Using the Body’s Immune System To Fight Cancer

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Immunotherapy is a new, groundbreaking approach to treating cancer that harnesses the body’s own natural defenses to fight tumors. Immunotherapy comes in many forms, including checkpoint inhibitors, which shut down a tumor’s ability to be invisible to the body’s immune system; antibodies that can stick to and attack a tumor; and genetically manipulated cells that become “natural killer cells.”

Ted Teknos, MD, President and Scientific Director of UH Seidman Cancer Center, explains how these medical wonders work and which cancers immunotherapies are most effective at treating.


Transcript

Macie Jepson

So, when are we going to have a cure for cancer? I mean, how many times have we heard that question? I hear it because I work for a hospital system. I hear it when I'm out with my friends for drinks. It comes up in all types of circles. And it's not like people are going to eventually one day in the medical field have this light bulb that goes off and we have found some miraculous cure. Like poof, here we are. This is what we've been asking for, right?

Pete Kenworthy

Yeah. It's not that easy. I mean, there are so many different kinds of cancer. There's more than 200 different kinds of cancer. And what's been learned really is that cancer is really as individual as the person who has it, right? Like identical twins could be diagnosed with the same exact cancer, and one could respond to cancer and one doesn't respond to cancer, right? So, so what gives really? And how close are we to finding a cure for cancer?

Hi everyone. I'm Pete Kenworthy.

Macie Jepson

And I’m Macie Jepson. And this is Healthy@UH. You know, the good news here is, is that while cancer, I mean, I don't know that we're going to find a cure all for cancer necessarily, but we have definitely come a long way since chemotherapy, radiation, surgery were really our only options. And what comes to mind for me is immunotherapy. It has really pushed to the forefront of options.

Pete Kenworthy

Yeah. Joining us today is Dr. Ted Teknos, President and Scientific Director at UH Seidman Cancer center. Dr. Teknos, thanks for being with us.

Ted Teknos, MD

Thank you for inviting me.

Pete Kenworthy

So, we know what our immune system does, right? It helps us fight off infections and other diseases, but we can apparently train it to fight things like certain cancers. So, before we get into specific treatments, I want to ask you what immunotherapy is, how does it work? And I want that high level view, but I also want to hear how the cells are manipulated to recognize and fight cancer cells.

Ted Teknos, MD

Yeah, immunotherapy really is the latest frontier, if you will, of our fight against cancer. So, it really started amazingly back in the late 1800s when Dr. Coley, who was actually an orthopedic surgeon, discovered that a patient who had a tumor on his face, when that tumor got infected with a bacteria, his tumor shrunk. And that sort of sparked a light bulb in his head that said, wait a minute, maybe our immune system, which fights bacteria, can also fight cancer. So remarkably, what he did then is he took a bunch of capsule proteins from bacteria and created a toxin. He called it Coley's Toxin, and he started injecting it into people's tumors. And lo and behold, a lot of tumors started to respond and get smaller just by this agent. And this was way before chemotherapy was on the scene. And it was a, it was a revolution at the time. But as with many things, it didn't stand the test of time. And as chemotherapy was developed in the 40s and 50s, 1940s and 50s and 60s, Coley's Toxin kind of went away. And the whole idea of harnessing the immune system to fight cancer took backseat to radiation, chemotherapy, and surgery.

So, the concept of immunotherapy has been around for a while. So, what is the concept? The concept is that our own immune system is incredibly powerful. It can fight viruses, bacteria, whatever foreign substances in our bodies, the immune system can develop a response to it. And not only can it develop a response, but it can create a memory to that response so that when we're re-exposed to that, we respond to whatever bacteria it was that we were exposed to previously, and it doesn't affect us again. That's how vaccines work. That's how, you know, COVID being the perfect example. You know, if you're exposed to proteins that are on the COVID virus, the next time you're exposed, you have a memory and an immunity to it.

So, immunotherapy is in essence then, allowing the immune system to identify cancer and fight it off. The problem is tumors are smart. So, tumors have learned as an adaptive mechanism how to survive in, against our immune systems by hiding from the immune system. They essentially create around them a force field that is really a protein that turns off the immune system. So, as our immune cells come and are looking for a cancer, tumors appear invisible to them. So, they cannot see them. It's almost like, you know, if you go into a room and if you haven't been in that room before, you don't know what's in the room until the lights turned on. And our immune cells in essence were running around our bodies blind trying to find tumors.

So, being able to harness the immune system's power to fight cancers is really what immunotherapy is all about. And there's multiple ways to harness the immune system. So, one way is essentially to block whatever that substance is that the tumors secrete that make them invisible to the cancer. So, those are, you know, the checkpoint inhibitors. So, Optivo (nivolumab), you know, Keytruda, all these drugs that you hear about, they're called checkpoint inhibitors. And what they do is they turn off, you know, these checkpoint ligands, if you will, not to get too technical, but it allows then the immune system to identify tumors. And those were approved really in 2014. So very recently, and they went into clinical trials within the last few years. And we've seen some miraculous responses to those drugs, particularly in melanomas. That's one cancer that's been particularly affected.

Pete Kenworthy

And you're talking about the body doing this by itself? Or is what you're talking about, pulling ourselves out of our body, manipulating them, and then putting them back?

Ted Teknos, MD

Well, that's another form of immunotherapy. So, immunotherapy really comes in many flavors. One is, you know, being able to turn off the hiding agents, like I described the checkpoint inhibition and activate the immune system against the cancer. So, that is essentially using our own immune system, but turning off the cancers’ defense, if you will. The other thing we can do then which also uses our own immune system as is without manipulating it, is developing antibodies, which are, you know, little flags, if you will, that go to a tumor and the tumor may express a very specific protein on its surface. Let's say, you know, EGFR is something that's on the surface of squamous cell carcinomas, as an example. HER2, you know, which is what, Herceptin. Those HER2 molecules are on the surface of breast cancers.

So, if you can create antibodies that stick to tumors exclusively… and the problem is many of, many of these antibodies don't stick exclusively to tumors… but when they can, you then can let your own immune system identify that antibody and then attack the tumor. So, that's another way that we can use our own immune systems augmented by these medications. And then the third way to augment our own immune system is to develop vaccines against cancer. So, the antibodies go and stick like a flag on a tumor and identify it. The other way we can do it is, say, okay, breast cancers express HER2. Let's vaccinate the body against HER2 so that whenever a HER2 molecule is seen in the body, our immune system fights it. And those are the vaccine strategies. So, if you can identify things that are unique to cancers and are separate from our body's natural proteins, then our immune system as is can attack it. So, there's three ways that we can use drugs to make our immune systems more effective.

The final way is what you're talking about, which is taking our own cells out of the body, putting them in the lab and genetically manipulating them so that they identify a protein on a tumor. And that's what CAR T-cells do. So, you know, we're fortunate enough here at University Hospitals to have a cell therapy facility where we can generate these CAR T-cells here on site. Now, there are commercially available products as well. What that involves is drawing a person's blood, just like giving blood, and then the blood is filtered. The white blood cells, specifically, the T-cells are taken out of a patient's, are filtered out of the patient's blood, taken to a lab, and then they're genetically manipulated to identify a specific part of a tumor that is not expressed anywhere else in the body.

And then those cells after they're genetically modified are expanded in the lab, and then they're given back to the patient like a blood transfusion. And then those cells circulate around the body and attack the tumor only and don't attack the rest of the body. There can be side effects, obviously, but, you know, those are highly effective treatments. Those are called cell therapies, and CAR T is an example, natural killer cells, which sound cool. Those, you know, those are another type of cellular therapy where they don't even have to be from the same patient. Some of those, because they lack surface markers, they can be from you and given to me. So, those are called off the shelf cellular therapies, and we’ve got investigations going in those as well.

Macie Jepson

This is so fascinating. This is so exciting. So, now we need to dig deep and find out what types of cancers are responding to this type of immunotherapy. So, what kind of cancers are we talking about? And what kind of treatments are we using for those cancers?

Dr. Ted Teknos

Yeah, that's a great question. So, primarily right now, these treatments are being used for blood related malignancies. So, lymphomas, leukemias, multiple myeloma. So, the most effective cell therapies at this, most effective treatments against cell therapies are CAR Ts for acute lymphoblastic leukemias, and those affect children as well as adults. And then Diffuse Large B-Cell Lymphomas. So, some lymphomas, and the reason they’re…so that that's another very effective treatment. And then there's a new one now for multiple myeloma, which is kind of traditionally what you hear about as being a blood cancer, or I'm sorry, bone cancer. So, but it is from the blood. And those are the ones that right now we have the best cellular therapies for. The reason is blood tumors, they all start from a single cell and they tend to be clones, meaning they look the same, just like that first abnormal cell.

So, acute lymphoblastic leukemia, Diffuse Large B-Cell Lymphoma, they have on their surface, a marker that's called CD19. That's a very specific protein. It's only on those cells, and they all look like the mother cell, if you will. So, the parents look like all the children. That's why the blood tumors are most effectively treated by these therapies because they all express it.

Now, solid tumors, they behave a little bit differently. So, pancreatic cancer, anything that isn't a, you know, a blood-related tumor, when you hear about tumors of organs, those solid tumors start out from a single cell, but then those cells branch out and can look very different. So, if you take a pancreatic cancer, all the cells are not the same. There are some that have gone down a path of looking a little bit different than others. So, it's harder to target those solid organ tumors because they have very different patterns of cancers. And then the other thing is their blood supply and the environment that they're in is very hostile to these immune cells infiltrating them. So, there's a lot of investigation going now into solid tumor cellular therapies.

Macie Jepson

For all of the hope that this gives us, people always want to know about the side effects though, because in the past, I mean, side effects were not, some people just couldn't handle them. What about here?

Ted Teknos, MD

That's a great question. So, I wish I could say that these are side effect free, the cell therapies, but there is significant risk to some of these cell therapies. Some of the early CAR Ts were a mix, believe it or not, of human and mouse DNA. So, you can imagine your body would react to having a mouse floating around in you. So, that causes some reactions. And also there's such a rapid kill of the tumor that you get what's called a cytokine release syndrome. So, as the tumor melts away, cause a lot of these cell therapies within 30 days, there's no tumor left from, you know, having a large bulky disease. But with all that, you know, death in the body, all these hormonal elements get released, and you have wide swings of blood pressure, and you can even have, you know, neurotoxicities that fortunately tend to be short-lived and there's ways to control them, but they are not without their, you know, without their side effects.

Now, the other types of immunotherapy, these checkpoint inhibitors that we talked about, the side effects of those, you know, are also well-known, and they tend to cause a ramping up of our immune system. So, in those folks, people can get arthritic changes, auto-Immune diseases like their thyroid doesn't work as well, or they develop, you know, other immune related side effects that are, you know, again like arthritis, like, you know, your immune system attacking normal parts of your body. But fortunately again, those are reversible for the most part, if you stop the treatment.

Macie Jepson

You know, we did a podcast about clinical trials, and there was that assumption that it was always a last resort, and we learned otherwise. What about immunotherapy? I mean, is it only after chemo and radiation?

Ted Teknos, MD

No. That's a great question. So, you know, a lot of clinical trials start when people are out of options. And I think CAR T started that way, too. It started as a treatment where people have run out of a lot of options and, and now CAR T is kind of the last resort. Checkpoint inhibitors, the same, you know, these medications. Particularly with the checkpoint inhibitors, now they've moved into earlier stages of treatment and as part of standard treatment for many cancers. So, we're now seeing them, in many instances, given before surgery or as part of the primary treatment and not after other treatments have failed. So, I can tell you our, you know, just to put it in perspective, I think over the last six years, you know, the proportion of our patients who were receiving some form of immunotherapy has gone up, you know, 30 fold, and it's now almost 25 to 30% of the therapies that we deliver at Seidman Cancer Center.

Macie Jepson

Let's talk about the standard of care and where immunotherapy fits in to certain types of cancers, before, during, after.

Ted Teknos, MD

Yeah. So, I think immunotherapy started out as a stand-alone treatment, but really what's happened now is it's become incorporated into the earlier parts of treatment. So, and the way that is occurred really is, like most things, serendipity. So, you know, as I said, what primes our immune system is identification of unique proteins in the cancer that our immune system can attack. So, what was found with some melanoma studies, again by accident, is a patient was on immunotherapy and was responding to treatment, but then, you know, then popped a spot in their lung that needed to be radiated and still had other areas. But the spot in the lung was large and was more life-threatening. So, they said, okay, we're going to continue the immunotherapy, but we're going to radiate your lung, so, to get rid of that big spot in the lung.

So, what ended up happening is they did the radiation, lo and behold then, the immunotherapy started working better. And that's because the radiation killed the tumor, released in its, by dying, the proteins that, you know, activated the immune system. And then the immune system revved up and fought the rest of the tumor. So, by killing a tumor while you're on immunotherapy, whether it be with radiation or with chemotherapy, the immune system is better able to identify the antigens of the tumor and then attack it. So, now it's been moved up in combination with chemo and radiation to make it more effective.

Pete Kenworthy

You talked a lot about fighting blood cancers with immunotherapy. And that’s the main use for immunotherapy right now. And before we get into the hope for fighting…

Ted Teknos, MD

CAR T therapy, not immunotherapy. So, yeah, so CAR T therapies are very effective against the blood cancers, but immunotherapy as a whole can be both solid and CAR T.

Pete Kenworthy

Okay. Thank you. Thank you for correcting me on that.

Ted Teknos, MD

Yeah, sorry.

Pete Kenworthy

No. Thank you for that. And we're going to get to this a little bit more on the solid tumors. But before we move on, I do want to just touch on the recent FDA approval concerning CAR T and multiple myeloma, right? What does that mean for multiple myeloma patients to have that?

Ted Teknos, MD

That is a dramatic development for patients with multiple myeloma. Multiple myeloma is a disease that, for many patients, is incurable. You know, I had an aunt who passed away from multiple myeloma. I've had very close friends who have it and have never been able to be rendered in remission. It's something that requires constant treatment and constant observation and can many times, you know, not be controlled and lead to a patient's death, unfortunately. So, having this new drug called Abecma, which is a CAR T against multiple myeloma’s proteins, is really game changer for patients with multiple myeloma. You know, there is a chance now with this CAR T therapy that there could be a cure for multiple myeloma. And, you know, the trials have started. We enrolled the first patient here at University Hospitals in the State of Ohio, because of our experience with these types of trials and, you know, knock on wood, he's doing well so far. And this is really, I think, a game changer for patients who were on this chronic chemotherapy regimen waiting, you know, for the, you know, shoe to drop, so to speak. And now having this as an option really has given hope to many, many patients with this disease.

Pete Kenworthy

Awesome. Awesome. That's great to hear. So, I'm glad you corrected me a moment ago that immunotherapy in general is used for both, right? It's used for solid tumors, one way of treating and then CAR T specifically has been used primarily for blood cancers. What about other ways, the future of immunotherapy, I guess, right? And a lot of that may come with the solid tumor cancers that haven't had as much success with these kinds of therapies. What is research showing us in terms of how we'll be able to use this going forward?

Ted Teknos, MD

I think there's no question that a vast majority of the efforts in research is looking at the mechanisms of resistance to immunotherapy and new ways to harness the immune system to fight cancer. So, if we look at, you know, what is likely to occur in the future, I think with our capabilities of identifying unique proteins or what are called antigens in tumors, and then being able either to vaccinate a patient against those antigens or develop a very targeted, you know, CAR T like, or NK like therapy to antigens or proteins that are only expressed on those tumors is going to be, I think, the Holy Grail of immunotherapy.

The other big area of research is, you know, checkpoint inhibitors, these, you know, this original therapy that's effective against solid tumors varies widely in its efficacy. So, in some cancers, solid tumors, it doesn't work at all. The patient’s resistant to it. In others, it works, for most, it works about 17 to 20% of the time where they get a dramatic response and can put the tumor in remission. In melanoma, it works about 50% of the time, but there's still that resistance to this therapy. So, a lot of effort is going into figuring out what is different about those patients who don't respond to these immunotherapy treatments? Can we add a second compound once we understand the way that they develop resistance? So that combinations of a couple of agents could then overcome that resistance and we can get, you know, the 20, 50 percent responders up to 100 oercent. So, that is a major area of focus. And there's been a lot of headway made in that as well.

Pete Kenworthy

Does that get into what I said at the beginning about two people can have the same exact cancer, but respond differently because it’s literally as individual as the person themselves?

Ted Teknos, MD

Yeah. So, tumors are, you know, genetically very different, you know. And up until the early 2000s, we treated everybody who had a certain type of cancer the same, just based on how they looked under the microscope. And we know that that is, you know, it's, I don't want to say it's inaccurate, because you are able to lump all lung cancers who are, that are adenocarcinomas, let's say, together. But morphologic appearance is very different from what the genetic makeup of a tumor is. So, even though two tumors may be exactly the same under the microscope, they're vastly different, you know, when you look at the genetic variability in the tumors. So, that is kind of the whole concept behind precision medicine. If you and I, you know, both had a skin cancer, let's say, because those are very treatable and curable, but…

Macie Jepson

If we're going to put something out into the universe. Yeah.

Ted Teknos, MD

So, if you look at my skin cancer and your skin cancer, they look the same, and they're both squamous cell carcinomas. You do a sequence of mine and a sequence of yours, they're going to be very different. And being able to identify those differences wasn't even possible until, you know, the mid 2000s. Now, we can say, all right, my tumor has, you know, gene X that it's dependent upon and yours may have gene Y and Z. So, how we treat those will be very different, even though they look the same.

Macie Jepson

You kind of touched on this when you talked about percentages, but what does this mean just overall about our fight against cancer? I mean, are survival rates going up?

Ted Teknos, MD

That's a great question. And yes, they are. So, when you look, you know, I always use as the, the benchmark, you know, the National Cancer Act, which was signed, you know, in 1971 under the Nixon administration, and that's where we declared war on cancer. And then, you know, our survival rates for cancer back in those days were a certain percentage. And then we didn't really see changes in that survival rate up until the 1990s. Really, even though we had begun investing more significantly in cancer research, all we really had to fight cancers were the surgeon’s scalpel, radiation therapy, which was, you know, effective for some tumors and chemotherapy. But if you look at the difference in survival between 1991 and the year 2016, there was a dramatic increase in survival rates in cancer. So, in just in that two decade period, cancer survival rates went up very significantly.

And a big part of that was our improvement in lung cancer, survival. So, lung cancer was, and continues to be a deadly disease, but using all the genetic markers in lung cancer, we're able to tease out lung cancers and identify better treatments. And the difference in just lung cancer alone survival, coupled with improvements and others as well, but a large part of it was because of lung cancer, cure rates have gone up substantially just in the last 20 years. And I think it's just the tip of the iceberg. Using genetics, using our genetic knowledge to inform our immune system on how to fight these cancers better, I think we're going to continue to see cure rates for cancer rising and rising on an annual basis, hopefully to the, you know, to the point where, you know, it becomes either we cure it or it becomes a disease we live with.

You know, the example I always use is HIV. HIV was a universally fatal disease that there was no treatment or cure for, you know, up until, you know, really the identification of one drug and then a second and a third. And then when they combined all three, now it's a chronic disease that people live with. And you know, my hope is that that same paradigm will work in cancer care.

Macie Jepson

This is exciting stuff. I love doing podcasts where we leave people with hope. And you do a really good job of explaining it so that people can like really get it. You know what I mean? It can't be easy to do. Dr. Ted Teknos, thank you so much for being with us. President and Scientific Director at UH Seidman Cancer Center. Really, really exciting stuff.

Ted Teknos, MD

Thanks for having me.

Macie Jepson

And we want to remind all of you that you can find and subscribe to this podcast on iTunes, Google podcasts, Stitcher and wherever you get your podcasts search University Hospitals, or Healthy@UH, depending on where you subscribe.

Pete Kenworthy

For more health news, advice from medical experts and Healthy@UH podcasts, go to UHHospitals.org/blog.

 

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