A worrying trend is emerging in colorectal cancer. Cases are rising in adults between the ages of 20-50, even though the overall rate dropping. Given the necessity of early detection for current treatments, there is a growing need for effective treatments for advanced cases, where immunotherapy shows tremendous potential. At the 2020 CRI Virtual Immunotherapy Patient Summit, we hosted a special breakout session on colorectal cancer and immunotherapy to educate and empower patients, caregivers, and advocates.
Scott Kopetz, M.D., Ph.D., FACP, the vice chair for translational research at The University of Texas MD Anderson Cancer Center, discussed what patients with colorectal cancer need to know and answered audience questions.
Dr. Kopetz opened the session with an overview of the characteristics of colorectal cancer, differentiating between microsatellite stable tumors (MSS) and tumors with high microsatellite instability (MSI-H). He also noted that colorectal cancer tumors with a high tumor mutational burden (TMB-H) are more prone to immune-attack and more responsive to immunotherapy.
He then reviewed available immunotherapies for colorectal cancers like checkpoint inhibitors and targeted antibodies, as well as ongoing immunotherapy research in colorectal cancer. Scientists are examining the role of the microbiome in patient response to immunotherapy as well as how biomarkers can be used to determine the best course of treatment for a cancer patient.
During the question and answer portion, Dr. Kopetz reflected on the importance of ensuring patients and caregivers are educated and aware of all treatment options and clinical trials available to them at the time of diagnosis. He explained that clinical trials are not only an “avenue” to provide patients with the best cutting edge therapy, but also to provide scientists with an opportunity to improve future therapies by gaining insight into “how well or if these therapies are working for patients.”
Furthermore, Dr. Kopetz discussed Lynch syndrome, a hereditary mutation that is associated with increased risk of colon cancer, endometrial cancer, and other types of cancer. He explained that screening for Lynch syndrome can allow patients to detect and prevent cancers from developing at early stages. He also explained that PD-L1 checkpoint inhibitors are a promising treatment for patients who develop Lynch-related colorectal cancers.
Colorectal Cancer and Immunotherapy Session Transcript
Tamron Hall: It's my pleasure to introduce Dr. Edmund Scott Kopetz, who will be leading the colorectal cancer immunotherapy breakout session. Dr. Kopetz joins us from the University of Texas MD Anderson Cancer Center in Houston, Texas, where he is a board certified medical oncologist in gastrointestinal medical oncology and a vice chair of translational research. Brian Brewer from the Cancer Research Institute will be joining us to share your questions with Dr. Kopetz. So please be sure to put them in the Q and A box. Thank you, Dr. Kopetz for being here with us today.
Dr. Kopetz: Thank you, Tamron, for the nice introduction and really pleased to be able to participate today in what is clearly a wonderful avenue and venue to share some exciting updates in the field. So wanted to start off with some overview of the landscape of colorectal cancer and some of the characteristics that we see. So there's two terms that we'll be using in our discussion that I think are really important for colorectal cancer to really understand the role of immunotherapy. And this is a microsatellite stable (MSS) and microsatellite instability high (MSI-H) tumors. And we discuss those as MSS or MSI-high tumors. Now because we always have to make these a little more complicated. We sometimes call this deficient mismatch repair tumors as well, the MSI-high. But these have very different characteristics. And what we see is that there is immune characteristics within these different cells that create a very different perspective and the MSS tumors that we'll be talking about, really 97% of colorectal cancer patients that are metastatic and the problem is either that the immune cells can't get into the tumor or that they're really no immune cells that are present.
And conversely, in the MSI tumors, the tumors are packed full of immune cells and they're primed and ready to attack the tumor with just a little bit of help. That little bit of help on the next slide comes in the form of immune checkpoint blockade. And in colorectal cancer, we have approval for three different checkpoint inhibitors, Ipilimumab, Nivolumab, Pembrolizumab, as seen in other tumor types as well. And we think about these antibodies as really being an immune checkpoint targeted, but sometimes we'll use the term immunotherapies to discuss targeted antibodies, but the goals are very different here. It's really about shutting down the growth factor pathways and it's less about stimulating the immune system. Next slide.
So I think the promise in immunotherapy in colorectal cancer is really fundamentally understanding where a patient's tumor is starting from. What degree of immune response is preexisting? And then understand what are the things that we need to do to get the immune system to engage and attack the tumor. And for most colorectal cancers, the microsatellite stable, it's really about how to initiate that first immune response or to overcome a hostile tumor microenvironment as we can discuss, and a lot of complex interactions, what biomarkers we can use to define those different subgroups and also understanding the role that the patient's microbiome may play in modulating some of the function of those immune cells. So really an area where we're learning a lot, but I think at the same time, as we'll discuss, for colorectal cancer, there's still a long way to go to really fully have the promise of immunotherapy for colorectal cancer for the large majority of our patients. In colorectal cancer I think there's a tremendous amount of opportunities, but also a lot that we still don't fully understand.
Brian Brewer: Well, thank you so much, Dr. Kopetz. Welcome. And thank you for joining us. I'd also like to thank the MD Anderson Cancer Center for being one of our partner host institutions and allowing you to free up your time to join us today. I know we've got a lot of questions coming in. Before we get to them I'd just like to remind our audience that you can put your questions for Dr. Kopetz in the Q and A box. And if you haven't scheduled a clinical trial navigator consultation yet those are free, confidential and one-on-one and available to you. So please feel free to do that at any time. So let's jump in. Our first question, Dr. Kopetz are there any promising clinical trials for colorectal cancer? And before you answer that, can you briefly explain what clinical trials are and why they're important?
Dr. Kopetz: Oh, absolutely. So in oncology, we think about clinical trials as really the avenue to provide best cutting edge therapy to patients, but also opportunities to really understand how well or if these therapies are working for patients. And so there are various different stages of clinical trials where the studies and the agents are more mature than others, meaning they've gone through more testing. And so it's really important when you think about clinical trials to discuss with your oncologist, what's the phase of the study as we talked about it, to understand what stage of development. And a key question when we're talking about clinical trials is saying, is this an agent that has shown activity in the past for other patients with metastatic colorectal cancer? And what we say is has it demonstrated proof of principle, meaning is it actually working like it says, even if it's just one patient. Or is it an idea that's still very early and we're still trying to understand how best to engage with it.
So the second part is, of course, what are those areas that we've seen activity? And as I mentioned before, really, we think about the treatment of colorectal cancer very differently for microsatellite instability high, MSI-high tumors, really we're getting activity with checkpoint inhibitors. Everyone's responding, but a very good, high numbers of patients responding. And amazingly when patients are responding, they're responding for a long period of time. And we're seeing patients that are cured, I think it's fair to say, in their metastatic disease with immunotherapy and MSI-high. We say that term very cautiously, but it's been now many years for some of these patients off of therapy that we've been monitoring and the disease hasn't recurred.
So I think the promise is actually very high for that subgroup, but it's a bit of a night and day because unfortunately the 97% of metastatic patients, the microsatellite stable, it's a very different barrier. And so we think about clinical trials here, we're thinking about ones that are very much earlier in development where we're trying to understand different strategies. So one, category of trials is really how do you release a preexisting immune response, right? The patients that may have an immune response already started in the body, the T cells, the attacking immune cells are already primed, but they're just prevented in that last little bit from doing what they need to do. And there, a lot of the studies that are promising are looking at how do you break down that microenvironment. And we say microenvironment, it really means that you've got this ball of the cancer and there are factors being secreted by the cancer that really preventing those T cells from getting in.
So these are areas like TGF-beta inhibitors, Adenosine, pathway, ones that are showing promise potentially to break that down. But the other is recognizing that a lot of colorectal cancer doesn't have that immune response already, right? The T cells don't recognize the cancer cells yet, so we have to train them. Right. And so the efforts around vaccine, for example, oncolytic viruses, things that can go in and lyse the cancer cells and generate an immune response against those. Those are all things that are, I think, promising in that space. You know, we're hopeful for example, because one of the same technologies being used for the COVID vaccine, one of the first ones they'll probably be out of the gate, is actually the exact same technology that's going to be deployed against colorectal cancer on upcoming studies. So there's a lot of novelty and exciting areas coming in that space.
And then the final category, I would say, is this brute force approach where you grab a T cell, you grab a tumor cell, and then with some very sophisticated immunotherapy you bring them together and kind of force them to engage each other, or bring in CAR T cells, engineered cells, into the environment that are designed to target those. So those kinds of brute force approaches are other areas.
So as you can see, it's a wide spectrum of different therapies, and I think a number of those that are showing some promise.
Brian Brewer: So in essence, how can you fan a smoldering immune response into a raging fire that destroys the tumor, or how do you just break on through, and get through that cancer's defenses?
Dr. Kopetz: That's right.
Brian Brewer: A question we have is, someone is on chemotherapy and wondering if they can get immunotherapy afterwards, and/or are chemo and immunotherapy being tested together in some of these trials?
Dr. Kopetz: Yeah. So they are, and we used to be concerned that you couldn't combine them, that they weren't, you maybe inhibit some of the activity of the immunotherapy by too much chemotherapy. But I think increasingly recognizing that these can indeed be synergistic, that there could be benefits of doing these two together. So, really there's no difference if you do chemo and then immunotherapy or the converse. And actually we have a number of studies in the field, including a study for patients with MSI-high cancer, where we know chemo works, immunotherapy works. Ask the question, well, what if we put them together? Is that area work? Will that work better? So I think some exciting opportunities, but really they can be complimentary approaches.
Brian Brewer: We have a question coming in now. I'm on maintenance therapy. And I think that means maintenance immunotherapy, which they say they'll have to do that for the rest of their life. Is that true? How long have you had patients on maintenance treatment?
Dr. Kopetz: Yeah, so we use the term maintenance to describe chemotherapies, and we can have patients that are on for prolonged periods of time. Most of the time with chemotherapy we eventually will see patients with the disease that will progress, meaning the cancer just finds ways around the chemotherapy and eventually will progress. And it may be two or three years of maintenance chemotherapy.
Immunotherapy, because it works in a slightly different way, what we see is that patients have been on immunotherapy and have had a response, especially MSI-high, predominantly talking about here, but where we see that response, at six months it's still there. At 12 months it's still there. Very rarely are patients progressing after that point. So, for patients that are able to have the disease control, a response can go on indefinitely. So the question is, how long do we keep the treatment going? And we don't know, to be honest. We think the practice patterns are somewhere between one and two years of treatment. And then typically stopping and watching at that point.
Brian Brewer: We have a question coming in on this, a similar topic, I think, or related. They were being treated with a PD-1 inhibitor. I guess it failed. And they've learned that many immunotherapy trials include ineligibility for patients who may have been treated with a PD-1 before. And they want to know why. Is there a change that puts that patient at risk from receiving a similar pathway inhibitor, or is it just a study reasoning for purity?
Dr. Kopetz: Yeah. I'm afraid it's typically more of the latter a lot of times. I think we are starting to see that that is less common now. So some of the newer studies are removing some of that restriction. As we're moving away from just doing studies of additional checkpoints, PD-1 plus another checkpoint, and another checkpoint, where there may be some concern. As we start to think about cellular therapies or vaccines, I think that becomes less of an issue.
Brian Brewer: Okay. Thanks for that. Here's another question. You mentioned MSI-high. And so the question coming in is how do you determine that you're MSI-high? What's involved? What sort of tests are involved, and are those given to every colorectal cancer patient?
Dr. Kopetz: So, they should be done to every patient. The guidelines now, for the last several years, is regardless of your stage, for your age, or your risk factors for a familial or hereditary syndrome, everyone should be getting tested for MSI-high. That's done traditionally by immunohistochemistry. So we stain four slides and look at four proteins and see if any of them are missing. But there are older techniques like PCR or other molecular approaches.
Increasingly though what we're seeing is that MSI testing is being built into the large sequencing panels that we have being done. So, many of the panels that you're getting a test back that has several hundred genes on it, they'll typically also incorporate some component of MSI testing. And failing that we can get a sense that patients are MSI-high, because one of the unique features of that is that the mutation burden is very high. And so this idea of tumor mutation burden, like we know in lung and other tumor types, you see the exact same thing in colorectal cancer. MSI-high will have a very high tumor mutation burden, 20 or above typically.
Brian Brewer: They're asking what are the specific tests that, should they be asking their physicians for these tests? Or are these done automatically? I'm wondering if this is about genomic sequencing or genetic testing.
Dr. Kopetz: Yeah. Yeah. Absolutely. So for colorectal cancer we recommend the testing for those four proteins by IHC, and that is probably done in the vast majority of patients. But also molecular testing, looking for KRAS, NRAS, BRAF mutations. But there's a lot of smattering of less common mutations that are now being captured on some of these larger panels. So I do think that the best practice is to do a larger panel testing to capture the most common ones, but also the broad ones. So I think, for interested patients, I think it's worth talking to your oncologist about doing a larger panel testing that could incorporate all of that, including MSI.
Brian Brewer: Well, we have another question coming in from a member of our audience. What is Lynch Syndrome?
Dr. Kopetz: Yeah. So Lynch Syndrome, also known as hereditary nonpolyposis colorectal cancer, or HNPCC, is a hereditary syndrome that is associated with increased risk of colon cancer, endometrial cancer, but also a smattering of other less common cancers as well. This is associated with the same phenotype of MSI-high that we talked about. So it's actually a mutation in one of those four proteins that are responsible for DNA repair. And so when there's a mutation in one of those mismatch repair genes, then you can get this high degree of tumor mutation burden.
We think about our normal healthy cells are dividing, and we have 3 billion DNA codes that have to be replicated perfectly. And the estimate is, in our normal healthy cells, when any cell divides, maybe there's only five or six errors in total. Which is just amazing proofreading ability. And that's because the body has these proteins that are responsible for proofreading all the duplication that's done, and these are the mismatch repair proteins. And so the problem in these hereditary syndromes is that you may have a defect in one of those. And so every time a cell divides it now may generate more mutations. And maybe it has 20 mutations that develop instead of the small ones. So that can then lead to this risk of cancer. But it does lead to a very immunogenic type of cancer, and so Lynch Syndrome is a part of the MSI-high sub-group that can respond to immunotherapy.
Brian Brewer: So people with Lynch, their genetic typos are getting passed to cellular proofreaders, so to speak.
Dr. Kopetz: That's right. Spell check is off.
Brian Brewer: Not good. So is immunotherapy the recommended treatment for cancers caused by Lynch Syndrome in all cases now?
Dr. Kopetz: Yeah, it is in many settings, yes. So if the cancer has spread outside of the colon and the lymph nodes, then it's considered a standard of care to just start right in on that treatment. There are studies ongoing right now, including a large study across the U.S., into NCTN, or the U.S. cooperative group system, to do studies that's looking at the role of immunotherapy, a PD-L1 inhibitor, in earlier stage, stage three.
We don't know that yet, we're hopeful, fingers crossed, that it'll be a positive study and show benefit, but right now it's standard of care for stage four for metastatic patients.
Brian Brewer: Great. We have a question coming in now about incidents and age. The recommended colonoscopy age these days, I think, is 45. This person is saying that they're significantly younger, I won't betray your age, but they're wondering why they've seen... and now there seems to be more and more younger people are developing colorectal cancer, even at advanced stages. Is there a reason behind that?
Dr. Kopetz: It's one of the big mysteries in the field right now. There's a big effort and a big push to try to understand that further. But the bottom line is that yes, what we are seeing is that incidents of colorectal cancer is increasing in younger patients, and it looks like that anyone born in the early to mid-1960s or later has a higher risk of colorectal cancer than the same age people were in earlier birth cohorts, as we say.
So what that means is that there are absolutely patients now in their thirties and forties who are seeing that rate increase. We know that there's differences in regions in the U.S., even around the world, this is a worldwide phenomenon. There are differences in the location of the tumor, they tend to be more rectal or rectal sigmoid in location. And we don't have a good understanding of what the underlying etiology is.
Brian Brewer: Etiology, what is etiology?
Dr. Kopetz: Oh, etiology means “the reason why.” Why is that? Why is that we're seeing that? The answer is, we don't know. There's a lot of hypotheses that something has changed in the environment, that there could be an exposure that we're not appreciating, could be that some of the changes in obesity over the years is a part of it; I think that's only a small part. And then thinking about, are there changes in the microbiome that could be part of this as well?
The cause of this is not clear, but it is something that we're definitely seeing an increase. And this is amazing, because due to screening, the incidents of colorectal cancer above the age of 50 is falling. So it's a success story for early detection, but at the same time, we're seeing that increase. The estimate was even by the year 2030, that we could see more than a doubling of rectal cancer under the age of 45. So it is something that we need to address. The good news is that we used to be, until very recently, that the screening age was 50, and now it's kind of come down to 45. But the problem, of course, is that there's still lots of patients getting diagnosed earlier. It's still less common than older age, but we're seeing that occur more frequently.
So I think there's a need to try to understand, are there other modalities of screening? We may not have the resources to screen everyone with a colonoscopy regardless of age, but are there other screening approaches that we can do? I think there's a lot of work in this area, and I'm hopeful we'll have some additional insights that appear over the next few years.
Brian Brewer: Absolutely. So no surprise, a lot of questions coming in about COVID. Any special consideration for colorectal patients, both in terms of are they at greater risk of contracting COVID, and should they have any concerns about getting vaccinated?
Dr. Kopetz: Yeah. Good questions. So when COVID first started, there was a lot of concern that the outcomes of cancer patients who develop COVID would be substantially worse than the general public, and I think we do see that the risks are slightly higher, but they're nowhere near as draconian a risk as we thought initially. So I think the message that I would say is that we don't think that colorectal cancer patients are necessarily at a higher risk of getting COVID, but they are at a higher, slightly higher risk of getting complications from it, of having a more severe infection. Although the healthcare system has learned a lot and the outcomes of patients treated with COVID is still much better, we indeed can still see cancer patients that get very sick and even die from COVID.
So with the vaccines that are coming now, we really do not have any concerns about unique risks associated with colorectal cancer patients. These are things that are safe to do, we think, with a variety of therapies. Of course, always talk these over with your oncologist, but what we understand at the moment is these will likely be safe for cancer patients.
Brian Brewer: Well, that is a relief, I'm sure, to many, many people. Another question coming in from our audience, and thank you all so much for keeping them going, makes my job easier. "What is the microbiome, and what role does it play in cancer immunotherapy?"
Brian Brewer: Yes. So the microbiome is a term that we use broadly to describe the different types of healthy, normal bacteria that is in and on your body. It is just an amazingly complex set of bacteria. Now, these can be and are beneficial in many areas, sometimes we hear talk about good bacteria in the gut and bad bacteria in the gut that can sometimes cause trouble if it grows too much. But this is an amazingly diverse population of bacteria.
And it turns out that the bacteria can metabolize a number of... or chew up and change a number of different proteins and other things in the GI tract, in the colon, and that some of the things that these cells can... these bacteria can then give off can change how our immune system may respond. It's a very complex relationship, but there's been evidence, a number of studies that say that the features of the bacteria in the gut may influence how well you respond to therapy.
Now, we're still doing these addition studies, so colorectal cancer, for example... so we're launching a study where we're actually taking the microbiome from patients that had a good response to immunotherapy and trying to transplant that over to patients that had a bad response to immunotherapy, and then trying to see if we can now induce a good response in those patients. This is an MSI-high patient. So our understanding of this is still very early, but I think the hope is that we can modulate the microbiome in some way, we may get a better immunotherapy response.
Brian Brewer: So someone is asking, "How can you transplant someone else's immune or microbiome to another person?"
Dr. Kopetz: Yeah. There's a few different ways in the field. One is that you can collect and preserve the bacteria from somebody's stool, the donor. You put them in little capsules after they're kind of freeze dried. The patient, the recipient can take these capsules, and it'll go down, and it'll repopulate. The other is that it can be done through a colonoscopy. You can actually instill the bacteria using a scope into the colon.
Brian Brewer: Another common question we get when talking about the microbiome, we've discussed this at Cancer Research Institute a few times, what can be done to improve one's microbiome through diet or nutrition? Do you often get that question?
Dr. Kopetz: We do, right. The short answer is we think a diverse microbiome is better. We do have to be a little careful because in some mouse studies, for example, if you decrease the diversity, the number of different bacteria, even if you're trying to replace it with a hundred percent good bacteria, you end up with things that are worse off than not. It really looks like the diversity is probably the best advice that we can give right now. It's not about trying to pick the right bacteria and put it in. We're not smart enough to know that yet, but just a diversity, keeping a healthy diet, a lot of fruits and vegetables. We think a lot of legumes, a lot of beans, things like that, they can help in maintaining that good microbiome.
Brian Brewer: A follow up, I think, to the COVID vaccination question: if someone is currently on immunotherapy, have there been any studies done on the potential risks or benefits?
Dr. Kopetz: There have not. We don't know that yet. I think the evidence and the biology about how these vaccines work in different ways are what we have to try to figure out. It really is about making sure that the cells that are attacking COVID don't cross-react with any of the other healthy cells in the body. Right? That's where the design of the vaccine really comes into play.
Brian Brewer: Another question coming in: my dad has stage four colon cancer with metastasis to deliver. His oncologist said that immunotherapy was not an option for him. Do you think I should get a second opinion?
Dr. Kopetz: Most likely your dad's tumor is what we call microsatellite stable tumor, again, 97% of the tumors. In that setting, there is no standard of care. There's no immunotherapy that we have shown that will give responses and improve outcomes. There are clinical trials that are showing promise. What I would say is if you and your father are interested, seek out clinical trials to try to explore the role of immunotherapy, but there's not a standard of care immunotherapy option that's being missed in that setting.
Brian Brewer: When you say bad response, what does that mean?
Dr. Kopetz: Yeah.
Brian Brewer: Are you talking about side effects or whether the treatment is working, I think?
Dr. Kopetz: Yeah. I'm sorry. I may have misspoken there, but yeah. The idea there is really to explore clinical trials, what options that may be. Right now, we don't have any immunotherapies that are clearly showing activities such that they've been approved for treatments and they're not part of the standard of care. It's really now about trying to explore clinical trials to understand and identify options for immunotherapy outside of the standard of care.
Brian Brewer: Well, thank you so much, Dr. Kopetz. Unfortunately, that's all the time we have today for everyone's questions, but I do want to let folks know that Dr. Kopetz will be following up, so keep those questions coming. If we didn't get to your question today, we'll try to answer them in a blog post at the Cancer Research Institute website. Again, I'd like to thank MD Anderson Cancer Center for being a gracious host institutional partner for us and this program. Of course, Dr. Kopetz, thank you for your time.
Dr. Kopetz: My pleasure, absolutely. Thank you for the opportunity.
Tamron Hall: Dr. Kopetz, thank you for sharing your expertise on colorectal cancer and immunotherapy. Thank you all for joining us and participating in the Q and A.