What is Immunotherapy and How Does It Treat Colorectal Cancer?

Podcast Transcript

Scott Steele: Butts & Guts, a Cleveland Clinic podcast exploring your digestive and surgical health from end to end.

Hi everybody, and welcome to another episode of Butts & Guts. I'm your host, Scott Steele, the Chairman of Colorectal Surgery here at the Cleveland Clin Taussig Cancer Institute. Alok, welcome to Butts & Guts.

Alok Khorana: Thanks, Scott. Delighted to be here.

Scott Steele: So, we're going to talk a little bit about something we have yet to talk about on Butts & Guts today, and that's immunotherapy and its relationship to colorectal cancer. But before we get into that, why don't you tell everybody where you're from, where'd you train, and how did it come to the point that you're here at the Cleveland Clinic.

Alok Khorana: Great. I'm a medical oncologist. I specialize in gastrointestinal cancers, which includes colorectal cancer. I did my oncology training in upstate New York at the University of Rochester, and I stayed on as faculty there for almost 15 years. Now I've been at the clinic for about eight years or so. So I'm kind of here in the Great Lakes area, and I have been for a while.

Scott Steele: Well, we are very excited to have you here, and doing a fantastic process of working hand-in-hand with us here with colorectal cancer. So, let's give a high level overview, if you will. People have probably heard of the term chemotherapy, but what is immunotherapy?

Alok Khorana: So, this is a really fascinating, from a scientific perspective a really fascinating area, and it's actually not new. We've known for over a century that activating the body's immune system can lead to tumor regression. There's case reports from the late 19th century even, talking about certain skin infections, that if you get those skin infections, they saw people's tumors regress. So there's been this understanding that the immune system's important for tumors to develop, in the sense that tumors need to regulate the host, which is the patient's body's immune system to make sure that it's sort of deactivated and that allows tumor cells to grow.

What's really changed in the past decade and a half or so is a very sophisticated understanding of how this immune regulation happens, which molecules are important for it, and most importantly the development of therapeutic agents that target those molecules. The two molecules that I think our listeners should know about are PD-1, which is the PD-1, PD-L1s, which together are known as the PD-1 axis program, that one, and CTLA-4, which is both of these sort of inhibit T-cell activation, which allows tumor cells to proliferate. If you're reactivate T-cells by shutting those two molecules down, and there's a host of different drugs that affect those two, those two targets. Then that revs up the body's immune system, makes it active against the cancer, right. So you don't need agents to actually combat the cancer because the body's immune system itself is going to attack the cancer cells and contain them.

Scott Steele: So are there only certain types of cancers that respond to immunotherapy or are you targeting the cancer or targeting specific cells that go towards that cancer? Then the second question to that is let's say I had two cancers; I've got colon cancer and prostate cancer. Could it give the one drug towards both?

Alok Khorana: So conceptually, no. Conceptually, every cancer that grows in the body escapes immune surveillance in a certain fashion, and, therefore, we should be able to identify ways to overcome that escape of immune surveillance and allow the body's immune system to attack the cancer. Having said that it's clear that the immune system's much more important and much more amenable to manipulation by drugs in certain types of cancers. The two in which we've seen the best results are melanoma and kidney cancer. Here it's been clear for several years now that immunotherapies is the way to go, and the success rates have been very high.

But as we've understood these agents a little bit better, it's also clear now that subgroups of nearly all solid tumors, and perhaps some liquid tumors, are also amenable to immunotherapy. One of the classic subgroups that works across all solid tumors is this MSI high or microsatellite instability high cancers, which it doesn't matter where the cancer starts. It could be colon cancer. It could be pancreatic cancer. It could be a cholangiocarcinoma. Immunotherapy is quite likely to work in that subgroup of the population.

So that's a long answer to your question. The short answer is no, it doesn't apply to specific cancers. We think we should get immunotherapy to be able to work across all different types of cancers.

Scott Steele: Great. So back to colorectal cancer, what is the regimen and where does it fit in? I've heard of FOLFOX, 5FU, Oxaliplatin, Irinotecan. Where does immunotherapy go into the regimen or go into the patient with primary? Does it come before the surgery treatment? Does it come after? Is it a third line treatment? How do you figure this all out?

Alok Khorana: Yeah, so that's a rapidly evolving target. In fact, just this week, the New England Journal of Medicine had a paper about pembrolizumab, which is one of the PD-1 antibodies being used up front; so, before any chemotherapy in advanced colon cancer. But the evolution of these agents has been true for the line therapies; so, metastatic colon cancer patients, who've gone through standard chemotherapy drugs and have markers that suggest susceptibility to immunotherapy, specifically the MSI high or microsatellite unstable tumors. In those patients, the initial trial suggested that in the second line, third line or higher line setting, immunotherapy was likely to be successful.

Once we saw the high degree of success achieved in that population, the clinical trials were moved up to the first line setting, and that's what this paper that just came out in The New England, KEYNOTE-177 is the name of the trial, is about is using immunotherapy upfront and comparing versus chemotherapy upfront. For many patients, immunotherapy upfront was very successful, was associated with better quality of life, and was associated with much longer duration of response than we typically see with chemotherapy.

So I think immunotherapy is rapidly replacing chemotherapy in certain segments of the colon cancer population. The one that's very clear is the microsatellite unstable population. A second that's somewhat clear is a high tumor mutation burden, which sometimes but not always goes along with microsatellite instability. So having a TMB that's elevated, and there's various papers describing what that elevation cut off should be, but having a high TMB is associated also with response to immunotherapy.

Scott Steele: A lot of patients when they get cancer, and then they have to go see an oncologist like yourself, you're very, very nervous. So what can a patient expect when they come to the Cleveland Clinic Cancer Center for immunotherapy or to meet with you? Walk us through that.

Alok Khorana: So the process for using immunotherapy is really not that much different than the process for chemotherapy. You meet with a medical oncologist and their team. We go over the expected side effects and how the drugs are administered. All of these drugs are intravenous, just like most chemotherapy drugs are. When the decision's made to move forward with immunotherapy, you go to the infusion center, and you get an infusion of the drug that lasts for a short period of time intravenously. If patients didn't know in terms of the process itself, there's really no difference between chemotherapy and immunotherapy. They're both given at varying frequencies and they're mostly intravenous.

The differences in the side effects with chemotherapy, the side effects are very well known. Because we've had chemotherapy for several decades now, most people know to expect nausea and vomiting, and in some cases hair loss and fatigue. Because immunotherapy doesn't work in a fashion that's anywhere similar to chemotherapy, you don't see any of those side effects. For most people, the immunotherapy is quite uneventful; you get the drug, you go home, and you're not throwing up on the way home, you're not throwing up the next day. But there are some patients who receive immunotherapy who can develop these new class of side effects called immune related adverse effects, irAEs. These are mostly autoimmune type of side effects. They can be as simple as a skin rash. They can be a little bit more complex like a colitis or a pneumonitis, or they can be really rare like an acute hypophysitis or some type of neurological damage and so on.

So there's a whole host of adverse effects, hypothyroidism, autoimmune hypothyroidism that we're increasingly recognizing as being associated with immunotherapy, but which are very different than the chemotherapy effects. But in terms of the logistics of getting the treatment, it's very simple, and it's just as simple if not simpler than getting chemotherapy.

Scott Steele: So Truth or Myth: you mentioned one of these before, but immunotherapy is typically given in a weekly treatment cycle.

Alok Khorana: No, the type of immunotherapy drugs, there's different types. Most of them are every three weeks, every four weeks. We are doing longer durations now so that people don't have to come in as frequently. So you can do them as far apart as every four weeks or even every six weeks depending on the type of drug. For most people, the weekly regimen is not needed.

Scott Steele: Truth or Myth: if I get immunotherapy, I am considered to be immunocompromised.

Alok Khorana: That would be a myth. If anything, immunotherapy enhances your body's immune system, which is why you get all these autoimmune side effects because your body's immune system's revved up and acting against things that are present in organs that are present in your own body. So I would say definitely a myth.

Scott Steele: Truth or myth: even after immunotherapy treatment ends, the body's immune system is able to recognize and attack cancer cells in the future.

Alok Khorana: Yeah, that's a fascinating aspect of this that we don't fully understand. I personally have patients, many oncologists have patients that have done nine, 12, 14, 18 months of immunotherapy. At some point, either they get side effects or they get tired of being on treatment. We stopped, and I've seen patients where a year out, two years out the cancer isn't coming back even though these patients are not on immunotherapy anymore. This is not a majority of patients, but it's definitely a certain subgroup of patients that seem to have longstanding durable responses. Some oncologists are even brave enough to use the cure word, although I don't think we have enough data to support that yet.

So I think more on that to come, but it's definitely one of the exciting things about immunotherapy is the potential for such long-term durable responses that we may be able to not have to treat patients long-term.

Scott Steele: So you mentioned this briefly, but what's on the horizon as far as new research or clinical trials that use immunotherapy for treatment of colorectal cancer?

Alok Khorana: Yes, as I mentioned, we've gone up the chain of treatments for metastatic colon cancer, and we've established that immunotherapy's successful in the first line, second line, third line setting for metastatic or advanced disease. Whether immunotherapy is also helpful in the adjuvant setting is being explored. There's a very large randomized trial in the stage three postoperative setting where immunotherapy is being used compared to standard adjuvant chemotherapy. Neoadjuvant therapy which is commonly used in rectal cancer is also a potentially very fruitful area for using immunotherapy in patients who are susceptible to it. In fact, at the clinic, as you know, Scott, we have a new adjuvant immunotherapy trial open for rectal cancer patients receiving radiation therapy.

Beyond that, I think the big issue is the subgroup of patients who are susceptible to immunotherapy is still a very small minority. It's maybe four or 5% of patients with the microsatellite unstable disease, maybe a couple more percentage with high TMB. I would love to use these drugs in the general colon cancer patient who doesn't have these mutations. So how can we expand the indication for immunotherapy and how can we make cancers that don't appear to be susceptible to immunotherapy become susceptible to immunotherapy, and that's really the biggest task at hand.

Scott Steele: Alok, do you think there's ever any chance that we're going to be able to take out some of the different anti-tumor cells within a patient stimulate them or change them one way, and then inject them back in to be their own chemotherapy or their own attack cells?

Alok Khorana: Yeah, that's one of the approaches that's being tried. I think that that type of approach seems very effective in certain types of liquid tumors, and hopefully we can adapt that to the solid tumor population as well. I mean, it's a really exciting time to be in cancer treatment. As you know, five years ago we couldn't even conceive or some of the drugs that we have now. The results we are seeing with some of these drugs are really, frankly, astonishing, and our hope is that this continues and, frankly, accelerates so that we can deliver more of these treatments faster to our patients.

Scott Steele: Wow, that's great stuff, and we always like to end up here with our guests a couple of quick hitters. So to get to know you a little bit better, what's your favorite meal?

Alok Khorana: Ah boy, I guess I'll say dosas which are a type of South Indian meal. It's one of my favorite.

Scott Steele: Yeah, they're fantastic. What's your favorite sport?

Alok Khorana: Basketball. I'm a huge NBA fan.

Scott Steele: As long as it's not the Lakers. What's the last non-medical book that you read?

Alok Khorana: I read The Overstory, which is I highly recommend to your listeners. It's about trees. It's a book that actually centers trees. It talks about the social life of trees. It has a lot of science in it, and it was really fascinating to me to learn about how forests are essentially really complex social networks where older trees take care of younger trees. There are sort of grandparent trees that take care of really young saplings and saplings develop faster and better and are more resilient to bad weather if their parents and grandparents are around, as opposed to ones that are just planted in the middle of nowhere. And it's a great read, so I highly recommend it, The Overstory.

Scott Steele: It sounds fantastic. I'd like to see if the grandparent trees can keep the young trees off of social media. So name something that you like about living here in northeast Ohio.

Alok Khorana: Other than the weather you mean? I joke, but we moved from upstate New York to here, which has half the snow. So our joke is that we moved to Cleveland for the weather. I got to shout out a museum here in Cleveland, which is, first of all, it's free. You can walk in anytime. If you only have five minutes and you want to see one thing and get out, that's fine. You can spend the whole day there. You can spend a whole week there. There's just this amazing collection of art and sculpture and I highly recommend it.

Scott Steele: Cannot agree more. So that's great stuff. Give us a final take home message for our listeners, the real nuts and bolts of immunotherapy for colorectal cancer. What should they remember?

Alok Khorana: We are in a rapidly evolving paradigm shift in cancer medicine, and immunotherapy is the leading edge of that paradigm shift. The science underlying immunotherapy was recently awarded the Nobel prize just last year, and I think we are just at the cusp of these new agents and ways to modulate the immune system. I would urge your listeners to pay really close attention to the science and the clinical trials because I think you'll be seeing some fantastic breakthroughs over the next couple of years, more than what we've already seen.

Scott Steele: That's fantastic stuff. And to learn more about colorectal cancer prevention and treatment, and to download a free treatment guide, please visit Clevelandclinic.org/coloncancer. That's Clevelandclinic.org/coloncancer. To make an appointment with Cleveland Clinic's Cancer Center, please call our cancer answer line at 866.223.8100. That's 866.223.8100. Again, please remember in times like these, it's still important for you and your family to continue to receive medical care. Rest assured that here at the Cleveland Clinic, we're taking all the necessary precautions to sterilize our facilities and protect our caregivers and patients.

Scott Steele: Alok, thanks for joining us on Butts & Guts.

Alok Khorana: Thank you. Thanks for having me.

Scott Steele: That wraps things up here at Cleveland Clinic. Until next time, thanks for listening to Butts & Guts.