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The University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of .25 AMA PRA category 1 credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.

Melanie Cole (Host):  Welcome. Today we’re talking to Dr. Steven Hughes, Professor and Chief of Surgical Oncology at the University of Florida and he practices at UF Health Shands Hospital in Gainesville. We’re going to identify limitations of current research models of pancreatic cancer with respect to immunity. We are going to understand the role of cell to cell communication within the pancreatic cancer microenvironment and describe potential mechanisms of tumor tolerance in pancreatic cancer. Dr. Hughes, I’m so glad to have you join us today. This is such a fascinating topic. Please just let’s set the stage a little with pancreatic cancer. Tell us a little bit about the incidence or burden of this type of cancer today. what are you seeing?

Steven Hughes (Guest):  The frightening aspect of this cancer is that the incidence meaning the percentage of the overall population that’s being diagnosed with the condition is on the rise coupled with poor options for treatment; pancreatic cancer is predicted to be the number two cause of cancer related death by the time of 2025 or 2030. So, it’s become a very important cancer which we need to find more effective treatments for immediately.

Host:  Well that certainly is true. So then, help us to identify limitations of the current research models of pancreatic cancer with respect to immunity. Please discuss for us, the evidence and unique properties of the tumor microenvironment in pancreatic cancer because that could contribute to its resistance towards immunotherapies as well as strategies to overcome some of those barriers.

Dr. Hughes:  Oh indeed. And this is a big subject. So, I’m going to try to distill it down into a couple of simple concepts so that everybody on the line has an understanding of what we are trying to do in our particular research effort.

First and foremost, the standard paradigm for finding new treatments for cancer starts in a petri dish with cancer cells. Success there leads to experiments in vivo models, typically in mice or rats. And then ultimately when success is met there, it’s brought on to humans. We have had a huge failure particularly in pancreatic cancer where things that appear to be effective in a petri dish looking at cancer cells and then effective in the treatment of mice given models of cancer have been effective only to fail when we try these treatments in humans. And in fact, only one or two percent of those things that look very promising in the in vivo models ultimately proved to be effective in actual patients.

What we’re come to realize is that these models first and foremost, have not been human and that the human disease appears to be somewhat different than that we see in rodents or other models. As a surgeon, that’s given us an opportunity. We are actually engaging our patients to participate in our research, and they have been very generous in offering up a portion of their tumor that is not necessary for decision making regarding their treatment following surgery to be incorporated in models that we believe mimic the human condition much more effectively.

That’s allowed us to start to understand the role of not just the cancer cells, but the host and how it responds to the cancer. And where that’s become particularly relevant is the immune system. And I think most folks have seen commercials about Keytruda or check point inhibitors. They’ve proven to be incredibly revolutionary in lung cancer, melanoma, bladder cancer and other cancers that appear to have ability to elicit an immune response.

At the moment, pancreatic cancer is thought to be for the most part, incapable of eliciting immune response but it would appear that that’s largely driven by the fact that that stroma, the noncancerous response of the cancer within the pancreas actually leads the immune system to believe that it should be helping the cancer instead of fighting it.

Host:  Isn’t that fascinating? So, help us to understand that role. You started to talk a bit about it of that cell to cell communication within the microenvironment of pancreatic cancer and also, while you’re talking about that, tumor tolerance. Tell us a little bit about that. And how this all ties together when you are looking at treatment.

Dr. Hughes:  Let me do that in the context of some large theories about how our immune system surveys for the formation of new cancers. The role of the immune system in helping us heal injury and I think then it will all bring it together.

So, first and foremost, our immune system is broken down into two large components. What’s referred to as innate immunity and this is very fundamental immunity and it plays a particularly large role in the healing of wounds. If you get a cut, it would become immediately infected with bacteria and would never heal if it weren’t for innate immunity. That’s a very different issue than if you develop influenza, a viral infection. In that circumstance, the second component which is a more complicated component, called adaptive immunity; is brought in to help fight off that influenza. It is an adaptive immune response that is the foundation for all of our strategies for vaccination.

What you’re talking about then is about how the innate immune system tells the adaptive immune system to either engage to fight a particular problem or to not engage because the innate system is in the process of healing a problem. In that setting, for the last few decades; there has been this notion of what’s called an immune escape hypothesis for cancer. And what its foundation is is that the rate of cancer is actually much lower than it should be given our understanding about how frequently mutations of DNA and therefore damage to genes occurs. The rate of cancer is much lower than it should be.

And so, years ago, the notion that most cancers that arise were immediately eliminated by the immune system started to gain enthusiasm. Then some cancers obviously, succeed so some of those cancers are not immediately eliminated and they form what we call equilibrium where they actually are allowed to survive but the immune system keeps them in check until some of those tumors actually escape and ultimately start to threaten the overall survival of the host.

So, this is the context where check point inhibitors, drugs once again like I mentioned, Keytruda which I have no ownership in or whatnot. So, I just use it because I think it’s the one that people know the most; actually help the immune system to go from that I’m going to let you be and help allow the innate immune system to fix the situation to the no this is not okay, I’m going to help the immune system fight you. Lung cancer, bladder cancer, other cancers like melanoma seem to be quite prone to being one that that therapy will work in part because they have a large number of mutations. Lung cancer, because it’s tobacco smoke and the mutational burden that that smoke brings on. Melanoma because of the exposure to the sun and then once again bladder cancer because actually all of the carcinogens from tobacco smoke are excreted by the kidney and ultimately bathes the bladder.

Pancreas cancer is thought of differently because it has fewer mutational burdens, is less likely to be caused by cigarette smoking or other carcinogens. It appears that the immune system has a harder time recognizing it as being something that needs to be eliminated. And part of that is we circle back to what I mentioned earlier clearly is that this supportive stroma, the host, is trying to help the tumor actually because it misunderstands the tumor as something that needs to be fixed rather than fought.

What we are interested in is understanding how the cancer cell fools the immune cells into believing that this is something that needs to be left alone. And we’re able to grow up cancer cells separate of all those other immune cells. We can grow the immune cells separate of the cancer cells. And then we can reintroduce them together either in a petri dish or in an animal model and understand how those interactions, that cell to cell communication that you asked me about may actually influence whether the immune system is being turned on or turned off.

And our evidence right now is that there’s clearly some factors that we’re trying to discover that turn that immune system off and strongly turn it off. If we can figure out what those are and turn those signals down; we can turn pancreatic cancer from a tumor that the immune system just can’t recognize into a tumor that the immune system can aggressively attack.

Host:  Wow. Really, it’s an exciting time to be researching this. Dr. Hughes, let’s briefly talk about the Whipple procedure itself and UF Health Shands Hospital’s expertise, as you teach this to other doctors; do you have any approach considerations that you would like to let other providers know and I’d also like you to tell us a little bit about your teaching process, how it’s influenced by your drive to improve healthcare in provide patient-centered care to all patients. Because I can hear it when you are describing this. I can hear the passion and your mission with this. So, describe that just a little bit for us.

Dr. Hughes:  Sure. That’s a big question. I’ll do my best to boil it down for you. So, first and foremost, our top priority in our training programs is to open up the minds of young individuals to challenge what I’m teaching them, to think independently and to get outside the box and to circle back to what we’re trying to do here at the University of Florida within our surgical training program is to not teach people how to just do what we’ve been doing for the last few decades or even the last few years but to change how we’re going to do it five or ten years from now. To identify where’s there’s opportunities for us to be better and to do better for our patients than we do right now.

And we’re really lucky here. The culture at least certainly in Gainesville and the surrounding area. Our patients come very open to the notion of participating in our research. It is very rare for a patient to not want to at least hear how they could perhaps participate in the research and after they’ve heard that, because we are always very careful to make sure that we never compromise their own personal outcomes, very rarely do they not engage.

When it comes to the Whipple procedure, the biggest message I would send to folks is that the biggest challenge we have isn’t in how safe we made the operation; it’s changing the current understanding even amongst medical professionals that pancreatic cancer is a futile disease. We actually have evidence within the last ten years that up to 40% of patients who are candidates for surgery and who are diagnosed with pancreatic cancer while it’s still in a curable state; never ever seek treatment within intent to cure. Many of them are sent home by their physicians innocently misunderstanding that there actually are treatment options with wonderful success for pancreatic cancer. And just sent home with a death sentence. It’s a misperception. Up to 40% of folks who we might be able to cure never pursue that.

That’s okay if they choose not to. And that’s my patient-centered approach to the disease. But at least let me have the conversation about what we can and cannot do. As far as what we’re trying to do from a surgical perspective is first of all, get those patients into our office so that we can talk with you about your options. The next step is to reduce the complication mortality rate to the lowest possible levels and at the moment, the mortality rate for surgery on the pancreas has been dropped from 20%, in other words one in five patients that undergo the operation dying as a complication of the surgery to less than 2% meaning less than one in fifty.

These are big operations. They are equivalent to open heart surgery, liver transplant. People are typically need to be in the hospital for a week to ten days in order to recover. But we – I think it’s going to be hard for us to do much better than a one or two percent mortality rate. It’s just a very complicated surgery with lots of opportunities for things to not go perfectly well. And so from that, the two things we’ve tried to do is we concentrate that experience into the hands of a small number of surgeons who are devoted to this particular disease and to this particular operation. So, everybody that’s involved in pancreatic cancer at the University of Florida is all in. This is what they do. This is what they are passionate about and they do it all day every day.

The next thing that we’ve been pursuing is how can we reduce the recovery period, the pain, the suffering of having to face the notion of an operation to try to overcome your cancer. And what we’ve done here, and I in particular have been focusing on is the use of minimally invasive surgery techniques. Others refer to that as Band-Aid surgery. Some may think of it as lap – it’s also referred to as laparoscopic surgery. An extension of that is with the robot. For the most part, when you talk about robotic surgery, you are talking about minimally invasive surgery or Band-Aid surgery but with the benefit of a robot.

All of those things are actively in practice here at the University of Florida and we apply them whenever possible mostly because it matters to our patients. They want smaller incisions. They want shorter hospital stays. They want fewer complications. And obviously we want that as well and so that is a wonderful partnership with our patients and our emphasis on the surgical treatment of cancer.

Host:  Well that was an excellent explanation Dr. Hughes. And thank you for that. Please wrap it up with us. In summary, tell other physicians what you’d like them to know about the Whipple procedure program at UF Health Shands Hospital, when you feel it’s important to refer to the specialists at UF Health Shands Hospital.

Dr. Hughes:  Absolutely. I think the biggest message I’d like to send to folks is that there are a number of centers that are engaged in high quality pancreatic surgery. There’s no question that there’s – I am not the only person that can do minimally invasive pancreatic surgery nor am I partners. I think what’s separate for us and what I’d like doctors to think about and patients is that we don’t just do good surgery, we use the opportunity to do good surgery on these patients to also figure out how we can do it even better five years from now. Or maybe not even have to do surgery because if you engage with us, you are going to participate in research that may discover the new cure to cancer.

But if you go to just a high quality center that is not actively engaged in the research of trying to cure pancreatic cancer; it’s a lost opportunity for us. The more patients we take care of, the better understanding we have of the disease, the more rapidly we can make progress.

Host:  Well said Dr. Hughes. Thank you so much for coming on and sharing your incredible expertise in this very complicated but comprehensive topic today. Thank you again. That concludes today’s episode of UF Health MedEd Cast with UF Health Shands Hospital. To learn more about this an other healthcare topics at UF Health Shands Hospital please visit www.ufhealth.org/medmatters to get connected with one of our providers. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. For more health tips and updates on the latest medical advances and breakthroughs, please follow us on your social channels. I’m Melanie Cole.