CAR-T and Other Novel Immunotherapy for Colorectal Cancer: Dr. Keenan (2025)

Manju George 0:00
Hello everyone. Welcome to COLONTOWN Doc talks. I’m Dr. Manju George the Scientific Director, and today we have Dr. Bridget Keenan with us. And I really recommend that everyone watch her first talk from 2021 and this will be an update on it, and she’s going to talk more about the new developments. So Dr Keenan, welcome, and before you start, I request you to tell us a little bit about yourself and how you got into doing this sort of work.

Dr. Bridget Keenan 0:32
Sure. Well, thank you for having me. I’m excited to be back with COLONTOWN to give this talk. I’m an assistant professor at UCSF, and I’m the co director of our cancer immunotherapy program, and I’ve had a long standing interest in cancer immunotherapy. I did an MD PhD program at Johns Hopkins, and during that time, I studied pancreatic cancer vaccines in the lab. When I came to UCSF later in my training, I spent time going back into the lab,and instead of focusing on mice, which I had done previously, started looking at patient samples from the clinic to understand why we sometimes see a response or other times resistance to immunotherapy using high dimensional single cell techniques. And I still do a fair bit of that lab-based research. And in my clinical practice, I see patients who are enrolling on clinical trials with a focus on gastrointestinal cancers in particular.

Manju George 1:31
Okay, thank you. So we can get to the talk, and then at the end of the session, please type your questions in chat, and then we will go through them. Thank you.

Dr. Bridget Keenan 1:42
Okay, so I’ll just get started by putting up my disclosures. If anyone has questions about that, happy to take them at another point in time, and just saying that I am a faculty member at UCSF, but these are my slides based oninformation that I put together. Today, we’re going to talk about the immune system and cancer. I do encourage people to watch that talk from 2021 but don’t worry if you haven’t, because I’m going to spend plenty of time going over the basics, understanding that people are coming in with different backgrounds in terms of what they know so far about cancer immunotherapy. Then I’m going to focus specifically on colorectal cancer and talk about two different subtypes of colorectal cancer called micro satellite instability and tumor mutation burden high, and how those affect using immunotherapy in the clinic. And then lastly, I’m going to talk about– this is really the updated part about some clinical trials that are ongoing right now for colorectal cancer.

Dr. Bridget Keenan 2:43
So first we’re going to start out with cancer immunotherapy basics, or immunology 101, Cancer Immunotherapy is actually a pretty large term that covers a lot of different types of cancer medicine. There’s some examples. Here in this cartoon, we’re going to cover some of these today. We won’t have time to cover all of them. And I covered probably a similar but different subset in 2021 so feel free to go back and check that out as well. There are a lot of more exciting things that are coming to the clinic and that are in trials, but I tried to focus today by talking about the cancer immunotherapy subtypes that are being tested the most right now in colorectal cancer. So we’ll focus on that. Before we get to that, I want to explain some things about the immune system that I think will be helpful to understand how we can use these therapies. So the reasons that we want to use immunotherapy as cancer treatments because it has some particular advantages. So our immune systems, all of the time, are recognizing things as foreign, and that can be viruses, bacteria, and even in the setting of cancer, this can be cancer cells and seeing them as mutated or different than the rest of the body. These responses can be highly specific, and so even one slight difference in the genetic code can be recognized by our immune system. They’re not limited. However, the immune system has almost infinite capacity to develop an immune response against different genetic mutations, and we also know that these responses, when the immune therapy does work, it can be rather long lasting. And you can think about when people get vaccines as children, they sometimes create immune responses that last for decades. One of the considerations for immunotherapy, that one and really, what I thought when I first got into this field is this would be fantastic. What if we could give a type of therapy that has less side effects than chemotherapy and radiation? However, over time, I think what we realized with immunotherapy is it has very different side effects, but I’m not sure it necessarily has less. Obviously what is tolerable is in the eye of the beholder, of the person who’s actually going through that type of cancer therapy. But I think in some ways, there are advantages of immunotherapy over more historical types of cancer treatment. And I’ll explain more about side effects in another slide. This slide here is just to give an overview. So I mentioned, I got into this field around a little bit after this time here on the slide in 2005 when we had very few approved immunotherapies. And since my training in cancer immunotherapy, this has really exploded. So this slide is already outdated. I have to say that every time I present this slide, because there’s been many more approvals since 2019, 2020 it’s hard to keep up with and it’s obviously expanded beyond what I can fit on the slide. But there are many tumor types where we have approved immunotherapies and then two that actually go beyond any particular cancer type, that go across any tumor that has particular biomarkers. And I’m going to cover what those are today.

Dr. Bridget Keenan 6:10
I said this is immunology 101, we’re not going to have time to go into what all the types of the immune cells are, but I do want to cover two particular types of cells that are very important in immunotherapy. So we have on the left side of this Venn diagram here, kind of what I would call earlier immune cells. These are sort of what picks up different particles, whether those are cancer cells or bacteria, and shows them to other immune cells that really are the soldiers, or create the response. And so one of those here is a B cell. These B cells produce something called antibody, an antibody you may have heard of that because there are many therapies now, which are engineered antibodies that we can make at companies and then give back to patients. And to explain a little bit more about what antibodies are, is you can think about them as a drug that can bind to different parts of cells within the body. So they see a signal on the outside of cells, and they’re able to bind to it. Sometimes that means that that pathway is blocked. Other times it’s a flag for another immune cell, like a T cell to come along, or Natural Killer cell to come along and to clear and get rid of that cancer cell. There’s another particular immune cell I want to point out, because I’m going to talk a lot about it today and that’s a T cell. So that’s this here, and I describe them to patients as like the soldiers of the immune system. So they are the ones that are out there doing the protection, their surveillance, and ultimately, the killing of cancer cells. And that’s why they’re so important, and why many of our therapies are either trying to target them to get them to be more activated, or in some cases, as you’ll hear about today, to actually give patients a modified T cell to fight the cancer.

Dr. Bridget Keenan 8:12
Another concept that I want to explain is about HLA or MHC. So our T cells are out there surveying all of our cells all of the time to see whether there’s any signs of danger. And the way that the T cells see is by their T cell receptor. Here, that’s the part of this T cell that’s sticking out and in blue and on the surface of immune cells called antigen presenting cells, as well as on the surface of cancer cells, there are molecules called MHC or HLA. They’re essentially the same. It’s describing the same protein. This protein here has or presents little pieces of what is going on inside thecell. So it’s kind of like a radio signal, and it’s putting it on the outside of the cell, allowing the T cell to survey it. Is thissomething abnormal that is part of what’s expected in the body, or is this something that is abnormal and needs to be attacked? And so all of our cells have these MHC or HLA molecules on them, but we all have a different code. I’m going to talk about that in the next slide. And so that’s so important, because the T cell recognizes the foreign particle here, that’s a little thing that says “a” in the setting of this other molecule. So we need to know the full code to know whether this T cell is specific for this particular cancer protein or infectious disease protein, or so on. To explain a little bit more about HLA and why it matters and why I’m making everyone go through a science course today is that this is involved in how some of these T cell based therapies are now being made and put into clinical trials. And you can see here that in the setting of the right HLA type and the right antigen, the a there, which is the particle from inside the cell, and the TCR can recognize it. However, if you have the wrong antigen or the wrong HLA type in either the middle or the right panels, you can see the T cell and the T cell receptor no longer recognizes this, so these are highly specific reactions that have to happen for our immune system to work. I mentioned that everyone has HLA molecules. There are actually six different genes or proteins that are make up the HLA system, and each one can have actually different forms. So that means, if you have six times many forms, that is actually a code that is very complex. I sometimes explain it, akin to blood type, like A, B and O, if people have heard of that. But it is a little bit more complicated, because there are many more besides the three blood types, AB and O. And that means if we’re using a therapy that uses this T cell receptor or TCR, we’re going to have to make sure that the patient has the right HLA type for that therapy. And I’ll come back to that when I talk about T cell therapies.

Dr. Bridget Keenan 11:22
Last before I recap on this section, I want to talk about immunotherapy side effects. So immune reactions are a balance of protection and having too much activity. And if too much activity happens from our immune system, we can get auto immunity. What autoimmunity is is when the immune system attacks its own normal body or cells, and that can happen in this setting of patients who have autoimmune diseases, things like lupus, psoriasis, rheumatoid arthritis. But it can also happen in patients who get immunotherapy, who don’t have any autoimmune problems to begin with. In fact, we don’t really have good predictors, and so we don’t really know, even if somebody doesn’t have an auto immune disease at baseline, if they’re going to be at risk of one of these autoimmune like side effects or not. These can be kind of non specific, kind of all over, feelings like fatigue or fever, or they could affect just one particular organ or cell type. So for example, if your immune cells are over activated against your joints, that can look and feel a lot like arthritis. If your immune system is over activated against the colon, you could get bad diarrhea and so on. And not every patient, even if they develop side effects, develops all of those, most of the time it’s just one specific side effect, but it is possible to have multiple and it’s very variable which patients and which therapies would really would result in getting particular side effects. I’m going to talk a little bit more about CAR T cell side effects later on, because those are very specific to CAR T cells, and I will say this problem of autoimmune like side effects is more particular to immune checkpoint inhibitors, which I’m also going to explain more, but I just want to give a general overview of what can happen if the immune system is over activated. I will also say that some patients don’t have any side effects from some immunotherapies, and you don’t always need to get side effects for the therapy to work, which is the good news.

Dr. Bridget Keenan 11:29
So to recap, on that part, I talked about how the immune system can be used to fight cancer. This is actually not a new idea, and there have been a lot of steps building up to this and where we’re at for a long time, but now, in the past 10 to 20 years, this field has really exploded, and we have many FDA approved immunotherapies across cancer types, and even regardless of the cancer type, for particular biomarker selected tumors. Everyone’s immune system is different, and that means a lot of things. It means that everyone has different HLA types that are recognized by their T cells and that may play into what kind of therapies they’re eligible for, and also, everyone’s immune system is different, so we can’t really predict who may have responses or side effects to these drugs. While the side effects are different than chemotherapy and radiation, it doesn’t necessarily mean they’re less. I would just say it’s more sporadicor hit or miss. We’re not very good at predicting yet how patients will be affected in terms of some of the potential side effects. So now I’m going to switch and talk more about colorectal cancer specifically, and I want to go into the biology of colorectal cancer a little bit so that people can understand what are some of the features we’re looking for as doctors in their tumor, and how does that inform what kind of therapies they might be eligible for?

Dr. Bridget Keenan 14:57
The first thing I’m going to talk about is a concept called Micro satellite instability. What this means, and it’s also sometimes called mismatch repair deficiency, if mismatch repair is impaired, is so as our DNA is being copied in the cell, there is potential that there will be mismatches. So every now and then, there can be mistakes that happen because our cells are constantly dividing and making new copies and making new cells. Luckily, there is machinery in place in our cells that is like a proof reader. If there is a mismatch detected, and some of these proofreader proteins are normal or active that leads to repair, and the outcome is no mutation. However, some people can, either, in the setting of a tumor, develop a mutation in one of these or, in some cases, actually have an inherited deficiency of one of these proteins. What that means is that the proof reading functions are no longer working very well, and there can be improper repair. If we’re missing these proofreading proteins, then many, many mutations can build up. And actually there are stretches of the DNA that are called micro satellite regions, and they can actually have a lot of changes in those areas when this these proofreading proteins are impacted. And that’s what that term micro satellite instability means. It means these regions, the micro satellite regions, have been affected, and now these are what we call micro satellite instability, or MSI high that is more or less the same thing as mismatch repair deficiency. That maybe confusing, because we have two different names for the same type of presentation within the tumor, and they’re really referring to parts of the same process. If these MMR or mismatch repair proteins are deficient, the result is MSI high, if that makes sense.

Dr. Bridget Keenan 17:02
I mentioned that this can be inherited or spontaneously happen in a tumor. When it’s inherited, it’s also often goes by the name of Lynch syndrome, and so some may have heard of that. It’s estimated that about 2 to 4% of colorectal tumors are related to Lynch syndrome, and Lynch syndrome can also sometimes lead to cancers of other types as well. Overall, including the lynch syndrome cases, about 15% total of colorectal cancers are estimated to be MSI high. So that means the majority of colorectal cancers do not fall into this and this is important because this affects selection of therapy. The micro satellite portions of this, of the genome being altered, and then the resulting many mutations that can happen, it turns out, looks very funny or strange to the immune system. So our T cells that are constantly surveying our cells find that these cells with all of the extra mutations look more abnormal than even the other cancer cells that are mismatch repair normal or MSS- micro satellite stable. And that means that the immune system is already primed to go after these tumors. This led researchers and doctors to do a clinical trial where they took MSI high tumors and used these checkpoint inhibitor therapies, which I’ll give more specifics on later. And what they found is, regardless of the kind of cancer you can see here on the left, all these different types of tumors that were included in this study, despite the kind of cancer, if it had this marker, MSI high, or MMRd, there were many responses. And you can see here what’s called a waterfall plot. It means that here zero is kind of the baseline, how big is someone’s tumor starting out? And then anything below the baseline means that the tumor is getting smaller. And you can see here, in some cases, 100% smaller, meaning that it was completely eradicated.

Dr. Bridget Keenan 19:08
So they went on to study these checkpoint inhibitors in colorectal cancer specifically. And what they found across many cancer types actually held up. And they showed, even in advanced tumors, that these checkpoint inhibitor immunotherapies worked better than chemotherapy as the first type of therapy to be given. However, what they also studied was they looked at patients who had MSS colorectal cancer, and unfortunately, they saw almost zero responses in patients with tumors that were MSS stable. This study came out in 2022 and I bring it up specifically because I had a lot of questions coming to me from patients after it was published. Just like many things that can kind of get sensationalized in the news, this results were taken a little bit out of context. They were really exciting for the cancer community. However, the finer details were really important. So this was a drug called dostarlimab that’s one of these checkpoint inhibitors. And this dostarlimab was used in stage II or III rectal cancer. However, the key thing here was these tumors were all mismatch repair deficient, MSI, high rectal cancers. So this was a group of patients with that was highly selected, is what I’m trying to say. And what they found was that the results were quite remarkable, because when they treated with this dostarlimab immunotherapy, all of these 41 patients had complete responses. And what that meant is it spared patients with locally advanced tumors from having chemotherapy and radiation and even surgeries. And they found later following up, that there were no recurrences. So essentially, you could get a cure with this dostarlimab alone, which was really remarkable. However, as I already shared, MSI high is only about 15% of colorectal tumors. So although this was very exciting, it didn’t apply to a lot of patients who are diagnosed with rectal cancer.

Dr. Bridget Keenan 21:19
Now I’m going to talk about tumor mutational burden. So this is a marker of response to immunotherapy in the same or similar way that MSI high is. I’ll explain what tumor mutational burden is and how it relates to MSI high. So it’s a measure of the total mutations in the tumor, and that the bottom, or what it’s divided by, is all of the tumor DNA. So we’re looking, we kind of give it a number per mega base, or Mb, that’s what that means, of DNA. What they found in doing this one study called the Keynote 158 study that used an immune checkpoint inhibitor in TMB or tumor mutation burden high tumors, which they qualified as 10 or more mutations per mega base, was that immune checkpoint inhibitors were very effective. However, the downside of this was that it didn’t include a lot of patients with colorectal cancer specifically. Before we looked within colorectal cancer specifically, this actually led to an FDA approval across all cancer types. So no matter what kind of tumor a patient has, if it is an advanced tumor and it’s TMB high, they may qualify to get immune checkpoint inhibitor therapy. However, subsequent studies were done to look at pembrolizumab, a checkpoint inhibitor in TMB high, this group defined it as nine or above instead of 10 or above, and they actually showed that in this group, the responses were about one in 10 or 11% total. So without selecting for MSI high, just looking at TMB high alone, it doesn’t seem like it’s potentially the best marker for colorectal cancer. The other statistic I want to share is that it’s actually very unlikely, I have seen it, I actually have seen plenty of patients who have shown me their tumor mutation report, and they do have TMB high and they don’t have MSI, but generally that is pretty rare. So most of the time, these two markers go hand in hand, so the tumor will be MSI high, and because of that micro satellite instability, it has a lot of mutations. So most of the time, it would be TMB high as well. There are other ways that tumors can be TMB high without MSI high, but what I’m showing there is that’s only about 3%, so that’s actually pretty low.

Dr. Bridget Keenan 21:24
So why don’t most colorectal cancers that are MSS or mismatch repair proficient respond well to immunotherapy? In those early trials of these checkpoint inhibitors, we saw that there are very few responses. Well, for one, we just talked about that most of them have a low proportion of mutations, so they don’t look very foreign into the immune system. It may also be that they’re what we call an immune cold tumor. So that’s here on the left. You can see that the immune cells are there, but they’re having trouble getting into the center of the tumor. The other thing is that there can be other cell types that are recruited to the tumor, and they can actually turn off or exhaust these T cells. So the T cells essentially are exhausted or tired. It’s actually in a scientific word we use that they’re exhausted, meaning they’re not very functional anymore, because they are not been very successful at clearing the tumor.

Dr. Bridget Keenan 24:46
So how do we think about getting colorectal cancers from cold to hot so we can get these therapies to work? And I’m going to talk about some of the ideas here. No need to memorize this table. I just want to use it to throw out a coupleof ideas. So I mentioned this idea about T cells being exhausted where they’re very poorly functional. They’re there, but they’re not effective against the cancer. Well, we can think about how to activate those. And historically, other checkpoint inhibitors that have been used, I showed that one example of pembrolizumab have not been very effective. However, there are some newer checkpoint inhibitors called Botansilamab and Balstilimab, which I’m going to talk about later on. There can also be T cells that actually become suppressive of these good T cells that we want to control the tumor. And we call those T regulatory cells, or T regs. They’re not just in colorectal cancer. We see them in many tumor types, and there’s actually drugs now that are starting to target these. So for example, one drug that targets something on the T regs called CCR8 is in clinical trials. There could be the problem that the T cells don’t really see the cancer, meaning maybe they’re not able to get in or maybe they’re just not recognizing the cancer in the right way. So one idea there to kind of circumvent that would be to kill the cancer cells in a way that is more visible to the immune system. And there was a request to talk about Oncolytic viruses, and I’ll explain how that works.Another idea was maybe we could pair some therapies, something like radiation or other targeted therapies to kill the cancer cells, and then use immunotherapy before or after that to try to get a better immune response. There could be just simply not enough cancer cancer specific T cells, that it’s a numbers game. And in that case, we could actually think about putting in new T cells. I’m going to talk about CAR T cells and other types of T cell therapies. Andthen lastly, maybe the T cells are there, but they’re not making it all the way to the tumor. They’re not finding the tumor well enough. And we have new therapies, we call bi specific antibodies, or bispecific T cell engagers that act like molecular glue. I’m going to give a specific example. So this is a big overview of all the things that we’re trying in the clinic.

Dr. Bridget Keenan 27:09
I know I just said a lot that was maybe kind of negative about how immunotherapy historically has not worked, but we’re actually making a lot of headway with some of these drugs in the clinic. So there is hope. Quick primer on clinical trials, because I’m going to go into talking about trials. Both phase I and phase II trials, I would put under the umbrella of early phase trials. The goal of these is mainly to learn about safety, but we also are trying to learn about how well the drug works. Oftentimes, we’re trying to figure out the right dose and schedule to give the drug. When something passes the phase I and phase II stage, where we’ve learned enough about it to know what the side effects are and to know what kind of dose we want to go forward with, it may be ready for a phase III trial. And phase III is typically a larger trial where we’re stacking up this new drug compared to the established treatments. So maybe we’re comparing the immunotherapy to standard of care chemotherapy. Sometimes that could be a placebo. Most ofthe time in cancer treatment, it’s not a placebo, because we do have other active drugs, and our goal is never to cause harm. So we want people to get the best standard of care there is, and then the goal of a trial is to see if we can improve on that.

Dr. Bridget Keenan 28:31
There are some more resources to find trials. I mentioned that I work in the cancer immunotherapy program at UCSF,where we specifically study early phase cancer immunotherapies. And so we have some information of that on our website. Patient organizations like this one, obviously are helping to give information about clinical trials. And then there are sort of a clearing house for all trials in the United States, called Clinical trials.gov. There’s a lot on there. So can be pretty daunting to search it, but it can help you locate trials that are close to you, and also specific trials. For example, if you’re searching for a CAR T cell, or you’re searching for a trial for a particular mutation, you may be able to search by those terms.

Dr. Bridget Keenan 29:19
So we talked a lot about how colorectal cancer responds or doesn’t respond to immunotherapy. So far, what we know about micro satellite instability or MSI high tumors is that they have a lot of mutations, they tend to be TMB high, and they have good responses to immunotherapy. Generally for MSS colorectal cancer, which is the majority of the cases of colorectal there’s fewer mutations. They tend to be TMB low, and thus far, they have not had great responses to immunotherapy. And so there are no FDA approved immunotherapy options outside of the other markerTMB high. So if that’s high, even if there’s MSS disease, those patients are eligible to get an immunotherapy. But mostof the cases don’t fit into either of those categories, and so we’re working in clinical trials to understand how we can improve immunotherapy. Now I’m going to spend some time talking about particular types of therapies and clinical trials.

Dr. Bridget Keenan 30:26
So going back to our slide about what is cancer immunotherapy? There are actually a lot of different types of immunotherapy, and I’ll do my best to cover as many as we can today. I’ve been circling around this term immune checkpoint inhibitor for a while during my talk so far. Now I’m going to have a chance to explain a little bit better what these are. So all of our cells in the body have something called checkpoints, and these are inhibitory signals that tell T cells to leave them alone. If we didn’t have those checkpoints in our bodies, our immune systems may be overactive. However, cancers are very good at using signals that help them grow and help them hide from the immune system. So they may have highly expressed some of these signals on their surface. Many of you may have heard of PD-1 or PD-L1, and so PD-L1 or B7 those are examples of inhibitory signals or checkpoints that the tumor puts up. These bind to their partner on T cells, and when there’s binding of that checkpoint with the T cell specific protein, then what happens is the T cell is turned off and it’s not able to kill the tumor cell. The idea of an immune checkpoint inhibitor is a drug, specifically an antibody, that can block that signal. Then if they cannot interact, the T cell can remain active. There are a couple different pathways, and therefore there’s a couple different drug targets. One of them is this protein called CTLA-4. Another one called PD-1. These are both on the T cell side, and then PD-L1, is on the side of the tumor. And so the antibodies are either targeting the T cell side or the cancer cell side. But the result, or the goal is similar, to block this pathway. By blocking the inhibitory pathway, I tell patients, it’s like taking the brakes off the immune system. I mentioned, however, that normal cells also use these pathways so that we don’t get auto immune disease. And now maybe that explains a little bit about why sometimes, although we’re not sure why, not all the time, we see side effects that are auto immune like in nature, when we give these therapies. There’s a couple examples here of each one of these drugs that inhibit CTLA-4, PD-1, or PDL-1. These are the generic names, and you’ll notice the name Mab at the end that is shorthand for monoclonal antibodies. So that tells us these are all antibody therapies. Historically, like I said, these drugs have not been very effective in MSS colorectal cancer, but some of them are approved already for MSI high colorectal and other tumor types.

Dr. Bridget Keenan 33:17
There are some newer checkpoint inhibitors that have been modified to try to get them to be more active, especially in refractory tumor types like colorectal cancer, where older generations of immune checkpoint inhibitors haven’t worked. And so one of these is Botansilimab. From here on out, I’ll call it bot. Bot or another plus, in a combination with another drug called BalBalstilimab, and I’ll call that Bal for short. As you can see, that’s a lot easier. These are drugs that inhibit two checkpoints, two that we already have other drugs that are targeting called CTLA-4 and PD-1. However, they made some modifications to get these to be more active and also potentially work in other ways, like getting rid of T regulatory suppressive T cells. There was already a phase one study that was presented at a cancer meeting called GI ASCO, or gastrointestinal ASCO cancer meeting that was from a couple years ago. And here, this is some of that preliminary data that then was published in 2024 and again, you see what’s called this waterfall plot, where we’re starting at the baseline. That doesn’t mean there’s zero tumor. It means that’s where people started off at when they entered the trial. And then in blue here you see that this kind of blue wave down here is the tumor shrinkage, because it’s becoming smaller. And again, you see that some of these were almost complete responses. The thing about the blue versus red here is that the blue were patients that didn’t have any history of liver metastases from colorectal cancer when they enrolled. In the trial, the pink is any active liver metastases, and green was liver metastases, but they had been treated, for example, with localized chemotherapy or radiation to try to get those liver metastases to be inactive. And you can see that there were more responses in the patients that did not have liver metastases, than in colorectal cancer, where it was metastatic to the liver. Based on that, the company decided that they would focus a phase II, a later phase study in patients that had colorectal cancer without liver metastases. There had been some early data released from that at our GI cancer meeting this year that shows that there is about a 20% response rate. And this is stacked up now because it’s a phase II study a little bit later, although still being used as a later line of therapy, and it’s been used compared to other drugs like regorafenib or Lonsurf. And there are a lot more responses we’re seeing in the Bot-Bal combination than in the other two chemotherapy types.

Dr. Bridget Keenan 36:10
I mentioned that there can be these autoimmune like side effects, and sure enough, we are seeing diarrhea or colitis and hypothyroidism as two of those autoimmune like side effects. So I’m going to switch gears now and talk about Oncolytic viruses. This is a very, I think, quite unique idea to take the idea of viruses that can infect our cells and then lyse them, or basically break them open in the process killing them, as a way to show our early immune cells what kind of proteins are present in the cancer. So the Oncolytic viruses are modified so that they won’t infect normal, healthy cells, but they will only infect and grow in cancer cells where there’s already some defect in their way that basically their antivirus software, there’s some defects there, and we’re taking advantage of that. So now we’re specifically getting these viruses into cancer cells. The cancer cells are breaking open, and these early immune cells here you can see, called dendritic cells, are taking up those parts of the cancer cell. Also, there’s some sort of red flags here going on in the way that the virus kills the cancer cell, and so that gets these dendritic cells very excited or activated. They can then show this to a T cell and get these T cells, or soldiers of the immune system, to go after the cancer. This is, I think, a very intriguing idea. There’s been some activity in other cancer types. I haven’t seen any data yet for colorectal cancer that’s that far along. There was one of these Oncolytic viruses that was further modified to also have an immune activator called CD 40 in it to further try to activate the immune system. This was a paper that came out recently, and they did enroll patients with colorectal cancer as well as other cancer patients,. And with the oncolytic virus that expresses CD 40, there weren’t any responses. With this alone, there were some cases of stable disease for a while, and so now they’re thinking about pairing this with other types of therapy. Just going back to this idea of clinical trials, with early phase we show that there is safety, that is our main goal, and hopefully some benefit as well. And then once we show that something is safe, but maybe we need to get more activity with it, we can think about how to best combine it with other therapies. So I would say Oncolytic viruses are exciting, but probably a little bit early on in terms of how they’re being used.

Dr. Bridget Keenan 38:53
Gonna move on to talk about CAR T cell therapy. I mentioned that one way we could overcome the numbers game in T cells versus cancer cells is just to give patients many, many T cells, millions, in fact. And the other thing we’re doing with a car T cell is that we’re putting other genetic modifications into this T cell. So we’re making sure that all of these T cells that we give back to a patient have a receptor. That’s what the CAR stands for, is Chimeric Antigen Receptor. So here is a quick diagram to show generally how this works, although this could be an hour long lecture in itself about CAR T cell therapy. So I’ll be pretty brief. I want to get to the end so we have time for questions. Essentially, we’re going to, oftentimes make these from a patient. Sometimes they’re also made from healthy donor blood. So we isolate these T cells, we put in the CAR or the receptor that binds the cancer, we grow up many of these, and then we give them back to the patient. After we give some preparative chemotherapy. There are variations on CAR T cell therapy.

Dr. Bridget Keenan 40:00
One of these is TCR T cell therapy. If you remember back to some of my early slides, TCRs depend on seeing a cancer protein in the setting of an HLA. So it does mean that these TCR T cell therapies are specific to someone’s HLA type, whereas the car T cells don’t depend on that. Yet another way to use T cells to fight cancer is to actually get them, instead of from the bloodstream, from the tumor themselves. These are called TIL therapy, and so often a large tumor mass is taken out or a biopsy, and then we can get these TILs out of the cancer, grow them up in a lab and get ready to give them back to a patient. Again, the idea here being a numbers game and also having more specific cancer fighting T cells. There are some specific side effects associated with CAR T cells, or other types of T cell therapy. Namely, one is cytokine release syndrome, and this is a flu like syndrome that happens from these cytokines or inflammatory proteins that are released when we give the CAR T cells to patients. It’s generally experienced as a flu like syndrome, so fevers, chills, it can lead to things like low blood pressure or higher heart rate, even problems with breathing. I would say the majority of patients have this come on within a few days of CAR T cells, and it can resolve pretty quickly as as long as we’re very efficient about treating it. And we have special, special medications that can treat the cytokine release syndrome. But there are cases where this can be more severe.

Dr. Bridget Keenan 40:00
Here’s one CAR T cell trial that I presented at the GI cancer meeting this January. This is a type of CAR T cell against something in the colorectal cancer called GCC. And what the company did here, was they combined it with another CAR T cell targeting something called CD 19. CD 19 is on our normal B cells, which live in the blood. And the idea here, without getting into too much science, is really just to kick start a reaction to get some of these bystander CAR T cells to help the GCC CAR T cells find and kill the colorectal cancer cells. So far, we treated nine patients across two different dose levels, and you can see here from our our smaller waterfall plot, that we are having some good responses, some patients that have had dramatic tumor shrinkage, and this is just looking at their target lesions that we’re studying for the clinical trial. One of the other side effects, in addition to the cytokine release syndrome, though, is that if the target of the CAR T cell is on a normal healthy tissue as well as the cancer, they can come under attack. And so in this case, GCC can be on the normal gut. And there have been patients who experience fairly severe colitis or diarrhea from that.

Dr. Bridget Keenan 42:49
Bispecific antibodies, I think this is the last kind of therapy I’m going to talk about today. I mentioned these are like a molecular glue. So what a bispecific antibody is is a drug that can bind to two things. Here you see an example whereit’s binding to an effector T cell and also to a cancer cell. Generally, we can make these bind to similar things on the Tcell, but what we’re really varying when we’re testing different drugs in the clinic is what it’s binding to on the cancer cell. And we already have some ideas of what we could target in colorectal cancer by binding both at the same time. It’s acting like molecular glue or a bridge to bring the T cell and the cancer cell together so that the T cell kills the cancer cell. It can have some side effects that mimic what happens with CAR T cell therapy, namely the cytokine release syndrome, although, I would say so far, would be seen as more, a less severe version of what we sometimes see with CAR T cells. And this also doesn’t require as much preparation as CAR T cells. These are drugs that are ready to give compared to CAR T cells, that often have to be made personalized for someone.

Dr. Bridget Keenan 43:56
Here is one example from a trial that’s ongoing, but already has some early results. This is a drug from a company called Regeneron. And the drug is Regeneron 7075 it’s a T cell engager, or bispecific antibody that targets EGFR on the cancer cell side and on the T cell side. It’s latching on here to one of the main receptors on the surface of the T cell, bringing them together. EGFR, some people may have heard of because it’s a target of many other cancer drugs, including some are that are already approved for colorectal cancer, but this is using EGFR in a slightly different way to flag it for the immune system. In an early result published about this at a cancer meeting back in 2024 there were 94 patients at that point that had been treated with this drug, also combined with a checkpoint inhibitor called cemiplimab, and 15 of those patients who had colorectal cancer and did not have liver metastases were treated. Out of that total 94, their response rate was about 20% so 20% of cases with tumor shrinkage. And disease control, meaning either stable disease or tumor shrinkage, was about 80%. There was one reported response in a patient with liver metastases, and they’re still analyzing further data about whether this idea of liver metastasis matters or not for this drug like it did for the Bot/Bal trial that I showed you. To recap on some of these clinical trials, there are many strategies that are ongoing right now. They have some similar side effects, but some of them can differ by the type of immunotherapy that’s being given. And we covered a couple types Oncolytic viruses, immune checkpoint inhibitors, and different types of T cell therapy, such as CAR T, TCR-T cell therapy and TILs. So hopefully I’ve allowed plenty of time now for some questions, and I’m I’m happy to cover anything that I didn’t get a chance to or go back and and talk through something that I may have gone through fairly quickly.

Manju George 46:08
Okay. Dr Keenan, thank you very much. That was a very comprehensive talk. I think if you can go back to the TCR-Ttrials and then tell us more. Like, for example, some of the CAR T trials have not been so successful, where they found that it was safe, but they were not seeing any responses. So what’s different in this particular strategy, that you are seeing some responses, right? Exciting to see that!

Dr. Bridget Keenan 46:43
Right. So actually going to talk a little bit more about this trial that I presented at GI ASCO this past year in an abstract there. I mentioned that a couple things that are unique about this program. So one is that we are using these CD 19 CAR T cells as sort of a bystander to jump start the response. And to explain more about that, we all have B cells in our blood. B cell cancers also express CD 19. So one of the first approved CAR T cells was a CD 19 targeting CAR T cell for types of hematologic malignancies or blood cancers. Those are already FDA approved, and they’re highly successful in some patients with lymphoma and leukemia. So the company that is running this trial is kind of used that idea of we know that those CAR T cells work well, can we use them to get an initial response that then helps the CAR T cell that targets the colorectal cancer?. I think that could be one factor in the success. The other thing is targets are hard. We don’t know what the right or best target is. So there’s a lot of clinical trials I gave, to try to give one example of each of these types today. But there are many, many other CAR T cells in the clinic, and they’re all targeting a variety of different cancer proteins on colorectal and other solid tumors. And right now, we just don’t know the right balance between safety and how well that target works in that cancer type. So that’s another factor. And then the third thing that goes into making these CAR T cells, or TCR T cell therapies, is other engineering. What that means is that in addition to putting in something that binds onto the cancer, there can be other, I call them bells and whistles, right. There can be other things that help that cell attack the cancer. It might be a cytokine, an inflammatory protein that that CAR T cell makes that helps it attack the cancer. It could be something that helps it track where the cancer is. It could be a proliferation signal that helps that CAR T cell survive in the tumor micro environment, helps it grow over time and makes it more durable. So there are a lot of things that are being tested, and we don’t know which one of these strategies is the best. And we can’t use them all at once, because right now, we’re still also working on safety, so we have to do this one step at a time, unfortunately.

Speaker 1 49:13
Okay, okay, thank you very much for that answer. So again, going back to this. So is it like combining, you know, the anti CD19 CAR T cells, like a certain proportion of it, and then taking the CAR T targeting GCC. Is that how it’s done? Or is it, like, very complicated other methods?

Dr. Bridget Keenan 49:34
Are you asking how is it made? How do they make the treatment?,

Manju George 49:39
You’re explaining it very simply, saying that you’re combining both and you’re targeting the T cells, and so is it like a certain proportion of those cells combined with a certain proportion of the actual the CAR T specific to GCC? Is that how its done?

Dr. Bridget Keenan 49:54
Yeah, so that’s another good question. In the case of this clinical trial, they’re actually giving two separate versions of the CAR T, they’re not on the same cell. But there are clinical trials that are also testing, what if we not only went after one thing on the colorectal cancer? What if we gave a CAR T, for example, that is targeting two things on the colorectal cancer? Maybe that would help it find the colorectal cancer or make it more specific. So that’s another idea that’s out there and being tested. And I think we don’t know which of these ideas is the best. I gave a couple reasons why we see responses in this trial, but we really don’t know which one of these strategies is the best yet.

Manju George 50:33
Okay, okay, so we can look at there are some questions in chat, and we can look at that. The first question is, what do you think about Immuno score, or other ways to get a sense if immunotherapy is a better fit.

Dr. Bridget Keenan 50:45
So the immuno score is something that has been studied. I haven’t seen it being used in clinical practice. I think one of the challenges is that when we get molecular testing done on a tumor, meaning when there’s a biopsy or surgery, and then we send it for first diagnosis, what kind of cancer is there? And then secondly, mutations, so, what kind of mutations are in the cancer? Immuno score is not a test that I have seen that’s run as part of that standard of care process. I’m not sure if there’s, like, more of a backstory there to why we do or do not use that. I’m sure there is data to suggest whether that should be done. However, it’s not something I’ve seen used in clinical practice, so it isn’t something that we have available to us as standard of care that’s being done. I know that some companies are starting to offer more advanced testing on patients tumors, looking at things like the immuno score, looking at proportions of T cells or other immune cells. One of the challenges is they just haven’t been prospectively tested because we don’t commonly get them and all have all that information available. So compared to something like the tumor mutation burden or MSS or MSI high status, we haven’t done the trial to show whether that correlates with response or not yet. So I think it can give us hints, and it’s good to have these hints when we’re thinking about how to navigate to which kind of therapy, but they’re not going to tell us about what’s available to you that is FDA approved or not.

Manju George 52:25
Okay. okay. I know a little back story about the immuno score.

Dr. Bridget Keenan 52:30
Feel free to share. Yeah.

Manju George 52:32
It seems that the company, it was a few years ago before the CT DNA testing became very popular. So once they saw Ct DNA testing, they just shelved the immuno score. But they had some kind of contract with some trials in Europe, so where it’s originally from, so they’ve done it. So I actually knew a representative who worked in the company, and then I did talk to somebody saying that there was a lot of interest now that they’ve shown that, especially immuno score, IC is the particular one used in this Atezo-TRIBE trial, they did it and they showed something. So we’ve been asking them to say that probably there is a lot of demand, maybe now is the time to bring it to market. So anyways, there are a couple of other questions. Do we know why CRC tends to be MMR proficient, low TMB?

Dr. Bridget Keenan 53:18
I don’t think we have a great answer to that, although I will say that it’s not unique to colorectal cancer. So actually it’s almost the counter is true that we more commonly see this MSI high pattern in colorectal cancers versus all tumor types in general. So especially when I talked about Lynch syndrome, the main cancer type, we think about looking out for if somebody knows that they have that inherited predisposition is colorectal cancer. And then there are a number of other cancer types as well, but so we actually maybe more commonly see MSI high in colorectal than in other tumor types. But we don’t really, I don’t think we have a good understanding of why that is, and why that happens spontaneously sometimes, which is the majority, only a small fraction of those are actually inherited within a family.

Manju George 54:09
Okay. The next question is, why is the presence of liver metastasis correlated with the lack of response to Bot/Bal or a low success rate with immunotherapy in general?

Dr. Bridget Keenan 54:19
Yeah, so that’s a great question. One I didn’t have time to get to, but I anticipated might come up. I also don’t have one single answer for that yet, but a couple comments. So it’s it’s a really big area of interest, and a lot of people /researchers are starting to look into this. One comment is that it doesn’t seem like it’s just related to colorectal cancer, there’s actually data from other tumor types, including ones that respond pretty well to immunotherapy, like melanoma, where it seems the presence of liver metastasis is a inhibitory factor in responses to immunotherapy. There’s probably something about the liver. It is a very, what we would call tolerant organ, where, it’s all of the time our blood is being filtered through there, and there are a lot of microbes from, for example, the gut, from everything we get exposed to. And so the liver can’t have a reaction all the time to those, or it would be constantly inflamed. So there’s a little bit already of a predisposition to dialing down the immune response in the liver. That might be one reason. There could also be suppressive immune cells that are generated in or around the liver, like these T regulatory cells that shut down that immunotherapy response. But I would say this is a great question, because it’s a big area ofinterest in the research field, and we’re trying to figure that out. The other comment I want to make is that we don’t know if this holds true for all kinds of immunotherapy or it’s just checkpoint inhibitors, and so that work is also ongoing. I mentioned that maybe there was some hint of that in one of the bi specific T cell engager trials, but that isn’t definitive yet. That was very early data. They’re analyzing further data now in liver metastases or no liver metastases, to understand that. And then in terms of CAR T, I don’t think we really have any data yet about whether that matters or not.

Manju George 56:14
Okay, okay. So, I mean, going back to, I think we have a few minutes, so going back to patient choices, like if they have say, for example, anytime there is anything new, people want to see how does that apply to colorectal cancer? Right? So, based on your experience with this particular CAR T trial, do you have any suggestions for people when they hear about a bunch of trials, especially CAR T ones, is there some criteria that they can use which — I know that you can’t predict which one will be successful– but are there some pointers to keep in mind when patients are looking at these kinds of trials?

Dr. Bridget Keenan 56:54
I think it’s really hard to know what type of therapy to choose if you have multiple options, because bi specific T cell engagers and cell therapies, both CAR T, TCR-T and TIL, they’re all pretty early, and we don’t have trials that are comparing one versus another, so that makes it hard to choose, and I think a lot of times, then other factors come into play, like what trial is available to you? Sometimes these early phase trials have very limited spots. Also they may only be available at certain centers. So thinking about the logistics of enrolling in a trial and how much time that might require somebody to spend traveling back and forth, and the last thing is balancing side effects. So the side effects for some some but not all of the CAR T cell therapies can be fairly severe and more, I would say maybe a higher level of risks, and then some other therapies. The thing is, we’re still learning with early phase trials, we don’t know for sure, so that any early phase drug is going to have some element of uncertainty about what to expect. And that has to be something that people are well informed about when they decide if a clinical trial is right for them.

Manju George 58:07
okay, okay. And then I think, right now, is it IL-12 that you can give for the cytokine storm, right, things like that? So there is more information.

Dr. Bridget Keenan 58:18
Yes, we do have a good drug, an anti IL-6, blocker for cytokine release syndrome that is commonly used. And we’ve learned a lot from these CAR T cells that I mentioned, that already got FDA approved for blood cancers. So a lot of the management of the side effects is the same because we know about how to deal with that.

Manju George 58:37
Okay, I will go to the next question and skip the next one. So it seems that there is some success with, targeted therapy towards VEGF receptors and then immunotherapy combinations in some trials for MSS, CRC, particularly in China. Do you think that there will be more of these combination trials?

Dr. Bridget Keenan 58:57
Yes. Short answer, yes. One of the things I didn’t talk about or have time to cover today is, how do we combine immunotherapies with other therapies that are already approved for colorectal cancer? One of those is a VEGF targeted antibody called Bevacizumab. Others have heard of Mvasi/ avastin, it’s the same type of medication. So we may be able to use those in combination with some of these immunotherapies that are in clinical trials. The advantage of that is those therapies try to inhibit some of the abnormal blood vessel formation and other suppressive immune cell types that are in the cancer, and so we combine that with immunotherapy, we may have a better effect than either therapy alone.

Manju George 59:42
Okay, okay, this is the last question. So question is, can a metastasis be used to harvest cells for TIL trials and then or is it only the primary tumor?

Dr. Bridget Keenan 59:52
No, it could actually come from a metastasis. And, I think, there may be some requirements about the size to make sure that they can harvest and grow enough TIL from it, but generally, it doesn’t really depend on where that cancer has started out.

Manju George 1:00:12
Okay, I think, that’s all the questions. And it’s 5pm here. Thank you so much. This was very, very informative, and hopefully we can have the next session in another two years, two or three years with more. By then, probably the field will change a lot.

Dr. Bridget Keenan 1:00:28
I sure hope so.

Dr. Bridget Keenan 1:00:30
Okay. Thank you very much. Thanks to everyone for attending. A recording of this video, and the transcript will be available on COLONTOWN University. Okay, everyone, take care. Bye.