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Immunotherapy 101 with Dr. E. John Wherry at the 2020 CRI Virtual Immunotherapy Patient Summit

October 27, 2020

Immunotherapy is transforming treatment for many cancers and shows incredible promise for the future of all cancer care. But what is immunotherapy, and how does it work? Is it different from other types of cancer treatment? At the 2020 CRI Virtual Immunotherapy Patient Summit, we simplified the science behind immunotherapy to educate and empower patients, caregivers, and advocates.

E. John Wherry, Ph.D., director of the University of Pennsylvania Institute for Immunology, led a presentation on how our immune system works and interacts with cancer, and then answered audience questions, moderated by Tamron Hall, award-winning TV host, journalist, executive producer, and philanthropist.

Dr. Wherry broke down the different components of the immune system, how it interacts with cancer, and how immunotherapy can unleash the power of the immune system to fight cancer. He described the different types of immunotherapy, focusing on the unique ability of the T cell to learn, find, and eliminate tumor cells.

During the Q&A, one audience member asked what it meant to be microsatellite instability-high (MSI-H) or tumor mutational burden-high (TMB-H). Dr. Wherry defined these terms, clarifying that each was a biomarker that describes a tumor’s identity and how mutated it is. “Immunotherapy,” he explained, “works better when tumors are more mutated.”

Dr. Wherry encouraged patients and caregivers in the audience to continue to learn about immunotherapy and ask their health care team questions. He explained, “I think one of our jobs as scientists and researchers in this field is to ensure that non-scientists and non-physicians have the tools to ask important questions.”

IMMUNOTHERAPY 101 SESSION TRANSCRIPT

Tamron Hall: Thank you, Jill, so very much for all you and the Cancer Research Institute do to help the many people who are watching today. I would like to now introduce you to the doctors we've heard so much about, the doctors that I know you are eager to hear from as well today. And we'll start off with Dr. John Wherry, director of the immunology program at the University of Pennsylvania. Dr. Wherry received funding from the Cancer Research Institute earlier in his career. Today, he's a leader in the field advancing exciting new science while mentoring the next generation of scientific researchers. Let's listen as he explains the basics about what our immune system is, how it works, and how this understanding has led to the new immune based cancer treatments available today. Now don't forget, you can leave your questions for Dr. Wherry in the Q&A box, and I'll be back soon to share some of them with him. So let's learn together. Dr. Wherry, welcome.

Dr. John Wherry: Thank you, Tamron, thanks Tamron. And thanks Jill, for all that CRI does. I look forward to talking to you a little bit about what the immune system does and how it works, and some of the background on immunotherapy. We'll talk a little bit through some of the details and hopefully make it not too scary and something you can take home with you.

The immune system is actually a system of our body that actually is important to protect us from pathogens and germs and other things. It's made up of cells that exist throughout the body. They develop in places like the thymus and bone marrow, but then they actually set up residence in our lymph nodes. That's why your lymph nodes get swollen when you have a cold, in the spleen and other places.

The cells of our immune system then travel around the body to survey and keep watch on all of our tissues and organs. And they do that moving through the blood, through the lymph. And then they actually can make sure to check and monitor places like your nose or your skin, or your lungs for pathogens that may come into your body, but also for cancer. And so it turns out that we can use this to actually help us fight cancer as it develops.

So if we take a closer look at the components of the immune system, what we realized is the immune system is made up of many dozens of individual cell types. And we're just going to talk about a couple of them here. And you can divide the job of those cells into two broad categories. You have cells that function very, very rapidly, and those work in something that we call the innate immune system. They're sort of always ready to go. And they often sit at places like the surfaces of your body or your airways in your lungs and so on. And they help protect us in the short-term.

But they have a critical job, whenever there's danger around or a change in your body, to alert something called the adaptive immune system. And we call it the adaptive system because it actually adapts and make sure to evolve to fight exactly the problem at hand, whether that's a virus coming into your body, or a tumor. And right in the middle of this are a couple of key cell types that actually are critically important for cancer immunotherapy. At the end of all of this, we want a T-cell that's capable of killing your tumor. And T cells have unique abilities to do that, but they first need to be educated and taught how to find and kill the tumor. And really the key cell type at the middle of all, this is called a dendritic cell.

And a dendritic cell, you can think about as a cell that actually is the educator of the whole system. This is like going to college, the T cells are great, but they don't really know what to do yet. And the dendritic cell comes in and teaches them where the problem is and how to recognize it. A dendritic cell actually takes up pieces of the cancer cell and then uses them to actually teach the T cell what to recognize.

And so again, you can think about this initially as the T cell not knowing what to do and the dendritic cell teaching it, that this little bit of red coming from the cancer cell is what the T cell should be looking for throughout the body. So you can think about that education as actually converting that sort of resting T-cell into a killer T-cell that then can go on a search throughout the body to find the red cancer cell.

What you see is these T cells, now that they're activated, go back out into the body, search out these cancer cells, and when they find them, that education, now they have the ability to recognize that little piece of red. The way this works is the pieces of the cancer cell have to actually be presented in a very, very specific way to the T cells. And these are these molecules that you see on the surface of the T cells. And that receptor allows the specific part of the tumor cell to be recognized, and then tumor cell gets killed and eliminated.

And so this whole process of getting pieces of the tumor cell into the dendritic cell, teaching the T cells what to do, and having the T cells go back out and find the cancer cells and kill them is really the core of how we think about manipulating the immune system for cancer immunotherapy. But the tumor cells have a counter attack. And they've evolved ways to actually escape that detection by the T cells.

And they use something that we've now come to call checkpoints. These are molecules that can be expressed by the tumor cell, here labeled PD-L1 in red, that interact with something on the T cell in this case, labeled PD-1 on the T cell. And what those two molecules come in together do is they actually tell the T cell to stand down or to shut off what it's doing. And the whole purpose of this is to prevent the immune system from accidentally recognizing your own body and causing auto immunity.

But the tumor cells, the cancer cells, have actually co-opted this or evolved this to actually allow the tumors to persist. And so the revolutionary discoveries that you heard about from Jim Allison and many others have made, have figured out how to actually interfere with this evasion mechanism by the tumor. So we now have drugs that stick in between that PD-1, PD-L1 interaction and prevent that inhibition of the T cell. So now when you do that, the T cell can once again, recognize the cancer cell and kill the cancer cell. So these checkpoint blockade drugs actually turn the T cells back on, allowing them to do what they were educated to do, and then eliminate the cancer cell.

There are many ways that this can fail. I just told you about one, where the tumor cells actually prevent the T cells from performing their function. But a second problem that we often see in cancer is what if the tumor cells don't have something that the T cell recognizes easily? What if the T cells can't be educated properly to figure out that there's a cancer cell there? Well, a whole other field has exploded over the last 10 years to figure out ways to do what nature is not doing well enough. Instead of requiring that dendritic cell to educate the T cell, how to find and recognize the virus, we figured out ways to engineer the T cells ourselves.

And so the way this works is we actually pull T cells out of the body, we activate them in the lab, we expand them, and we actually give them a new receptor. We give them a new way to find and recognize the tumor that allows them to go in and kill it. So if we go to the next slide, what we call this is a chimeric antigen receptor. So the yellow piece here is what's being inserted into the T cells in the lab to create a new T cell with a new receptor. And so what this does is if the original receptor on the T cell can't recognize the tumor, this new yellow receptor can replace it and perform that function. This works the same way as if we had educated the T cell with a dendritic cell. But when that part of the equation is the problem, we can replace it, engineer the T cells, these so-called CAR T cells, and now the T cell can kill the tumor cell again.

There are a couple of other ways that the system can fail, and if you go to the next slide, where we don't have the ability to make CAR T cells, one of the other problems is that the cancer cells, the pieces of the cancer cells that the T cells recognize simply don't get taken up by the dendritic cells. That innate part of the immune system isn't working properly. Well, we can infect cancer cells with things called oncolytic viruses. There are classes of viruses that actually have a preferential ability to infect tumor cells. And when they do, not only do they kill the tumor cells, a small number of them, but they actually create inflammation that brings the dendritic cells and helps the dendritic cells pick up those pieces of dying tumor cells and present them back to the T cells.

So basically when the lesion is at the dendritic cell, you can replace that activity by these oncolytic viruses. You educate a T-cell again, the T cell now gains the ability to kill the tumor cell. And we've restored this sort of cycle of immunotherapy effectiveness.

The other way that we can do this is that part of the equation is not working very well, is we can actually just replace the whole idea of extracting pieces from the tumor cell and supply those pieces as part of a cancer vaccine, where we inject parts of the tumor cell or what we call antigens, pieces of the tumor cell the T cells can recognize, as a vaccine. The dendritic cell picks them up and then the T cells get activated, return to the tumor, and kill the tumor cells.

So this whole cycle of figuring out where the problem is and why a patient's immune system doesn't do this on its own has provided us a number of tools now in our arsenal of immunotherapy to actually reinvigorate or restore the immune system's function and ability to actually activate the immune system. There are a lot of other pieces of the equation, including a patient's own background genetics, a patient's own preexisting immunity, and ways that we can take those into account when selecting the types of immunotherapy that we might use for a patient.

We can think about this at the level of tumor mutations. We can think about this at the level of whether the tumor expresses those evasion molecules, like a PD-L1 that put the brakes on the immune system. And in fact, by using information from individual patients, we can often envision creating individual plans for treating that patient's specific type of tumor from the immune system standpoint, not just whether it's a melanoma or lung cancer.

And so there are a lot of areas of ongoing activity. We're obviously making great strides, but we aren't yet at the finish line so to speak. We continue to discover new ways of understanding whether our treatments are working or not working, and biomarkers or things we can measure in the blood to tell whether a patient is responding to immunotherapy or not, and then adjust to other therapies.

We're trying to improve the way we use immunotherapies by combining multiple types of immunotherapy. So perhaps providing a vaccine while also removing those checkpoints that are keeping the tumors protected from the T cell. And then really trying to minimize any of the off-target or side effects from immunotherapy, which are completely different than chemotherapy or radiation. If we can reduce those side effects, we can treat more and more people. So I'll stop there. I'm happy to take questions and answer any of the things that were unclear.

Tamron Hall: Dr. Wherry, we have a few questions in for you already. So I'll start with the first here. Is genetic testing an important step to determine if immunotherapy is the right treatment choice?

Dr. John Wherry: Yeah. Thanks Tamron. That's a great question. And one that our patients should be asking their doctors. There are a number of different kinds of tests that, that can be run to determine whether patients are likely to respond to immunotherapy. Genetic testing is one, where often we look to determine whether the tumor cells have lots of those mutations that might make them more easily recognized by the immune system. But we can also perform other tests, for example, looking for these checkpoints and whether they're expressed in the tumor, and asking whether the patient's immune system has the ability to recognize the tumor in the first place.

Tamron Hall: What are common side effects of immunotherapy?

Dr. John Wherry: Yeah, this is an important question. The side effects from immunotherapy are really very different than the side effects normally associated with chemotherapy or radiation. So the side effects often have to do with autoimmune consequences. So when you rev up the immune system, the potential unintended consequences, the immune system starts to recognize your own tissues, your own organs. Some of these are highly manageable, but some of them are quite serious. So they have to be thought about ahead of time.

Tamron Hall: The next question we have is, how do I get immunotherapy or get on immunotherapy clinical trial?

Yeah, thanks. This is a really important question. So it's always important to be your own advocate for your own healthcare. You should be asking questions of your physician. You should be looking for second opinions when you feel you need, you should be going to advanced medical centers for more complicated kinds of cancers, and you should use the resources that are out there. Clinical trials.gov is an amazing resource to understand what clinical trials are available. And CRI has some of the best resources available on their website to try to track down the best and most innovative clinical trials.

Tamron Hall: Another interesting question here, doctor, what does MSI-high and TMB-high mean? Why is immunotherapy more effective for cancers that are more mutated?

Dr. John Wherry: Yeah, this is a great question and really important because these are terms that you might hear, but are a little bit vague and hard to really get your head around. So immunotherapy works better when tumors are more mutated. When they're more different from your own tissues, the immune system is more likely to recognize them as foreign. And so MSI is a mutation that actually makes tumors mutate very fast. From the standpoint of developing cancer, that's not a good thing. You can develop cancer more quickly, but it also makes those tumors much more sensitive to immunotherapy because there are more targets for the immune system. So TMB stands for tumor mutational burden, and it's a way we can measure how mutated the tumor is, which is a surrogate in many cases for how likely it is that the immune system can recognize the tumor.

Tamron Hall: How long can a patient stay on immunotherapy?

Dr. John Wherry: Well, this is an important question. And I'll say we don't yet know the answer to this question in most cases. Usually you need a therapy that works quickly, but not always. Sometimes you see responses late in treatment. And so right now, the balance is when it does not appear to be doing harm, patients are kept on it for quite some period of time. That's balanced with some of the autoimmune consequences sometimes. For some forms of immunotherapy, you might see patients on immunotherapy for a year, sometimes longer. For other forms, it's a single treatment in the case of CAR T cells. Those CAR T cells then stick around in the body a long time.

Tamron Hall: We have another great question from our audience here. What is the microbiome and what role can it play in cancer immunotherapy?

Dr. John Wherry: Yeah, so there's a lot of interest in the microbiome, both in scientific press, in the lay press. So the microbiome are the bacteria that we all harbor in us and on us. And in our guts, we have billions and billions of bacteria. They're really useful, they help us digest food. And surprisingly, they actually keep our immune system fit. They interact with our immune system by the products that they make. And by the way that they interact in the mucosal environment, in your intestines. They're a great thing for us. They vary in all of us. We'd like to keep our microbiome fit and healthy because it helps keep our immune system tuned properly and in the ready state to respond to things that shouldn't be there.

Tamron Hall: Another question here about diet, is my diet important during immunotherapy? Can nutrition play a role in how effective immunotherapy is?

Dr. John Wherry: Yeah. We're seeing increasing evidence of this. And this is a very hot area of science. But we're also starting to understand the interaction of diet through the microbiome, at least in part, then with our immune system. And so what we're finding is that there are certain things you eat that may actually help your microbiome work better, and by extension help your immune system stay fit. But I think the simplest answer to this question is that a balanced whole food diet is often going to be the best thing to keep your immune system and the rest of your body in good shape. There are some specific examples of what to do, but I think that that's a good take-home message.

Tamron Hall: That is a good take-home message. We have another common question that we're receiving from the audience doctor, due to COVID-19, my cancer treatment was disrupted by over six weeks. Will the efficacy of the immunotherapy be affected by a long period of time between infusions?

Dr. John Wherry: Yeah, I wish I had a straight answer to this question, but the answer is we don't know yet. We're still very early in the pandemic from the standpoint of answering a question like this. We are seeing some concern for our cancer patients. Of course, they're at a higher risk for severe consequences of COVID-19. I think the answer to this question may depend on the specifics, on the specific cancer we're talking about, the specific phase of immunotherapy. If you're on what we call maintenance immunotherapy, the potential negative effects are probably minimal. If you're in the early stages of immunotherapy or depending on what the immunotherapy is, this probably warrants additional attention. We are trying very hard at most of our institutions to get our cancer patients back into treatment as quickly as possible. And most places are getting back up to speed. So I would talk to your physician very specifically about where you are in your own cancer immunotherapy cycle.

Tamron Hall: That is very positive news. As you pointed out, some are moving forward. The next question, coming in from our audience. What is the difference between chemotherapy and immunotherapy? Is it possible to develop resistance to immunotherapy like chemotherapy?

Dr. John Wherry: That's a great question. So fundamentally chemotherapy and immunotherapy work completely differently. Chemotherapy, the intention of chemotherapy is to actually kill any cells that are dividing or metabolically active. That's tumor cells and other cells. And it has off-target effects. Its mechanism of action means that it often works slowly. You see the effects of chemotherapy over the course of weeks to months, sometimes even longer. So, that means that the types of resistance that develop are different from a therapy that might work very rapidly like immunotherapy. And immunotherapy, of course, is harnessing the power of the immune system rather than just killing all dividing cells. So it's much more specific when it works properly.

You can develop resistance to immunotherapy and the principles are in some ways the same, that whenever you apply pressure to a biological system, the system often evolves around that pressure. But the exact mechanisms are completely different. We will see resistance develop in some cancers where those cancers develop a very high expression of some of the checkpoints, like I mentioned, like PD-L1, but sometimes if you're targeting PD-L1, the tumors might develop other checkpoints that suppress the immune system other ways. So you can also see mutations in tumor cells that actually lose that thing that the T cell is recognizing. So now the T cell is sort of ignorant that there's a tumor cell there, and we may need me to engineer the immune system to re-recognize the tumor. So yes, the answer is you can get resistance to immunotherapy, but the mechanisms behind it are different than chemotherapy.

Tamron Hall: Doctor, you referenced PD-L1. This next question asks, what other pathways are being used with the up and coming immunotherapies other than the PD-L1 pathway?

Dr. John Wherry: Yeah, this is a tremendously vigorous area of science. So PD-L1, PD-1 pathway is one of several. Actually the pathway discovered by Jim Allison that really kicked this whole field off that you heard about in the video is a different pathway called CTLA-4. And there are a whole family of those kind of molecules that are now being targeted in the clinic.

But we're also thinking about what we call orthogonal approaches, drugs that actually hit other parts of the immune failures. And I mentioned oncolytic viruses or cancer vaccines. And there are different ways you can approach those problems with the immune system recognizing the tumor. And we're of course, seeing an explosion in the area of engineered cellular therapies, the CAR T cells and other T cells. So there are many other types of cancer therapies that we are now looking at combining, for example, targeting PD-1 PD-L1 combining that with CAR T cells in some cases.

Tamron Hall: Our next question, coming in doctor, a person writes, I have an autoimmune disease. Can I still receive immunotherapy?

Dr. John Wherry: Yeah, the answer is sometimes. It depends on the severity of type of your autoimmune disease and it depends on the type of immunotherapy. And so your physician will want to be extra cautious and monitor very carefully. And it may warrant thinking about the specific type of immunotherapy and the kinds of autoimmune disease that are provoked by that therapy.

Tamron Hall: Patients often ask when immunotherapy will be broadly available as a first-line treatment. Doctor, what timeframe do you see for this to happen?

Dr. John Wherry: Yeah, this is a great question. And of course it's something that we're striving for, for the cancers where immunotherapy works extremely well. Get this out there as early in disease as possible. We all know that treating cancer early in disease increases the chances for long-term cures. So the answer to this question gets to the idea that cancer isn't one disease. And so we can answer this question for perhaps melanomas, envisioning a day where immunotherapy is frontline treatment for all forms of melanoma. But the answer to that question might be extremely different for colorectal cancer, where the biology is different.

So I think the answer to the question, Tamron, is that we're getting there. We're starting to see frontline use in some cancers. We're starting to move those frontline uses early and earlier in disease stage, moving back to stage three and even stage two disease for some cancers where we're seeing immunotherapy as the first choice. But the specific answer is going to depend on exactly which cancer type the patient has.

Tamron Hall: Well, that is phenomenal. These have been in very broad and a wide range of questions, doctor, very thoughtful and detailed. Is this what you were expecting today in the first virtual event of this sort?

Dr. John Wherry: Well, I think so. There's tremendous interest in immunotherapy these days. And I think one of our jobs as scientists and researchers in this field is to ensure that non-scientists and non-physicians have the tools to ask important questions, ask questions of their physicians, and ask questions of the research and immunotherapy field to push us and to ensure that the answer to the last question is we're ready now for frontline treatment with immunotherapy in different diseases. So I would encourage people to, again, be educated. And if things are not making sense, to ask questions and push us as physicians and researchers to be able to convey why and how things work in a way that's digestible.

Tamron Hall: Well, Dr. Wherry, that was a thorough overview, as I said. Actually, there's another question that's come in. This virtual world, things just pop up, but here we go. I would love to know more about neoantigen vaccines.

Dr. John Wherry: Yes, great question. So I sort of touched on this in the slides a little bit, but the neoantigen vaccines are vaccines that actually are taking advantage of the mutations in a patient's own tumor. These are the definition of a personalized therapy because we sequence the DNA of the tumor, we identify the mutations that make that tumor different from the rest of the cells of the person. We incorporate those mutations into a vaccine, and provoke immune responses to those specific antigens in that person. So that vaccine will work for person A but will not work for person B. So there's a lot of effort in doing this. There's a lot of science on how to define those neoantigens for a given person. And there's a lot of science on how to deliver them and how to make sure that the delivery provokes the right kind of T cell response. We're moving forward quickly on that and trying to understand how to make them most effective.

Tamron Hall: Our next question is very timely. Will taking the flu vaccine effect a person taking immunotherapy?

Dr. John Wherry: It's a great question. And in fact, we are currently studying that in my group and many others. Right now, the flu vaccine is very safe even when you're on immunotherapy. Our physicians, at least in my institution are very comfortable with this. Get your flu shot. It's really important.

Tamron Hall: I've already gotten mine. And I'm sure a lot of people are prepared for that now. Well, that's all the time that we have Dr. Wherry. Thank you so much for the information that you've provided. Dr. Wherry, we'll be answering more of those questions that you have coming in, in a post-summit blog post. So please follow along with that as well. And, now I can officially say, I know what CRI means when it says the answer to cancer is already inside of us. So thank you again to Dr. Wherry for that information. I should also remind you, that the clinical trials talk is coming up. And you can also go to CRI's resource guide information on how you can make a CRI clinical trial navigator appointment. Now let's learn about clinical trials.

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*Immunotherapy results may vary from patient to patient.

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