Transcription:
CAR T-Cell Therapy: An Overview

Dr. John Leonard, MD (Host): Welcome to Weill Cornell Medicine CancerCast: Conversations About New Developments in Medicine, Cancer Care, and Research. I'm your host, Dr. John Leonard, and today we will be talking about CAR T-cell therapy. I'm really happy to have today's guest here today, my friend and colleague, David Maloney. Dr. David Maloney, who is the Medical Director of Cellular Immunotherapy at the Fred Hutchinson Research Center in Seattle, Washington. Dr. Maloney's research interest is in the development of immunotherapies for lymphoma, myeloma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia, or ALL. 

Currently Dr. Maloney's major interest is in the development of chimeric antigen receptor, or CAR T-cell therapy, and he's really been a leader in this field among many. So David, thank you very much for joining us today. It's great to have you.

Dr. David Maloney, MD (Guest): John, it's a real pleasure to be here. Looking forward to talking with you.

Dr. Leonard: So David, we've known each other for awhile, and collaborated, and talked, and interacted around lymphoma and new therapies, including immunotherapies over several years, and your background in this area is one that I think is quite remarkable, and I just wanted to take a second- I mean you were one of the- you were right in the middle of, and one of the leaders of the development of Rituximab, the anti-CD20 antibody used commonly in B-cell lymphomas, you've been a leader in the transplant field, and now one of the leaders in CAR T-cell therapy, which is clearly a major innovation for immunotherapy. So just briefly, how did you end up in immunotherapy, and how have you kind of continued to chase after all of these exciting new areas, and be in the forefront of all of them? I think the listeners would be interested to know how your interests and expertise developed. 

Dr. Maloney: Yeah, I actually feel incredibly fortunate to kind of had the career that I've had thus far. I started back in the late-seventies when I went to medical school at Stanford University and actually did my MD and my PhD, and worked with an incredibly talented mentor there, Ron Levy, who was just entering the field of trying to develop antibody therapy for treatments of cancer, and he had some ideas, and I actually used that as my PhD thesis, and had spent seven years doing medical school rather than the typical four, so that I could get my- I also got my PhD. 

And at that point we actually developed the first antibody therapy that was successful in treatment of some lymphomas, and it was really remarkable. Early days of learning some of the principles of how to make an antibody, how to safely administer it to people, and to learn about some of those reactions. And just for your listeners, the antibodies are obviously proteins of your immune system, and it's like a target, a cancer antigen or an antigen, and what we've learned was you could make an antibody using a technology called hybridoma technology in a mouse where you could actually make a single antibody specific for whatever target you wanted, and this ushered in the very early days of antibody therapy. 

I then was in Boston at the Brigham and Women's Harvard program for my medicine residency and then came back to Stanford for oncology, and picked up the antibody story there, and that's when we did the early pioneering works with Rituximab, which eventually got approved in 1997 for the treatment of B-cell, low grade B-cell lymphomas, and has now been widely used in nearly all forms of lymphoma, and antibodies are now obviously big business in nearly every other cancer.

So I was at Stanford through about 1994 or so, and then moved up here to the Fred Hutch in Seattle, Washington, and worked in the development of what is termed reduced intensity transplant. These are bone marrow transplants from another donor, and what that taught us is that we could safely do these kinds of transplants, even in older patients up into their mid-seventies, and that the graft of the donor, or the donor bone marrow, the cells of the immune system of the donor was actually instrumental in attacking the cancer and could result in curing many patients with some types of lymphoma such as CLL, or the low-grade lymphomas, or mantle cell lymphoma. 

So this was really kind of the first hint that T cells are really important in the effect of a transplant. And then in just this kind of strange coincidence, we kind of married the early data that we had with antibodies, and the data with T cells, and that's what the CAR T-cell is. It's a T-cell that is being redirected to a tumor antigen by using a chimeric receptor, one part of which is actually the combining molecule of an antibody. And so it's really kind of a strange- I would say serendipity that all of these things came kind of together, and I feel incredibly fortunate to have worked with such brilliant people at Stanford and here at Seattle to be able to accomplish these areas of focus.

Dr. Leonard: So part of your research, and that of others, is to kind of engineer CAR T-cells to make them effective. But for those who are less familiar, what exactly is a CAR T-cell? How is it different from just a standard T-cell that we have in our bodies? What's done to it? And then I think it would be helpful to have you go through briefly kind of the experience for a patient getting CAR T-cell, the idea of collecting T-cells, manipulating them, and giving them back. And just in a nutshell, what is that like for a patient in general terms?

Dr. Maloney: Yeah so I think you have to step back I think just a bit to kind of look at what is cellular immunotherapy, and that's what this broad topic is. And there have been a couple areas that have been successful. One is called tumor infiltrating lymphocytes where you actually take out a tumor biopsy, and then look in that tumor biopsy for T-cells in the patient that can kill the cancer. And this area of research has been pioneered at the National Cancer Institute, and for example you can take a melanoma mass from a lymph node, isolate the T-cells in there from that, and then grow those T-cells, expand them in the lab in tissue culture, and then give them back to the patient. 

Only a minority, like one in a zillion, or just a minority of those T-cells are actually against the tumor, but if you can grow them in the lab and expand them, then this has been associated with dramatic responses in some patients with some cancers. Unfortunately it's relatively limited and it's very difficult to find these T-cells, and the way a normal T-cell recognizes a cancer is very complicated. It actually has to do with the patient's own HLA type, or essentially their blood typing, to where the T-cells have to recognize in the context of that patient. So it's very difficult to export this kind of technology with the T-cell receptor that would work against different cancers.

So the way around that is to- instead of trying to find the one in a million T-cell that reacts with the cancer, it is to actually modify the normal T-cells to express a receptor that will enable them to kill the target you want them to, and that's this whole revolution in CAR T-cell technology. 

Now there's actually two ways you could do this. One is actually where you can put a T-cell receptor against the known antigen into the T-cells, but then again that has a lot of kind of complications, and it only works if you're going into a certain type of what's called the HLA system, and that's very dependent on the patient's background, and again it gets quite complicated. 

The way of making it more universal is to use a CAR, and a CAR is a molecule that combines an antibody with the portions of the T-cell receptor, and it delivers essentially an artificial signal to the T-cell that can cause it to then kill whatever it binds to, and it also then causes that T-cell to grow and divide. 

So how do we actually do this? Well the process is both complicated and somewhat simple. The process first starts with the patient having their normal T-cells collected by a process called leukapheresis or apheresis, and this is where commonly- a process commonly used when people are donating platelets, for example, and patients have a catheter or an IV put in- for example in each arm, and blood runs out of the one arm through this machine and back into the other arm, and the machine takes off a very small percentage of the cells that contain the T-cells. So the process is kind of like being on dialysis, but it's only for one time, two or three hours generally, and it's a pretty boring procedure, frankly. Patients tolerate it quite well, relatively few risks, and it's the same way we would collect stem cells, for example, from donors or before other types of transplants, except we don't need to give any mobilization to get those cells.

So these cells are then collected and they're taken to a lab, and in this lab they may be purified into different types of T-cells or not, but those T-cells are then genetically engineered to express this receptor. And this is generally done by using a virus, and the virus has a gene in it called the CAR, which is a combination of these proteins, and when the virus infects the cell, it's essentially a one-way infection, and this modifies the T-cell to now express the CAR. And so all the T-cells that express the CAR now will be able to kill the targets you're asking them to kill, and they won't kill generally anything else.

So we're essentially redirecting your normal T-cells to now go after the target we have chosen. And so far, the bulk of the data has been with a target called CD19 which is on most B-cell malignancies, but it can also- other targets can be used, and I'm sure we'll talk about that a bit later.

So once these T-cells are grown in the lab, and that process takes about two weeks, the patient usually receives a cycle of chemotherapy, and we call that lymphodepleting chemotherapy, and what it's really doing is just making some space for the T-cells to grow. And then the T-cells are infused through an IV, and about a thirty-minute infusion, and there's usually no symptoms or few symptoms associated with the actual infusion of the cells. But unlike any other kind of treatment, this is really a living therapy, and these cells then hopefully will start to grow and divide, and when they do that, they will increase in number. The estimates are that they can double every twelve two twenty-four hours, so if you think about it, then after two or three days, you have ten times more than you started. Another couple of days and you're now at a hundred times than you started. So essentially there's an exponential growth of these cells, and as they're recognizing the tumor antigen, they should try to kill that tumor hopefully, and then they also will grow and divide.

And so it's a living therapy where we're putting in a very small number of cells, and they're actually growing and expanding in the patient, kind of like a normal T-cell would as they're reacting and trying to kill the tumor. And then when the tumor has essentially hopefully been eliminated and the target is gone, then those T-cells will slow down and contract back to a low level, which is similar to what would happen in a normal immune response.

So this whole process of monitoring the patient after the cells are given takes about one to about four weeks, and usually around four weeks, patients are recovering and are going home. We can talk about toxicities in a minute, but that's the typical overall process. 

Dr. Leonard: So it sounds really great, and as people know, like anything it's a double-edged sword. But for right now, clearly there are patients who have developed or demonstrated some clear benefit when they received CAR T-cells. So we'll get in the future in a few minutes, but what are the standard indications for CAR T-cells? I know it's primarily lymphoma and acute lymphocytic leukemia, but what patient populations so far seem to have benefitted from this? And I think- and also the side effects that you alluded to, if you can give us a brief sense of that. 

Dr. Maloney: Well right now we actually have three indications for CAR T-cells, two different products. The first product approved was Tisagenlecleucel, or Kymriah, and that is approved for pediatric and young adults. Acute- or ALL. This goes up to the age of twenty-six, and so this has really been approved in patients who have exhausted most other treatment options and are beyond their second remission or have a refractory disease.

This drug got approved based on pretty astounding results in this pediatric and young adult population where the majority of patients will have a remission in the first one to two months after treatment. But what we've now learned is that not everyone stays in remission and there certainly is a risk of relapse, and we can talk about those causes, again, in a bit. 

But this was really an astounding result in this patient population, many of whom had already failed an allogeneic bone marrow transplant and really had no reasonable options for anything to cause a significant tumor response. So that was the first approved drug. 

Now subsequent to that, a drug called Axicabtagene Ciloleucel, or Yescarta, was approved for the treatment of adults with aggressive lymphomas such as diffuse large B-cell lymphoma, and this is in patients who have failed at least two prior regiments of therapy, and that's a population where often including transplants, once that has failed, there aren't great options for treatments that have a potential cure. And the data with that drug is just about 40% of patients have long-term remission, at least now more than a year to a year and a half, and it looks very encouraging that some of those patients might be cured.

So that's really the excitement that led this field to rapidly explode, and it's absolutely amazing that both of these drugs were approved relatively within a few years of beginning their pivotal trials. Subsequent to this last one being approved, Yescarta being approved, the first one, Kymriah is also now approved for that same general population of relapsed aggressive lymphoma.

Now your question about side effects, there's two main side effects that have emerged in this field. The first is called cytokine release syndrome, or CRS, and that's where essentially the T-cells are- when they're proliferating they're either inducing the body to make inflammatory proteins called cytokines, and these cytokines can go to very high levels, and they're associated with a variety of symptoms. The most common symptom is high fever, but then that can lead to all kinds of other issues including problems with blood proteins that control the clotting of the blood, it can lead to other associated symptoms of low blood pressure, and so patients are essentially feeling like they have the worst case of the flu they've ever had.

And so it's similar to the type of immune response that your immune system would go after fighting infection, only in this case, your immune system is fighting your cancer. And so cytokine release syndrome can happen anywhere from a few hours after the T-cells are given to as long as maybe two to two and a half weeks after the T-cells have been growing in the person- in the patient. And really typically this occurs around four to five days after the CAR T-cells have been given, and it usually lasts two to seven or eight days. In most cases, this is 100% reversible. We do have some new drugs that can block some of these cytokines. One called Tocilizumab can block IL-6, and that can often dramatically improve the symptoms of fever and low blood pressure. 

But some patients can get very ill from this and end up in critical care, in an ICU, and very rarely patients can die from complications of cytokine release syndrome. But fortunately this is not a real common occurrence, but it is definitely a risk.

Now the second toxicity that is even more difficult to understand, again CRS we think is related to the proliferation of the CAR T-cells, but the second toxicity is the neurologic toxicity, and this is one we don't completely understand what the exact cause is. It is definitely associated in most cases with patients who have had some cytokine release syndrome, but then it's characterized by patients developing an inability to speak, or talk, or comprehend, and often this can progress to a very frightening consolation where people look like they've either had a stroke, or almost even be in a coma, and in very, very rare cases, patients can again die from complications of this such as a brain swelling or cerebral edema. 

Again, 90%+ to 95%+ of patients completely recover from this, but it is definitely frightening both for the patients and for caregivers and for physicians alike. This neurologic toxicity doesn't happen to everyone, it happens in up to 30% of patients, for example with Yescarta, and generally occurs after the peak of the cytokine release syndrome, and often four to five days later. It usually lasts a few days and we generally treat it with drugs like corticosteroids or Dexamethasone. We're not absolutely certain if that's beneficial or not, but that's the direction the field has gone. And again, in almost all cases this is completely reversible, but again, it can be quite dramatic.

So those are the two major toxicities. In most cases, these occur in the first few days after CAR T-cells, and are pretty much over by a couple weeks after CAR T-cells have been administered, but in some cases if it's severe toxicity then obviously that can drag out longer, and it can be, as I said, life-threatening. 

Dr. Leonard: So David, there's a lot of work going on, and I know you're participating in much of it in trying to make the next versions of CAR T-cells or CAR T-cell therapy, i.e. either add drugs to CAR T-cells or re-engineer the CAR T-cells to potentially either be more effective or less toxic. What are two or three of the key maneuvers or manipulations that you think have some promise? And obviously this is a work of research, but may in the coming years be a newer way of delivering or administering CAR T-cells.

Dr. Maloney: Yeah, so that's a great question, John. Obviously the field is both new and trying to move forward all at the same time, which is obviously complicated because once you go through all the work to get one of these processes approved, and you're already trying to figure out how to make changes, it leads to a lot of questions about how to get these kinds of processes approved through the regulatory system. 

But right now, the two products that have been approved are just taking whatever T-cells they can isolate from a patient and give them back to the patient after they've been modified to express the CAR. A slightly different approach has been taken by our group here in Seattle and by Juno Therapeutics, who's recently been purchased by Celgene. But our approach in that compound is to actually believe that not all T-cells are the same, and we actually make two different CAR T-cells. We make one from a type of T-cell called a helper T-cell, and one called a killer T-cell, or a CD8 cell, so CD4 and CD8 cells, and we make two CAR T-cells and then give them back in an equal mixture. And by doing this, we believe we give a much more uniformed CAR T-cell product, and because of that, we've been able to see a better dose toxicity and dose response relationship. So the approach we've done in Seattle appears to be even safer than some of the data that's been presented with the currently two approved products, and we're certainly hoping that this will move forward through the regulatory channels in the next year or so, and yet be another approach that could be FDA-approved and would potentially have a better safety profile. So that's one option. You can just actually genetically engineer a different population of T-cells. 

The second way to do it, as you mentioned, is come up with a different CAR, I mean just make a different receptor. And there are such things as armored CARs, and lots of names where you can actually put an on/off switch into the CAR T-cells where if they get out of hand or cause too much toxicity, you can actually give a drug that will stop them or suppress them. 

Another option is to have them make their own growth factors so that they don't rely on external signals as much. And then a third way of doing it is to actually do combinations, as you implied. So maybe we don't- maybe we need to do more than just CAR T-cells, and one approach is to give a checkpoint inhibitor antibody. We know that some CAR T-cells just run out of gas. There's either too much tumor and they can't multiply and divide enough to be able to kill all that tumor, and we think the tumors are actually giving signals to slow those T-cells down or tell them, "Don't kill me," to give them that kind of a signal, and by giving an antibody, there might be a way such as a checkpoint inhibitor antibody of PD1 or PDL1, you might be able to revive the CAR T-cells. And there've been a few anecdotal reports in the literature, and there are several ongoing trials. Both Kite has one and we have one here as well. So those are a few examples of what I think are the most promising things going forward.

Dr. Leonard: So as we kind of wrap up our discussion here soon, I want to get you to pull out your crystal ball, and you've been at the forefront of a lot of different advances in cancer therapy, lymphoma therapy. What do you think- how do you think this is going to evolve over the next five years or so from the standpoint of right now the indications within acute lymphocytic leukemia and aggressive lymphoma are really for a relatively small population of patients who've been through other treatments? Do you think that we will be using these earlier in the course of the disease in the near future? And also if you could touch on your thoughts on solid tumors. I know there's a lot of CAR T-cell work going on in myeloma which seems very promising, but what about other areas outside of lymphoid malignancies?

Dr. Maloney: Yeah well that's a ton of questions, but I think a few points I think we need to keep in mind, first this is a custom product for each patient and so there's a lot of logistic issues to being able to make a product for every patient. There's a lot of manufacturing problems. The companies, if they're going to do this, they need to make this reliably, they need to make it in a timely fashion so the patients can have access. Many of these patients are too sick to even hardly wait, and so that needs to be fixed. 

There have been attempts to consider making universal CAR T-cells where you wouldn't have to use the patient's own cells, and I personally think that's going to be a problem to really be able to successfully do that, but some people are focusing a lot of effort into that arena.

Once we have CAR T-cells, we need to figure out why do they not always work? In leukemia we're getting about 85% to 90% of people in remission, but some people don't go into remission, so why does it not work in that setting? So we need to improve that. In addition, some people relapse, and in some cases they relapse because they don't have the target anymore. The tumor has genetically lost the target. It's called antigen negative escape, so these tumors become essentially in this case PD19 negative. And so the only way to really probably attack that is to give more than on CAR at the same time, targeting another antigen. Just like you would if you were treating a really serious infection, you wouldn't give just a single antibiotic because the infection would essentially escape. 

So those are a couple things going forward. I envision that this is going to get a lot simpler in the future. I mean, I could see certainly how you could get a diagnosis, come in, have a few tubes of blood drawn, those could be manufactured into a CAR very quickly, and then within a day or two you could get that back potentially.

So I think the future is extremely bright for the hematologic malignancies, but the Holy Grail is really is this going to work outside of the hematologic malignancies? And as you said, we're already seeing really interesting success in multiple myeloma, another potentially incurable disease where I think we're making really great progress with CAR T-cells. But what about the other cancers? Breast cancer, lung cancer, prostate cancer; these are the common solid cancers, and there we haven't had as much success. And what seems to be true is that the tumors are expressing a much more immunosuppressive environment, and the tumors are making it much harder for the T-cells to either get in there, or to even actually be able to kill the tumor cells. 

In animal models, we've been pretty successful in being able to make the CAR T-cells work against these breast cancer lines, but in patients it's been a little more of a challenge, and I suspect we'll need combinations of checkpoint inhibitor antibodies and CARs, and maybe combinations of CARs, but I am really optimistic about this, John. I think this is the most exciting thing I've done, and I feel very, very fortunate to be involved in this field.

Dr. Leonard: Well that's a really great summary. I think if you could just leave us with kind of one message for patients, or patients listening to us that say this sounds potentially interesting. Let's say somebody dealing with recurrent aggressive lymphoma where this might be an option that could be considered by them. What's kind of your advice to a patient who's thinking about this, if they make a decision to pursue this, any kind of words of wisdom? Or just go do it and go from there? Or how would you help people think about these issues? 

Dr. Maloney: Yeah, I think there's a number of issues that I've come across. You have to think that this is essentially like going for a transplant. It's not a transplant, but it is a complicated procedure. So it does require a bunch of logistic issues from a patient. The patient has to be pretty much mindful that they need to maybe relocate to another place. All of these CAR T-cells are being given under a very restricted access program by the FDA, so there's only about forty centers in the nation that can do each of these CAR T-cells, and so often this does require traveling to an institution where this can be done. And that obviously means you have to come up with housing and ability to do this. 

Many of these treatments do require some stay in the hospital, but some can be done increasingly as an outpatient with just checks into a clinic on a daily basis, or then admission to the hospital if there's complication. So I think you need to- patients do need to ask their doctors about this if they have a type of disease, and then to find out where the nearest center is. All of these things are on the web, and you can find out the nearest center that has experience, and call those centers up, and come for a consultation and evaluation.

In addition, we have many other studies that are still in clinical trials, so patients can always call the various centers and find out about their clinical trials. We have a very active intake group here in Seattle, at the Fred Hutch, and at the Seattle Cancer Care Alliance, and a very experienced team that can walk people through a clinical trial option if the commercial CARs aren't available for their disease. 

Dr. Leonard: Well thank you, David, and yes, I know that you have a number of different studies and options for patients, and clinical trials, and I'll just throw in our pitch for audience that there are a number of trials including CAR T-cells available here at Weill Cornell, and certainly both of our centers are very excited and available to help patients sort through their options. And obviously these are not decisions that one makes kind of in a vacuum, or by hearing a podcast, or watching a video, but really kind of complicated things that you really have to individualize to the situation. But it's really great that this work is progressing, and I expect will continue to progress, and hopefully continue to improve outcomes for patients. 

So thank you very much, David. It's been really great to have you here, and maybe before long we'll have you back to talk more about this, because it's a very complicated area and much more happening in the future.

I'd like to invite the audience, as we wrap up, feel free to write to us at CancerCast@med.cornell.edu with questions, comments, and topics you'd like to see us cover more in depth in the future. That's all for CancerCast: Conversations About New Developments in Medicine, Cancer Care, and Research. I'm Dr. John Leonard, thanks for tuning in.