Researchers Study Vaccine to Prevent Lynch Syndrome-Related Cancers

Speaker 1: From the research bench to the patient's bedside, this is Bench To Bedside with your host vice chancellor and director of The University of Kansas Cancer Center, Dr. Roy Jensen.

Dr. Roy Jensen: Colorectal cancer is the second leading cause of cancer death for men and women combined. Thanks to improvements in early detection and treatment, the number of people who die from this disease has dropped steadily over the last few decades. And today, there are more than one and a half million colorectal cancer survivors in the United States.

Good morning. I'm Dr. Roy Jensen, vice chancellor and director of The University of Kansas Cancer Center. Joining me this morning are Dr. Anwaar Saeed and Dr. Ajay Bansal, physician scientists who are exploring ways to better treat colorectal cancer and even prevent it from ever developing.

Also joining us is cancer survivor, Tom Conley, who is with us today because he participated in one of Dr. Saeed's clinical trials.

Tom, your cancer journey is a long one but it eventually led to you being treated and working here at the KU Cancer Center. And I believe you were diagnosed with prostate cancer back in 2006 and then more recently diagnosed with advanced colorectal cancer. Could you tell us a little bit about your story please?

Tom Conley: Well, as you said, it is about a 15-year story, so I'll try to be quick. It began in 2006. I was diagnosed with stage III prostate cancer. At that time, I had surgery and radiation and after that, the cancer was not detectable. And in 2007, I actually had a clear colonoscopy. And then about 10 years later, 2009, 2016... I'm sorry, 2015, '16, my PSA started rising again. And so I had a second round of radiation. And after that, there was no detectable prostate cancer.

During all this time, I was having what we all assumed were side effects from the radiation therapy which very much mimic colon cancer symptoms. And so it wasn't until unfortunately about after the second round of radiation, the side effects got significantly worse and in 2018, I believe it was my primary care doctor sent me for a colonoscopy which found a rectal tumor that was about 10 to 12 centimeters long. And that's when I ended up getting referred to Dr. Saeed which was quite frankly one of the best things that's ever happened to me.

But after we did a CT and MRI that confirmed the stage IV rectal cancer with lung metastases but fortunately at the time there were no lymph node involvement. So at that point, I started chemotherapy. Did that for roughly two and a half years or so. Tried every single approved chemotherapy I think there was for my particular type of cancer. All of them worked to some degree or another, but they were also toxic. I could not tolerate them. I'm not sure I was on any for more than just a few months at a time before I had to be taken off of them.

So then in 2020, Dr. Saeed put me in the CAMILLA trial which has proven very effective. The side effects are extremely tolerable, fairly simple, like dry mouth, some edema, things like that. And most important thing is for the last 18 months, my cancer has been stable while I've been on the trial.

That's in a nutshell what my journey has been.

Dr. Roy Jensen: Well, that is quite a journey. And thank you so much for sharing that with us.

So Dr. Saeed, I want to move to you now and let's hear some more about this CAMILLA trial which obviously has had a huge impact on Tom and his journey. And my understanding is that is now going to go into a national phase III trial. So tell us all about that.

Dr. Anwaar Saeed: So the trial rationale or the idea behind the study is the published preclinical data that showed that targeting the angiogenesis pathway modulate the tumor micro environment by upregulating certain immune checkpoints like PD-1 and PD-L1 through the hypoxia pathway and this provides a great rationale to combine such agents with immune checkpoint inhibitors like PD-L1 inhibitors.

So at that time, a few years ago, when I proposed a concept, this preclinical work was clinically validated in other tumor types like renal cell carcinoma and me starting my career as a GI oncologist, I was looking at the most common GI malignancies at that time like colorectal cancer, gastric, esophageal, and liver cancer and we use antiangiogenic agents in those diseases. So we know that the angiogenesis pathway is active in those diseases. And so it was a prime time at that time to propose a concept to combine such agents with PD-1 inhibitor.

And so I proposed a GI basket trial to look at cabozantinib which is a VEGF multityrosine kinase inhibitor with a PD-L1 inhibitor called durvalumab. And that's the CAMILLA trial.

So we completed the phase I part of the study which showed encouraging data and prompted the expansion of the study to a large phase II multi cohort trial and the colorectal cohort was part of those cohorts. And we completed enrollment to the colorectal cohort recently so I was able to present the data at the American Society of Clinical Oncology Gastrointestinal Cancers meeting couple months ago in January. And our results was very well received by the global GI community. We've shown an overall response rate to the combination of around 28% and disease control rate of around 86% with a median progression free time of 3.8 months with a median overall survival of nine months.

We have done... And one thing about the population just like Tom explained 100% of the patients who went under study failed the standard of care regimens, all the standard of care regimens in the first and second line setting in patients with advanced colorectal cancer, and we did not have any patients who went under trial who have a microsatellite instability which is the minority of colorectal cancer that responded well to immune checkpoint inhibitors. So all of the patients who went under study had microsatellite stable disease.

We did some deep diving into the data and did a subgroup analysis looking at the results for the subgroup of patients with RAS wild-type. And Tom happened to belong to that subgroup. And we have seen a superior outcome in this subgroup with an overall response rate of 50%, median progression free survival of six months, and median overall survival of 21 months.

So this superior outcome in this subgroup was fascinating because there's no other trial that combined an angiogenic inhibitor with a PD-L1 inhibitor looked at this or showed this impact. So this is very interesting with this agent that's called cabozantinib.

So this triggered the post hoc analysis for data from a clinical trial that was running in parallel to the CAMILLA trial examining cabozantinib with another PD-L1 inhibitor called atezolizumab and the post hoc analysis revealed similar finding that the RAS wild-type population derived better outcome to the combination than the study population as a whole.

So those two findings relate the foundation or sets the stage for the next level of evaluation. And I'm really proud and thrilled that this has led the development of the phase III clinical trial that is planned to be launched later this year. It's called STELLAR 303 trial. It would be an international large clinical trial of around 600 patients testing an agent called XL092 which is similar, targets cabozantinib in combination with atezolizumab versus regorafenib which is the standard of care agent in the data line setting for this population.

So we're looking forward to launching this trial and the results.

Dr. Roy Jensen:

So, Tom, how did you hear about this trial first of all and then what made you decide to be part of the trial population?

Tom Conley:

Well, I am director of radiation safety for the health system and part of my job is to review and approve human research studies that use radiation.

And while this particular study only uses radiation for tracking, I get a CT scan every two months. About the time that I was diagnosed, Dr. Saeed was pushing her protocol through the approval process and it came across my desk and I saw it. So, hey, this looks like something very interesting that I would be interested in.

So we discussed it. And obviously, at the time it hadn't quite been approved. It was approved very shortly after but until I failed the standard of care, I was not eligible for it. That's one of the inclusion criteria is that you have to fail the standard of care. So because the standard of care was so toxic for me, I basically failed all of them. And so Dr. Saeed got me into the phase II study and I couldn't be happier.

Dr. Roy Jensen: Well, you look great. How are you feeling?

Tom Conley: Well, actually, I do have my ups and downs. There's days that I'm just totally wiped out, fatigued, no stamina, but then there's days like... Today is a good day. I'm feeling really good. Overall, I actually think I feel better now than I did before I was diagnosed.

The chemotherapy did have one good side effect. I lost 120 pounds during that period and also was able to get off all of my diabetic medications.

Dr. Roy Jensen: Well, that's a fantastic outcome.

Tom Conley: That's basically how I got into that.

Dr. Roy Jensen: Yeah.

As they say, two heads or more are certainly better than one when it comes to treating those at high risk for developing colorectal cancer and the result and the lesson I think is that a whole team, a multidisciplinary team that can help patients, that every step of their journey is critically important. And that's where I want to bring in Dr. Bansal.

You are a gastroenterologist and Dr. Saeed, you're an oncologist. So both of you are a physician scientist and that means that people like Tom have a chance to really participate in leading edge clinical trials. And Dr. Bansal, I want you to tell us a little bit more about why this multidisciplinary approach is so important when it comes to treating our patients.

Dr. Ajay Bansal: Thank you, Roy. That's a great question.

So these days, majority of things have become complex and the biology of cancer has been understood to a great extent so we can use a multidisciplinary approach to do much better job to treat with much less toxicity and come with new ideas.

So at KU Cancer Center with the help of Dr. Roy Jensen and his support and Dr. Saeed, we have this multidisciplinary clinic where we have people like me who are gastroenterologists do colonoscopies, use special imaging techniques. We have Dr. Saeed who's an oncologist. We also have colorectal surgeons, cancer psychologists, nutritionists because takes a whole team, and GI radiologists, to do high quality work and do the best work in this field.

Dr. Roy Jensen: Patients often have a lot of questions when it comes to participating in clinical trials and one of their concerns is that they'll just receive placebo and not be treated for their cancer. And as both of you know, obviously that is simply not the case.

But Dr. Saeed could you take some time to explain why that is and why that just never happens for cancer patients?

Dr. Anwaar Saeed: Yeah. So there is that misconception that when we offer clinical trials to our patients, they think that they will be treated like a guinea pig or will be just given a placebo and that's really not the case because the drug exploration or drug development trials go through phases.

And when we highlight, for example, in early phase clinical trial or first in human clinical trial, those trials typically are single arm, open-label clinical trials that test a single agent or a novel agent in combination with another novel agent or in combination with a standard of care in multiple dose levels. We call it dose escalation followed by dose expansion, but this whole process is a single arm. So typically, there's no placebo in this type of trial designs.

Once we establish a good amount of safety data and we see that there is an early signal of efficacy, then we decide about whether or not we're going to go with the next level of exploration or evaluation. And that's a phase II or a phase III trial.

Depending on the strength of the efficacy signal, those phase II and phase III trial are typically randomized controlled trial. So this novel agent is being explored either against the standard of care regimen if the efficacy signal was strong in the early phase exploration or in combination with the standard of care versus a standard of care regimen. In this later type of design, if the design is double blinded, they typically add a placebo to the standard of care regimen in the control arm.

And so when I propose such trials which are double blinded placebo controlled to my patients, I tell them at worst case scenario when you go on the study you will not get list then what we offer as standard of care regimens or options because if the patient lands on the standard of care arm, they will get the standard of care regimen plus the placebo and not the placebo alone.

And most of the research that we do in any academic institution or any research organization are governed by ethical committees and institutional review boards and those committees function as reviewers and policemen to make sure that a concept that try to bypass the standard of care regimen doesn't get approval because it's not ethical. So we don't have placebo only arms really nowadays.

Dr. Roy Jensen: So if you're just joining us, we're here with Dr. Anwaar Saeed, Dr. Ajay Bansal, and Tom Conley discussing the latest, most exciting advances in colorectal cancer research. Remember to share this link with people you think might benefit from our discussion. Use the #BenchToBedside. Also, Alexis Del Cid is here to take your questions.

Hi, Alexis.

Alexis Del Cid: Hello.

Bill has a question for Tom. He wants more of an idea of what it was like to go through the trial. What did you have to do on a regular basis? Tom Conley:

Well, it's actually very simple. I take one pill when I first wake up because Dr. Saeed doesn't want me to eat for an hour after I take it. And then once every four weeks I get an infusion and that is basically the extent of it. I occasionally get an infusion of magnesium because magnesium sometimes get low. Although I have found a solution to that and I haven't had to do that for over two months. So that's basically the extent of what I... My participation is to take a pill, get an infusion every two months, get a CT scan and keep on going.

Alexis Del Cid: And that's it? Sounds very simple.

Tom Conley: It is. It's-

Alexis Del Cid: And lifesaving.

Tom Conley: ... surprisingly simple for the impact it's had.

Dr. Roy Jensen: So Tom, what struck me about your cancer story is that it is so important to advocate for your own health and why should someone get a second opinion on their cancer diagnosis.

So let's talk about the cancer center's high risk gastrointestinal clinic which you lead, Dr. Bansal. It is one of the only such clinics in the region. What is the purpose of the clinic and who do you think would best benefit from your clinic?

Dr. Ajay Bansal: Absolutely. So this clinic has been running at least for the past five years and in fact has been one of the fastest growing clinics at KU Health System in part because there's a big need to figure out people who are at increased risk for cancer of different types and prevent cancer before it's happening, not to take away work from Dr. Saeed, but we want to help our patients either prevent cancer or get diagnosed with cancer at a stage where we can cure it.

So in this particular clinic, one of the ways to benefit from this clinic would be to get along with your family. So one of the best ways to know your cancer risk is to get a sense of what kind of cancers run in your family.

So, for example, you go to a Thanksgiving dinner, maybe that's not the best topic on Thanksgiving dinner at the table, but maybe later you found out that your grandfather had colon cancer and then by the way, your uncle had colon cancer. So those are two cancers in the same family, stuff like that can be a clue to your own risk.

Maybe one of your family members had pancreas cancer the age of 55 or a young age and those kind of clues in the family should tell you to reach out to your primary care doctor or to us at KU and we can advise you about the next best steps.

Dr. Roy Jensen: Okay. So there may be many people out there who are at high risk for gastrointestinal cancers including colorectal cancer and not even know it. And you're obviously very familiar with Lynch syndrome and I think many of the patients that come to this clinic are Lynch syndrome patients. And it turns out that, if I got this right, one out of 300 patients may have Lynch syndrome. So could you tell us a little bit about the risk that's attendant with that diagnosis and really what should they be doing to optimize their health?

Dr. Ajay Bansal: Absolutely. So Lynch syndrome is the most common GI cancer syndrome in the population, and 90% of all people who have Lynch syndrome do not know that they have Lynch syndrome. So this syndrome can increase the risk of colon cancer, cancer of the uterus, cancer of the stomach, small bowel, pancreas, bladder, and kidney. And that depends also on the family history of cancers. But if you do have the gene, then you should definitely get extra care so we can prevent cancer or detect cancer early.

And the way to do that would be, again, look for clues among the family history. If family members have cancer which are occurring more often, they should. So a bunch of people have cancer or at a young age, then you should reach out to the primary care physician or to us where in this clinic we would do genetic testing and look at the genes which have been previously discovered to result in Lynch syndrome. And once we have the gene proven diagnosis, then we can use a multidisciplinary clinic at KU to have the right specialty to take care of you.

Dr. Roy Jensen: So just to put some data behind the level of risk for Lynch syndrome patients, those folks may have as much as an 80% chance of developing colorectal cancer at some point in their lifetime. And I know that both of you are leading research studies that may lead to discoveries that might help this group in particular.

And Dr. Bansal, I first want to start with you about a very exciting national clinical trial which is actually a vaccine that has been designed to prevent colon cancer from developing in this group of patients. Could you tell us a little bit more about that?

Dr. Ajay Bansal: Absolutely. So that's a very exciting trial. We should start in the next three or four months. So the trial is still in the process of being approved and so we have to be careful about the stuff I discuss here. But to summarize, the idea is that this vaccine can train the human body and the immune cells to find those cells in the body which have abnormal proteins and then those abnormal proteins can be cleared by the immune cells even before they turn into polyps or cancer. This is having a bunch of different bodyguards in the body 24/7 365 because these immune cells are constantly circulating throughout the entire body looking for these abnormal cells.

So what we want to do is use a vaccine to promote the body's own immunity to do a better job of what we call immunosurveillance where body's immune system can fight cancer. That's one of the best ways to prevent cancer in a very exciting field of immunoprevention.

Dr. Roy Jensen: That would be an incredible result and I certainly wish you luck with that.

Now, Dr. Saeed, I want to turn to a study that you have that's ongoing looking at the effectiveness of fish oil supplements that contain omega-3 fatty acids. And I think for a lot of people out there, they understand that omega-3 fatty acids are pretty exciting right now in terms of potential health benefits. And you've designed a trial to look at patients with Lynch syndrome and what more aggressive screening schedule may impact them and also, obviously what impact fish oil may have in this group. So could you tell us a little bit about that?

Dr. Anwaar Saeed: So there's a great unmet need to identify safe noninvasive strategies or approaches that are chemopreventive in patients with Lynch syndrome.

Currently, the only agent that have showed cancer preventive properties in patients with Lynch syndrome is aspirin and aspirin dose that proven to have cancer preventive impact in patients with Lynch syndrome is 600 mg daily. And this is six times higher than the baby aspirin dose which is the cardioprotective dose for aspirin. And as you could imagine, prescribing 600 mg daily to a patient who have hereditary condition like Lynch syndrome to take this lifelong is really not feasible because of all the potential toxicities that will happen with this high dose including gastric ulcerations, inflammations, and bleeding and other toxicities. And so there's a great unmet need to identify alternative approaches that are way safer than aspirin that could be used lifelong in this population. And so this clinical trial really served that purpose.

We're looking at omega-3 polyunsaturated fatty acids using a prescription drug called Lovaza which is a drug that we prescribe in patients for cardiovascular protection and we proposed a moderate dose of this agent to be used in patients with Lynch syndrome.

So the trial is ongoing. We are collecting samples from the Lynch population or patients who enroll on the trial at baseline and post-treatment and those samples include colon mucosal samples as well as blood, stool, and urine samples so that we can run a comprehensive correlative testings to identify whether this approach will have a meaningful negative impact on the inflammatory and proliferative pathway that could lead to defective mismatch repair which is the hallmark of adenoma-carcinoma cascade in the population with Lynch syndrome.

Dr. Roy Jensen: So that's a great story of academic medicine there of two different types of physician scientists that are coming together and making a study possible that could have tremendous benefits for a group of their patients. Alexis, do you have any questions?

Alexis Del Cid: I do. Denise has a question for Dr. Saeed. Denise wants to know how much do you think diet and eating fish with omega fatty acid would have to do with reducing your colon cancer risk versus genetics. Dr. Anwaar Saeed:

So it's a very complex question and there's no definitive answer because there are ongoing studies trying to address whether modification of the diet just like this trial by supplementing moderate doses of omega-3 fatty acids which is a type of fish oil would lead to preventive effect.

So there are ongoing studies. It's really hard to put any definitive word there. But there are a number of observational studies that showed that people who really rely on seafood diet versus red meat has lower incidences of colon cancer than the population who really depends on red meat for their main meals.

Alexis Del Cid: And Sonya's question is, does red meat increase your risk of colon cancer or is it processed meat like cold cuts and sausages?

Dr. Anwaar Saeed: It's mostly the processed meat.

Alexis Del Cid: Okay. So steak not as bad as sausages and baloney and things.

Dr. Anwaar Saeed: Yeah. Typically, we say that very well done is not good because of the way it's cooked, grilled. But there's no definitive answers to this. There's no definitive studies that shows that, hey, this is linked to this. Really hard to say.

But I typically advise my patients to decrease the amount of red meat in general because the oxygen radicals that comes from eating and digesting red meat is way higher than other type of products.

Alexis Del Cid: Okay.

Dr. Anwaar Saeed: There are certain data showing that ingesting or eating certain amount of tree nuts per day may have a colon cancer protective impact.

Alexis Del Cid: Protective.

Dr. Anwaar Saeed: Yeah.

Alexis Del Cid: Okay. Interesting.

Dr. Roy Jensen: All right. So I have one last question for each of you and I'm going to start off with you, Dr. Saeed. What are you most excited about right now in terms of the research that's going on within your group? Dr. Anwaar Saeed:

So I'm excited about the potential for the immunotherapy combinatorial strategies and approaches which I believe will change the horizon for many type of malignancies including gastrointestinal malignancies. We have learned from the first generation checkpoint inhibitors like PD-1 and PD-L1 inhibitors that those agents have very limited efficacy when given as single agents in many type of cancers including the most common gastrointestinal malignancies. And so we are now exploring different type of checkpoints in combinations with those main checkpoints.

And so there are other checkpoint inhibitors like TIM3 and targeting TIM3 and LAG3 with the later showing some early nice data in combination with PD-D1 and other tumor types.

And I'm very much interested and invested right now in an agent called 9-ING-41 which is a novel first in class GSK-3beta inhibitor that have shown chemosensitization effect and also shown immunomodularity impact impacting LAG3 and PD-1 in the tumor micro environment. And so this agent is very novel agent to combine with PD-1 inhibitor.

So earlier this month, I have launched the RiLEY trial combining this agent with PD-1 inhibitor and chemotherapy in patients with advanced pancreatic adenocarcinoma. And I think this clinical trial will, if we show a signal, lay the foundation for this approach not just in pancreatic cancer but possibly in colorectal cancer as well.

Dr. Roy Jensen: All right. Dr. Bansal, your turn. What are you most excited about in the research going on with your folks?

Dr. Ajay Bansal: So I would say I'm most excited about immunoprevention. So that's the future of cancer prevention in which we will use things like vaccines to promote body's own immunity to fight cancer.

The second thing which would be happening is that we are learning from Dr. Saeed's work and an oncology of work, we are using drugs which have been used to treat cancer in smaller doses to prevent cancer. For example, there's a rare syndrome called polyposis in which people can have more than 5000 polyps that can increase the risk of colon cancer to a 100%. So there's a drug called erlotinib which used to be used for lung cancer but smaller doses and less often it decreased the number of polyps by 90%.

So approaches like those where we can modify the body's immune system so that the body's immune surveillance mechanism can clear the cancer cells on its own to empower the human body, to prevent cancer would be the future frontiers.

Dr. Roy Jensen: Yeah. All right, Tom. So I'm going to let you round us out here. And so many of our viewers relate to your cancer story. What advice do you have for those who may be in their own journey and what would you say to them?

Tom Conley: Well, first of all, be vigilant any time that you've had pelvic radiation therapy like I did in 2006. I have since learned that your risk for colorectal cancer is about the same as if you had a family history. I've never had a family history that I know of. And when I had a colonoscopy in 2007, the doctor at the time, not related to KU, told me, "Well, it was clear. I'll see you in 10 years." Well, what he should have said was, "I'll see you in three to five."

But that's the past. There's nothing I can do about that except help try to get that word out. And I do know that the doctors that I've interacted with during my journey now do that more often. It's no fun getting a colonoscopy. It's even less fun having chemotherapy.

Some of the other things that I found very helpful is having a support system. When I was first diagnosed with the colorectal cancer, my wife, who is a licensed professional counselor, enrolled in a class at KU on mindfulness for people with cancer and their caregivers. I wasn't able to go to it because it was during working hours.

But she went and the group that was in the class it was an eight-week class decided to stay together after the class. And we'd been together ever since and have been supporting each other when one of us needs something, we can contact the others and they'll help out or if we just want to talk. It's really helpful to have that support system.

And I have to put a plug in for my wife. She has been the biggest support that anyone could ever hope for.

Last thing I'd say is maintain a positive attitude. I've seen a lot of people, relatives and friends, who have had various diseases and they let it get to them. Yes, it's a terrible disease. The effects are bad. But the way I look at it, I woke up breathing this morning and I'm still on top of the dirt. So that's a good thing.

Dr. Roy Jensen: I think we can all agree on that, Tom.

Tom Conley: Yeah.

Dr. Roy Jensen: Maybe some controversy there, but I think we-

Tom Conley: Yeah, there may be. And I intend to stay on top of the dirt as long as possible.

Alexis Del Cid: Nice.

Tom Conley: When Dr. Saeed first told me I had stage IV with metastases in my lungs, it also had gone to my liver. She told me at the time that people with my type of cancer typically have two and a half years with an 11% chance of making it five.

First of all, that was four years ago and secondly, when she said I had an 11% chance of making it five years I told her I'd see her in six.

Dr. Roy Jensen: There you go. Well, thanks so much, Tom, for sharing your story. I'm sure you're an inspiration to many of our viewers. And Dr. Saeed and Dr. Bansal, obviously, thank you for updating us on your work which is giving Tom and so many patients like him hope and a reason to be optimistic.

And finally, of course, we want to thank everybody for tuning in and being a part of this week's episode of Bench To Bedside. To learn more about colon cancer, visit kucancercenter.org/coloncancer. That's it for today. Join us next week at 10:00 AM for Bench To Bedside. Thanks for watching.