Immunotherapy is transforming cancer treatment and care today—and shows even greater promise for the future. Discover how this innovative treatment works across several cancer types both alone and in combination with other treatments. Dr. Ellen Puré of the University of Pennsylvania will explore how our immune system works, break down into basic concepts the complex science underlying immunotherapy, describe the different types of immunotherapy, and discuss potential side effects and benefits patients can anticipate. After the presentation, ask your questions during a live Q&A moderated by Tamron Hall.
Tamron Hall: Now, it’s time to meet the experts kicking off our program as Dr. Ellen Puré, director of the immunology program at the University of Pennsylvania and an associate director of CRI Scientific Advisory Council. Dr. Puré is one of the world’s leading scientists in the field. Her research is advancing everything we know about immunotherapy, and at the same time, she is also mentoring the next generations of top scientists. Let’s listen, as Dr. Puré explains, the basics of our immune system what it is, how it works, and how studying it has led to new immune-based cancer treatments. So let’s listen together. Dr. Puré, welcome.
Dr. Ellen Puré: Thank you very much, Tamron, for that introduction, and it’s a pleasure to represent the Cancer Research Institute today. Let’s start right off with you a bit about what we are all doing and why we’re so excited about immunotherapy for cancer. Due to the ongoing pandemic, I dare say that most people have given more thought to their immune system in the last one and a half years than ever before, and indeed, the immune system did evolve, first and foremost, to protect us from infection by microbes like viruses and bacteria. But, the immune system also detects cells that have been altered by other processes, such as aging and being damaged through abuse of the system, infected or altered by microbes, and for the focus of today’s discussion, the changes that occur in cancer can be recognized by our immune system, and then the immune system can be activated, and it’s tasked with then trying to eliminate those cancer cells. You might ask then, well, then why does cancer grow and why do we have this clinical challenge that we all face? You’ll hopefully hear the answer today, which is that the immune system does try to eliminate cancer, but often the cancer wins out and the goal of immunotherapy is to enhance our immune systems in ways that lead us to win the war.
So, a quick introduction to an elegant system that has evolved in the human immune system. So first and foremost is let me introduce you to the components of the immune system and other defense mechanisms we have to protect ourselves from infection. The first is actually not technically part of the immune system. It’s a physical barrier that’s provided by the hairs and mucus that trap foreign particles in our nasal passages and the skin. Both together act as barriers to prevent microbes from entering an organism.
So, what about the immune system per-sae? Well, the immune system is really quite an elegant system, and it has many cell types and it turns over at an enormous rate, and so the body is designed to produce trillions of new immune cells on a daily basis. Most immune cells are made first in what we call the primary lymphoid organs, or immune system, including the bone marrow, and a second organ, the thymus. The bone marrow generates and is involved in the generation of almost every cell type in the immune system, whereas thymus is dedicated to the development of T-lymphocytes that we will talk about quite a bit more today and are the critical cell often in effective anti-tumor immune responses that can help to destroy cancer cells. Next, please. Additionally, we have what we call secondary lymphoid organs. Those are shown now here in purple, and they include the spleen, lymph node, tonsils and lymphatic vessels, amongst other organs throughout the body, and the point of this system is to give specialized tissues a structure where the immune system can most effectively generate its immune response. But it’s really critical that our immune system be able to survey the entire body and the dangers that lurk anywhere within.
This is accomplished by immune cells entering into circulation or the blood, and they are immune cells are the white blood cells that we talk about, whereas the rest of the cells in the circulation are, of course, the red blood cells that we won’t talk about today. So these white blood cells need to circulate everywhere, searching for any sort of alerts of danger, either infection or to detect damaged cells anywhere in the body.
As I said, there are many cells within the immune system. There are two major categories of cells. The first are referred to as innate immune cells, and they include cells that are referred to here as monocytes, macrophages, and neutrophils, as examples, and the first this these are the first responders. They stand ready to attack at the first signs of danger, and they do so quite rapidly. You pay a slight price for that rapid response in that those responses are not the most specific. So they are alerted to danger signals, but they don’t really define exactly what those signals are. That requires transition, or invoking the adaptive immune cells, mostly referred to as lymphocytes of which again, there are two major flavors: B-lymphocytes, which make our antibodies that can neutralize, for example, infectious agents like the coronavirus or COVID; and T cells, which mediate T-cell cellular immunity and are particularly critical to effective immunity to cancer, as you’ll hear more about. These are the second wave of responders, and these cells take the time as they expand to be able to identify very precise changes in our cells, and that way, give us a more specific response. In the middle, you see two cells designated as dendritic cells and, in this case, natural killer cells, and these are two examples of cells that act at the interface of the first responders of the innate immune response and the adaptive immune cells or lymphocytes.
So today, what we’re going to focus on are the most prominent of the tumor immune cells that exist, and these are killer T cells. Killer T cells, bear on their receptor on their surface, as shown in this schematic with a green figure outside the cell that sits on its surface and has the ability to recognize proteins expressed by other cells that are not cells that are not exactly what the cell is used to seeing, but rather an altered or change in other cells, such as cancer cells. These are called killer T cells, because once this receptor is engaged by the protein that they recognize so selectively, it activates them to attack that cell and to kill it.
So once that receptor is engaged, as shown here, it can carry out its function through the killing of the cancer cell, as shown here, and then hopefully begin to eliminate the tumor as a whole. So, in the next slide, how does the immune system actually normally respond to cancer? Well, in fact, the simple procedure I just showed you on the left side that killer T-cells can kill tumor cells requires a very important process, which is that the cells at the interface of adaptive and innate immunity, such as the dendritic cell that I showed you earlier, actually can ingest pieces of tumor cells, and or proteins that they make, and then they present that to the T cell on its cell surface. That primes the T cell, allowing it to now go off, as shown in the next slide, and circulate around the body, find the tumor cells, and if they find tumor cells expressing that same marker that was presented to them by the dendritic cell, they’re now primed to be activated and kill the tumor cell. So again, we have this issue where if this is how if the immune system can recognize tumor cells, why do we have cancer? And the rest of our talk will be on about what the mechanisms are, by which cancer cells escape the immune system and the immunotherapeutic approaches that we are now taking and developing to help overcome those escape mechanisms or to enhance the ability of the immune system to kill.
So, if you look at the next slide, one process is that one of the things we have to be concerned with the immune system is that sometimes it can get overzealous. When it gets overzealous, it can do one of two things. One is the response is so robust that it causes damage to the local, other normal cells surrounding the cancer cell. The other problem can be that you can have a response that lasts too long, and again, causes damage to surrounding normal tissue. So, the immune system has developed a way to prevent this overzealous response. Eventually, what we call the checkpoints, or developed braking systems, that will limit both the levels of the response, but also the length of that response and thereby prevent destruction of nearby cells. This was really an important mechanism that was developed in evolution to prevent us from attacking our own cells in a way that would actually cause damage and hopefully only get a more robust response when we’re responding to foreign antigens like an infection, or to a cell that’s been markedly altered like a cancer cell. So the question is, can we use this system to engage that the immune system uses the cancer cell uses and the immune system uses to prevent to suppress the response? Can we overcome that and beat cancer at its own game and allow killer T cells to effectively eliminate cancer cells?
Well, in fact, we can. So we have developed a system in which we now can prevent those breaks from being turned on or prevent them from functioning, and inhibit the checkpoint control, called checkpoint inhibitors.
So checkpoint control will allow us to turn off those brakes and allow the endogenous immune system to overcome that mechanism that the cancer cell uses and block that response from the from the tumor cell that inhibits the immune system. So that’s one mechanism, the checkpoint inhibitors, that’s one therapy that we can discuss some more. But the second approach is what we call cell therapies. In cell therapies, we take out the T cells that we talked about, from the blood, from large volumes of blood collected from an individual patient. We then can engineer them and activate them in a test tube and give them back to the patient in a form that more vigorously can approach and attack cancer cells.
Ok, so this is an example of the way that we can modify T cells to enhance their efficacy at recognizing tumor cells. In the normal immune system, any one marker of tumor cells will only be recognized by one in a million or one in 10 million T cells, and that’s just not enough to have effective immunotherapy. So we can use a biosynthetic approach in the laboratory to create a receptor that will very robustly be expressed by all T cells and give those T cells expressing what we call chimeric antigen receptors, which have enhanced recognition function, and put them into the patient’s T cells that we’ve collected, forcing all of them virtually, or many of them, to now express a receptor specific for the marker on the cancer cells. We can then re-infuse those now activated T-cells into the patient, and that we can also modify those T cells in ways that will enhance their trafficking to the tumor and their ability to kill the tumor cells through multiple changes in their genetic material that we introduce into them.
So with this said, we now have a car T-cell that doesn’t rely on having its own T-cell receptor that recognizes the tumor, but rather this genetically engineered version shown in yellow, all of which can still recognize the marker of the cancer cell, engage it, and we also can, as I said, engineer that T-cell receptor to have enhanced killing activity for the tumor cell. We have actually shown in several blood cancers that this can work very effectively, and it is a therapy of the future for other tumor types as well, although we are still perfecting the method for using CAR-T cells as they’re called in solid tumors. But that day is coming.
So a second approach is something called oncolytic viruses. In this case, we take advantage of the fact that certain types of viruses selectively prefer to infect cancer cells rather than normal cells, and when they do, they selectively kill them. In this case, however, the immune system still has an important role to play because as the oncolytic virus kills the cancer cell, they will lose some of those markers we’ve discussed. They can be ingested by nearby dendritic cells and presented to killer T cells that have the receptors that recognize these markers, and then again, lead to their activation, so that once the oncolytic virus clears, the immune system now has an enhanced capacity itself to continue to kill the tumor cells.
Another very attractive approach that is being developed is the idea of vaccinating against cancer. In this case, we have to know more about the molecular makeup of these markers that I’ve described, and we need to be able to present them to the immune system in a formulation of a vaccine. That vaccine will then get those dendritic cells to take up those antigens or markers and again present them to the immune system, and the immune system can then be enhanced at having enhanced killing activity on the cancer cells that it engages because they express that same marker. Importantly, this can work both in existing tumors or be used like conventional vaccines for infectious materials to educate the immune system in advance of the cancer being developed and therefore being primed and armed to go, if, in the future, you develop a cancer with that specific marker. That has some unique challenges compared to vaccine for infectious agents, but with certain tumor types and very high-risk patients that might be expected to develop certain tumor types, this is an attractive approach.
So what is the future? Well, one is that we want to personalize treatment, we want each patient to be understood at a level where we can treat them with the best options possible for that particular cancer type and the particular cancer that that patient themselves has, because even from patient to patient, the same cancer type can vary dramatically in its characteristics. So what do we mean by personalizing or individualizing treatment? Well, one is we need to understand the patient’s existing immune response. That tells us a lot about which therapies might work better or less well for an individual patient. We also want to know a lot about the cancer that they have. We want to know about their genome stability and how many mutations that tumor has. What does that mean? Well, mutations and genome instability lead to an increase in the accumulation of a number of changes that cancer cell undergoes that can alert the immune system to each of the changes, and broadens the response from the immune system and can sometimes make it more effective. So, although these mutations are what make a cancer cell a cancer cell, at the same time, it has a positive impact to have more mutations because it more strongly alerts the immune system. In addition, every patient that we consider for immune therapy, we need to understand the status of the immune response and the ability of that tumor cell to escape the immune response. So, for example, we want to know if that tumor cell actually expresses some of the break mechanisms I mentioned, including the one that’s most commonly targeted to date, which is PD-1 and PD-L1. So these are all the things that we now know can help us stratify patients and determine whether or not their system bodes well for applying immunotherapy in their particular case, and importantly, what type of immunotherapy might be most effective for their particular case?
So where do we go in the future? Well, there are a few things that we really are making headway on at this time. One is that we have to validate and identify those pieces of the cancer or those modifications of the cancer at a molecular level, so that these markers that I mentioned and were recognized by the T cells, and that technology for detecting those is really happening is advancing at a very rapid rate. Importantly, we have to also identify the ones that are least often expressed by normal cells to avoid what we call “off- tumor but on-target” side effects where you get killing of cells that might express a protein very, very similar to the one that you’re using is your marker for the cancer cell and cause side effects by killing those normal cells. So we have to identify markers and hope that we can find those markers that will give us the least off-tumor, on-target effects and are still effective at killing the tumor cell. A second important area is to give more than one to one approach, so you understand that when we attack things, if we can attack them at more than one level, we often are more successful at overcoming them. So the same is true for treatment with cancer, where if we combine therapies that enhance the immunological response with either other cancer immunotherapies or with chemotherapies or radiation, then we might have an even increased response overall to the cancer that might last for prolonged time. So, for example, there are some people who call, however, all therapies for cancer immunotherapies because like what I showed you for the oncolytic virus, radiation therapy and conventional chemotherapies and targeted therapies kill tumor cells directly, and in so doing, release those markers that the immune system, the dendritic cells in particular, can take up and again, present to our killer T cells, and by doing so, those cytolytic therapies for cancer cells can enhance the immune response in the host, and allow a cooperation between chemotherapy radiation, for example, and the immunotherapies that we now apply. Again, we also need to minimize immunotherapy’s potential side effects, and that’s something we are again making nice headway on, but there’s still work to be done, and finally, this was a real revolution in cancer, understanding that we can’t just develop drugs that target the cancerous cell itself and expect long term cures. That has not, in many cases, worked. We realize that, well, how about if we engage the immune system and over the last decade or so now that proof of principle is, beyond a doubt, that the immune system can be engaged to effectively fight cancer. But it hasn’t given us cures across the board and we still have work to do. But in addition, I’ll just mention the area that is being developed for the future, which is within the tissue where tumors exist, there’s not just tumor cells and immune cells, but there are other normal cell types what we refer to as stromal cells, and these cells often help support the growth of tumor cells or block the ability of the immune system to physically access those cancer cells or prevent them from functioning as killer cells to effectively eliminate the cancer cell, and that tumor microenvironment and the additional components of that environment will hopefully be able to be used in combination, and targeted in combination, with our typical cancer targeted therapies, as well as our immune therapies to yet further enhance the number of patients that respond, respond long term, and hopefully eventually are cured of their cancers, for all practical purposes.
So, this isn’t about all the science we do behind the scenes, however, all our motivation comes from our patients, and here are two patients Sharon Belvin, who will actually be moderating tomorrow’s session on melanoma, and Emily Whitehead, who was one of the very first patients to receive CAR T cells here at the University of Pennsylvania, actually back in 2010, and as you can see, she was quite a young girl at the time, and Emily is now a thriving teenager and doing terrifically well and was cured of her cancer back in 2010. Not without trials and tribulations, but we have to thank our patients for allowing us to develop this work and to hopefully have an enormous impact on future patients as well, and with that, I’m happy to take your questions.
Tamron Hall: Thank you so much, Dr. Puré, for that overview, and there is so much to discuss, so thank you. I would love to read some of the questions that we’ve received from those in the audience, and I’d like to also remind anyone watching right now, be sure to add your questions for Dr. Puré in the Q&A. So, doctor, let’s start here. The first question: “If given the choice between chemotherapy and immunotherapy, what should I consider? What is the difference between chemotherapy and immunotherapy?” I’ll let you start with that question.
Dr. Ellen Puré: Ok, well, first off, as I said, we don’t have immunotherapy yet for all tumor types. So, you won’t always have that option quite yet, but when you do, it’s good to know a little bit about how they each work. So, chemotherapies are what we call non-specific cytotoxic drugs. They have some preference for killing tumor cells, either because they grow more rapidly or they have different metabolic demands and other reasons, but they’re fairly non-specific. So, there’s a window of what we call a therapeutic window where it’s the right dose. They will kill the tumor cells, but there are quite a bit of side effects, as I’m sure you’re all aware, although we get better and better at that and managing that, as well as preventing it all the time, but chemotherapy is fairly non-specific. Immunotherapy is aimed to be more specific, either to enhance the killing by your immune cells that specifically are recognizing the cancer cells as different than your normal cells, and also by educating the immune system long-term. It’s possible that your immune system stays primed and you either go into remission or even if you have recurrence, your immune cells will already be geared up to better respond the next time around. So we hope that longer term immunotherapies, especially those where we activate your own immune system rather than passively give you immune cells that we’ve engineered, that that might give us prolong therapeutic benefit. As I mentioned, though, what might be most effective is combining them. In each of the different tumor types, today, you have to speak to your physicians. There are standards of care. Sometimes immunotherapy is included in those. There are some what we call first line immunotherapy indications, but often immunotherapy is still in some tumor types, a secondary or third step in treatment of cancer, and that you first go through standard of care, which is often chemotherapy or radiation. So it really depends on the tumor type and your own immune status and some of the things I discussed about personalizing your treatment.
Tamron Hall: Doctor Puré, a follow up to that: “Is it possible for our bodies to develop a resistance to immunotherapy like chemotherapy?”
Dr. Ellen Puré: Unfortunately, yes, so there are indications that you can develop resistance to immunotherapy. One approach, though, is that again, it depends on the type. There are many different types of immunotherapy. Again, if we engage our own immune systems and we can treat multiple times, for example, if we treat with a checkpoint inhibitor, we get a good enough response. We reverse that escape, and now the immune system can effectively treat, but they eventually can become resistant. Well, how does that happen? There are multiple ways. One of which is that there are multiple other checkpoints, for example, the one I talked about most today, PD one and PD-L1, and one might engage and turn on these other checkpoints or brakes. So there are mechanisms by which we can become resistant to immunotherapies over time, and the thought is that we will have multiple options, and that over time, we can treat with different options of different types of immunotherapies.
Tamron Hall: Earlier in your presentation, you mentioned possible side effects, and we have a question about side effects of immunotherapy. One patient viewer writes to us: “I am about to begin a checkpoint inhibitor immunotherapy. What are common side effects?” The follow up to that is: “How long can these immunotherapy side effects last?”
Dr. Ellen Puré: So the first question is the immunotherapy side effects. What are they? The most common side effect of checkpoint immunotherapy in particular is these autoimmune reactions. So as I said this, the system of checkpoints developed to limit the immune response in cases where it might affect normal cells and respond to our normal proteins, and therefore, if we have a checkpoint inhibitor and we prevent that break from coming on, we observe autoimmune-like responses that these are meant to stop in the first place, or limit. So that’s an important one in the checkpoint. How long will they last? Whether you have autoimmune reaction and how long they will last is extremely dependent on the individual patient. It varies enormously. So this is a really important point. One has to follow the patients carefully. We manage those side effects when we have to, but we also can stop treatment when they occur, and that’s one of the driving forces that decides how long an immunotherapy or a checkpoint inhibitor might be administered to an individual.
Tamron Hall: One more question under this umbrella of side effects: “Is there anything patients can do to avoid side effects?”
Dr. Ellen Puré: That’s a great question. I think that’s an area we’re going to learn more about down the line, but the bottom line is that overall health, as a rule, bodes well for good responses with less side effects, but the side effects are at no fault of the patient, and these are almost impossible to predict which patients will and which won’t have side effects and how severe they’ll be. So it really is an individual’s case where we have to just watch each patient’s response, and there really is nothing at this point that an individual could do to avoid those side effects. That might change in the future. Instead, we watch the patients and manage the side effects.
Tamron Hall: The next question is from a patient viewer here: “This summer was the one-year anniversary of my car T cell infusion for non- Hodgkin lymphoma. While I feel well, and I’m considered cancer free, I’m worried about the cancer returning. Does immunotherapy provide lasting results?”
Dr. Ellen Puré: So great question. So, yes, immunotherapy can provide lasting results. Of course, it’s not been around long enough to know just in terms of decades if that’s a permanent solution or not. But, and again, it varies for each patient. What a cure would be is if we’ve eliminated every single tumor cell that wouldn’t come back. That’s not necessarily a very feasible achievement in many cases, but one of the hopes of immunotherapy is that, because your immune system is now primed and has shifted the balance where the car T-cells reduce the amount of tumor that what response you have to any remaining tumors, if there are any, is that your immune system may keep them in check, and or, you could take repeat therapies. That is also a consideration. But again, we must watch for progression and re-establish tumor disease. But if it’s eliminated, it’s eliminated, it’s hard to know if every last cell is eliminated. But, it sounds like you’re doing well, which we’re thrilled to hear! We can’t guarantee cures, but we certainly have hopes that many of these will be very long-lasting responses and or cures in the long run.
Tamron Hall: Let me go to the next question. The patient or viewer writes: “I have been receiving immunotherapy for nearly two years for melanoma. How long do I need to be on immunotherapy? When is treatment complete?”
Dr. Ellen Puré: Now that’s again, a very individualized issue, but nonetheless, the things that dominate decisions about whether to stop immunotherapy or not is following the disease itself. If disease progresses in the face of immunotherapy, then the immunotherapy will typically be ceased. The other is, what are the side effects? Medicine is a risk-benefit analysis. If the risk of side effects, or side effects, not just risk of them, but actual side effects, become what we call dose-limiting, we then would, again, cease the treatment. So it really depends on the course of your individual cancer, whether or not it is wiser to remain on immunotherapy, versus to take a break, or to stop immunotherapy.
Tamron Hall: Dr. Puré, that is all the time we have for questions today. Thank you so much for getting through as many as possible. We appreciate your time today.
Dr. Ellen Puré: Thank you all very much.