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Scott Webb: Did you know, it's possible to train our T-cells to fight cancer. It's called CAR T-cell immunotherapy. And joining me today to educate us about this innovative approach to fighting cancer is Dr. Luke Akard, a Blood and Marrow Transplant Specialist with the Franciscan Health, Indiana Blood and Marrow Transplant Program. This is the Franciscan Health Doc Pod. I'm Scott Webb. So doctor, thanks so much for joining me today. I'm going to abbreviate this after my first question, but what is Chimeric antigen receptor T-cell therapy also known as CAR T-cell therapy?

Dr. Akard: I like that CAR T-cell term. It makes it sound like we're going for a drive. And in some ways driving might be a good way of thinking about it, but Chimeric antigen receptor T-cell treatment, it's a cellular therapy. We modify these normal cells that are called T-lymphocytes that are present in the blood, and we modify them using genetic engineering. The Chimeric antigen receptor, the CAR of this, the driver is a combination of a couple of genes that are engineered and put into the patient's own T-lymphocytes that are called the T-cells. So using special techniques, specific genes, when to recognize a target, the other to activate the cell. So it turns on or turns against what it binds to. That's the Chimeric antigen receptor part. So the T-cells are removed, genetically modified. There is a two prong. That's the Chimeric part, Chimera meaning two part two prong gene put in, and those two prong gene elements go to the surface of these T-cells.

And so, this becomes an anti-cancer therapy. You have to have those two genes that are modified. One is able to recognize a target on a cancer cell. So in order for this to be effective, there has to be a good target on the cancer cell for this targeted therapy, if you will. So there are a variety of different cancers that have good targets on their surface, that you can direct an antibody. That's part of the two part molecule. You have to have a good target that is recognized by the T-cell. In order for this cellular therapy to be most effective, one of the things that we learned early on is all by themselves. These modified CAR-T cells didn't work very well and nobody fully understands why that is the case, but you have to give chemotherapy first to allow these to work.

And the chemotherapy goes by the name lymphodepleting chemotherapy, lympho implying lymphocytes. We have to somehow diminish a person's own immune system cells before we give them back these modified cells that actually came from that person. So usually three to five days of chemotherapy is given, these modified cells are given back and then the treatment starts to do its attack. So there's a target on the cancer. These modified T-cells contain material that recognizes that target and then turns on and attacks once that T-cell is bound. So the notion is this is an intravenous treatment. And as those cells go through the body, they're searching for the target. And when they come across the malignant cell, it sees the target, sticks to it, and then kills whatever it is bound to.

Host: There's a lot to unpack there. And this is so fascinating. We were kind of talking before we got started here today. And I guess I was under the impression that, you know, CAR T-cell therapy replaced typical cancer treatments or therapy. So when we think about cancer treatments in general, how does CAR T-cell therapy differ from the other therapies that we have for cancer treatments?

Dr. Akard: There are two broad types of therapy for a car T-cell one is the specific chemotherapy. And they're only a few different regimens that have been used. These lymphodepleting chemotherapy programs. So that is part of the treatment, but the more important part is the cell therapy. So are there other cell therapy treatments that we use in modern medicine? Well sure, the most common are autologous and allogeneic bone marrow or STEM cell transplants. And in those treatments, those also are a combination of some kind of chemotherapy, usually quite aggressive chemotherapy followed by the administration of a person's own cells, that's to rescue a person's bone marrow after having been injured or even destroyed by the chemotherapy program that is given with an autologous bone marrow or STEM cell transplant. And then allogeneic the patient is rescued by somebody else's bone marrow cells. Those are similar, but completely different because it's a completely different kind of cell.

So, in the whole armamentarium of managing malignancies, obviously we have surgery, radiation have been around for years, drug therapies, chemotherapy, more specific therapies, targeted drug therapies that are, have been developed in the last many years, immune therapies that are drug therapies that turn on the immune system. And then these CAR T-type treatment, which in many ways is an enhanced immune delivery. So this specific target is bringing along the cell. That's going to try to kill what the CAR T is aiming at. So in some ways the CAR part kind of fits for this technique is the payload. If you will, as being driven to where it needs to go, and the payload is this cellular therapy. I need to explain some other differences between the current CAR T-cell treatments and other treatments.

These are treatments that are unique and specific to each patient because each patient provides their own cells. So the cells, these blood cells are obtained by a procedure called a apheresis. So the patient, it takes about three or four hours to remove enough of these white blood cells from a person's own body. Those white cells are then sent to a manufacturing facility where the genetic engineering is done. The generic engineering, where genes are put into these cells after they've been purified. So the total white cell population about a third of the white cells are going to be the lymphocytes. And about two thirds of those lymphocytes are these T-cells. And those T-cells are then used enhanced, and then genetically altered to express these receptors that are protein receptors that are put into these T-cells, a person's own T-cells. Those cells are frozen delivered back to the center, during the treatment.

The center then gives the lymphodepleting chemotherapy treatments over three to five days. The cells are then administered and they have some unique potential toxicities. When given back, one of the hopes with this sort of therapy would be that it was a relatively symptom-free, but it turns out that killing cancer with these activated lymphocytes can create all kinds of killer molecules. If you will, that not only might injure the cancer, but can also injure the host. So one of the areas of intense interest in the world of cellular therapy is making newer products that are less toxic and there's been a lot of improvement. And so we're going to see a lot of new CAR T-cell molecules and CAR T-cell outcomes as time goes by.

Host: Wow, that is really fascinating stuff. And you were talking about to the hosts or the patients in this case. So let's talk about that. Who can be treated with CAR T-cell therapy, is it for all cancer patients?

Dr. Akard: In order for CAR T treatment to work, you have to have a target on the cancer cell. So that has been a limiting factor. Right now, the cells, the malignant cells that have had the best activity are in a couple of families, the acute lymphocytic leukemia, which is the most common malignancy in childhood that has had effective CAR T-cell treatments. Another that is FDA approved. Another disease diffuse large B-cell lymphoma also has had effective treatment with a couple of different products. There's another type of lymphoma, much less common than the one called diffuse, large B-cell lymphoma called mantle cell lymphoma that also has had effective treatment. So those are the three subtypes of disease that currently have FDA approved CAR T-cell products.

There are literally hundreds of clinical trials ongoing right now in the us and around the world, looking at almost every malignancy from melanoma skin cancers that have metastasized to other parts of the body, breast cancer, colon cancer, lung cancer, and so forth. Research is ongoing. And the limiting factor has been trying to find that good target on the cancer cell. So, so far the best targeted sites, the best targeted malignancies have been the acute lymphoblastic or lymphocytic leukemia, the large B-cell lymphoma, mantle cell lymphoma, and also a couple other ones that have not yet been approved, but probably will be approved soon against the disease, multiple myeloma, against the disease chronic lymphocytic leukemia. So there are a number of different targets that have been very, very effective.

Host: Yeah, that's good to know that there are some very specific targets out there. And you know, one of the videos I was watching to educate myself about this was trying to understand, you know, cancer cells and that they can disguise themselves. They can make themselves very difficult for the T-cells to attack. Is that one of the many reasons why we're still doing a lot of work on this? It's still in its infancy stage? There still hasn't been a ton of FDA approvals because cancer is difficult?

Dr. Akard: It's difficult because the cancer cells are sneaky. They, they know how to hide. They learn how to overcome certain attacks, whether it's a chemotherapy attack, whether it's an immune attack. They're able to because they grow fast, they can genetically alter so that they can then develop resistance mechanisms. So both immune resistance, as well as drug resistance happens. The beauty of CAR T though, is it is attacking something on the surface of the cancer cell. And because of that, it's a little different than some of our other therapies. And by bringing the attacking cell right to where it's needed, it is very unique compared to other immune therapies where you're reliant upon random chance for an attack by a cell. This is the cell being brought right where it needs to be.

Host: I know that we were discussing earlier about how we're still in the early stages here and not, you know, let's not get ahead of ourselves, but what, as far as you know, right now, what are the long-term outcomes and survival rates with this type of therapy?

Dr. Akard: Let me talk about outcomes as relates to both side effects and then how well it works, the efficacy, there are side effects from this therapy. It's been somewhat toxic, especially early on, but we've learned a lot in the last three years about how to deal with and prevent side effects. So the side effects have to do with anytime we give a cell therapy preceded by this chemotherapy that causes depletion of immune system cells. A person temporarily have risk of infection. The treatment also makes the blood platelet count fall, making a person at risk of bleeding. So those are issues that have to be attended to, but then there are two unique problems, unique side effects that have been seen with this type of CAR T-cell therapy. One is called cytokine release syndrome or CRS for short. And I alluded to this before when the cancer cells are attacking.

When these lymphocytes are attacking, they release materials that are in some ways like snake venom, they can cause rash. They can cause fever, chills. They can make a person feel quite ill. It can cause lung problems. There are treatments to turn that reaction off. And it happens depending upon the CAR T product. It happens at least 50% of the time, but it can be mild to more serious. One of the areas of development of research is trying to make that reaction much less. And that is being accomplished by using different kinds of molecules that are inserted into as part of this insertion of gene therapy. So cytokine release or CRS is one side effect. And another second problem is called. ICANS, it's a T-cell associated neurologic injury anywhere from a person feeling sleepy, hard to wake up. There have been some patients who've had seizures.

Some patients who've gone into a coma like state. These side, whether it's a CRS or this neurologic toxicity, almost always reversible, medications to deal with that. But it is a significant side effect that requires treatment. Usually patients who are having these, those side effects are in the hospital for a period of time. So this is a therapy that is offered and usually done by people who have experience with cellular therapies that cause unusual side effects, as far as effectiveness, the efficacy of these treatments. It depends on the disease, but it's been very encouraging. When these treatments have been used, the original studies were in patients who had no other good therapies, they had failed every effective therapy. So childhood ALL, those patients who were treated were basically those who would have failed all other therapies, who then got the CAR T-cell treatment after lymphodepleting treatment.

And the thing that made everybody really take notice most patients, it was 70 90% of patients had significant response with this refractory leukemia situation. And many of those patients went on to what was considered curative therapy with what's called an allogeneic transplant. In the setting of refractory leukemia, where the last treatment failed, the third of the second, third, fourth or fifth treatment failed, the chance that anything would have even a 5% chance of being effective is remote. And this cellular therapy over half, close to 90% of patients having improvement was just startlingly good. So in childhood ALL, what we don't know is what percent of those under 25, who have this therapy all by itself, what percent of those patients would have long-term durable responses that remains yet to be seen.

The other disease that has the largest experience diffuse large B-cell lymphoma. Again, used in patients with relapse refractory disease, no other good therapies, patients destined to die. When it's been used in that setting, again, a high response rate, 70%, 80% of patients have a favorable response, lymphoma improves. And so far 30 to 40% of those responses have been durable beyond three years. So we're hoping some of those patients who had no other chance of survival are going to be cured. The other disease mantle cell lymphoma, the outcomes have been similar to the diffuse large B-cell lymphoma. So this is very encouraging treatment therapy that not only has caused temporary, but maybe permanent elimination of these malignancies. It's really quite remarkable.

Host: Remarkable is the word that was in my head, listening to you speak. And you also mentioned in there about expertise and how important that is, who offers CAR T-cell therapy does any, or every cancer center now offer this type of therapy?

Dr. Akard: The therapy is usually available in each State in the US, there is usually one or more treatment center, but it's not every cancer center. So for example, I'm in Indiana. There are two sites in Indiana currently doing CAR T treatments, our side at Franciscan Health and another site at Indiana University Health. So it does require a certain level of not just expertise, but you have to have laboratory sophistication so that the product that's being stored is tracked in a correct way. Pharmacy has to be involved with the, we have to always have antidotes if you will, on hand for treatment of side effects. So, it really is a program that is necessary within an institution with it, a treating center to offer this sort of therapy. Oftentimes it's in the centers that also have expertise in doing bone marrow or STEM cell transplant.

Host: Will there be other types of CAR T-cell therapies? I think we've covered this, but let's go through them for different cancers that you picture being developed in the future.

Dr. Akard: One of the advantages of this cellular therapy is it's a one-time treatment. So that's also part of the remarkable thing. So you give this lymphodepleting chemotherapy, you give the cells and then it seems to continue to work. So a one-time therapy and it's done. So patients recover. They don't have to keep getting treatment over and over and over like we do with many of our therapies. So the cancers that have some additional promise, I mentioned multiple myeloma. There's a product that will likely be approved in the next year. Chronic lymphocytic leukemia is also one that's on the horizon. But as I said before, it's even the diseases for which we have these current CAR T products, there's already work on the next generation of treatment that hopefully is going to be less toxic and maybe even more effective. How can we make it more effective?

Well, we know that we can target one part of the cancer cell let's target two or three at the same time. And so those studies are ongoing against two or more targets on the same cell. Those kinds of approaches are also being done in other solid tumors. Like all of the solid tumors we mentioned, but so far the success in the solid tumor area has not been good. And it's partly, we have to find what are the best targets. Some are even looking at trying to find a target inside the cell, rather than on the surface of the cell. So far, all of the targets have been on the surface of the cell and for the diseases that we've been talking about that has been very effective. There may be some cancers that maybe an inside the cell target might be better.

Host: Really fantastic. Having you on your expertise, your knowledge, your ability to make it somewhat understandable to someone like me and the rest of us. Doctor, thank you so much. Keep up the great work and you stay well.

Dr. Akard: I appreciate the opportunity to discuss this.

Host: To learn more about CAR T-cell immunotherapy, or to schedule a second opinion with Franciscan Health Cancer Center, visit Franciscanhealth.org. And we hope you found this podcast to be helpful and informative. This is the Franciscan Health Doc Pod. I'm Scott Webb. Thanks for listening.