00:00:00: Hello, everyone.

00:00:01: Welcome to this episode of the YouTube podcast.

00:00:04: It's Pradeepundra here, gastroenterologist and podcast host.

00:00:08: Now, GI cancers are changing in various domains.

00:00:13: Firstly, in the way they're being diagnosed and also how they behaved in the course of their illnesses.

00:00:20: However, probably the biggest change is in the diagnosis of such cancers.

00:00:25: And one big factor that has made in the medical oncological treatment of these cancers.

00:00:32: Now, when it comes to gastroenterology, three important areas have seen a huge leap in the medical treatment.

00:00:38: One is IBD, we all know, obesity management is another, if you want to call it gastroenterology, and immunotherapy for GI cancers.

00:00:47: Now, as gastroenterologists, most of us may not be fully directly involved in initiating medical oncological treatment for our patients, but I certainly know in some countries and depending on the training and some gastroenterologists are heavily involved in initiating such treatment.

00:01:03: but we are certainly involved heavily in the journey of our patients with GI cancers, whether it is the diagnosis or some specific treatment delivered by gastroenterologists, but more importantly in the management of any complications from any form of treatment, whether it is surgical, medical oncological or endoscopic.

00:01:23: So knowledge on these things are important and inevitable for us to learn about these things.

00:01:29: Now immunotherapy is something that has probably revolutionized treatment of GI cancers lately.

00:01:35: And in this episode, we want to discuss about this.

00:01:39: We want to discuss about the basic concepts of immunotherapy and how it works, how immunotherapy has changed the outcome for our patients, I guess different roles of immunotherapy, whether in metastatic disease or locally advanced disease or an adjuvant treatment.

00:01:58: Now, today's guest is Dr.

00:02:00: Jeroen Derkowal, who's a GI oncologist and also a gastroenterologist, a dual accredited at the Department of Gastroenterology at University Hospitals Lerven in Belgium.

00:02:12: Jeroen is also an associate professor of oncology at the Catholic University in Lerven, Belgium, and is a clinical and translational researcher in the field of immunotherapy for GI cancers.

00:02:28: Welcome to the EugeoPodcast, Jiren.

00:02:30: Thank you for having me.

00:02:31: It's great to be here.

00:02:32: Jiren, can you start by explaining when did the concept of immunotherapy start?

00:02:38: How did the idea come to us in terms of treating cancer with immunotherapy?

00:02:43: In fact, it's a little history lesson.

00:02:45: It's quite interesting.

00:02:46: More than a hundred years ago, There were already some hints that the immune system was very important for cancer biology.

00:02:53: For example, there was this one surgeon in New York City working in Memorial Sloan Hospital, and he was observing together with some of his colleagues that, well, patients with cancer, with visible cancer, so for example, sarcoma, soft tissue cancers, that got infected with streptococcus, like severe infections, sometimes had spontaneous remission.

00:03:16: of those cancers.

00:03:16: So together with the infection came a remission of the cancer.

00:03:19: And he started wondering why would that be?

00:03:21: And maybe it has something to do with the immune system.

00:03:24: So he started to inject cancers as a treatment with some form of inactivated streptococcus mixture.

00:03:31: And of course, this was a very rough form of immunotherapy, but he saw some remissions and some effects in those patients.

00:03:41: At the same time, of course, there was a few decades later, the emergence of chemotherapy and radiotherapy also as powerful tools to treat cancer.

00:03:50: So this kind of approach was a little bit discarded back in the days by the colleagues.

00:03:55: And it's only until quite recently, a few decades ago, that this concept of the immune system being important was re-adopted, so to speak, and that it was further explored.

00:04:07: Because then at that time, we had more tools.

00:04:10: to look into the biology of cancer.

00:04:12: And what we, for example, learned is that while the immune system is indeed very important, that cancers, we know they are genetic diseases.

00:04:20: And so cancer cells have an aberrant DNA.

00:04:23: They have mutations.

00:04:24: They have other changes in their DNA, which make, of course, that they multiply very fast without control, that they can invade and they can metastasize.

00:04:33: But also this aberrant DNA results in peptides.

00:04:38: proteins that are foreign to the body and foreign to the immune system so called tumor neo antigens or tumor associated antigens.

00:04:45: and these are peptides that normally the immune system would recognize.

00:04:49: and how it goes.

00:04:50: what we learned in the nineties is that of course anti-gen presenting cells and this is a bit of biology they would go to the tumor they would find the antigens they would take them up they would traffic to the lymph nodes and their present these peptides.

00:05:05: to the T cells, to the immune system.

00:05:07: And the T cells, these naive T cells, which reside in the lymph nodes, they would then be activated and trafficked through the blood vessels, infiltrate the tumor, find the cancer cells that are expressing the same antigens.

00:05:21: and attack the cancer cells, a so-called cytotoxic thesis, would then, of course, do their job and kill the cancer cells.

00:05:27: And this is what we call a very important concept in biology, the cancer immunity cycle.

00:05:33: And this is what we learned over the decades, a very important role of the immune system in cancer surveillance and cancer control.

00:05:40: Okay, so it looks like our body is already equipped to kill these stream cells.

00:05:47: So I guess with immunotherapy you're kind of guiding it or directing or making them more powerful.

00:05:54: Well, if the country immunity cycle would work perfectly fine all the time, then I would be out of job.

00:05:59: That would be great.

00:05:59: Then I could do something else.

00:06:01: And of course, a lot less suffering would take place.

00:06:05: in order for a cancer from a perspective of the cancer then to become relevant and to become a disease to indeed grow and metastasize and so on and so forth.

00:06:14: the cancer needs to evade this cancer immunity cycle.

00:06:18: And this is exactly what happens.

00:06:19: And so the cancer has put in place all these breaks on this immunity cycle, on different parts of this immunity cycle.

00:06:26: It can be the presentation of antigens.

00:06:29: It can be the trafficking of T cells.

00:06:30: It can be a block on the cytotoxic effect of the T cells.

00:06:34: So there are many, many places in that cancer immune cycle that the cancer can put breaks.

00:06:39: And immunotherapy is very simply put It is taking away as many breaks as possible to reinvigorate the immune system against the cancer, so to reactivate the immune system.

00:06:53: And so you have many forms of immunotherapy, of course.

00:06:55: And so, for example, what we have learned over the years is that chemotherapy and radiotherapy is probably also a form of immunotherapy.

00:07:05: And probably in part, the effect that we see with chemotherapy is indeed immune-driven.

00:07:11: For example, you can have a so-called immunogenic cell death by chemotherapy and more antigens are released by this cell death and then the cancer immunity cycle can get a boost.

00:07:23: So it's not only the immunotherapy that we talk about with our patients and the new innovative drugs.

00:07:28: These are very important, but probably in general for cancer treatment, immune system is very important.

00:07:34: Okay, so nicely explained how the cancer, the body's immune system work.

00:07:40: Are there different ways in which the immunotherapy medications are developed?

00:07:46: So are there different stages or different steps where you target this treatment?

00:07:51: So

00:07:51: in general, if we talk about the immunotherapy, we do not talk about chemo and radiation therapy.

00:07:55: And so we talk about specific molecules.

00:07:58: And well, it's all related to what we call the checkpoints.

00:08:02: The checkpoints are in fact one of these breaks on the cancer immunity cycle.

00:08:06: Checkpoints are inherent to the body and so we have them everywhere and they are expressed on T cells.

00:08:14: And when they interact with their ligands, these checkpoints, then the T cells are calmed down.

00:08:19: And so they are not attacking, they are in fact inhibited.

00:08:23: And this is in our body a very important mechanism to prevent the immune system from becoming too active.

00:08:30: But on the other hand, the cancer will abuse this mechanism, so to speak.

00:08:34: So they will express these checkpoint ligands on the surface.

00:08:37: Cancer cells will express the checkpoint ligands.

00:08:40: They will interact with the checkpoints on the T cells, and the T cells will be inhibited.

00:08:45: And this is one way of immune tolerance of the immune system towards the cancer.

00:08:50: And one of the most important interactions there, now I'm naming some molecules, but is the interaction between PD-I, which is a checkpoint on the T cell, and PD-L-I, the ligand on the cancer cells and other immune cells.

00:09:01: This interaction inhibits the immune system.

00:09:04: And what we do with our checkpoint inhibitors, which are monoclonal antibodies that are directed against PD-I or PD-O-I, we try that this interaction cannot take place.

00:09:16: So there's no interaction between PD-I, PD-O-I, and so the T cells, they wake up, so to speak, and they have their cytotoxic activity.

00:09:24: Another example, and the second most frequently used checkpoint inhibitor is against CTLA-IV.

00:09:30: CTLA-IV is equally so at checkpoints.

00:09:33: More important in T cell priming, so in the lymph nodes, not specifically in the cancer, but it's the same principle.

00:09:39: And so these drugs... are now what we call, if we talk about immunotherapy and cancer, NGI cancers, for example, it is ninety percent of the time or ninety five percent of the time.

00:09:50: we talk about checkpoint inhibitors.

00:09:52: So it's not a personalized treatment.

00:09:54: It is indeed infusions.

00:09:55: Patients get them every two weeks, every three weeks, every four weeks.

00:09:58: It depends on the brand.

00:10:00: And it is exactly that monoclonal antibodies directed against those checkpoints or checkpoint ligands.

00:10:06: Nice to explain.

00:10:07: So the these checkpoints are over expressed, so to say, in the cancer cells.

00:10:14: So that would mean that they would interact with the T cells and prevent being destroyed.

00:10:21: With checkpoint inhibitors, you are essentially inhibiting these so that they become more, so to say, they become more susceptible to being killed by a body's immune system.

00:10:33: and that's how they work.

00:10:35: Yeah, exactly.

00:10:36: Okay, that's great.

00:10:38: So that's the new mechanism.

00:10:39: So these are monoclonal antibodies.

00:10:41: All of them are like they're not small molecules or anything like that.

00:10:45: No,

00:10:45: that's not something that has been developed to clinical practice yet.

00:10:48: No.

00:10:48: Okay.

00:10:49: So these are new molecules, I'm assuming they've developed in the last many years.

00:10:54: So what was the problems in the past with the previous chemotherapy agents in GI cancers?

00:11:00: Why was there a need to change?

00:11:03: Well, I have to be clear that chemotherapy remains one of the very important pillars that we use in GI cancer treatment.

00:11:10: Chemotherapy is specifically potent in what we call neo-agevant or agevant setting, which is the treatment before or after mainly surgery.

00:11:21: And their chemotherapy is sometimes potent enough to kill remnants, for example, in the agevant setting.

00:11:27: patient gets surgery for colorectal cancer.

00:11:30: For example, there is some microscopic remnant of the disease left.

00:11:33: You don't see it on a scan, but it's there because that is, in fact, the source of a relapse after a certain amount of time after surgery.

00:11:43: And chemotherapy can sometimes eliminate, not in all patients, but sometimes eliminate that remnant.

00:11:48: So in this setting, it really provides cure, extra patients that are cured with GI cancer.

00:11:55: again, a very important pillar.

00:11:57: However, if we use chemotherapy in a more metastatic setting, so with patients with metastases, active disease, it often results in a remission of the disease, so we can get the lesions under control, we can make them smaller, but it is very hard, if not impossible, to cure this disease, to completely eradicate every cancer cell that is there and to cure this patient and to go for a very long-term good effect.

00:12:22: So that is, I think, the main problem, and this is because cancer cells get used to the chemo, they get resistant.

00:12:29: And at a certain point in time, and this can be very fast, for example, in pancreatic cancer, which is notably quite resistant to any treatment, but it can be also after many years, like some colorectal cancers who are more susceptible to treatment, but in the end, people develop resistance to those drugs.

00:12:47: And then, of course, it becomes a very, very difficult story.

00:12:50: Also, chemotherapy, as we know, has quite some side effects and is affecting the quality of life of our patients.

00:12:56: So there was certainly room for improvement.

00:12:58: And with the checkpoint inhibitors, what we have seen, at least in some cancer types, and we can go into detail about that in a minute, but in some cancer type, which we call immune hot, these are probably the cancer types that have not so many breaks in the cancer immunity cycle.

00:13:13: And so maybe Just a few breaks, maybe just that last step of the cytotoxicity with the checkpoints.

00:13:19: If you take away that one break, then you see sometimes dramatic effects.

00:13:24: And now, for the first time, what we saw is really deep remissions and sometimes even cure in patients with metastatic disease, at least in those patients with what we call immune hot tumors.

00:13:36: So tumors that do not have that many breaks in the cancer immunity cycle, and they only need that small push.

00:13:42: from the checkpoint in Ibiter to really have that dramatic effect.

00:13:45: So this was a revolution in oncology and also... in terms of side effects, it's a whole different story compared to chemotherapy.

00:13:54: There are side effects and we can talk about that, but it's not the classical side effects that you see with chemotherapy like hair loss, like anorexia, nausea, gastrointestinal toxicities for all patients.

00:14:08: what we see with chemotherapy.

00:14:09: It's a different actually different story with immunotherapy.

00:14:14: It's a different profile.

00:14:15: So in summary, it looks at the differences or main thing that I picked up is that they, of course, work differently.

00:14:22: That means that depending on the type of tumors, the efficacy can be amazing, even Cure, who you're talking about.

00:14:29: and the side effect profile is very different from conventional chemotherapy.

00:14:35: Maybe we should delve into a little bit about the now that you're talking about efficacy.

00:14:40: Where have they changed?

00:14:41: Where are these the game changes in which cancers, you know, focus on GI cancers?

00:14:46: Yeah,

00:14:47: so if we look... to cancer type specific efficacy of immunotherapy, then probably one of the immune hottest tumor types there is in the GI field is primary liver cancer, hepatocellular carcinoma.

00:15:00: So a bit surprising because this has been a very difficult to treat disease for many years, but we have seen with immunotherapies that at least the proportion of patients have very And this is about one in five patients have very, very deep remissions and long term effect of immunotherapy.

00:15:16: And we use immunotherapy in that disease as the only approach sometimes.

00:15:20: And so this is one of the more immune sensitive tumors.

00:15:23: And then you have tumor types like, for example, gastric cancer or biliary tract cancer, which are still sensitive to immunotherapy, but not that sensitive.

00:15:33: And in those cancer types, we will mostly use it in combination.

00:15:37: with chemotherapy.

00:15:38: And so we did already use chemotherapy.

00:15:41: And now we add immunotherapy to the treatment regimen for metastatic disease, for example, in order to prolong survival.

00:15:47: And of course, clinical trials have shown this effect.

00:15:50: So this is some kind of an intermediate immune sensitive tumor type.

00:15:54: But then you also in GI specifically, you have quite a lot of cancer types that are immune cold and where immunotherapy Unfortunately, today has very limited or no role to play.

00:16:06: And for example, this is the case for the majority of patients with colorectal cancer, which have microsatellite stable colorectal cancer.

00:16:14: We will go into microsatellite instability in a minute, but microsatellite stable colorectal cancer is the majority of colorectal cancers.

00:16:21: And these are immune cold tumors with very limited efficacy of the current generation checkpoint inhibitors.

00:16:28: And the same is true for pancreatic ductal adenocarcinomas or pancreatic cancer.

00:16:32: Also there, we still have to use only chemotherapy with limited efficacy, as I said, but immunotherapy also there was tested in clinical trials and did not show any effect or any added value.

00:16:45: So that's the spectrum of GI cancers going from very immune sensitive tumor types like squamous cell cancers like liver cancer to more intermediate to really immune cold cancer types where immunotherapy does not play a role today.

00:17:00: On that role, I'm sure some of us who sit at the MDTs understand these different terms and I think some of us don't.

00:17:09: So just briefly explain what is the difference between neo-anguement treatment versus anguement treatment versus pallid treatment.

00:17:17: I guess there's three different ways we use these trucks.

00:17:21: Yeah, so of course the palliative treatment.

00:17:25: I'm not a hundred percent fan of that term.

00:17:26: I'd rather use non-curative intents, we sometimes say, because of course we want to make cancer a chronic disease and there are a lot of diseases which are not curable in medicine and they're not necessarily treated with palliative treatment.

00:17:41: But okay, it's nomenclature, it's not so important.

00:17:44: So indeed, those are the patients with metastatic disease where we try to have the disease in remission, but we know we cannot cure it.

00:17:51: When we go for a curative intent, it's often surgery as the mainstay of treatment still today.

00:17:57: But then we use sometimes systemic approaches before surgery or after surgery to improve the chances of cure, to have more chances that the disease stays away.

00:18:08: And for example, new adjuvant is then before surgery and adjuvant is after surgery.

00:18:13: And it's really typical in oncology that we are developing drugs first in that palliative or non curative setting.

00:18:20: And if we see an effect there, we probably, then in the second phase, move the drugs also to the perioperative space, so to speak.

00:18:29: And this is exactly what happened with immunotherapy in GI cancer, also in non GI cancers.

00:18:34: And so what we saw is some effect in or sometimes a very good effect in advanced disease.

00:18:39: And then we learned that also in the perioperative setting, immunotherapy worked well.

00:18:45: And that was very interesting.

00:18:46: So what we saw in the adjuvant setting, we had some efficacy, but if we took the same drug and we put it before surgery, so in a neo-adjuvant setting, it works even better.

00:18:58: And we think that is because at the time of neo-adjuvant, you still have the tumor in place, right?

00:19:04: You still have all the antigens in the body, so the immune system can be trained against these antigens.

00:19:11: While in the adjuvant setting, you only have this very, very limited remnant of disease left in the body.

00:19:17: And so the immune system, well, has more hard time to recognize the antigen.

00:19:21: So that's really why we are exploring more and more immunotherapy, immune checkpoint inhibition, sometimes in monotherapy, sometimes in combination with chemotherapy in the neo-adjuvant setting.

00:19:31: And gastric cancer, again, is the nicest example of that phenomenon.

00:19:36: Maybe some of the listeners know the chemo regimen flots.

00:19:39: You might have heard it during the MDT.

00:19:41: flots is what we use already for many years.

00:19:44: chemotherapy for gastric cancer in the neoadjuvant setting before surgery.

00:19:48: Now we have learned that adding a checkpoint inhibitor to FLOT will increase the efficacy and will increase the cure rate and the survival of patients with gastric cancer.

00:19:59: Exactly that concept.

00:20:01: Excellent.

00:20:02: Really nicely explained.

00:20:02: It's really nice to understand when you know the science behind it.

00:20:07: It sounds very fascinating.

00:20:10: Now, you were talking about the colorectal cancers being called immunologically or immune-wise.

00:20:16: And you briefly mentioned about MSI+.

00:20:20: Can I kindly ask you to say what it means?

00:20:23: What is MSI?

00:20:25: What is plus or rich MSI rich?

00:20:29: How is it tested?

00:20:31: And why is it important in your field, in the field of immunotherapy?

00:20:36: Yeah so this is really an important concept and again at TMDT and also with early lesions that are sometimes taken away endoscopically.

00:20:44: we will test for that.

00:20:44: so it's indeed important that we go deeper into that.

00:20:48: The correct terms are either deficient mismatch repair or DMMR or MSI high.

00:20:54: so micro-satellite instability high.

00:20:57: They're not completely interchangeable, but for the sake of simplicity, I think we can use both terms to describe the same phenomenon.

00:21:06: The mismatch repair machinery is in all of our cells, and it's a machinery that is important to correct mistakes in the DNA.

00:21:14: specifically mismatches, of course mismatch repair.

00:21:18: So mismatches are, for example, minus.

00:21:20: C is in front of a T in the DNA.

00:21:22: That's not right.

00:21:23: We know this from our lessons of cell biology.

00:21:25: It should be C in front of a G. And so the mismatch repair machinery will repair that.

00:21:30: They also will repair insertions and deletions, so small portions of the DNA that get lost or that get inserted.

00:21:36: These are things, so this is a complex of proteins, this machinery that will scan the DNA and that will repair those types of mistakes.

00:21:45: And now in some cancers.

00:21:47: This machinery becomes deficient, deficient mismatch repair.

00:21:52: And as a result, you can imagine that the whole tumor DNA is pure chaos.

00:21:58: There are a lot of mistakes happening and they're not corrected.

00:22:01: So there are a lot of mismatches, there are a lot of insurgents, there are a lot of deletions.

00:22:05: Now, you can ask yourself the question, why does it happen in a cancer cell?

00:22:08: Well, one example and the most well-known example is patients that are born or people that are born with a germline mutation in a gene that encodes for a protein that forms this complex, this mismatch repair machinery complex.

00:22:23: And for example, MLH-one.

00:22:26: If you're born with a mutation in MLH-one, well, of course, already all of your cells have one copy that is dysfunctional.

00:22:33: If you then lose the other copy in the cancer, this cell becomes mismatch repair deficient.

00:22:40: being born with a mutation like that is called Lynch syndrome.

00:22:44: And this certainly rings a bell for many of the listeners.

00:22:48: Lynch syndrome is indeed an hereditary syndrome, which of course increases the risk for colorectal cancer and other GI and non-GI cancers.

00:22:56: And all the cancers that emerge in the context of Lynch syndrome are normally DMMR, MSI high.

00:23:03: A hundred percent does not exist in medicine, but many, many, many are DMMR, MSI high.

00:23:09: Now, as a result, so I said that the DNA has a lot of mistakes, a lot of insertion solutions.

00:23:14: As a result, and what I told you in the beginning of this podcast, there will be a lot of antigens, right?

00:23:20: The DNA will produce a lot of foreign peptides.

00:23:25: All these antigens are very high quality.

00:23:28: So the immune system, well, has a lot to play with, has a lot to recognize.

00:23:33: And so these are Yeah, one of the most immune hot tumors out there, and if not the most immune hot tumor.

00:23:40: So these are very sensitive to immune checkpoint blockade.

00:23:44: And it's, as you understood, I think correctly, it is a phenomenon that we see not in one cancer type exclusively.

00:23:52: And we can see it in colorectal cancer, but you can see it in gastric cancer, you can see it in endometrial cancer.

00:23:57: And all these cancer types have a proportion of patients with DMMR MSI.

00:24:02: The problem is it's a small proportion.

00:24:04: And so, for example, in colorectal cancer, metastatic disease, it's about four percent.

00:24:10: So that's a very, very small proportion.

00:24:12: Of course, colorectal cancer is a frequent cancer type.

00:24:14: So we see from time to time, we see these patients.

00:24:18: If in early stage disease, for example, stage two, stage three disease, the proportion is somewhat higher, fifteen percent, sometimes twenty percent.

00:24:26: But it is a minority of cancer patients.

00:24:29: Nevertheless, we do not want this any DMMR, MSI high.

00:24:34: case, because we know we have a very good tool to treat those patients.

00:24:38: So we test everybody with GI cancers, with some exceptions, some cancer types, for example, hepatocellular carcinoma and squamous cells cancers, they are never MSI, so we do not test them.

00:24:49: But all adenocarcinomas, pancreatic cancer, even although it's very rare in pancreatic cancer, we will test.

00:24:55: because we want to identify that needle in the haystack, so to speak.

00:25:00: And how do we test?

00:25:01: There are multiple ways to test, but the most easy one, the most cheap one also, is to do a staining in immune histochemistry for the four proteins that form the complex of the mismatch repair machinery, MLH-I and some others.

00:25:16: You do the staining, and normally in the cancer, the staining Well, you see the protein light up.

00:25:23: So the expression is maintained, which means that cancer is proficient MMR or microsatellite stable.

00:25:32: And so, for example, in colorectal cancer, we know that this is then an immune called tumor, and these are the majority of cancers.

00:25:37: If one or more of these proteins is lost in terms of expression, so there's no expression anymore, then, of course, we call it DMMR cancer.

00:25:47: And then we know that immunotherapy could be a very potent rock.

00:25:51: And of course, we use it in metastatic setting.

00:25:53: very much for these DMMR cancers, but we also learned that their neoadjuvant treatment with these checkpoint inhibitors for those specific cases can be very attractive.

00:26:04: For example, in those cancers that emerge in very tough locations for the surgeon.

00:26:10: You think about rectal cancer, for example.

00:26:12: Rectal cancer is, of course, a place that, well, you want to keep your rectum.

00:26:16: If you do a TME, so total mesorectal excision, this comes with consequences in terms of quality of life, in terms of stool habits and so on and so forth.

00:26:25: So what we do now is, if we see a DMMR, rectal cancer, we will treat with immunotherapy.

00:26:32: And in the majority, almost all patients that we do this, the cancer goes away completely.

00:26:39: without surgery, without radiation, without anything else.

00:26:42: So just immunotherapy.

00:26:43: And we can spare the rectum.

00:26:45: We can go for an organ preservation.

00:26:47: And this is, of course, very, very attractive.

00:26:49: It's not so attractive in the right-sided colon, because, of course, a right in the rectum, to me, is not so morbid.

00:26:55: And it's quite simple procedure that is done by laparoscopy.

00:26:58: So for those tumors, it might also be interesting.

00:27:01: But rectal cancer, but also is a fageal cancer that is DMMR, or gastric cancer.

00:27:05: These are the cancer types we look at when we think about... organ preservation when we think about using only immunotherapy when they're really sensitive to that and try to avoid all other options.

00:27:16: So it looks like a bit of game changer for a subset of the colorectal cancers and you mentioned there about sparing the organs and maybe we can talk a little bit more about that.

00:27:29: but with regards to these subset of correctly cancers.

00:27:34: What sort of efficacy are we looking at?

00:27:37: I think it's important for us to know, as gastroenterologists who may not treat these, so that it helps us to manage their other conditions as well.

00:27:46: Just, I think, could you outline briefly in the metastatic setting?

00:27:51: Yeah, in metastatic setting, it's a difficult question.

00:27:54: Also, for communication with the patient, it's quite hard as an oncologist, and I will explain you why.

00:28:02: In most patients has some effect in terms of making the disease or getting it under control, putting it in remission.

00:28:11: But as I said, already we get resistance early or later in the course of the disease.

00:28:16: Immunotherapy is different.

00:28:17: For example, if we talk about hypotocellular carcinoma, for example, which is one of the most immune sensitive tumor types, well, we will have almost no effect in eighty percent of the patients.

00:28:30: And then we will have this twenty percent of patients with a dramatic effect.

00:28:34: So it's more black or white.

00:28:36: Chemotherapy is more gray.

00:28:37: Immunotherapy is more black or white.

00:28:39: So it's possible that when we start immunotherapy that we still can cure this patient putting it really dramatic.

00:28:47: But it's also possible that in three or four months time we will see liver decompensation due to tumor progression.

00:28:53: And unfortunately the patient dies from the illness.

00:28:56: And so all these kind of scenarios And we have to take into account when discussing this with the patient.

00:29:01: So it's very, very hard.

00:29:02: We have to take it into account worst case scenario, but of course we can also not ignore the fact that there's a possibility for the best case scenario.

00:29:10: And also when it comes to the comorbidities and the other diseases and should these patients still go to intensive care or should we have a DNR in place and should we discuss this with the patient?

00:29:21: It's getting tough now because we used to know, okay, we do not have so many options.

00:29:26: We will be always with our best against the wall at a certain point in time with the disease that is not under control.

00:29:32: So yeah, it's better to go for palliation and not for very invasive and hard procedures.

00:29:39: Now we have always this kind of scenario in mind that it might still go very, very well with this patient and we still have to put in efforts to do everything we can to get through this very, very difficult time.

00:29:50: So this really It's very important that we have a very good communication between all health care practitioners involved in a certain patient case, for example gastroenterologists, but also intensive care doctors, emergency departments, and so on and so forth, that everybody knows what is the best case scenario for this patient, what is the worst case scenario, and what is the sense of being very aggressive in terms of care.

00:30:16: It's getting more and more complex.

00:30:17: I guess if you're not fully aware of the situation, if you're knowledgeable about these things, it's best to talk to somebody, the oncologist, who treats these things before making any decisions, especially in terms of ICU care, DNR status, and what other diseases that we treat.

00:30:40: Now, that's nicely explained, Jeroen.

00:30:42: You briefly mentioned about the organ sparing in rectal cancer, and that's becoming increasingly important, I think.

00:30:48: And we've made huge strides, especially in the endoscopic treatment field, where we are increasingly tackling early cancers, or even slightly early advanced cancers, with endoscopic root, as we know more about the residual disease risk and things.

00:31:08: How is immunotherapy changing the organ-sparing approaches in the GI cancers?

00:31:14: So also there we have this really black and white situation.

00:31:17: So you have the DMMR cases, which I already talked about, that are very immunotherapy sensitive, and we can use only immunotherapy with a very, very high chance of complete remission.

00:31:29: And indeed or inspiring and this has been published i think now two years ago in new england journal medicine it's of course not a randomized controlled trial because it works so well.

00:31:38: you don't have to do this.

00:31:39: i mean you see you see these these dirty cases that were treated this way with an anti pd one antibody and they're all.

00:31:46: in incomplete remission.

00:31:47: So it's something that we very rarely see, I think, in medicine in general.

00:31:51: On the other hand, you have the vast majority of rectal cancers who are proficient in MMR or MSS.

00:31:57: And here in immunotherapy, unfortunately, still has no role to play in the organ sparing strategies for these patients.

00:32:05: Are they completely insensitive to checkpoint inhibition?

00:32:08: Well, there's still a lot of signs going on.

00:32:11: is a little bit more activity of immunotherapy in the early setting compared to the advanced setting.

00:32:17: Also in MSS colorectal cancer, we are learning this.

00:32:20: Will it actually practice changing, come into clinical practice?

00:32:23: It's very uncertain right now.

00:32:26: But of course, as you said correctly, organ-sparing strategies being an endoscopic resection, local excision, but also using combination of chemotherapy and radiotherapy.

00:32:35: to achieve clinical complete response and then follow up the patient with an active surveillance program.

00:32:40: These are strategies while they are not going away any longer.

00:32:42: These are implemented in standard practice and show that indeed these conventional treatments like chemotherapy, like radiotherapy also still have a very important role to play in these diseases.

00:32:55: So it looks like things are changing and changing rapidly with huge strides made in this direction.

00:33:02: What do you think gives the future hold or a new developments and any novel therapies or any different direction of travel when it comes to an umbrella of human therapy at all?

00:33:13: So we now learned this cancer immunity cycle and taking away breaks in this cancer immunity cycle and the success we can have at least for now in a proportion of patients.

00:33:24: So we are looking into taking away other breaks in this cancer immunity cycle to reinvigorate the immune system even more and maybe have better effects also in these so-called tumors.

00:33:34: And one of the approaches could be to inhibit other checkpoints.

00:33:38: And this is now being reported in many trials.

00:33:41: So there are other checkpoints besides PD-I, PD-O-I, or CTLA for TIGET, for example, Vista, TIMP-III.

00:33:48: I mean, the names are not important, but there are many other checkpoints that are inherent to the body, and that we can try to attack with monochromal antibodies.

00:33:56: This is one strategy, not for clinical practice yet, but something we are looking at.

00:34:01: There are also other approaches.

00:34:03: of immunotherapy, which are not checkpoint inhibitors.

00:34:06: For example, what we call T-cell engagers.

00:34:09: What are T-cell engagers?

00:34:10: T-cell engagers are molecules that bind to the tumor, to a certain characteristic receptor at the tumor site, and then also to a T-cell, like CD-III binding, so a T-cell marker.

00:34:23: So it brings together T-cells.

00:34:25: With the tumor and tries to in that way activate the immune system against the tumor.

00:34:30: their cell therapies people might have heard of CAR T treatment.

00:34:34: It's of course well known for hematological.

00:34:36: Blignancies where it's used in clinical practice, but also we are looking into these cell therapies where the principle is that we give an infusion to the patient.

00:34:46: of immune cells modified, activated immune cells, which then, of course, should go to the tumor sites and attack the cancer cells.

00:34:54: And the last branch of immunotherapy we're looking at are the so-called vaccination strategies.

00:34:58: This is already very old, but of course, it makes sense if we think that one of the problems that the immune system does not act.

00:35:06: against the cancer is antigen presentation.

00:35:09: so the antigens of the tumor are not well presented to the immune system so the immune system cannot cannot act.

00:35:15: then it makes sense to think about the strategy where you put the antigens of the tumor in a vaccine, you vaccinate against it, the immune system gets presented with the antigens and goes in the whole body and attacks all the cancer cells that are expressing these antigens.

00:35:28: And these approaches, which we think will mainly work in a very well limited disease setting, like adjuvant setting, for example, these approaches are now being tested in large trials using, well, the mRNA technology, which we have, well, now very much experienced with, but thanks to the COVID pandemic, of course, and the whole technology is now completely worked out and we use it to put in those vaccines, not COVID antigens, but tumor antigens.

00:35:55: And of course, we'll have to see what the results are.

00:35:58: For now, it's not definitive yet, but it's promising.

00:36:01: Sharon thanks for explaining all that and explaining all these logical concepts really rekindled my interest in immunology.

00:36:08: I was so much interested as a medical student.

00:36:11: it's gone the other way since my gastroenterology career certainly looks like things are changing and traditional concepts of you know chemotherapy may not hold good and I think it's very important.

00:36:26: for all of us to understand that things are changing and it's important to understand these things.

00:36:30: If we do not know, it's important to talk to people who know about these things when we manage such patients.

00:36:37: Any final thoughts, any take home messages for us in the field?

00:36:41: Yeah, I think you really summarise this nicely.

00:36:43: So communication between the different specialties who are taking care of patients with GI malignancies is very, very important.

00:36:53: We come from a time where there was sometimes a little bit of nihilism towards cancer patients that we say, okay, this is a cancer patient, so there's nothing else to do.

00:37:02: And unfortunately, sometimes this is still the case.

00:37:06: cannot ignore that, and there's still a lot of work to do, but it's becoming more complex.

00:37:10: And it's not because there is cancer in the file of the patient, even metastatic cancer, that the prognosis is necessarily very, very poor, or there are some unknowns at certain times.

00:37:21: And so we need to be aware of the fact that there might be options for these patients, and that we still have to try our best to tackle all the problems that present themselves.

00:37:31: And of course, we did not talk about side effects, and we can do this maybe in another podcast.

00:37:35: But there are side effects of immunotherapy.

00:37:38: Of course, all drugs have side effects.

00:37:40: And you can imagine that the side effects here will be some kind of autoimmunity because you take away the break of the immune system.

00:37:46: And they can present themselves, as many listeners will know, as GI diseases, which very much resemble IBD, for example.

00:37:53: And so, yeah, that's another way or another message to my colleagues gastroenterologists that they need to be aware that there's a new disease spectrum even opening.

00:38:03: due to these immunotherapies.

00:38:05: And if you see what the future holds with more immunotherapy, with taking away more breaks of the cancer immunity cycle, well, you know that we will have to pay the price in terms of more side effects for these patients as well.

00:38:18: For now, they're manageable for sure.

00:38:20: Better manageable than chemotherapy side effects.

00:38:23: But yeah, it's always an attention point.

00:38:26: Sharon, thanks for your time today.

00:38:28: And I hope you have a lovely day.

00:38:30: Yeah.

00:38:30: Thank you for having me.

00:38:31: Goodbye.

00:38:31: Cheers.

00:38:32: Goodbye.