21:58but you see actually a number of other hormones that are produced in the brain that can also be altered,
22:05and these can be be more rare,
22:07but can be pretty dramatic if you see them.
22:10So given the side effects of immunotherapy,
22:14is immunotherapy really better than classic chemotherapy?
22:18You had mentioned that immunotherapy has now become standard of care for Melanoma.
22:24Is it better than what we used to do?
22:29We used to give chemotherapy for Melanoma,
22:31right?
22:33And Melanoma is not particularly responsive to chemotherapy,
22:37and I think what excited everyone in the field and it's given us all
22:41a lot of excitement and a lot of hope is not even that
22:45everyone responds to these immunotherapy's because they don't,
22:48not enough patients do, and that's something we don't really understand.
22:52We're trying to understand it in the lab,
22:55but it's that some of the patients who respond seem to just keep responding,
22:59and some of them respond so well and for so long that we've actually started to believe that we can take the patients off of the drugs,
23:07the immunotherapy drugs, and that the cancer won't return.
23:10And this is true even in some cases for very aggressive disease.
23:15And so seeing those effects are the ones that have really made everybody excited.
23:20And you see that in clinical trials when we study how patients survive on different drugs and
23:27it was no contest between the immunotherapy's and chemotherapy.
23:31When we talk about therapy for cancer a lot of times we're talking about personalized medicine and we're talking about how we can figure out what a cancer likes to
23:44eat, what receptors cancer has,
23:48what genes are turned on and turned off,
23:51and then we target our therapy accordingly.
23:55Talk about immunotherapy. It seems to me like we're talking about a blanket turning on supercharging the immune system,
24:04is that right, or are there ways where we're actually tailoring this therapy?
24:10Are we looking at who those people are that are super responsive to immunotherapy versus the people who are not super responsive to immunotherapy?
24:20And which immunotherapy might work better in particular patients?
24:25Yeah, so this question is near and dear to my heart.
24:29We in general don't do a great job of selecting patients to get particular immunotherapy, there is one biomarker which is the expression of PDL1 in the tumor as
24:39we talked about PDL1 and PD1 is one of these key pathways,
24:43so if you have PDL1 expressed in the tumor microenvironment either by immune cells in the micro environment or by the tumor,
24:51we know that you are more likely to have a response to targeting the PD1 PDL1 axis.
24:58But basically everyone in the field spends a lot of time complaining about this biomarker because we know there are a lot of patients who will have PDL1 expression
25:08in their tumor who won't respond well to these drugs.
25:11And conversely, there are a lot of patients who won't have PDL1 expression in the tumor who will still respond to these drugs.
25:18So what's the point of the biomarker then?
25:20We know it's better than not using it in terms of you have some predictive value and in some cases you might not even be able to see
25:29a signal of the drug working in a patient population and unless,
25:32you used a biomarker, and also it's a stand in because we haven't done a good enough job yet of
25:37finding better ones.
25:41So we have this biomarker that if you have it,
25:44you won't necessarily respond to the immunotherapy, if you don't have it,
25:49you may still respond to the therapy,
25:52so either way you're likely going to get immunotherapy if you have Melanoma,
25:57regardless of whether you have the biomarker or not.
26:01That's true, and that's where I think we have the potential to do much better,
26:07particularly as we talked about these two pathways,
26:11there are a lot of other immuno regulatory pathways that can activate immune cells or can activate the tumor to recruit immune cells.
26:20And we're still at the beginning of understanding these.
26:24But as these drugs come out and as they are available we have the potential to start thinking about OK for a given patient.
26:32How can we assess that patients immune system and how can we understand the tumor,
26:37the genomics, the genetics of the tumor in such a way that we can find the best combination of drugs to work for that patient.
26:46That sounds really interesting,
26:49because that sounds like the stuff that we've been doing for awhile now in terms of cancer and looking at cancers in figuring out which therapy is going to work
26:59better. What targeted pathways are turned on versus turned off.
27:03Should you be using, you know an anti HER-2 agent in somebody who's got a HER-2-positive breast cancer?
27:10Or should you be targeting KRAS in lung cancer?
27:13Sounds like you're moving in the same direction in Melanoma.
27:17But looking at it from an immune perspective,
27:19and I should say this is mostly on the research side,
27:24right now we're trying to understand the flavors of inflammation in the tumor microenvironment.
27:30The composition of the immune cells that are there and why they're there,
27:35and then once we understand that, we're simultaneously starting to look at OK if we take pieces of the tumor and study them in tissue culture,
27:44if we study them in a dish and treat them
27:47with different immunotherapy drugs, can we see patterns of response from some patients but not from others?
27:53Those are things that we're working on here,
27:56and others are working on as well that we think could lead to the development of better biomarkers.
28:01That's one kind of major approach.
28:03Another one is focusing on the technologies that have emerged to sequence patient genomes.
28:09The immune cells from patient genomes.
28:11We do technologies now to look at individual cells in sequence.
28:15Everything that that cell is expressing.
28:17Basically everything it's doing and we can do that for a bunch of cells in the micro environment all at once,
28:25and the thought is that we may find particular genetic lesions in the tumor that lead to a better response to immunotherapy A versus B.
28:34We may find particular features of the immune system that interact with the tumor as well that predict that,
28:41and so I think that in the next 5 or 10 years we're likely to see progress in this direction.
28:47Whether that will translate affectively into
28:50guiding precise therapy choice for a patients
28:54Melanoma, I'm not sure.
29:00When you talk about,
29:02essentially taking tumors and looking at the micro environment and seeing the composition of these cancer cells,
29:09and what kinds of immune therapy they may benefit from,
29:13you can also look at the immune system and see,
29:17maybe my immune system is different from your immune system in terms of attacking a particular cell.
29:24Is that on the right track?
29:26It's exactly on the right track,
29:29and you know, even taking a step back when we first started to see that these therapies could work for patients,
29:37people started to ask,
29:38why do they work for some patients but not for others?
29:42And we started to look inside patient tumors and one of the things that was clear is that some patients have a lot of attacking immune cells
29:51even prior to immunotherapy and others don't.
29:54And just unpacking that basic
29:57observation is something we're still doing,
30:00but as I was mentioning, as we start to understand it as we start to understand the chemical signals that the tumor in the immune system makes.
30:09It's giving us a lot of inputs to try to determine which drugs could be affective in each case,
30:15and what the basic flavors of immune micro environment are.
30:19Doctor Jeffrey Ishizuka is an Assistant Professor of Medical Oncology at the Yale School of Medicine.
30:25If you have questions, the address is canceranswers@yale.edu and past editions of the program are available in audio and written form at Yalecancercenter.org.
30:35We hope you'll join us next week to learn more about the fight against cancer
30:40here on Connecticut Public Radio.