Acute lymphoblastic lymphoma is the most common childhood cancer, with about 3,100 patients younger than 20 diagnosed every year, according to the National Cancer Institute. Children’s Mercy contributed to the trial of the first U.S. approved cancer gene therapy, Kymriah, for children and young adults with acute lymphoblastic leukemia that is resistant to treatment or has relapsed.
Doug Myers, MD, Children’s Mercy oncologist, was an early investigator of immunotherapy using chimeric antigen receptor t-cells to treat pediatric cancer and led the hospital’s participation in the Kymriah trials.
Join us as Dr. Myers discusses immunotherapy, the science behind chimeric antigen receptor technology, and it significance for patients now and in the future.
Selected Podcast
Cancer Immunotherapy and the Promise of CART19
Featured Speaker:
Learn more about Doug Myers, MD
Doug Myers, MD
Doug Myers, MD, is a pediatric hematologist/oncologist at Children’s Mercy Kansas City and Associate Professor of Pediatrics, University of Missouri-Kansas City School of Medicine. Dr. Myers received his medical degree from the University of Oklahoma School of Medicine. He completed a residency in Pediatrics at Children’s Hospital of Oklahoma and a fellowship in Hematology/Oncology at Baylor College of Medicine. He has been an early leader in the study of CART19 therapy for pediatric cancers.Learn more about Doug Myers, MD
Transcription:
Cancer Immunotherapy and the Promise of CART19
Dr. Michael Smith (Host): Our topic today, is Cancer Immunotherapy and the Promise of CAR-T19. My guest is Dr. Doug Myers. He is a Pediatric Hematologist and Oncologist at Children’s Mercy Kansas City and Associate Professor of Pediatrics at the University of Kansas City School of Medicine. Dr. Myers, welcome to the show.
Dr. Doug Myers (Guest): Thank you, very much.
Dr. Smith: Why don’t we start this way? Let’s have you do a nice overview of immunotherapy for us – where we’re at in the research, where we’re at and where we’re going with the clinical application.
Dr. Myers: Sure. Well, immunotherapy is quite a broad topic. There are lots of agents that can be used to alter the immune system or enhance the immune system to turn it towards a specific target. In the case of cancer immunotherapy, we may be talking about medication that helps inhibit a tumor by suppressing the immune system. The small molecules we might say – or agents that help the immune cells overcome the suppression of the tumor environment. That’s one-way tumors escape the immune system.
We could be talking about tumor vaccines or other agents to enhance the immune system. You can vaccinate patients against their tumor or a target that their immune system might be able to grab ahold of, so to speak, of the tumor. Tumor vaccines again, prostate cancer comes to mind. In the case of CAR T Cells or Chimeric Antigen Receptor T Cells, we’re talking about genetically modifying immune cells to target cancer. There’s a lot of research going on there to enhance all of those aspects of immunotherapy for cancer.
Dr. Smith: Right, right. And when you look at those different ways you can categorize immunotherapy, which one is showing maybe the most promise? Is it revving up the immune system inside that microenvironment of the tumor suppressing it? Where do you find most of the promise of immunotherapy?
Dr. Myers: Right, I think that especially when the Chimeric Antigen Receptor T Cells targeting CD-19 or targeting Leukemia showed so much promise whereas so many attempts in that field had failed to show much promise. That really launched CAR-T Cells – and research in CAR-T Cells into the spotlight. It’s been really exciting to see some of the initial medications that get in the way of suppressing the immune system being successful in cancers like Melanoma and other things there – lung cancer.
I think that there – and for those of us who believe that targeting cancer from multiple aspects or multiple angles using small molecules together with tumor vaccines, together with tumor CAR-T Cells, the promise is actually in multimodal therapy where maybe we’re learning how to combine these treatments.
Dr. Smith: Right.
Dr. Myers: I think we need to maybe not stress one area too much, but really enhance our research in all of that area because it’s going to take more than one agent.
Dr. Smith: Well, let’s talk a little bit about the CAR-T Cells because I know that you are doing some research or are involved in that Chimeric Antigen Receptor Technology. Tell us a little bit about the CAR-T Cells, and what is so special about them?
Dr. Myers: Sure, absolutely. I think it might be helpful to talk about what a Chimeric Antigen Receptor or CAR is. I was really fortunate to be involved in some of the first human trials when I did my training at Baylor College of Medicine and Texas Children’s Hospital. They had been working on that technology for a while. A Chimeric Antigen Receptor is Chimeric; it’s part one thing, part another. One end of the molecule – or this protein is like an antibody -- kind of like the proteins we make against vaccines. This antibody is capable of binding to its target.
In the case of CAR-T19 or Chimeric Antigen Receptors against CD-19, which is something that’s on a lot of different types of Leukemia. The antibody can bind to the CD-19 and hold tight. This antibody is hooked to some of the things – the signaling molecules that are normally in the cell. Maybe this T-Cell that it’s a part of is designed to bind to a cell that’s infected with the flu virus in your nose and kill that cell before the virus attacks other cells. Well, when the T Cell recognizes that infection is there through its T-Cell Receptor, it sends a signal to kill that cell. Well, in the case of a Chimeric Antigen Receptor, that antibody we talked about is attached to some of the signaling proteins in the T Cell, so now you have something that’s part antibody, but capable of attaching a T Cell or a T Lymphocyte – a virus-fighting cell – to a cancer cell now. Now, the T Cell is signaling itself as if was killing the flu-infected cell, but it happens to be attached to a tumor cell. So now the antibody has bound it there, and the signaling molecules of the T Cell are telling it to kill. It may think it’s killing a flu cell, but it’s actually now killing a Leukemia cell. So we’re able --.
Dr. Smith: So where are we at then when you look at the research and stuff? What does this mean right now for patients – or in the future, where are we at with bringing this then into a common way to treat Leukemia?
Dr. Myers: Right. There have been several institutions that have been running research trials of these Chimeric Antigen Receptors. I believe in 2012/2013, Children’s Mercy was one of only five or six institutions in the country that had their own investigator-initiated – or, you had to come to this site to get that form of therapy – in the country. We were one of very few institutions. What’s really exciting is when this Chimeric Antigen Receptor against this form of Leukemia showed so much promise, it was picked up by a pharmaceutical company, and it had begun its clinical trials at the University of Pennsylvania when they saw such positive responses. These patients who had had multiple relapsed cancers – very refractory cancers -- very little else was having any effect. They were seeing up to 90% of these patients go into a complete remission, and some of them were maintaining that remission for quite awhile.
What a pharmaceutical company is able to do is take something that’s going on at a single institution and produce that agent and get multiple institutions involved – that’s not the only way you can involve multiple institutions, but that was one way --.
Dr. Smith: One definite way, yeah.
Dr. Myers: So, that made it possible for someone who has this disease and wants this therapy or wants to participate in this research, instead of having to fly from California to Philadelphia, they can go somewhere closer hopefully, where this new agent is being provided in a research trial. It was really exciting when the success at one institution of this agent was now going to be available to multiple institutions. That’s something that in the world of cell therapy – CAR Therapy – had not been available before. It was very much a boutique institution agent. Does that make sense?
Dr. Smith: Yeah, absolutely. We were able to open this up to a larger population --.
Dr. Myers: Right.
Dr. Smith: And study that, and that gives more confidence in the results that we see. As it’s moved to a multicenter type of setup, are we still seeing some of these amazing results?
Dr. Myers: We are. That’s one of the best things about this is that by opening up at multiple sites and demonstrating that you could get the same response rate that other institutions who maybe didn’t have experience with these CAR-T Cells, could adhere to the protocol standards, treat patients with high-quality care, and adhere to the regulatory requirements, it just showed that the FDA and hopefully patients could trust that this was something they didn’t have to travel so far for. That’s what moved it towards – well it’s now been approved – moved it towards approval.
Dr. Smith: So right now, the focus is again on the CD-19 receptor on Leukemia cells, is this going to be applied to other cancers? Where do you see this going?
Dr. Myers: Right, so that is a big home. When you see something that is so successful in reducing remissions as this agent was for patients who were really in a bad position, there wasn’t much else that was going to provide any real help. When you see this agent coming out, you hope that it will work for more than just one type of cancer. The question is, “Will it?” I have a feeling – and this is just my feeling – that we’re going to find that treating solid tumors is a little bit more difficult with this technology. When you give a T Cell a Chimeric Antigen Receptor – at least at this point – generally, they are able to kill a cancer cell, but only a cancer cell that has that particular target on it.
We know that in the same way we give antibiotics to patients and kill off lots of bacteria that we’re going to select for and enhance the ability to grow bacteria that are not susceptible to that antibiotic. It turns out in many research models we already are seeing that if you – and even with CAR-T19, you can kill off all of the targeted tumor cells, but you will sometimes see the outgrowth of tumor cells that don’t have that target on it. And the answer may not be just targeting more things in that tumor because we know that a lot of these cancers can eventually continue to lose those targets and evolve somewhat. I think there are going to be strategies to get around that, but I think it’s going to take more time than we had hoped.
Dr. Smith: Right, and as you mentioned before, it’s that multifactorial or multimodal approach. On one end you are using immunotherapy, but on the other one, maybe you’re changing the environment of the tumor cell, maybe inhibiting how it can grow its own vessels to metastasize. There’s a lot of different approaches there, and if you put it all together, it does look very promising.
Dr. Myers: Absolutely, so already clinical trials are being developed where these CAR-T Cells are being given concurrently with one of the medications that can hopefully block the inhibition of other immune cells that may be already in the tumor trying to do their job, but had been suppressed by chemicals that the tumor secretes – chemicals that we normally use to control our immune system, now they’re being used against us to control our immune system against the tumor.
Dr. Smith: Well, Dr. Myers, I want to thank you for the work that you’re doing. It really is fascinating, and it does seem to be very promising. I want to thank you for coming on the show today. You’re listening to Transformational Pediatrics from Children’s Mercy Kansas City. For more information, you can go to ChildrensMercy.org, that’s ChildrensMercy.org. I’m Dr. Mike Smith. Thanks for listening.
Cancer Immunotherapy and the Promise of CART19
Dr. Michael Smith (Host): Our topic today, is Cancer Immunotherapy and the Promise of CAR-T19. My guest is Dr. Doug Myers. He is a Pediatric Hematologist and Oncologist at Children’s Mercy Kansas City and Associate Professor of Pediatrics at the University of Kansas City School of Medicine. Dr. Myers, welcome to the show.
Dr. Doug Myers (Guest): Thank you, very much.
Dr. Smith: Why don’t we start this way? Let’s have you do a nice overview of immunotherapy for us – where we’re at in the research, where we’re at and where we’re going with the clinical application.
Dr. Myers: Sure. Well, immunotherapy is quite a broad topic. There are lots of agents that can be used to alter the immune system or enhance the immune system to turn it towards a specific target. In the case of cancer immunotherapy, we may be talking about medication that helps inhibit a tumor by suppressing the immune system. The small molecules we might say – or agents that help the immune cells overcome the suppression of the tumor environment. That’s one-way tumors escape the immune system.
We could be talking about tumor vaccines or other agents to enhance the immune system. You can vaccinate patients against their tumor or a target that their immune system might be able to grab ahold of, so to speak, of the tumor. Tumor vaccines again, prostate cancer comes to mind. In the case of CAR T Cells or Chimeric Antigen Receptor T Cells, we’re talking about genetically modifying immune cells to target cancer. There’s a lot of research going on there to enhance all of those aspects of immunotherapy for cancer.
Dr. Smith: Right, right. And when you look at those different ways you can categorize immunotherapy, which one is showing maybe the most promise? Is it revving up the immune system inside that microenvironment of the tumor suppressing it? Where do you find most of the promise of immunotherapy?
Dr. Myers: Right, I think that especially when the Chimeric Antigen Receptor T Cells targeting CD-19 or targeting Leukemia showed so much promise whereas so many attempts in that field had failed to show much promise. That really launched CAR-T Cells – and research in CAR-T Cells into the spotlight. It’s been really exciting to see some of the initial medications that get in the way of suppressing the immune system being successful in cancers like Melanoma and other things there – lung cancer.
I think that there – and for those of us who believe that targeting cancer from multiple aspects or multiple angles using small molecules together with tumor vaccines, together with tumor CAR-T Cells, the promise is actually in multimodal therapy where maybe we’re learning how to combine these treatments.
Dr. Smith: Right.
Dr. Myers: I think we need to maybe not stress one area too much, but really enhance our research in all of that area because it’s going to take more than one agent.
Dr. Smith: Well, let’s talk a little bit about the CAR-T Cells because I know that you are doing some research or are involved in that Chimeric Antigen Receptor Technology. Tell us a little bit about the CAR-T Cells, and what is so special about them?
Dr. Myers: Sure, absolutely. I think it might be helpful to talk about what a Chimeric Antigen Receptor or CAR is. I was really fortunate to be involved in some of the first human trials when I did my training at Baylor College of Medicine and Texas Children’s Hospital. They had been working on that technology for a while. A Chimeric Antigen Receptor is Chimeric; it’s part one thing, part another. One end of the molecule – or this protein is like an antibody -- kind of like the proteins we make against vaccines. This antibody is capable of binding to its target.
In the case of CAR-T19 or Chimeric Antigen Receptors against CD-19, which is something that’s on a lot of different types of Leukemia. The antibody can bind to the CD-19 and hold tight. This antibody is hooked to some of the things – the signaling molecules that are normally in the cell. Maybe this T-Cell that it’s a part of is designed to bind to a cell that’s infected with the flu virus in your nose and kill that cell before the virus attacks other cells. Well, when the T Cell recognizes that infection is there through its T-Cell Receptor, it sends a signal to kill that cell. Well, in the case of a Chimeric Antigen Receptor, that antibody we talked about is attached to some of the signaling proteins in the T Cell, so now you have something that’s part antibody, but capable of attaching a T Cell or a T Lymphocyte – a virus-fighting cell – to a cancer cell now. Now, the T Cell is signaling itself as if was killing the flu-infected cell, but it happens to be attached to a tumor cell. So now the antibody has bound it there, and the signaling molecules of the T Cell are telling it to kill. It may think it’s killing a flu cell, but it’s actually now killing a Leukemia cell. So we’re able --.
Dr. Smith: So where are we at then when you look at the research and stuff? What does this mean right now for patients – or in the future, where are we at with bringing this then into a common way to treat Leukemia?
Dr. Myers: Right. There have been several institutions that have been running research trials of these Chimeric Antigen Receptors. I believe in 2012/2013, Children’s Mercy was one of only five or six institutions in the country that had their own investigator-initiated – or, you had to come to this site to get that form of therapy – in the country. We were one of very few institutions. What’s really exciting is when this Chimeric Antigen Receptor against this form of Leukemia showed so much promise, it was picked up by a pharmaceutical company, and it had begun its clinical trials at the University of Pennsylvania when they saw such positive responses. These patients who had had multiple relapsed cancers – very refractory cancers -- very little else was having any effect. They were seeing up to 90% of these patients go into a complete remission, and some of them were maintaining that remission for quite awhile.
What a pharmaceutical company is able to do is take something that’s going on at a single institution and produce that agent and get multiple institutions involved – that’s not the only way you can involve multiple institutions, but that was one way --.
Dr. Smith: One definite way, yeah.
Dr. Myers: So, that made it possible for someone who has this disease and wants this therapy or wants to participate in this research, instead of having to fly from California to Philadelphia, they can go somewhere closer hopefully, where this new agent is being provided in a research trial. It was really exciting when the success at one institution of this agent was now going to be available to multiple institutions. That’s something that in the world of cell therapy – CAR Therapy – had not been available before. It was very much a boutique institution agent. Does that make sense?
Dr. Smith: Yeah, absolutely. We were able to open this up to a larger population --.
Dr. Myers: Right.
Dr. Smith: And study that, and that gives more confidence in the results that we see. As it’s moved to a multicenter type of setup, are we still seeing some of these amazing results?
Dr. Myers: We are. That’s one of the best things about this is that by opening up at multiple sites and demonstrating that you could get the same response rate that other institutions who maybe didn’t have experience with these CAR-T Cells, could adhere to the protocol standards, treat patients with high-quality care, and adhere to the regulatory requirements, it just showed that the FDA and hopefully patients could trust that this was something they didn’t have to travel so far for. That’s what moved it towards – well it’s now been approved – moved it towards approval.
Dr. Smith: So right now, the focus is again on the CD-19 receptor on Leukemia cells, is this going to be applied to other cancers? Where do you see this going?
Dr. Myers: Right, so that is a big home. When you see something that is so successful in reducing remissions as this agent was for patients who were really in a bad position, there wasn’t much else that was going to provide any real help. When you see this agent coming out, you hope that it will work for more than just one type of cancer. The question is, “Will it?” I have a feeling – and this is just my feeling – that we’re going to find that treating solid tumors is a little bit more difficult with this technology. When you give a T Cell a Chimeric Antigen Receptor – at least at this point – generally, they are able to kill a cancer cell, but only a cancer cell that has that particular target on it.
We know that in the same way we give antibiotics to patients and kill off lots of bacteria that we’re going to select for and enhance the ability to grow bacteria that are not susceptible to that antibiotic. It turns out in many research models we already are seeing that if you – and even with CAR-T19, you can kill off all of the targeted tumor cells, but you will sometimes see the outgrowth of tumor cells that don’t have that target on it. And the answer may not be just targeting more things in that tumor because we know that a lot of these cancers can eventually continue to lose those targets and evolve somewhat. I think there are going to be strategies to get around that, but I think it’s going to take more time than we had hoped.
Dr. Smith: Right, and as you mentioned before, it’s that multifactorial or multimodal approach. On one end you are using immunotherapy, but on the other one, maybe you’re changing the environment of the tumor cell, maybe inhibiting how it can grow its own vessels to metastasize. There’s a lot of different approaches there, and if you put it all together, it does look very promising.
Dr. Myers: Absolutely, so already clinical trials are being developed where these CAR-T Cells are being given concurrently with one of the medications that can hopefully block the inhibition of other immune cells that may be already in the tumor trying to do their job, but had been suppressed by chemicals that the tumor secretes – chemicals that we normally use to control our immune system, now they’re being used against us to control our immune system against the tumor.
Dr. Smith: Well, Dr. Myers, I want to thank you for the work that you’re doing. It really is fascinating, and it does seem to be very promising. I want to thank you for coming on the show today. You’re listening to Transformational Pediatrics from Children’s Mercy Kansas City. For more information, you can go to ChildrensMercy.org, that’s ChildrensMercy.org. I’m Dr. Mike Smith. Thanks for listening.