How can our bodies’ immune systems be programmed to fight cancer? What is the difference between immunotherapy and chemotherapy? What other diseases could be treated using this method? Founding Director of Baylor’s Center for Cell and Gene Therapy Dr. Malcolm Brenner explains.
Malcolm Brenner, M.D., Ph.D., is a professor of molecular and human genetics, pediatrics and medicine and Founding Director of the Center for Cell and Gene Therapy at Baylor College of Medicine. He is also a member of the Dan L Duncan Comprehensive Cancer Center.
See more of Dr. Brenner’s research:
Cell Wars: The Rise of Immunotherapy | Transcript
Erin: Welcome to Body of Work, an exploration of health topics in the news and important issues facing science with experts from Baylor College of Medicine. I'm Erin Blair, and my guest today is professor of genetics, medicine, and pediatrics, Dr. Malcolm Brenner.
Before we get into defining immunotherapy, can you explain the relationship between cancer and the immune system?
Dr. Brenner: Well, that's a very controversial question, and it's one that people have changed their minds about many times over the past years. Originally, people observed that individuals who had chronic irritation, like chimney sweeps, developed cancer at the sight of the inflammation. So there was an association made between the inflammatory response and cancer. Then subsequently, immunologists said that the immune system was able to act as a kind of surveillance mechanism, go around the body looking for cancerous cells. Cells that had abnormalities on their surface, or in their behavior, and picking out and destroying these cells, also called an immune surveillance. But for a long time that that theory was debunked, really. No very few, people came to believe it. But gradually, more and more immunology showed that cancer and the immune system could be very closely related, particularly with the discovery, for example, of virus-associated cancers. And as there was greater success I suppose in identifying the cellular mechanisms and the molecular mechanisms underlying cancer, and underlying the function of the immune system, investigators began to discover ways in which those two things could be connected, and show that the immune system did indeed have an important part to play potentially in the control and even the origin of cancer.
Erin: So how does immunotherapy work?
Dr. Brenner: The immunotherapy essentially is a way of targeting cancer. So most of the research on cancer therapy over the past few years has been into developing targeting mechanisms, whether that small molecules, or better radiation, or better surgery. And the immune system is a superb targeting system, it's what it's designed to do. And it has two major elements that can target cells and potentially recognize, discriminate, between normal and malignant cells. And one of those involves the production of soluble factors, like antibodies. And the other involves the direct activity of various different cell types that can recognize abnormalities on the cancer cell surface, and attack the cells that have those abnormalities.
Erin: How long has immunotherapy been used as a cancer treatment?
Dr. Brenner: Most people generally accept that the first true immunotherapy was well over a hundred years ago. It was William Coley, Memorial Hospital as that was, and he developed the so-called Coley's vaccine which was a mixture of different bacteria, and he'd inject the bacteria into patients with cancer. And there was no doubt that, a significant doubt, of the significant proportion of them had tumor responses, and some of them appear even to have been cured. It’s difficult to know exactly what cancers they had because of record-keeping at the time, but certainly there were responses. The problem was that it was a mixture of bacteria, lots of different bacteria. It was very difficult to get the same mixture every time, and the patients had to be injected on a regular basis. And one of the things that they had to have was quite a severe fever in order to see the response. So the patients fell ill for a considerable period of time, and gradually this group fell out of favor and was replaced by chemotherapy and by radiation, although it sort of made occasional comebacks. But after that time really, people developed approaches that were more readily reproducible, such as monoclonal antibodies, and more recently cell based therapies, in which we can predict with much greater accuracy how well and when they're going to work.
Erin: So what is monoclonal antibody?
Dr. Brenner: Monoclonal antibodies were first discovered where I did my Ph.D. in fact, in Cambridge. And they are antibodies that can be made with in almost unlimited quantities, from a single, originally from a single cell, which has made to multiply and produce these antibodies. A very defined specificity and very defined behavior, so you know exactly what they're recognizing, exactly how they're going to recognize it, and how much quantity you can produce from them. In other words, it's the exact opposite of what we talked about earlier. This Coley’s toxin which was a huge mix of different things that nobody could ever exactly replicate. So these are very specific very defined unlimited quantity antibodies and we can, therefore, work with them to show how best to administer them, and to make them as safe and effective as possible.
Erin: And what is the antibody action in the cell?
Dr. Brenner: The antibody recognizes structures on the surface of the cell. It binds to those structures, and then can either attract in other components of the immune system to kill that cell, or it can itself contain a poison that is taken up by the cell. A targeted drug in other words that it's taken up by the cell and specifically kills the cell to which it binds. And they can do both of those things it can have a drug attached to it and attract the immune system.
Erin: So what's the difference between immunotherapy and chemotherapy?
Dr. Brenner: Well immunotherapy is based essentially on the immune system, which is endogenous, it's within ourselves. Whereas chemotherapy is based on agents that come from outside ourselves, and capable of producing changes, potentially in all cell types, but which are targeted to particular molecular lesions or behavioral characteristics of the cancer. The immune system essentially recognizes structures on the cell surface, either external structures or internal structures, that have been taken out of the cell and pushed onto the cell surface, recognizes those patterns, if you like, as foreign and attacks the cells that bear them.
Erin: So are there any cancers for which immunotherapy has proven significantly more effective than earlier chemotherapy radiation surgery ways of treating them?
Dr. Brenner: I think there's no doubt that immunotherapy, for some cancers, can produce responses, and its long-term responses, where radiation and chemotherapy have failed. Examples include Hodgkin's disease, acute lymphoblastic leukemia, some lung cancers, and so on melanoma, but whether they can replace the other therapies is another question. At the moment these immunotherapies are very rarely frontline therapies. They’re mostly brought in as reserve therapies, but the other therapies have failed. Now if they can be brought into the frontline and shown to produce better, superior responses, superior survival, then yes they'll be better. But at the moment we can only say they can work even where other therapies have failed. that sort of sounds like a strange distinction, but I think it's an important one.
Erin: So when in treatment is immunotherapy generally introduced? Is it only after failure of the chemotherapy or radiation gradual?
Dr. Brenner: At the moment that's it's mostly a second, third, or fourth, or in one case in a series we've been doing 17th line of therapy.
Erin: 17th, wow.
Dr. Brenner: Yeah 17th line, it’s been successful at that level. So as we get more know more about it and how successful it is and where it works, gradually it will be taken further back into being part of primary therapy. And that has already happened with monoclonal antibodies, which have been around a lot longer. For example there's a monoclonal antibody to malignancies of one cell type B cells lymphoma, in which the antibody is used as a part of the frontline therapy. But it's also combined with more conventional chemotherapy and/or radiation so it's not a complete replacement, it's an add-on. So I think that's what will be the pattern. We'll see these immunotherapies coming earlier and earlier in treatment, becoming a component of that early treatment, and gradually as we learn how to combine them, the different components the cell-based ones, the antibody-based ones, all the other ones, we’ll see it becoming more widely used.
Erin: Because of the memory of the immune system, is immunotherapy a more long-term solution to preventing recurring cancer?
Dr. Brenner: So one of the big advantages of cell-based therapy, not so much the antibody therapies, but of cell-based therapies is that many of the immune system cells have what you might call stemness. In other words they can be present essentially for patient’s life. Some of the very first patients we treated with cell-based therapies 30 years ago still got those same cells circulating. We can detect the genetic modifications we made to them to track them we can still see them 30 years later and they're still potentially protecting the patients from their cancer. So yeah in principle one cell one time could cure a patient for life.
Dr. Brenner: Yes, but its potential at the moment.
Erin: Are there different types of immunotherapy treatments better suited for treating different kinds of cancers? Does it depend on the patient are you still in a sort of mix-and-match combination?
Dr. Brenner: Yes, so for the moment the cell-based therapies have been probably most successful for blood cancers. Although, other some other cancers like melanoma, or cancer of the skin, and certain other ones have responded to cell therapies. Antibody therapies have been effective for some solid tumors or example HER-2 antibody very widely used as part of the treatment of breast cancer again, in combination with more conventional chemotherapy, and, or radiotherapy. And so I would say that for the moment immunotherapy has a most dominant place in the blood malignant sis lymphoma and leukemia, while antibodies have a broader place in the treatment I saw the tumors, but I think those will converge.
Erin: A friend of mine is preparing to have a bone marrow transplant. Is that a type of immunotherapy, or is that a different thing altogether?
Dr. Brenner: When bone marrow transplant was first mooted, and first implemented, the idea was that the patients would have very high dose chemotherapy and radiotherapy that would cure their cancer. But it was realized that at the same time that higher dose of drugs and radiation would destroy their normal bone marrow. So the idea originally was that the bone marrow would simply transplant, would simply be a rescue from the damaging consequences of the treatment. But as time went by, people realize that that wasn't the main mechanism by which benefit was produced. Instead it was what was called a graft versus leukemia, or graft versus cancer effect, where the incoming immune system from the donor recognized the cancerous cells, along with some of the normal cells in the recipient, as being foreign and rejected, killed them, eliminating the cancer. So the bone marrow transform probably works by combination of mechanisms by reducing the burden of tumor, and then by eliminating those that are left behind.
Erin: Chemotherapy is known to have some side effects hair lost, exhaustion. Are there adverse reactions associated with immunotherapy as well?
Dr. Brenner: I think every effective drug has adverse effects. With immunotherapy, they depend on the type of immunotherapy being used, and also what's being targeted, and what component of the body is being targeted. And some of the effects are due to damage to normal organs that are also attacked by the immune system, or by the treatment used. and some of the effects are due to the immune system itself getting overexcited when it's introduced into this environment kill tumor cells, and releasing products that cause inflammation, and so-called cytokine release syndromes, and brain toxicities, and various other complications that are slowly being overcome and resolved. But in general it's a very powerful system, and these off-target effects, and the effects of the immune system itself can be very devastating, and have to be controlled.
Erin: Could immunotherapy lead to some kind of an autoimmune disease in a patient?
Dr. Brenner: One of the big dangers of having an immune system that's been activated or over-activated is that it won't confine itself to attacking the malignant target. That it will start recognizing your normal tissues as being part of the disease and will produced this so-called graft versus host disease, in which it attacks normal components of the body and damages them. And after bone-marrow transplant, that was for many years a very feared complication. It damaged the skin, the gut, and the liver, sometimes the fatal consequences. Certainly we've been able to control that more, and we have many more tools to control it now, but it is still a risk, absolutely.
Erin: How affordable and available is immunotherapy at this point?
Dr. Brenner: One of the big problems with immunotherapy, certainly cell based immunotherapy, is the very high cost. Every drug has high cost of development because of the various rules and regulations that you have to go through. But once the development is over, then the drugs can be manufactured extremely cheaply, for a few fractions of a cent per dose. Well that's not what's charged to the patient of course, but that's the actual per item cost. The problem with cell therapies in particular is that they are very continued to be very expensive, and complicated to manufacture. Those sort of handcrafted or artisanal products rather than something you buy and that's mass-produced. It’s a three-star Michelin restaurant on McDonald's so to speak. The issue also is that they are given in a different way. Very few chemotherapy drugs are curative, and they have to be given over a long period. The hope with cell therapies, in particular, is that one dose one time is curative, as we mentioned earlier. And that means that the initial cost can be quite eye watering, and so more and more people are trying to work out ways of breaking down the cost over a period of time, so that you have a few like a reverse annuity. The longer you live, the more you pay, or that you only pay if the drug actually works. There’s various advantages and disadvantages to that and other models, but for the moment it's not that huge a problem because most these cell based therapies are confined two relatively uncommon diseases. But as they get to apply to much more common diseases, than these issues of cost and availability are going to become quite troubling.
Erin: What other diseases could be, or are currently being treated with immunotherapy besides cancer?
Dr. Brenner: There's a lot of interest in using monoclonal antibodies to do the opposite of what they're doing in in cancer therapy. In other words, using them to lock immune attack and to minimize the immune response. So for autoimmune diseases and for inflammatory diseases, like Crohn's disease and other inflammatory bowel diseases, monoclonal antibodies and rheumatoid arthritis, monoclonal antibodies are proving extremely useful. And I think almost certainly, the same will be true once we can invert the findings we have for cancer with the cell therapies that we'll be able to develop cells that can inhibit these autoimmune attacks, and prevent inflammatory disorders, and autoimmune disease. And that, of course, opens up a much wider spectrum of disorders because there are probably many diseases, degenerative diseases, that have a significant component of information and an immune response within them, and being able to deal with those will be very important. All the more reason to get the costs down.
Erin: So what's next for immunotherapy?
Dr. Brenner: I think the main increase in interest now is in applying these to a broader range of cell therapies, and antibodies to a broad range of solid malignancies, solid tumors rather than the blood cancers. And the second big push, I would say at the moment, is to make these products off the shelf. So instead of having to make an individual product for each individual patient-
Dr. Brenner: Artisanally, exactly, you can have a bulk product, freeze it down, and then use them when you need it. You take it out of the freezer and inject it immediately into the patient. And there are huge resources going into this, in part because it's much easier to scale, and in part also because then become this prohibitive.
Erin: Could you talk a bit about your own research?
Dr. Brenner: Yes, so we're interested in really in moving cell therapies into additional blood cancers, and we're treating now t-cell malignancies with some very promising results, and a disease called Hodgkin's lymphoma, again with very promising results, and these are some of the patients who really have failed every other therapy, multiple different types of therapy. We’re also pushing to treat solid tumors more effectively, and the way that we're trying to do that is to make use of the immune system's ability to recognize virus infections. That’s really, probably, what its primary purpose is. So what we do is we take a virus, and we modify it so that will only grow within malignant cells. And we inject that virus into the malignant cells, and we put within that virus, a kind of reverse Trojan horse. So a kind of signal that attracts the immune system into the tumor, and helps remove virus infected cells. But at the same time, because the virus doesn't get into every tumor cell, we recruit in a whole range of different immune cells that can recognize other abnormalities on the tumor, even if they're not infected by viruses, and start to attack them and destroy them. And we can do this very successfully in animal models, and we are a launching now, or in the middle of launching, a clinical study of this within the next six months. The danger of it, of course, will be that we do too much as we were discussing earlier, and start to get autoimmunity. But we're hoping, and certainly the animal models suggest, that there's a gap between enough immune activity to kill cancer, and so much immune activity that you get autoimmunity. So we want to identify and exploit that sweet spot.
Erin: Are there any particular solid cancer solid tumors that you're focusing on right now?
Dr. Brenner: Well we're going to start with head and neck, cancers of the cervix, and cancers also of the lung.
Erin: So at least some of those are ones that do have a viral component to them?
Dr. Brenner: And some of those do, you're right. Some of are already got potentially viral tumors, some of them have papillomavirus in them. So we hope that that will help us along, give us a double dose of virus as it were.
Erin: It's really exciting. I am sure that all the people who have cancer, had a family with cancer, are following these remarkable accomplishments, and steps forward and immunotherapy with a lot of interest.
Dr. Brenner: Yes it's been a long time. I've been one of the few people who's lasted the course, really. I started doing immunotherapy of cancer in about early 1980s. And it's been a long road. I remember when we were always confined to the very last session, of the very last day, at any meeting on cancer therapy, and now, of course, we sort of front-and-center. I think it is going to be continued to be a long road, but we are at least somewhere along it, and we are beginning to see some very nice results.
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