t we talk about tonight with these revolutionary targeted therapies, we're always going to qualify and say, but there are significant side effects and some patients still may have intolerable, unacceptable, dangerous side effects.

So they're not, these aren't trivial medications, but the vast majority of patients can live years and years by taking a pill a day.

Host: I remember hearing about it and learning about it the way back then and just how exciting it was. It was really, you know, I was a molecular biology major in college and, this was in some ways the fruit of all of that stuff we had learned that was in some ways, you know, it was obviously basic science, but it hadn't really resulted in anything real up to that point.

So this was an exciting moment. And now, let's evolve that a little further, because that's a drug that you take by mouth and so forth. And then, but I think it evolved from there into the whole use of monoclonal antibodies, right? Where you were using an antibody to deliver the drug or substance or whatever you're trying to block more directly to the cell. And it seems like a lot of the evolution in cancer therapy came o

Kendal Williams, MD (Host): Welcome everyone to the Penn Primary Care Podcast. I'm your host, Dr. Kendal Williams. So I'm really excited about today's podcast because we are going to talk about, in broad perspective, the advances that have happened in cancer therapy over the last 20 years. For many of us who trained maybe in the early 2000s or the late 1990s, how we treated cancer was actually very different and the approaches particularly with the relationship to chemotherapy were very different.

And there's been a lot that's changed, and many of our patients are now going for these advanced therapies and coming back to us, and there's a whole sort of spectrum of things that are happening. And for many of us in clinical practice, particularly in primary care, it's a little hard to keep up.

And this on a sort of a societal level has also been a very exciting time where real advances are being made in some of the, the thorniest cancers that we've faced. So, in order to sort of have that high level discussion about cancer therapeutics, I invited two experts at Penn to talk about it.

You really can't get much more expert than the folks I have on. Dr. Lynn Schucter is here. Dr. Schucter is the former chief of the Division of Oncology at Penn. She is the immediate past president of the American Society of Clinical Oncology. She is the Madeline and Leonard Abramson Professor of Clinical Oncology at Penn. She directs the Tara Miller Melanoma Center and has had expertise particularly in melanoma where there have been great advances in the last decade or so. So, Lynn, thank you so much for coming.

Lynn Schucter, MD: Thank you. Glad to be here.

Host: Joining us also is Dr. David Porter. Dr. Porter is a liquid oncologist. He is the director of, for the Center of Cell Therapy and Transplant at Penn. He is the Jody Fisher Horowitz Professor of Leukemia Care Excellence and the President Elect of the American Society of Transplantation and Cellular Treatment. So, thank you, David.

David Porter, MD: Well, thanks for having me.

Host: And Dr. Porter gave a grand round presentation on the new sort of immune cellular treatments that, you know, really sort of stimulated me to want to put this together. And I'm, so happy to have, and honored to have both of you on.

So let's start very basic. Because, ultimately when we talk about cancer, it's a war, right? It's a fight in which the cancer is trying to survive and we are trying to stop it from overtaking the person. But I want to go back a little bit to cancer biology, and what we now understand is happening on the cellular level, when a cell decides to go rogue, to begin to replicate and to grow beyond its limits to spread to other organs and eventually, of course, cause the death of the human and, and the organism. But that's not a process that happens overnight.

That's a process that happens through multiple different stages, but also it requires the cancer cell to develop new qualities that will allow it to do this destructive business that it does. Now I'm going to highlight all this because we're going to talk about cancer therapeutics and many of the things that we're going to talk about are going to be focused on what the cancer cell is doing in order to do its nasty job. So then let me start with just cancer biology in general. What's happening in a cancer cell?

Lynn Schucter, MD: Well, so cancer, you know, first of all is, many, many different diseases. And so really any cell of the body could become abnormal and become a cancer cell. And that happens because of maybe exposure to certain carcinogens. And maybe we'll have a chance to talk about that, but let's just say smoking or sunlight or other toxins. But what happens is you, is that you acquire more and more genetic abnormalities in that cell. Genes become broken. And so one of the big things we've learned and why there's the advances we're going to talk about is that we understand what's driving a cell to grow. And we understand what these mutations are all about.

And each of the cancers in our body actually acquire different mutations. And that's why the therapies are different for breast cancer, different for lymphoma, different for lung cancer. We also know that the immune system probably plays or does play a really important role in recognizing these changes that can occur from a normal cell to a precancerous cell to a cancer cell.

And the cancer cells are able to evade the immune system. We think about this concept called immunosurveillance, where maybe our immune system is actually recognizing cells as they become abnormal and turn into cancer. And maybe there's a failure of this surveillance that allows cancer cells to grow.

So we've really learned a lot also about the importance of the immune system in maybe helping to prevent the development of cancer, but especially to treat cancers. And as you said, cancers, cancer cells develop this process to invade. So it still is the goal that we detect cancer very early at the very beginning, before it has acquired all of these features to invade and travel and metastasize throughout the body, live in a hostile environment, another organ, say something that started in the breast, travel to the liver, but those cancer cells need to be able to have that soil in the liver to be able to grow. But this still, the idea is identify early.

And so early detection still is key and maybe we can just remove a cancer surgically before it actually has had the chance to metastasize or travel. We use this word metastasis which means really traveling beyond the primary site, either to a lymph node or if it can also then travel through the bloodstream.

And the cancer cells acquire all these ability to do those kinds of things, invade, travel, set up shop in another location. And all of the therapies we're going to be talking about tonight really harness these really amazing basic science discoveries that have identified all these new processes that allows our treatments to be so much more specific and so much more effective.

Host: David I'm going to just pose the same question to you in terms of how you explain cancer to your patients.

David Porter, MD: I think that was a excellent explanation. When I explain it to patients I probably explain it a little bit more simply as maybe how I think about it. So, the human body and the cells in the body are really quite remarkable. Our cells know what to do, and they know how to grow.

And if you look at people, right? So to us, everyone looks a little bit different, but basically all people are kind of the same, right? Similar proportions and similar features. Our cells know how to grow. Cells know how much to grow and they know when to stop growing. That's, that is a feature of just about every cell type.

Cancer cells lose the ability to regulate themselves. They lose the ability to know when to stop growing. In certain cancers, which we may talk about, leukemia called CML, chronic myelogenous leukemia, for instance, develops a mutation. And I explain this as almost short circuiting all of the control mechanisms.

The wiring gets short circuited so the cell is always on. It doesn't know when there are enough of the cells. It doesn't know to stop and it keeps growing out of control. And I think that happens in all cancers. Another feature which you touched on is that typically, to become a cancer or a metastatic cancer, a life threatening cancer, cells develop an abnormality, but then they develop more abnormalities and more abnormalities.

Cells that are short circuited and are growing out of control, are more prone to develop more abnormalities. So one begets another begets another, and sometimes having that first mutation puts that cell at risk to getting a second and a third that then leads to it becoming more aggressive, more invasive, and in fact, more life threatening. So I think about it as a loss of the standard control features that all of our cells should have.

Host: You know, as it develops, as a cancer cell or a clump of cancer cells develops the ability to metastasize and so forth; as you noted, Lynn, there are a lot of failed cancer cells, right, that get attacked by the immune system through immune surveillance, they get taken out of commission and so forth. But, you know, a cancer colony, if you will, as it grows, it's almost like a new city.

I mean, it has to lay down new blood vessels and so forth. It has to be able to avoid the immune system and develop countermeasures to the immune system and so forth. So it's not simply that cells start growing and spreading everywhere. They really actually have to develop some mechanisms, in order to be successful.

Lynn Schucter, MD: Right. The machinery of this cancer cell is incredible in terms of the skills and the sneaky nature of it. And so it does develop these very specific ways that it can as you said, lay down new blood vessels, which are required to get nutrients and grow. It figures out how to invade.

What's unbelievable is that cancer cells actually develop a way to shield themselves, actually hide from the immune system, and so we see these, this very powerful effect of literally a cloak being put over a cancer cell to evade being recognized by a T cell. And this is really well documented in laboratory studies.

And so you used this word war at the beginning but yeah, what these cancer cells are armed with to sneak around, evade, is really astonishing actually. But I do feel like we're beginning to outwit many of this machinery. But, you know, as we'll talk about, we develop a successful therapy, the cancer cells may shrink.

But then they develop again, new mutations, new ways to overcome what we just threw at them. And so this concept then often of multiple treatments or sequential treatments to go after preventing cells from regrowing, preventing resistance is a, is another really important area that we're currently using and of investigation.

Host: As I was reading about this, it reminded me a lot of antibiotic resistance, you know, in terms of the ability of the bacteria or the cancer cell to really develop its own strategies to avoid our therapies. So, you know, I, completed my training in the year 2000 and, I'd say about that time, most cancer therapy, took advantage of the fact that cells grow very quickly in cancer and so if you wanted to treat the cancer and not harm the patient, you needed something that was specific to the cancer and not to the patient, and oftentimes we were focused on the fact that they were replicating their DNA quickly or they were growing quickly and so forth. And so a lot of traditional, what we call cytotoxic chemotherapy, was directed at this specific aspect, right? And so folks who got that chemotherapy would lose their hair, they would have impacts on the patient's, the normal cells that were growing quickly and that's still in use before.

But that's where I want to start our discussion, if you will, is, you know, that's kind of the baseline for most of us. That's what chemotherapy means to us.

Lynn Schucter, MD: Right. And you know, when your say chemotherapy, I mean, everybody can picture somebody receiving chemotherapy. You know, the point is, it's like at the level of killing DNA and every, yes, the cancer cells, but so many normal cells. Our traditional chemotherapy generally lacks specificity.

That's why there's so many side effects. You see patients with hair loss and you're familiar with fever and low white blood cell count and risk of infection. But as we talk about tonight, the newer therapies are targeting really specific features of the cancer cells, sometimes extremely unique to the cancer cell that we don't see on normal cells.

And so we're gaining much more specificity to attack the cancer cell and spare much more normal cells, sparing more and more normal cells. And so, patients today getting treatment, they look like you and I. They have, don't have hair loss. They're not throwing up. They're really functioning. They're living, they're working. And I still can't believe in my lifetime, the changes that we've seen in the treatment of melanoma, for example, where we hardly ever use chemotherapy anymore. I mean, it's amazing. And yeah, patients living so much longer, that's why they're in your clinics because so many more patients are cured, living well, but as we talk about unique side effects still that we all need to recognize and manage.

David Porter, MD: Another difference, you know, the year 2000, you mentioned that's when you were sort of coming into this, was really a turning point. The chemotherapy we used to use and sometimes still do use with all of those side effects as you're talking about was also chosen very often empirically.

We didn't really understand the differences between different types of cancers well. And different drugs were tested in different kinds of cancers. Patients with different kinds of cancers got a number of different drugs to figure out which one worked best. Often it wasn't particularly scientific.

It was just chosen empirically without exactly knowing why certain drugs worked better in some cancers and not others. And even to this day, some of that's not known. And now not only do we have much better, more targeted therapies; but we understand how to choose the therapies better for a specific cancer.

Host: So, I guess the evolution that's happened would be described as maybe now we're doing targeted cancer treatment, right? Is that the term? Is that the appropriate term?

Lynn Schucter, MD: Well, there's different ways to use the terminology. When I think of targeted therapy, I am thinking especially about agents that are targeting a particular mutation. I mean, some people use the word precision as a, you know, in terms of getting more specific about our treatment, but sometimes we use targeted therapy to really be using treatments, often pills, that are taken every day that target a specific mutation. So for all cancers now, pretty much, when we make a at some point, depending upon the stage of the cancer, we will figure out what gene is broken in that cancer. What is the gene especially responsible for causing those cancer cells to grow. And sometimes we have a drug that really targets that particular mutation.

That's what we think of often as targeted therapy. David, tell me how you would think about the term.

David Porter, MD: Very similar. I think of targeted therapy as choosing a therapy because you know what you're trying to target, what abnormality in the cell you're trying to go after with your therapy. I'm trying to think of an example of a targeted chemotherapy, and you could use it that way if you know how a chemotherapy is affecting a specific mechanism in a cell, but we generally think of it as targeting a certain protein, a certain molecule, something that we kind of know what we're doing, not just empiric choices.

Host: So, as this evolves, we sort of look at the historical development of the big changes that have occurred in the last 20, 25 years. I think one of the first was in your area, David, and that would be the development of tyrosine kinase inhibitors, which targeted, right, a specific mutation that was known to occur in CML, a BCR ABL, Trans abnormality mutation.

And, you know, we knew about this. I knew about this. I read about this in medical school. And I remember I was out in Pittsburgh. I probably in my early faculty career and I was out for a run. And I heard an NPR story that I was listening to on the radio talking about that they interviewed this man who was running on his treadmill five days after he'd been basically given Last Rites for CML. And it was because of this new therapy that had come out. So let's talk about that in terms of you know, I think that was a category, as I understand it, of small molecules, right, that could be used to target a specific mutation specific to that cancer. And that was kind of a watershed event, right?

David Porter, MD: Yes. The whole story is absolutely fascinating and really, I think, revolutionized cancer therapies. CML is a great example. Chronic myelogenous leukemia is what's considered a chronic leukemia. And before about 2000, the median survival was about five years. If you pick up a textbook, if anyone had textbooks anymore, you would read the median survival was five years.

The only curative therapy, but the only therapy that would provide some long term benefit was bone marrow transplant, an allogeneic bone marrow transplant, which back then, and even to this day, has tremendous morbidity and mortality. About 20 percent of patients don't survive the procedure. Now, in a uniformly lethal disease like CML, it made sense to do bone marrow transplant. You could cure perhaps 60 or 70 percent of patients, yet still one in five would die of a complication of the side effect. What was known about CML, it was the first disease where a recurrent genetic mutation was identified. Peter Noll here at the University of Pennsylvania in 1960 looked under a microscope and saw abnormal chromosomes under the microscope, that there were two chromosomes that are broken in the middle and came together the wrong way.

That was termed the Philadelphia chromosome. They learned it was chromosome 9 breaking in half and chromosome 22 breaking in half and they come together. And the result of that translocation was forming a new protein that was not supposed to be in the cell. It links part of a protein called BCR, which stood for breakpoint cluster region, to the ABL tyrosine kinase.

The result of that was a new tyrosine kinase that wasn't supposed to be in the cell that sent this signal to the cell to just be on all the time, like we were talking about short circuiting.

So this BCR ABL protein sends signals to the cell to be on all the time. And, as we were talking about short circuiting the wiring of the cell, so it would grow out of control. Over the next several years, scientists learned the structure of this abnormal kinase and they started screening for chemicals that would turn it off, that would bind to the active region of the kinase.

So not only was it the first targeted therapy, but I think one of the most exciting parts of that whole story is that it was rational drug development. They knew the crystal structure of the BCR ABL kinase. They screened for chemicals that could bind there and then through chemical processes were able to develop even a better binding protein right into the active site of BCR ABL and developed a drug, which was later termed imatinib, which was a revolutionary therapy for CML.

It is a pill. People take it. They can live for years and years and years. There are now five different BCR ABL directed tyrosine kinases. We rarely do bone marrow transplants anymore for patients with CML. It's incredibly well tolerated in most patients, though, I think anything we talk about tonight with these revolutionary targeted therapies, we're always going to qualify and say, but there are significant side effects and some patients still may have intolerable, unacceptable, dangerous side effects.

So they're not, these aren't trivial medications, but the vast majority of patients can live years and years by taking a pill a day.

Host: I remember hearing about it and learning about it the way back then and just how exciting it was. It was really, you know, I was a molecular biology major in college and, this was in some ways the fruit of all of that stuff we had learned that was in some ways, you know, it was obviously basic science, but it hadn't really resulted in anything real up to that point.

So this was an exciting moment. And now, let's evolve that a little further, because that's a drug that you take by mouth and so forth. And then, but I think it evolved from there into the whole use of monoclonal antibodies, right? Where you were using an antibody to deliver the drug or substance or whatever you're trying to block more directly to the cell. And it seems like a lot of the evolution in cancer therapy came out of that universe, right? From that point forward?

David Porter, MD: Yeah, I think that they were a little bit on parallel paths. So, the tyrosine kinase inhibitors, drugs like imatinib and some of these other small molecules are chemicals, you take a pill and these chemicals get into the cell and they find their abnormal target inside the cell and they bind to it, they keep it from doing the bad things that they're doing.

At the same time, technology was evolving so rapidly in the 1990s, early 2000s with technology where you could determine what the cell surface of a cell looked like, what proteins are on the cell surface, you could essentially make a fingerprint. And normal cells have specific proteins on their surface.

And cancer cells, in fact, in large part have many of those same proteins and sometimes other proteins on their surface. So these monoclonal antibodies were developed so that they could bind to either a normal or abnormal protein, they could target that protein on the cell surface of the cell you wanted.

If there was something specific on a cancer cell, you can make a monoclonal protein to bind to that protein on that cancer cell. Those monoclonal proteins can be therapeutic in a couple ways. They can bind to the protein, and by binding to that target on the outside of the cell, they can activate the immune system to come in and kill the cell.

That's one of the ways antibodies work to kill bacteria, for instance. Alternatively, in really clever biochemical engineering, you could take that protein and you could link a toxin to it. You could link a molecule that had radiation, you could link a molecule that could kill a cell so that now that antibody binds to the outside of the cell you want to target, and it gets internalized, and as it gets internalized, it can bring in a chemical that once inside the cell can start killing it.

It can inhibit DNA synthesis, it can inhibit other cell processes so that cell now dies, or it can bring in radiation but brings it in specifically to the cell you want to target so you're not causing toxicity to tissue that you don't want to be involved. So a little bit different process that targets the surface of the cell as opposed to a small molecule which gets into the cell.

Lynn Schucter, MD: So for these targeted therapies, an approach can be with, as you said, the tyrosine kinase inhibitors, which are pills, which end in IB, the ibs or it can be a monoclonal antibody and the medicines like Herceptin, trastuzumab end in AB, but it is targeting on the cancer cell, a specific either a mutation or extra copies of something.

And you know, just again, for the, your listeners, we are now really talking about somatic mutations. And so these are mutations that are just present in the cancer cells. And this is not about hereditary cancer syndromes where people have abnormal genes in ever cell of their body.

And I know that for our patients, when we say you have a mutation in your melanoma, they think, oh, my children are going to inherit it. But these are totally different things. We are talking tonight, right now, so far, about mutations that are just in the cancer cell. These are called sort of acquired somatic mutations. And there's different ways, as you just said, Kendal, to target either with a pill, a tyrosine kinase inhibitor, or the monoclonal antibodies.

And as David just said, this is like a whole new thing of these antibody drug conjugates where you have this antibody that recognizes a cancer cell with this payload of a toxin and it's this way of delivering in such a precise way, a toxin mainly to the cancer cell. We hope that it spares normal cells.

Of course, it's not that specific, but that's how far we're getting right, of imagining a delivery system now with a payload that is just going to the cancer cell. And so as you've just described for CML, imagine lung cancer has a specific mutation. Let's say it's EGFR, melanoma has BRAF, you know, breast cancer, all these new mutations, colon cancer, their own.

This is why, for patients, it's sometimes confusing. Many share a similar mutation, like let's just say RAS. That's a particular mutation that's shared amongst different cancer types, but the drugs sometimes work differently. We can't always predict in a given cancer that mutation drug, this drug will work, but you know, so much more specific now with having that knowledge of what's driving that cancer cell to grow and then selecting the most precise treatment for it. Totally changed, as you said, how we approach the treatment now.

Host: Oftentimes when I ask questions, I know the answers already because I try to be prepared. But, I'm going to ask a question I don't know the answer to, and that is, when you talk about EGFR mutation or RAS, you know, that's happening, in the DNA level. That's the mutation. It's obviously got to be expressed. I assume what's happening is that when you say EGFR, for instance, that's resulting in the expression on the cell surface of a protein that you can then target with a monoclonal antibody that is specific to the cancer cell. That protein is specific to the cancer cell that allows you to then use all the mechanisms David mentioned about, whatever you're choosing to put in that payload, that monoclonal antibody is going to send to that cell.

But because they have that specific protein on their surface, I guess, you know what I'm asking Lynn, but.

Lynn Schucter, MD: Right. So it either can be just overexpressed, too many copies, so there can be overexpression and sometimes then an antibody directed against EGFR can be helpful, or it can be mutated or broken. And it actually functions differently. The enzymes have different ways that they're working. And some of these new tyrosine kinase inhibitors, let's just say in melanoma, the medication has greater specificity for the mutated version of this than normal.

You're right. Every cell of the body has BRAF. That's part of its mechanism. But when it's mutated, it functions differently. And the medication sometimes can have specificity for the either it's broken and is different. And the medicines are really specific only to the mutated version, or as you're describing other situations where it's not broken or mutated, it's just overexpressed.

And so this is, a shout out to our pathologist colleagues and our, the molecular pathology core is this really important collaboration between the clinicians and the pathologists. I mean, Tuesday, a young woman came in with melanoma in her heart and her liver and her bilirubin was 10 and she had also a cutaneous metastasis on her skin.

We had her come in the next day. I just did an FNA, fine needle aspiration, tiny amount of materials needed. We got BRAF results in 24 hours. She had a broken BRAF gene and the next day medications were shipped to her house. And today, a week later, she feels so much better. Her bilirubin is down. The lump on her leg is decreased.

But that was unbelievable collaboration with our pathologist, with the pharmacist, but that's what we're doing. Like tiny sample, a needle, and can get so much information.

David Porter, MD: Kendal, I was just going to add a little bit from my world and these monoclonal antibodies which we use all the time. It is true that sometimes we target normal proteins on the cell surface and as much as we're talking about how sophisticated medicine is and targeted therapies are, sometimes we still target things that are maybe less specific that are nonspecific.

So in the world of lymphoma and leukemia, we use monoclonal antibodies. The most common one, probably a drug called rituximab targets a protein, CD20. It turns out it's on all normal B cells, most normal B cells. It's on just about every B cell lymphoma. Much like we talked about chemotherapy at the beginning, when you were saying how it kills cells that are growing faster.

Sometimes these antibodies that we use that may be on normal cells as well as the cancer cells tend to be a little bit more specific because they kill the cells that maybe are growing faster or you're combining it with things that help kill those cells like chemotherapy. So sometimes these antibodies are less specific.

I understand your confusion because I have that too. They're not always, they still do some damage to the normal cells that may have that target, but you're hoping they do more damage to the cancer cells than the normal ones.

Host: Well, my takeaway is also that the monoclonal antibody platform, if you will, is a very fruitful platform in which to really use for a wide variety of specific targets and so forth. I really want to get into sort of the cellular immune approach, but I want to talk about checkpoint inhibitors because they come up quite a bit.

My understanding of checkpoint inhibitors is inhibiting the capacity of a tumor cell to evade the immune system. And that you're sort of taking away the tumor cell's own defenses and then leaving it vulnerable to the native immune system to kill it or control it. Is that right?

Lynn Schucter, MD: Yeah, so there's normal brakes that are put on the immune system. So you know, if you have an infection and your immune system is turned on we have a normal braking mechanism to shut the immune system off. And so these new medicines basically take the brakes off the immune system and allow for your, our T cells and other types of immune cells to be more activated.

So it, it enhances the effectiveness of the immune system by basically taking brakes off. So you can imagine driving a car, you know, moving a car, because you put the accelerator on or you take the brake off and the car goes. So some of these immunotherapies are more about taking the brakes off and others are about putting the gas on the gas pedal and accelerating.

And this also, we talk about revolutionizing treatment. We've understood the power of the immune system for a long time, but we didn't know how to harness it. And what's so new and what, you know, people won the Nobel prize in medicine for is really understanding how to stimulate, especially T cells.

And what's been so interesting with the checkpoint inhibitors and the, so PD 1 antibodies like pembrolizumab or nivolumab; your listeners who see TV commercials, it's on TV every night, Keytruda or Opdivo. But what's so amazing is that these treatments are effective for so many different types of cancer.

So it's the opposite of what we've been talking about for the most part. It's not a specific target. Sometimes we want to know for certain cancers, if we have something called PD1 expression, but it's actually not necessary for all cancers. So what's been amazing is that there's probably at this point 25, 30 different cancers that we're using these immunotherapies for.

Started in melanoma, I will say, but now even in breast cancer, which we haven't thought of as a cancer that really responds to the immune system, but lung cancer, head and neck cancer, liver cancer, we're just using, kidney cance. Really amazing how many different cancers are responding to these treatments.

And for all the treatments we're talking about, I'm saying patients with advanced cancer, even that has metastasized or traveled to the brain, having a complete response. And we're starting to use the word cured of their cancer with these therapies. I mean, really, really amazing.

Host: Incredibly exciting. I want to be sensitive to our time and I really do want to jump and talk about T cells specifically and the use of T cells directly against cancer. So this is a little bit different, you know, we're going to get into what's called CAR-T therapy, which evolved out of work done at Penn, right?

And, David, you've been on the front lines of this therapy, but maybe with that little intro, you could tell us what's happening in this new and exciting area of harvesting lymphocytes to use them as troops to attack the cancer and be reinjected into the patient. You can tell us about that.

David Porter, MD: Yeah, sure. I agree. This has been one of the most exciting areas of medicine in the last decade. We've been talking about using the immune system to fight cancer. We know from all kinds of areas of cancer therapies that the immune system is important. You were just talking about checkpoint inhibitors.

And we know that one of the most important cell types of the immune system that fights cancer are the T cells. And we know the T cells probably go around the body and they're killing cells that go haywire all the time. But sometimes, as you said, cells escape the immune system. If a patient has cancer, then by definition, their immune system is not able to recognize it and kill it for whatever mechanism.

And so in the early to mid 2000 era, there were a number of people, but Carl June here at Penn was one of the leading pioneers and developed a technology that allows us to take a patient's immune cells, their T cells out of the body, and genetically modify them, put new genes into the cell to allow them to now recognize and target a cancer cell.

They can recognize and target something on the cancer cell and then kill it. And so it's using gene therapy to change a patient's own T cell so it can now recognize their own cancer and kill it. We do that. The gene is called a chimeric antigen receptor. Chimeric refers to from old Greek mythology, the chimera, that mythical Greek beast that's made of different parts.

It's got the head of a lion, the tail of a serpent, the body of a goat. A chimeric antigen receptor is a synthetic protein developed in a laboratory made up of different parts. On one end, it has a piece of a monoclonal antibody, like we were talking about, that antibody can target whatever you choose to target.

In the middle of it, it's got sequences that allow it to be stably expressed in the membrane of the T cell. And then a lot of the work happens with the piece in the middle, which sends activation signals to the T cell. So when the, T cell is genetically modified to now include this new gene, that gene is expressed, the gene is translated and then transcribed or transcribed and translated to a protein.

That protein's on the cell surface. The antibody now, can recognize its target on the cancer cell. When that antibody binds to its target, the sequences on the inside of the cell get activated. And there, it's usually the CD3 zeta activation domain. That's the part of T cell receptor that activates the T cell.

And there's a signal to the co stimulatory molecules. And those signals tell the T cell to become activated and to kill, but they also tell the T cell to grow. And so these cells expand in the body and they can expand up to about 10,000 fold we have seen. So you use the body as its own bioreactor. For every cell we put in, the body can grow up to 10,000 more of those cells each which, which can kill multiple different cancer cells.

That's scientific explanation. Before you ask me, I'm going to tell you how I explain it to my patients. The cancer cell has a piece of Velcro on it. That's the antigen on the cancer cell. The T cell doesn't have that piece of Velcro that can stick to it. So we use gene therapy to put a new gene into the T cell so that it will express that other piece of Velcro on it.

And now when that T cell goes by the cancer cell, those two pieces of Velcro can stick together. By sticking together, it activates the T cell to start killing. And how CAR-T cells work. They have been applied initially to patients with blood cancers, with hematologic malignancies, largely B cell cancers.

There is a protein on just about every B cell, CD19. Almost doesn't matter what it does, just that it's on every B cell malignancy. It so happens that it's on normal B cells as well. The first CAR-T cells targeted CD19 for a couple reasons. It is on just about every B cell malignancy.

And we know that even if it targets normal B cells, patients can live without normal B cells. We know how to manage that. That wouldn't be effective if you were targeting something on a lung cell or a heart cell, because you can't live without your normal lungs, your normal heart. So CD19 was the most low hanging fruit.

But this has now been, we treated our first patient in 2010. It was initially applied to patients with multiply relapsed and refractory leukemias and lymphomas. The vast majority of these patients had no probability of cure, let alone remission. They had really no effective treatment options and anywhere between about 40 to up to 100 percent of patients respond.

Complete responses are common. And somewhere between 30 to 50 to 60 percent of patients have gone on to have long term, ongoing remissions. And I will say easily, I think many of these patients have been cured of previously incurable cancers. Patients, we now treated our first patient in 2010, still alive and well, 14 years later with a previously, you know, rapidly growing incurable disease.

Host: And you're giving them long lasting treatment without having to give it exogenously because now they have these T cells floating around that are going if cancer emerges again, they're going to attack it and take care of it. And so you've developed a surveillance system, right, within the body itself. It's remarkable.

David Porter, MD: Absolutely. This is, and what you're describing is a living drug. This is indeed a living drug. It can grow in the body. As I said, so the body grows the cells, but these cells survive for long periods of time. They persist. Folks in our laboratory here at Penn have been able to identify these cells beyond 10 years after the infusion.

So they can persist for very, very long periods of time and provide that kind of surveillance that you're mentioning.

Host: The use has been mostly in liquid tumors, right? Now solid tumors have been a little bit more challenging, I understand, right, in terms of using that approach.

David Porter, MD: It has been tested in just about every solid tumor. It is extremely logical. It makes so much sense. But yes, solid tumors have a number of really difficult challenges. The B cell malignancies have a fairly obvious target, the CD19 protein, or it might be something called CD20 or CD22. It is harder in solid tumors to identify a unique target that is only on the cancer cell, but not on the normal tissue.

So with the B cell malignancies, if these cells kill all normal B cells, we can manage them. But as mentioned, if you don't have something on a lung cancer cell, that's only unique to the cancer cell, this is not possible, right? You can't target every lung cell in the body, or whatever organ. So that's one, finding the specific target.

But the other is that even when there is a specific target, these cells don't seem to work the same way in many solid tumors like they do in blood cancers, in part because of some of these mechanisms that Lynn was talking about. And I love the term you said, these sneaky features. Solid tumors have all these mechanisms to inhibit the immune system that blood cancers don't have. And so even if you have a specific target to go after with cell therapy, like CAR-T cell therapy, often these solid tumors have a shield. They don't allow the T cells in. Sometimes they have suppressive mechanisms that keep the T cells from being active.

And there are probably other mechanisms that keep these immune cells from working that we don't even understand yet. Though I will say there's tremendous amount of interest and research and activity trying to overcome these blockages. For instance maybe you can give these CAR-T cells with a checkpoint inhibitor like you were just talking about to it activate them in an environment that doesn't normally allow them to be activated. So there are ways to combine all the things that have been learned that we were just talking about with some of these newer cell therapies to try and overcome some of those barriers. We're not there yet, but boy, I'm confident this will work at some point.

Host: It does seem right now that it's almost like tht, ball of yarn, you know, at the beginning, you're just picking at it. You're trying to find a free end, you know, and you get, maybe get a couple or when I'm trying to unravel my extension cord, you know, I got a couple of loops in there, I got it, but then once you get it, it starts to, and I feel that's happening in cancer, that things are starting to roll and become synergistic so that we're making real advances.

Lynn Schucter, MD: Absolutely. I mean, on so many fronts as we've discussed tonight, and one new concept with immunotherapy, especially in solid tumors is this concept of neoadjuvant therapy. So if we have time, we could just briefly chat that, we've been starting to use these therapies, mainly for advanced cancer stage four that's traveled, but we've been moving these therapies to earlier and earlier stages, much easier to use the power of the immune system and immunotherapy to treat more microscopic disease.

But, you know, there's that patient that will present with an enlarged lymph node where it hasn't traveled throughout the body. And we, what we've learned recently is that giving the immunotherapy when the tumor is still present is much more powerful than giving the treatment after the surgery. So, usually, this concept of adjuvant giving the immunotherapy adjunctively or post op after the surgery.

Now we know, in certain settings, that giving the treatment while the tumor is still present is much more effective. There's something about the presence of the tumor antigen to really most effectively train the immune system and make this revved up T cells, much more potent and specific against the cancer cells.

So, so many new areas of research. It is new discoveries that the translation of the basic science discoveries to the patient now to the bedside and the pace of that; has been really remarkable and then applying these therapies is just totally different. And you know, we work so closely with our internist colleagues to help us with these really more unique, sometimes chronic side effects.

And so partnering with the internist, about some of these unique side effects, especially, immune adverse events, thyroid dysfunction, colitis, Diabetes, these new side effects that we didn't previously see, now we're seeing. And as you said, many, many more survivors.

So they're in your clinic, they're in our primary care physicians, helping us, you know, co manage, long term management of potential side effects, screening, and, especially, we're not talking about it so much today, but early detection and how to really detect cancer at its very earliest when it's most treatable.

Host: So I wish we had more time, I have five or six more questions I'd love to ask, and maybe we can do that in the context of discussions about specific cancers, and David, maybe we can have you back to talk about liquid oncology, and Lynn, you with the variety of things that you work on.

So, we wanted this to be an intro to really sort of the new frontier of cancer therapeutics. And then as we get into those specifics, we can highlight additional aspects. Thank you both so much for coming on, and to the audience, thank you again for joining us on the Penn Primary Care Podcast. Please join us again next time.

disclaimer: Please note that this podcast is for educational purposes only. For specific questions, please contact your physician, and if an emergency, please call 9-1-1 or go to the nearest emergency department.