Hello Ben. We're joined today with Dr. Ben Schlechter, who is a senior physician at Dana Farber Cancer Institute. And we've had the privilege of working with Dr Schlechter for a number of years now, particularly in the context of our lead programs with BotBal. So maybe you can start with defining what the neoadjuvant setting is and what is typically different about those patients in the neo adjuvant sitting versus the typical patients in the late state setting who are in a much more desperate predicament. Yeah. So in colon cancer and in a lot of solid tumors, we're talking about solid tumors here, not for example, blood cancers, but in solid tumors everything rotates around the axis of surgery. Surgery is sort of this very important point. And traditionally, we did surgery, and then chemotherapy was given after surgery as a helper to prevent recurrence. That's the term adjuvant. Adjuvant's a helper. So that was the role of chemotherapy, and we used risk factors at surgery. So the surgery is done. We look at the pathology and the biology, all the specimens under the microscope. We make a guess about how high likelihood it is of recurrence, And then if the likelihood is high enough of a recurrence, we give chemotherapy to prevent that recurrence. Nealadjuvant just means the exact same chemotherapy or immunotherapy or other targeted therapies before surgery. And that can be used in a number of ways. Number one is if a tumor is big and scary and just can't come out, you can use nealadjutant therapy to shrink it. It's actually relatively uncommon. For the most part, that's not the case, at least in colon cancer. But another way to think of it is that surgery is hard on patients in a member of ways And sometimes if chemotherapy is challenging and surgery is challenging, chemotherapy is critical, but it can become too challenging after surgery. And so increasingly in certain diseases, it's moved to before surgery as a way of getting it in, letting someone heal and then go to surgery. It's a little bit different when we talk about immune therapy, because immune therapy is fundamentally different from chemotherapy. And that's what's really important for the discussion today, really, is not just what is neoadjuvant therapy, but why is immune therapy so different from chemotherapy, and why it's probably better in the neoadjudant setting, the preoperative setting, than the postoperative settings. So, based on what you're saying, patients, when they're first diagnosed with cancer, I'm assuming then that their initial reaction is, let's get the cancer out of our body. And so when you are trying to explain why certain treatments prior to surgery, including chemotherapy for that matter, but particularly with immunotherapy, make sense, how do you convince them? what is their reaction typically? And also, what is the interaction between, for example, your discipline as an oncologist and the surgeon who is typically accustomed to getting the tumor out, provided that, as you said, the tumor is operable? They want to do surgery at the moment that is best for the patient. And so if a patient is sick in some way, they want us to get them healthier, but they also want to set the patient up for success. The goal of surgery is to cure patients of cancer. And so if you say to a surgeon, this is a patient with cancer, your job is cure, my job is pure. And I think there may be an advantage to doing a treatment before surgery rather than after surgery. They're going to sign up for that. We're not taking away surgery. We'RE simply changing the time of surgery so that we can sort of boost the benefit to patients. And So in terms of the surgeons, surgeons can work with this. Surgeons know how to work with this. We have many paradigms within colorectal cancer to do this. So within the time that I've been a doctor, we went from, before I was a doctor surgery first in rectal cancer, and then all these treatments afterwards. And then there was an era of radiation first in retinal cancer and then surgery and then chemotherapy. And now we've moved to all the chemo, all the radiation, everything before surgery, and we finished with surgery. So these are not novel concepts for surgeons and they're not novel concept for oncologists. The benefit of treatment before surgery with immune therapy in particular, is that surgery does something. Surgery does something good. It removes a big tumor. But surgery also removes things that are there for a reason. Your lymph nodes play a role in your immune system. Your lymp nodes are the surrounding immune tissue in your colon and every organ, really. And there is immune cells in there that are learning how to fight infection and cancer and viruses and all these things. And you have to remove those with surgery. Because by removing those, you remove lymph nodes that may be contaminated with cancer. But by removing them, you also sort of remove the university system of the immune system. The immune system needs to learn how to fight cancer. And so we have to get those lymph nodes out. But by doing that, we actually handicap the immune systems a little. So immune therapy in particular, after surgery, is uneducated immune therapy. And so giving immune therapy before surgery is where you have the most infrastructure to teach the immune system how to fighting cancer. So by giving these treatments earlier, and the same surgery you're going to do anyway, You actually end up with a more vigorous immune response because you haven't yet removed those lymph nodes, which play such an important role in fighting cancer, even though they have to come out because they could be contaminated by cancer. So it's interesting because even though chemotherapy also works systemically, what you're saying, Dr. Schlechter is that immunotherapy seems to have a longer term potential memory sort of response. So you're training the body to remember so that if there's a residual emergence of disease that the immune system will remember and shut it down. Whereas chemotherapy may not do that exactly the same way. Yeah. Chemotherapy is sort of agnostic to when you do it. If you do it, it's the same. Immune therapy is quite different. It's like a vaccine, right? You don't get the flu and then get your flu shot. You get your flue shot, so you don't get the flue. And so it's not a vaccine. It says a different biology, but there's a lot of things in common. And, so, activating the immune response when the immune system is at its best is really what you want to do with cancer immune therapy. And. so, giving patients the opportunity to derive the most possible benefit from their own native immunity is really important when you think about the best application of immune therapy. So let me switch gears for a bit. Now, of course, when immune therapy came to existence with some of the leading targets like CTLA-4 and PD-1, the first emphasis was melanoma, which is typically known as a a cancer that is visible to the immune system and then that was followed by to some extent with lung cancers as well not quite the same level of success perhaps but but still very successful now when we look at colorectal cancer we have heard of course some very striking developments in colorectal cancer with a minority of patients that comprise the colorextal cancer population known as MSI high patients. Now, but the majority don't benefit from immune therapy. Can you explain a little bit more about what is the difference between the two different types of colon cancers and what has changed based on your experience of the last few years? So when you say colon cancer, you really just mean the typical colon cancer, not MSI high, because that's actually quite uncommon. In advanced disease, it's rare. It's like 3%, probably a little bit more in earlier stage disease. MSI-high cancer is, the term is genomically unstable. Its DNA is wet and wild. Its RNA is profoundly different from the normal colon. And so there's a lot of stuff for the immune system to recognize. The immune system's job is to find differences. And when you have something which is radically different than normal, it's easier for it to do its job. Andso there'salot of stuff for theimmune system to latch on to and generate inflammation against and attack. And so it doesn't take too much to push the immune system from the off state to the on state. Now, the cancer is fighting back. That's what all those drugs are doing. They're fighting back against the immune system. We interfere with that giving these drugs. But MLRD cancers or MSI high cancers, those are wet and wild. They are weird looking. They really strange genetically. And so the immune systems has something to work with. More typical colon cancer is actually quite different. More typical cancer is profoundly similar to the normal colon. And there's not a lot of things to latch on to. And you need to kind of coax the immune system more. The other thing is more typical colon cancer has a profound kind of immune suppressed desert around it. It produces things that suppress the immune system. And so the immune therapies that work in other cancers need to be kind of jiggered a little differently, not just to take T cells that are sort of asleep, but know there's a cancer there, but instead get rid of the guardrails. And some of those drugs had early successes in melanoma. But honestly, they were overkill in melanomas. They weren't necessary. But in colon cancer, they're not overkill. And so you need to think differently about immune therapy. And so the experience of the last 10 years has been beginning to understand that averaging all cancers was a mistake and thinking much more nuanced about cancers and averaging all immune therapies was a mistakes and thinking more nuancedly about the different drugs and using the right drug with the right disease. So I'm the first to say that I had become a pessimist for these classes of drugs. We had 10 years of failure, something like that. We also know more about the immune system. We can think less simplistically and more complexly about where these different things are operating, in particular CTLA-4. And so botanosilumab is that sort of like rationally designed CTLA4. The first generation CTLA5s are good drugs and the right disease, but they didn't work in colon cancer. And with some careful work, really, it's your work. I'm not going to take credit for it. Careful work, things were identified that could be done to alter CTLA-4 drugs to push them a little bit harder, make them behave a littlebit better in ways that are relevant in colon cancers. So colon cancer has a ton of these T cells that are bad actors. We want to get rid of those. We want to get read of bad T-cells. Okay, but we want good T-Cells. And so, botancillinab is good at kind of doing that nuanced approach. Baostilumab, the thing that works with it, is also important because there's different components to the immune response. There's regulatory T- cells. We can get rid of those with botancilinab. Those are bad T cells. There are good T cells, but cancer fights back. Cancer delivers a knockout punch to those T-cels, just really like wounds them. And baostilinib and similar drugs like nivolumab for example, and pembrolizumab, those work on that more chronic wounding of the immune system. So you need different components. You have to turn on the immune response with botansilumab by removing regulation, by taking off the brakes. You need to prevent the immune systems from sort of tumbling down into sleep by using balstilumib or those other PD-1 drugs to keep that active. Yeah. So I'll brag a little about our clinical cancer research paper that just came out. How about that? And it's yours as well. So that was from the C800-01 study. That was the original trial of BOT and BAL in colorectal cancer, among other cancers. And there was an initial presentation a couple of years ago in Nature Medicine. This is a follow-up paper in clinical cancer research looking at Nature Medicine with 77 patients with colon cancer. This is 123 patients. Nature medicine was short-term follow-up. This is long-term follow-ups, three years of follow-on. And there's a couple really important findings. So the first thing is that who it worked in is relevant. It works really best outside of the liver, and there's some interesting biology about that, and we could talk about that for hours. It's not the most relevant point today. But the further from the liver you get, the better things get. And so that's very clearly demonstrated in the paper that we just put out. The other thing that we noticed is that a subset of individuals derive deep benefits, like major responses. Some of them, as far as we could tell, like all visible cancer disappeared, which is called a clinical complete response. And that's a great thing. We don't know what that means in the long run because it's just too new, but it's certainly no patient is sad if all their cancer is gone from a scan. The other important point from C800-01 was that a significant number of patients, and this was a really, really sick population. These were not early stage. These were not first and second line. These are late line patients. A significant number of patients just kept living. They failed to get sicker from their cancer. And that's an important point. So something like a third of patients in this very, very advanced disease population are alive three years out, which is quite remarkable when you think about how bad colon cancer is. And 17% of patients, so around half of those alive, have never gone on to need other therapy for their cancer. And so there's something called the tail of the curve in immune therapy, and that is different than chemotherapy. Chemotherapy works and doesn't work. Andso you get a deep response for a period of time, and then it fails, and eventually it stops working in everyone. Chemotherapy does not cure colon cancer in the advanced disease setting. And in immune theory, there's going to be a subset of individuals who just keep doing well, and they keep living in spite of their cancer, they may be disease-free, they maybe disease managed. It might be the immune system just kind of like knows what it's doing here. And those tails of the curve are really important because they're not accounted for in averages. And so you have to look different. You have to Look at these landmark points, like how many people are alive at one year, how many at two years, and now we can say how many three years in three years is a big number in advanced colon cancer. So I'm very proud of this work. A lot of people put a lot of effort into getting these patients on at a really tough time in the world. And we got them through treatment and they did well. And there's patients still alive today who I see in my practice because they received those drugs. So first of all, pretty much every trial of immune therapy before surgery or radiation, immune therapy is better than if you do it after. And so immune therapy gets better the better the patient, the better of the patient fitness, the bed of the patient anatomy. So that's point number one. Point number two, investigators in Italy and the GONO group the unicorn study and investigators the united states um did a clinical trial called nest one and then nest two and they took patients with colon cancer not rectal cancer and they gave them bot and a few doses of bowel and then they did surgery they did it as a test they gave bot they gave bowel did immediate surgery and like like wow the cancer was already reducing even in a few weeks compared to what we would have expected to see at surgery okay So that was pretty cool and then it was bought and a little bit more bowel and wait a little bit longer and the longer you waited, the better it got. The NEST study showed that we could majorly reduce the amount of cancer in a subset of patients and it's very important because maybe we could reduce it so much we can avoid chemo and that's a big deal. We've done a lot of work to try and reduce chemotherapy in colon cancer and so that's where NEST lies. So this could be a game changer, of course, for patients who would benefit from it, because I'm assuming, Ben, that there are competing priorities here, meaning a surgeon may indulge in taking as much of the organ out as possible so that they can be sure of not leaving cancer behind. Yeah, I mean, colorectal surgeons, I think, are a particular breed. They've actually, they have led the research on not doing surgery. And that tells you a lot about how these surgeries go. So I think coloreictal surgeons really have weighed in on understanding that a good cancer surgery can have a bad functional outcome. And so I want to give a lot of credit to the colorector surgeons who've led this field. And so they deserve a lot OF credit for that. Um, but yeah, I mean, the, the problem is the right surgery is, is rough on patients. We don't want to jeopardize the chance of cure because of a functional issue, but we don't want to jeopardize function if we could cure people anyway. Thank you very much for all of this, by the way. And I know that, um, you're a physician who cares about patients because we have referred some patients to you that were in desperate need. Unfortunately, some of these patients, men, are very young. Yeah, I mean, it's pretty scary, right? The leading cause of cancer-related death under the age of 50 is now colon cancer. And in women, it's going to surpass breast cancer pretty soon within the next couple of years. That is new. That did not exist 30 years ago. Something is happening that colon cancer is the disease that is getting worse over time. And honestly, we don't know what it is. There's really not a major genetic hallmark these are just average colon cancers that generally don't respond to conventional therapies and the younger the patients are the worse they do and so this is this is as far as i'm concerned this is a medical crisis there should be alarms going off that you know i've treated a 16 year old that like 20s and 30 year olds are dying of colon cancer that's not acceptable and we need to sort that and we're working on it but um boy is painfully slow. And yeah, boy, do we need new drugs.