Pancreatic cancer is the world's most lethal cancer and the fourth-leading cause of cancer-related death in the United States. With limited effective treatments for advanced pancreatic cancer, most patients are highly encouraged to seek clinical trials and emerging treatment options. At the 2020 CRI Virtual Immunotherapy Patient Summit, we hosted a special breakout session on pancreatic cancer and immunotherapy to educate and empower patients, caregivers, and advocates.
Elizabeth M. Jaffee, M.D., deputy director of the Sidney Kimmel Comprehensive Cancer Center and the associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy, discussed what patients with pancreatic cancer need to know about immunotherapy and answered audience questions about clinical trials, COVID-19, and side effects, among other topics.
Dr. Jaffee reviewed three areas of research that are helping scientists understand how to awaken the immune system to fight pancreatic cancer with immunotherapy:
- understanding how to bypass immune suppressive signals in the tumor microenvironment
- understanding tumor heterogeneity
- developing quality T cells that have the ability to enter the tumor
She also discussed clinical trials that combine immunotherapies with each other or other anti-cancer treatments to help induce an immune response to fight cancer.
Dr. Jaffe addressed several questions from the audience, including:
- What are some of the most common targets for cancer vaccines?
- Is immunotherapy an immediate option? Is it generally recommended you undergo other types of anti-cancer treatments first?
- Why is pancreatic cancer so often diagnosed late? Are there any new early detection tests for pancreatic cancer?
- Are there any tests to predict what type of response a patient may have to immunotherapy?
Pancreatic Cancer and Immunotherapy Session Transcript
Tamron Hall: Welcome back. If you're just joining us right now, it's so good to have you with us for the Cancer Research Institute first ever virtual Immunotherapy Patient Summit. It's my pleasure to introduce to you Dr. Elizabeth Jaffee, who is here to answer your questions about pancreatic cancer immunotherapy, Dr. Jaffee joins us from Johns Hopkins in Baltimore, Maryland, where she is the deputy director of the Sidney Kimmel Comprehensive Cancer Center and the associate director of the Bloomberg Kimmel Institute for Cancer Immunotherapy, please be sure to leave your questions for Dr. Jaffee and the Q&A box and Brian Brewer from the Cancer Research Institute will pass them along to her. Thank you so much, Dr. Jaffee.
Dr. Elizabeth Jaffee: Thank you, Tamron. I'm excited to be here. Good afternoon to everyone and welcome to the session. I want to thank the CRI as well for inviting me to speak to all of you today.
So I want to just give you a sense of what we've learned so far about pancreatic cancer and how the immune system either sees it or ignores it. And unfortunately, for the most part, under normal conditions, a patient with pancreatic cancer, their immune system does not recognize their tumor. And there are a number of differences between a pancreatic cancer that does not respond to immunotherapy and those cancers such as lung cancer and melanoma that do.
The first is that we know now that pancreatic cancer has few genetic alterations or mutations in their cancer's DNA that are able to attract an immune response. Most of the cancers that do respond to immunotherapy have very high numbers of mutations. And those mutations are constantly turning over.
Another important difference is PD-L1. PD-L1 is a protein expressed by cancer cells, as well as some of the inflammatory cells that are in the cancer. Those inflammatory cells are there to help the cancer grow. However, they can be reprogrammed to actually help T cells, the immune cells, come in and kill the cancer. And so when we block that pathway, PD-L1, through our immunotherapy agents such as anti-PD-1 or anti-PD-L1, then you're blocking an inhibitory signal and allowing T cells to come in. But in pancreatic cancer, PD-1 and PD-L1 blocking antibodies don't work because they don't express PD-L1. In addition, because of these problems, the immune system basically does not even know the pancreatic cancer is there.
So what you're seeing here is just a picture of a tumor cell. The T cells are outside of the tumor. Rarely do they come in. Sometimes they are there, but they're not functioning. In other words, they don't really know that the tumor's there. They're just sitting in the area. Dendritic cells and macrophages are the inflammatory cells that can either help the cancer grow or they can help bring in the T cells if they are taught to recognize the tumor. And that's what we're going to talk about. Next slide. And so there are three areas of research that are helping us to better understand how to awaken the immune system to see a pancreatic cancer. So the first is understanding the tumor micro environment. And what that means is just the neighboring cells next to the tumor cells. And as I mentioned, some of those cells are in the tumor under normal circumstances, trying to help the tumor grow. They're normal immune cells, but the tumor basically has co-opted them to help it proliferate or divide and to also metastasized, so to go to other areas in the body. And as everyone knows, it's one year tumor metastasizes that you're most at risk for having very bad consequences from the cancer.
So the tumor micro environment, those cells I just talked about, the tumor cells, the macrophages, the dendritic cells, they express signals. There's a lot of crosstalk that occurs. Symbols on the tumor cells giving signals to the monocytes or the macrophages and dendritic cells. And it's those signals that we're learning a lot about. And so we're going to have to develop new agents, and some of them are already being tested in the clinics, in order to be able to make immunotherapy work well. We want to block those signals between the tumor and the cells that are now helping the tumor so that the T cells or the immune cells that come in and can kill the tumor have that ability to do so.
Another concern is tumor heterogeneity, and that's looking here. So one tumor cell isn't like the next tumor cell. So you may have a tumor growing and you could have hundreds of millions of cells. Basically we see tumors that are hundreds of millions of cells, and it's very complex. It's not one single cell that just divided to make hundreds of millions of cells. And in fact, again, because these cells are different, we can't just give one immunotherapy agent because there are many different signals. So we need to understand what all those signals are in the tumor before we can have the best immunotherapy.
And the third is the quality of T cells. And again, this is very important. These are the cells that get educated to seeing the cancer as being different from the normal tissue that it derives from. And they're the cells that come into the tumor and kill the tumor. That's what our current immunotherapy agents work on, anti-PD-1, anti-PD-L1. And so basically we need to make sure we can get the best quality that have the ability to come into that tumor and kill that tumor in order to have success with immunotherapy against pancreatic cancer. Next slide.
So this is an example of what we're testing in the clinics in order to make those good T cells, to get a high quality T cell that can respond to immunotherapy. And so basically we have been developing vaccines. Now you think about vaccines for prevention, such as for COVID or for the flu, but you can also make vaccines that see the proteins in a cancer, those tumor mutations that I talked about, that lung cancer and melanoma have lots of. Well, pancreatic cancers have a few of those, but for some reason, because there's not a lot of them, the immune system doesn't see them. So vaccines are just a good way to alert the immune system to specific antigens that are expressed by, that are on the tumors, so that the immune system now is awakened to the fact that that tumor exists.
And so we've been developing vaccines. And now once you have a vaccine, the T cell is a good quality T cell that it develops. It can get into the tumor. And now you have to give immune modulating agents, such as anti-PD-1 and anti-CTLA-4, and also other agents that might target those pathways I was telling you about that define heterogeneity of the cancer. And if we can combine the two and figure out the right combinations, then what we find is that we can actually see responses in our patients. And we're already seeing some responses. We're not where we want to be yet of course. I'm not telling you we have a cure yet. But what we're finding is that, in fact, when you give our vaccine alone that we've been
Developing, you get some T cell response, but the tumors grow. If you give combinations, we start to see the tumor shrinking. Even tumors that have metastasized to the liver or metastasized to the lung. Next slide.
And so where are we going with this? Well immunotherapy, I think we've just really hit the low hanging fruit. So immunotherapy currently is able to help maybe 15 to 20% of all cancer patients with metastatic disease. So that deadly form of any cancer. What we now know is that we can take just even a small piece of a tumor, pancreatic tumor, or any other kind of tumor, and within a week, we can sequence those tumors and find out what all the mutations are, or the proteins that make that cancer different from the normal tissue. And we can make vaccines. We can also look at the signals that make up the heterogeneity of the tumor. So the differences between the different tumor cells, and figure out potentially what are the best combinations of immune agents we want to give to a patient.
We can also start to subtype our cancers. So one pancreatic cancer is not the same as another pancreatic cancer, and that's true for any type of cancer. Each patient is pretty individual. And we also know that there are some cancers where patients are susceptible based on genetic susceptibilities. And so we're able to narrow genetically define cancers based on their subtype, rather than based on where they started, such as the pancreas or the lung. And importantly, we've already seen immunotherapy approved for some cancers that are genetically determined, such as the high mutational burden tumors, Lynch syndrome, and other forms of genetic cancers.
But also the future is going to be in combinations. And so again, understanding the biology of a cancer will help us to develop the best and most effective anti-cancer combinations for the treatment of these diseases. I'll stop there and I'll entertain any questions.
Brian Brewer: Thanks so much Dr. Jaffee. First, I'd like to begin by welcoming you and thanking you for joining us today. It's always a pleasure to have you part of Cancer Research Institute programs. I'd like to remind before we get going with the questions, we already have a bunch of rolling in as you're talking, which is exactly what we like to see, that if you haven't yet submitted a question or if you think of one as we talk, please feel free to submit those through the Q&A box. Also, if you haven't yet scheduled your consultation with a clinical trial navigator free and one-on-one and totally confidential, you're always able to do that. And we'll send more information on how to do that if you haven't done it yet. Now, let's jump into the questions. We'll start first. You mentioned vaccines, and vaccine targets, and you talked about personalization. The question coming in are what are some of the more common targets of vaccination, and let's start there.
Dr. Elizabeth Jaffee: Yes, it's a great question. So these proteins or antigens that pancreatic cancers express come in different categories. So we have the shared antigens. So that means that more than one patient's tumor has that antigen. And we've been developing vaccines targeting a few of those shared antigens. One of which is mesothelin. It's not mutated, but it's over expressed. It's just expressed in an abundance by the pancreatic cancer compared to the normal pancreas. And it's not expressed by other cells in the body except by some other kinds of cancers, and so it's been a good target for trying to redirect the immune system to the cancer.
Then you have the mutated proteins that actually cause the cancer. So oncogenes. And for pancreatic cancer, the one that we're testing most readily is mutated KRSA. And there's a number of clinical trials that are targeting mutated KRAS right now throughout the country. And then the third is unique to each patient and those proteins are those antigens, we don't know what they are. It depends on the biopsy we take from the patient, and then on the sequencing we do, and then we identify. An often they may not even be proteins that are that important to the development of the cancer itself, but it's still expressed by the cancer, and the immune system can use that to kill the cancer.
Brian Brewer: I think looking at the questions we might want to take a step back here, and the question is, is immunotherapy an immediate option? When does it become an option for a patient? When should they begin considering this form of treatment?
Dr. Elizabeth Jaffee: Right. So unfortunately immunotherapy is not the first treatment for any stage of pancreatic cancer, except under experimental therapies. And so there are a couple of situations where immunotherapy is being given as part of standard of care, but in the experimental setting. So we can offer you a clinical trial. If you are undergoing surgery, there are a couple of studies where we might begin with immunotherapy for a couple of weeks or a month, and then come in with the standard of care, which would be surgery, and then chemotherapy and radiation, and then more immunotherapy. And that's a clinical trial approach that has been tested in a number of institutions.
A second way would be if we combine immunotherapy with standard of care chemotherapy. And that has been done as well in a number of circumstances, including when patients have a cancer that is confined to the pancreas, but it's not yet surgically treatable. So it may be a way with a clinical trial to improve on standard of care. And the same is true with metastatic disease where we could improve. But for the most part, we usually give it after you've exhausted standard of care.
Brian Brewer: I think this might be related, but we have a question coming in. They want to hear more about compassionate use an off off-label use of immunotherapies in pancreatic cancer.
Dr. Elizabeth Jaffee: We don't support that. The FDA doesn't support that either. The only time compassionate use really of benefit is if you have a drug, whether it's immunotherapy or non-immunotherapy, that's been shown to work in that patient population. It's been shown to be safe. And it has not yet gone through the FDA approval process. At that point, typically these drugs are in the hands of companies and they're willing to have such a process, but when you're at earlier stages, I really don't recommend it. It should only be done in clinical trials
Brian Brewer: One of our patient audience members ... Well not a patient. Actually it looks like a caregiver. "I lost my mother brother and onto pancreatic cancer. Why is pancreatic cancer so often diagnosed late? And are there any new early detection tests?"
Dr. Elizabeth Jaffee: First of all, I'm very sorry to hear that. And we certainly take care of a number of families who have been unfortunate, but I'm very sorry to hear that you have also experienced this. So currently we don't have anything that is standard for screening. And the reason pancreatic cancer is so difficult is because it sits in the back of your abdomen, and you don't feel symptoms until it's pretty advanced. We don't have any good screening tests yet. There's a lot of work ongoing, a lot of studies. There's a couple of potential studies that are looking somewhat promising, but it's still probably will only detect pancreatic cancer once it's a small tumor.
Ideally, we want to detect it at a pre-malignancy when it's first starting to form before it becomes a malignancy. And I think there's a lot of work ongoing, but it has just been very hard. One of the problems may be that there aren't a lot of proteins that an early pancreatic cancer expresses. For families who have a high rate of pancreatic cancer, I do recommend becoming part of a pre cancer screening clinic environment where you're followed regularly and we do do ultrasounds or cat scans to follow, and we have picked them up at a very early pre-malignant stage and it's been lifesaving. I hope that your family has connected, but I'm happy to provide information on that if you'd like it.
Brian Brewer: Well, thanks for that. Dr. Jaffee. Is there, is immunotherapy- Another question coming in. Is there a role for immunotherapy in preventing recurrence, including after chemotherapy and/or after the Whipple procedure?
Dr. Elizabeth Jaffee: Right. I think that's an excellent question as well. And that would be a good place to try to have an immunotherapy that would work. What I can tell you is there a number of clinical trials that are ongoing looking at that right now. And so in the setting of a clinical trial there are opportunities, but again, we haven't identified anything yet that has been approved that is standard of care. But I would recommend considering if you're interested in one of those trials.
Brian Brewer: So this is a question coming from me, actually. Since clinical trials are where you can get immunotherapy for pancreatic cancer right now, obviously Johns Hopkins is a center of excellence here, are there other places around the country? Or where can patients look if they're all over the country to find quality treatment?
Dr. Elizabeth Jaffee: Very important question. So the good news is we do have two foundations that provide a listing of all of the studies that are available throughout the country. PanCAN has a pals program if you haven't already contacted them and they will take a look at your information and then tell you what trials are available for that situation. The second is the Lustgarten Foundation, and they will do the same for you. They don't have a formalized program like PanCAN, but they can also help and refer you.
There are a number of good centers. In fact, we all work together. I have to say, this is a bad disease and we don't work in silos. We try to work together. And University of Pennsylvania has some good studies, Memorial Sloan Kettering in New York, Dana-Farber. There's some work being done at MD Anderson, UCSF, so all over the country. So depending on where you live, you may want to contact one of those institutions, but I can tell you that we also will, you contact one institution and we'll all tell you about the best studies out there for you.
Brian Brewer: That's very good to hear. We have now questions coming in around side effects. What are some common side effects of immunotherapy that your patients have experienced?
Dr. Elizabeth Jaffee: Great question. So, there's been this fallacy out there that pancreatic cancer patients don't have a good immune system and that's wrong. So we have found that pancreatic cancer patients do suffer from the autoimmune consequences that patients who are treated with the other cancers and receive immunotherapy also experience. So most common is going to be a colitis. We also see, which is inflammation of the colon. So you have diarrhea. And as soon as we see that, we will stop the immunotherapy to evaluate it. And if it's due to the immunotherapy, we would treat it quickly. And most people can go back on immunotherapy if we catch these side effects quickly, but there are a few that make us not want to resume. We've seen a low incidence of kidney inflammation. We've seen a low incidence of liver inflammation, very rarely do we see pulmonary inflammation, although that's seen more commonly when you have lung cancer and you're treated with immunotherapy.
Dr. Elizabeth Jaffee: And then the other is endocrine. So what is endocrine? So thyroid, parathyroid, those sorts of problems, but we can replace a lot of the endocrine factors. So again, that wouldn't necessarily stop us from re-treating. And the other important point is that we can't predict at what cycles. So is it going to be the first time you take the drug, the third time you take the drug, everyone is different, but what does seem to be similar is that just because you experience autoimmunity the first time, that doesn't mean if we continue the therapy, you'll get it again. So that is good news.
Brian Brewer: So someone could have an auto immune response, have that taken care of and managed and continue to receive immunotherapy?
Dr. Elizabeth Jaffee: Right. And the important point, I just want to point out is that you have to tell your physician right away, because the sooner we can treat it, the better you'll be, but also to allow us to re-treat you. If it gets very bad, too serious, then it's unlikely we would be able to treat you again. So very important to make sure any symptoms, you contact your physician or the nurse that's working with your physician.
Brian Brewer: This is a really good question coming in. Are there any tests to help predict who may or may not have a bad response to treatment with immunotherapy?
Dr. Elizabeth Jaffee: Yeah, that's a great question. So we do worry about people who have had a history of autoimmunity in the past. And again, if you have an active auto-immune medical problem, we're probably not going to want to treat you with immunotherapy, but if you've had it in the past, it's been controlled, it hasn't affected a vital organ such as your heart or your kidneys or your liver, then I think that we would treat you. But the problem is we don't have any blood tests yet to tell us who is going to more susceptible.
What I could tell you is that because it's so rare, it's not as easy to study. It's a rare problem, essentially. Even though a significant number of patients will have some form of autoimmunity, there are different organs that are affected. And so we're still trying to collect information, collect specimens and study them to try to come up with biomarkers that would predict. And again, there are a number of national trials that are working together to try to do this. There's been a number of conferences that we've had nationally to discuss these problems.
Brian Brewer: Of course, top of everyone's minds at the moment is COVID 19.
Dr. Elizabeth Jaffee: Yes.
Brian Brewer: And the vaccines that are being developed for COVID. First set of questions has to deal with vulnerability as a cancer patient to the virus itself?
Dr. Elizabeth Jaffee: Right. So as you might've heard from Dr. Kopetz just before, he's absolutely correct that most cancer patients are not more susceptible to COVID. I mean, you want to protect yourself, wear your mask no matter where you are, stay away from anyone infected and also social distance. I mean, I can't say that enough to everybody, whether you have cancer or not. If your immune system is otherwise functioning, if you're not on high doses of chemotherapy, if you haven't had a bone marrow transplant, if you're not immunocompromised where your immune system just can't function well, then you're like anyone else when it comes to COVID, you're susceptible to COVID, but not really any more so.
And we have actually found that people on immunotherapy, we do not have to stop immunotherapy in order to prevent a patient from getting COVID. We don't know that being on immunotherapy helps, but it certainly doesn't hurt and make you more susceptible. So again, it's your physician, your oncologist is the best person to discuss all of this with. But again, based on what we know so far.
We know that most cancer patients are not at higher risk as long as they're not immunocompromised. And again, we're studying this. The National Cancer Institute has a study that's national, that many of us have joined. So, cancer patients are asked to provide some blood samples to be a part of this, so we could further define who might be more at risk. But so far, we don't think that in general it's a big problem. Of course, we want to treat it, the way we would treat any other patient with COVID.
Brian Brewer: As far as you know, has there been any assessment of the risks of receiving one of the COVID-19 vaccines for patients who have cancer, and/or who are currently on immunotherapy?
Dr. Elizabeth Jaffee: Right. I think that's a really good question. So, I do want to preface this by saying that the vaccine data has not been published in a medical journal yet. So, we just know what we're hearing in the press like you are. But, also from Dr. Tony Fauci who talks to the medical community regularly. And, he has seen the data.
It is believed that there does not seem to be any safety risks from COVID. If you have a normal immune system, again, not immunocompromised, you should do well with the COVID vaccine. Just like you would get a flu shot, if you're eligible for a flu shot, you're eligible for the COVID vaccine. From what I understand from Dr. Fauci, there has been no evidence of safety risks. And, I do believe the FDA will make sure that they're looking at all of the data. That's why it's taking a little bit longer. But again, you want to ask your oncologist. But, more than likely, cancer patients, unless they're immunocompromised, will be offered the vaccine when it's available.
Brian Brewer: Thanks to COVID, or no thanks to COVID, I should say, many of us now rely on telemedicine to receive consultations and so forth. How has this changed your practice?
Dr. Elizabeth Jaffee: Right. We think telemedicine has a major role now. In particular, it's more convenient for patients during treatment, whether it's experimental or not. Often, we see patients just to make sure they're not having any side effects from the therapies. And so, doing a telemedicine visit makes a lot of sense, because it's a check in, you see the patient, the patient can ask questions, you can answer them. And, they don't have to be inconvenienced by coming to the hospital. Of course, when you need blood work, those sorts of things, we still need you to come to the hospital. So, the way we're looking at this is it's going to be a hybrid long-term of trying to make it more convenient for patients when it's safe to do that. But also, of course, we want to see patients when it's necessary to see them.
The caveat, though, I do want to mention one of the issues with telemedicine. A good point, a good outcome of telemedicine is that I can reach people all over the country. If they want a particular therapy we have, that's something that might be easier to distribute by having these telemedicine conferences so they don't have to come as often.
However, the issue that still needs to be resolved, right now, we all get regulated, our medical licenses are regulated by individual states. So, I'm regulated by Maryland. I have to register with different states in order to treat someone in a different state. They've allowed us to do that temporarily right now. And so, there's a big push by the federal government to change the rules so that we can do that permanently. Of course, every year we'd be reevaluated, and we'd have to pay a certain fee for that. But, that's okay if we can do that. But, they do need to make it easier for that to be done for physicians to be able to do telemedicine across states.
Brian Brewer: Wow. It really has transformed from the smallest things to the biggest. I'm glad to see that at least patients are able to continue to receive quality care, especially at Johns Hopkins.
So, we have another question. We're kind of going back to this word, neoantigen, which I think is related to ... You spoke about personalized vaccines. The question specifically is, are there any promising approaches to this type of vaccine that you've see in clinical trials?
Dr. Elizabeth Jaffee: Yes. So, I think we certainly are doing these neoantigen vaccine approaches for pancreatic cancer. We're also working with some investigators at the University of Washington, actually Washington University in St. Louis, Missouri, which is another place for some immunotherapy. And then also with the investigators at University of Pennsylvania. I've worked with all those groups. And, those are the places where we're doing it for pancreatic cancer.
We are seeing ... I mean, it's early, targeting these neoantigens. It's just started. But, we are seeing immune responses. And of course, we have preclinical evidence that patients will respond, immune responses. It's too early to say whether we're getting clinical responses yet. But, we have some hope for these.
There are different ways of delivering these neoantigen vaccines. And, that's still a question that we're trying to better understand. But, there are a number of ways to deliver them that seem very efficient. We're hoping that this is going to be a new and effective therapy in the long run.
Brian Brewer: That's good to hear. Of course, the recent death of Alex Trebek has raised the profile of pancreatic cancer and treatment there. His statements have always been rather positive about the experience and how the different treatments he received prolonged his life. We'd like to ask, how has in general, immunotherapy and everything that's happening right now, changed your outlook or the outlook of others who are treating pancreatic cancer?
Dr. Elizabeth Jaffee: I think that's an important question. I'll just say to everyone that we're not there yet. However, even five years ago, I would have told you, "I don't know when we're going to be there."
Now, we're actually seeing some patients respond, even with metastatic disease. So, I am very hopeful in the next five years immunotherapies will have a role in pancreatic cancer.
Brian Brewer: That's fantastic. We all need to hear that. Dr. Jaffee, that's all the time we have. Thank you, everyone, for submitting your questions to Dr. Jaffee. If there were any that we didn't get to, we'll be following up in a blog post at the Cancer Research Institute website. Once again, Dr. Jaffee, thank you so much for your time.
Dr. Elizabeth Jaffee: Thank you, Brian.
Tamron Hall: Dr. Jaffee, thank you so much for the informative discussion on pancreatic cancer immunotherapy. And, thank you all for joining us and participating in the Q&A.