Presenter: Juan Carlos Varela MD, PhD, AdventHealth
Recorded August 15, 2019
Summary: The immune system fights both infection and cancer. When cancer cells evade the immune system, the patient's T-cells, which are part of the immune system, can be genetically engineered to fight the cancer cells. This is called CAR T cell therapy.
Highlights of Presentation:
- CAR T therapy offers hope for patients with certain blood cancers who have been unable to get into remission with standard chemotherapy, or who have relapsed after several types of treatment
- CAR T therapy is FDA-approved for patients with B-cell lymphoma and ALL
- More than 350 clinical trials are underway worldwide testing CAR T therapy in patients with other diseases, in combination with other drugs, or at different time periods during the disease
Key Points:
00:03:28 The immune system fights infection as well as cancer
00:08:31 CAR T-cells are different than normal T-cells that fight cancer
00:14:26 There are currently two CAR T therapies that are FDA approved for patients - Kymriah® and Yescarta®
00:18:08 The two major side effects of CAR T therapy are cytokine release syndrome (CRS) and neurotoxicity
00:21:35 CAR T therapy may be offered before or after a transplant
00:24:48 CAR T therapy may be given in the hospital or outpatient clinic
00:25:58 Low-dose chemotherapy is given to the patient prior to infusing the CAR T-cells
01:07:28 At this time, patients who are in remission are not candidates for CAR T therapy
Transcript of Presentation
00:00:01 Introduction of Dr. Juan Carlos Varela: Good evening. I'd like to welcome you to BMT InfoNet's webinar CAR T Therapy and Other Immunotherapies Before and After Transplant. I'm delighted you can join us this evening, and I hope you find this presentation valuable as you consider your treatment options. Before I begin, I'd like to thank Kite, a Gilead company, and Celgene, whose support helped make tonight's presentation possible.
For those of you who are not familiar with BMT InfoNet, we are a patient advocacy organization that provides high quality information and support services to patients and their loved ones before, during, and after transplant or CAR T therapy.
Now it's my pleasure to introduce to you Dr. Juan Carlos Varela. Dr. Varela leads the Cellular Therapy Program in the Blood and Marrow Transplant Program at AdventHealth in Orlando, Florida. He specializes in bone marrow transplantation and cancer immunotherapy.
Dr. Varela's research is focused on the development of novel immunotherapies for the treatment of cancer. He has been the principal investigator for several clinical trials studying novel therapies for patients with leukemia, lymphoma, and multiple myeloma.
Dr. Varela was rated as one of the top two speakers at BMT InfoNet's Celebrating A Second Chance at Life Survivorship Symposium last May in Orlando, and I know he will do a great presentation this evening as well. Please join me in welcoming Dr. Varela.
00:01:41 Overview of Points covered in the CAR T presentation: Thank you, Sue, and welcome everybody that's joined us tonight. We'll now be talking about cancer immunotherapy and CAR T-cells over the next 20 to 40 minutes. We'll get started with talking about what are the goals that we're going to achieve tonight, what are we going to do.
We're going to be talking about the bone marrow and the immune system, just to give a background of what the immune system does and how it controls cancer.
We're going to be talking about tumor immunology, which is the study of how your immune system is able to kill cancer cells.
We'll be talking about chimeric antigen receptor T-cells, so CAR-T cells, which is, in my view, one of the greatest advances in immunotherapy ever.
Finally, we'll be talking about some things that are relevant to patients. What are the CAR-T cell therapies that are approved to treat patients with hematological malignancies.
00:02:38 The bone marrow produces all the body's blood cells: We'll go ahead and get started. We're talking about bone marrow and the immune system. This is the schematic of your bone marrow. Your bone marrow is the factory of all the cells in your blood, and it's inside of all of our bones, and all of the components of the bone marrow are made from stem cells. For those of you who have had a bone marrow transplant in the past, what do we transplant? We transplant stem cells.
Those stem cells divide and they develop into the three different kinds of cells in your blood, which are red blood cells, white blood cells, and platelets. Red blood cells are the ones that carry oxygen around. White blood cells are the ones that are in charge of defending you, or they're your immune system, and platelets are the types of cells that prevent you from bleeding and form clots.
00:03:28 The immune system fights infection as well as cancer: When we talk about the immune system, the immune system is not only the white blood cells. The immune system is the combination of cells, organs, and substances in your body that work together in combination to protect us from disease. The most common thing that everybody thinks about is that it's just the protection against infections, against bacterial infections, against viruses, or against fungal infections, but in truth your immune system can also protect against cancer. White blood cells play a huge role in all this, and the bone marrow plays a whole huge role in this as well.
00:04:07 How does the immune system fight cancer? What is tumor immunology? I know a lot of us have heard that term over the last few years because of the explosion of immunotherapy in the cancer world, but tumor immunology is the study of how our immune system is able to protect us against cancer. I know this is a complicated slide, but we're going to take it step by step, and we're going to be talking about how is it that the immune system is able to detect cancer cell, recognize them, and then kill them.
We'll start over here with number one. The first thing that happens is that tumor cells within the tumor microenvironment, whether it is a solid tumor or in our case a liquid tumor, there are components of the tumor cell that spill into the circulation once the tumor cell dies. We have these cells in the immune system, which are called the dendritic cells, and their job is to police the environment and pick up little pieces of tumor cells that may be falling into the microenvironment.
Once they pick up those little pieces, then they take them to a lymph node, and in the lymph node is where the training of the immune system happens. We're all born with a number of cells that are called T-cells that are able to protect us against infections and also against tumors. So when the dendritic cell goes to the lymph node, it has little pieces of tumors that are recognized by T-cells, and those T-cells become activated. Once those T-cells become activated, they go from the lymph node through the circulation, and they go back to the tumor microenvironment.
The third step is, once the cells are in the tumor microenvironment, there has to be an interaction between the white blood cell, in this case a T-cell, and the tumor cell in order to kill it. Now that interaction is fairly complicated and it requires multiple steps that have to happen in a specific sequence in order for that cell to kill that tumor cell. This process works very efficiently, but sometimes, or in many cases, what happens is that tumor cells develop ways to evade the immune system.
00:06:10 How do cancer cells evade the immune system? What sort of things can tumor cells do? Well, it turns out that they have developed ways to stop this immune response at every point in the pathway. They have ways of inhibiting the dendritic cells so that the little pieces of tumor don't get picked up by the dendritic cells. They have ways to inhibit the activation of the T-cells of the lymph node. They've also developed ways to prevent the transfer of the cycle that would take those to the tumor microenvironment. They have developed ways to break up the interaction between activated T-cells and tumors, which leads to the immune system not being able to kill the tumor.
00:06:53 Understanding how cancer cells evade the immune system has led to the development of cancer immunotherapy: This is not all bad news, because as we've studied the ways in which tumor cells are able to evade the immune system, we've actually picked up some clues and we've developed ways to bypass these blockages so that we can reactivate the immune system against cancer and develop cancer immunotherapies. So really by learning how these tumors evade the immune system, this is how we've developed these therapies, including CAR Ts, that now we're using in the treatment of cancer.
Just a quick mention about cancer immunotherapy. For the past few decades the main types of treatment that were available for cancer were three. It was chemotherapy, surgery, and radiation. It wasn't until about 2011 or so that we really started considering immunotherapy as the fourth modality in cancer treatment, and now when I see patients today, most patients are asking about immunotherapy, so now we can say that immunotherapy has arrived as the fourth pillar of treatment for cancer. Again, this all comes from the fact that we have been studying for years how is it that these tumor cells evade the immune system. Because of the knowledge that we have gained, now we have been able to develop these therapies.
One of the most exciting therapies that have been developed in the past few decades have been CAR T-cells, and I know there's been a lot of excitement about CAR T-cells, there's been a lot of news about CAR T-cells, so let's take a step into what is it? What are CAR T-cells?
00:08:31 How CAR T-cells differ from normal T-cells?: I think that in order to understand how CAR T-cells work and why they're so special, we need to just take a step back and think about how do normal T-cells work?
We learned a little bit about that a few slides ago when we saw how the cells get activated. This is just a reminder. We have our tumor cells over here that's spilling pieces of the tumor into the microenvironment. The dendritic cell picks it up, picks up those little pieces. They go to the lymph node. These T-cells that are there resting ... These are the dendritic cell with the little pieces of tumor. They get activated. Those cells then transition or travel to the tumor microenvironment, and there's a direct interaction with the tumor cell. There are receptors on the T-cell that will recognize the pieces of the tumor that are being made by the tumor cell, and that leads to the killing of these tumor cells. So it really is a complicated, but very well regulated and very successful process that leads to the activation of T-cells and to the killing of tumor cells by these T-cells.
Now when you think about CAR T-cells, you really skip a lot of the steps that it takes to activate these T-cells. Instead of going through the whole process of picking up the pieces of tumor, going through the dendritic cell, taking it to the lymph node, what this CART T-cell therapy allows us to do is we genetically modify the cells and we have a cell that is able to recognize the tumor right away. Another thing that's very important to understand about CAR T-cells is that the interaction between at CAR T-cell and a tumor cell is completely different from what a normal T-cell and a tumor cell is. This interaction is much simpler. It doesn't require the same number of steps that it does to kill a tumor cell by a normal T-cell, so that makes this therapy very easy and very effective.
One way I like to describe this is, for those of you guys that have played Simon Says before, you can compare normal T-cells and the process of activating those cells as having played Simon Says and having to press the button in order -whatever it is, blue, blue, red, red, green, but it has to be in the right order; otherwise, that process will not work. CAR T-cells, we can just compare them to the easy button. Just press a button, the cells get activated, and they're ready to go, ready to kill tumors.
00:11:04 How are CAR T-cells made? One of the most common questions that I get from patients is, how are these T-cells made. For those of you that have had a stem cell transplant in the past, this process is very similar to what you've had before, especially for those of you that have had an autologous stem cell transplant in the past.
We'll take this step by step. The first thing that happens is we have to collect the patient's T-cells from the peripheral blood, and this is represented here. The second thing that happens is those cells are typically shipped to a lab. We have several labs throughout the country, and there are several companies doing this, and in those labs is where the CAR T-cells are going to be made. Remember, we said CAR T-cells are genetically modified cells. They're modified cells that come from the patient.
How do we modify those cells? Well, we actually use a virus and in most cases this is a virus that belongs to the same family as the HIV virus, but it's a virus that cannot cause disease in humans. It's a virus that's been modified, and we only use it as a delivery method for genetic material, for genetic code. We take the viruses, we put a little piece of genetic code, which is encoding for that CAR receptor. We put it into the normal T-cells, and after a process we get this chimeric cell. Chimeric just means that there's two different types of genetic code inside a cell. You have the normal code from the cell and the CAR code that has been put in by the virus. Once that code is inside the T-cell, the T-cell is able to read it. It produces the CAR T-cell receptors and it puts them on the surface of the cell. Then we take those cells and expand them to many millions of cells, and we have a lot of CAR T-cells that are now ready to recognize the tumor. This is a process that happens outside the body, but compared to what has to happen inside the body when a normal T-cell is getting ready to kill a tumor, this process is really straightforward and streamlined.
00:13:01 How are CAR-T cells given to the patient? Once those cells are made, those cells get shipped back to the hospital, to the place where the patient is being treated, and they get infused back into the patient. Like I said before, this is a process that is very similar to what folks that had an autologous transplant have undergone in the past. The main difference is that instead of taking stem cells, like we do for a stem cell transplant, we simply take T-cells. In the case of a stem cell transplant, we do not genetically modify the stem cells. We just take the stem cells out and then we put them back into the patient after giving them some chemotherapy. In this case, we take the T-cells out and genetically engineer them, grow them to an appropriate number, and then put them back into the patient.
So that's the general process of, number one, what is the immune system, what is tumor immunology, how does a normal T-cell work, how does the immune system work to recognize tumors, what have we learned from that process, and how do we take advantage of those evasion mechanisms to develop cancer immunotherapy. And we focused on talking about one specific type of cancer immunotherapy, which is CAR T-cells, how are they different from normal T-cells, and how they're made.
Now we have the background, and we can move forward to talking about now that we've made them, how do we apply them to the treatment of patients.
00:14:26 There are currently two CAR T therapies that are FDA approved for patients - Kymriah and Yescarta: Currently, there are two FDA approved CAR T-cell therapies. One of them is called Kymriah, and the other one is called Yescarta. Both of them target a protein called CD19, which is on the surface of specific cancer cells, and it's actually on the surface of many types of B cell lymphomas. We'll talk about indications in just a second.
We'll talk about Kymriah first. That was the first product that was FDA approved. It is approved for the treatment of relapsed/refractory acute lymphoblastic leukemia in patients up to 25 years old, so pediatric patients. It's also approved for certain types of relapsed/refractory non-Hodgkin's lymphoma, specifically diffuse large B cell lymphoma, high grade lymphoma, and diffuse large B cell lymphoma transformed from follicular lymphoma.
The second product that has been approved is Yescarta. The Yescarta is approved for the treatment of certain types of relapsed/refractory non-Hodgkin's lymphoma, just like we spoke before, very similar to the other product. This is approved for diffuse large B cell lymphoma, high grade lymphomas, and diffuse large B cell lymphomas transformed from follicular lymphoma.
00:15:47 Which hospitals offer CAR-T therapy? Depending on where you live, there's likely a center that's able to give this therapy to you. Both companies that produce these products have websites you can refer to, and you can look and see if this treatment is right for you if this treatment is close to where you live, but the high likelihood is that somewhere close to you there will be a hospital or a center that's able to provide this product.
00:16:13 Does CAR-T therapy really work? Now one of the main things that we all want to know is do CAR T-cells work, and my answer is an emphatic yes. I think that I mentioned this before. This is one of the most exciting therapies that have been developed for the treatment of cancer in the past few decades, and some of the data that we have now that's complete from clinical trials, in pediatric and adult ALL, acute lymphoblastic leukemia, we have complete response rate at somewhere between 81-83%. This is really remarkable considering that the patients that have gone into these trials are usually patients that have failed multiple lines of therapy, so this really is a home run as far as treatment goes.
In adult non-Hodgkin's lymphoma we've also had some very good results. Again, the patients that have been treated under the trials that have been recorded in these studies are patients that have failed multiple lines of therapy, patients that have received lots of chemo, lots of other things, but they also respond. We've had overall response rates in the range from 52-82%, and we've had complete response rates at the rate of 40 to almost 60%.
00:17:27 Now what is the difference between overall response rate and complete response rate? Complete overall response rate includes everybody that had a response, so whether you had a complete response or a partial response, that's included in this number, and the complete responses are the ones where we cannot see any evidence of lymphoma anymore. Again, I want to emphasize again, 40%-59% may seem like a low number, but before CAR T-cells came around, we couldn't dream to achieve 40% or 50% response rates with the therapies that we had available for these patients, so really this is a fantastic new tool that we have to treat our patients.
00:18:08 Are there side effects with CAR T therapy? Whenever we have a treatment that is as effective as this, we can expect that there's going to be some risks and some caution that we have to have with these therapies. CAR T-cell is no different. CAR T-cells have a specific side effect profile. There's a specific group of side effects that come along with it. When we first started the trials with CAR T-cells, the side effects tended to be more severe. As we learned more about how the therapy worked, how to change it, how to make it safer, now we are pretty good at treating and controlling the symptoms, but they can still happen.
00:18:44 What is cytokine release syndrome (CRS)? There's two things that I want to mention here, which are the two most common side effects of CAR T-cell therapy. One of them is called cytokine release syndrome. How does that present? That presents with fever. It can present with low blood pressure, and low level of oxygen in the blood, but the most common presentation is fever. What exactly is this?
Cytokines are one of those substances that we talked about before that are part of the immune system. It's kind of how the immune system talks to each other, to each of its cells. When you have an interaction between a CAR T-cell and a tumor cell, the cytokines are made and the interaction is so robust that sometimes you can make too much of these cytokines, too much of these substances, which leads to the symptoms of fever and low blood pressure and a low level of oxygen in the blood. There' are different grades of cytokine release syndrome, and the treatment could be as simple as observation or the treatment could be as severe as having to take the patient to the intensive care unit, watch them very closely, monitor them very closely.
00:19:51 Neurological problems (neurotoxicity) after CAR-T therapy: The second type of side effect that's unique to CAR T-cell therapy is neurotoxicity. What does that mean? It means that the patient may have neurological symptoms, and the symptoms could be something as simple as confusion, maybe they forget what day it is, or they're a little somnolent, they have a little headache, but the symptoms could also be very severe. Patients could have seizures, a patient could have symptoms of stroke. What's really unique about this side effect is that the majority of the time, more than 95-98% of the time actually, these symptoms recover on their own. We watch the patient very closely. We'll give them all the supportive care that's needed, but the symptoms resolve on their own. Patients do not have any lasting side effects that would affect them as far as in a neurological way.
00:20:44 Centers that offer CAR-T therapy have been carefully trained: I put it here, again, but we have developed ways to deal with the adverse side effects, both the cytokine release syndrome and the neurotoxicity. We're still very careful with whom we give CAR T-cells to. The centers that are being selected to give CAR T-cells have to go through a very rigorous process of selection, and the FDA and the companies that are working to bring this to patients have a very strict pathway that has to be followed in order to be able to give this product. Whenever you go to a center that is able to give CAR T-cells, they've already gone through a very strenuous process of activation and approval, so these folks are able to give these products safely.
00:21:35 Is CAR T a therapy offered before or after a transplant? One of the things that we wanted to talk about was the treatment with CAR T-cells, where does that fall in the transplant process? Do we do it before transplant? Do we do it after transplant?
In the trials that have been done, a number of patients that underwent CAR T-cell therapy actually had the treatment done after transplant. We had patients that had the treatment done after an autologous transplant for lymphoma, or they had the treatment done after an allogeneic transplant for ALL. There are other clinical trials that are ongoing right now for which patients with multiple myeloma are having CAR T-cell treatment after transplants.
It appears lymphoma patients can have the treatment after transplant. ALL patients have had it after transplant, and we're trying to understand how does it fall before transplant. In some cases, we can use CAR T-cell therapy as a bridge to transplant. For example, if a patient has had a very hard time getting into remission or getting into a level in which it's safe to do a bone marrow transplant, we can use CAR T-cell therapy to get them there. We don't have the perfect answer yet, the perfect algorithm, and this is very much personalized treatment. Every patient is going to be a little bit different.
00:22:54 Does CAR T therapy cure patients? One of the questions I get asked a lot is can CAR T-cell treatment lead to a cure? I think we don't know the answer to that yet. I think that it's going to be disease specific. We have some very promising data in the lymphoma field. We don't know yet whether that will be the case with myeloma. We do not know yet if that will be the case in leukemia, but it's possible. Like I said before, it is perhaps more likely that we will have to combine CAR T-cell with something else to get to that point, but this is still a very promising treatment. It gives us an option for folks that did not have any options in the past.
00:23:40 What kind of testing is done on the patient prior to CAR T therapy? The last few slides here, what I want to talk about is some of the frequently asked questions that patients ask that have been brought up in the past. The first one is, what kind of testing is involved prior to treatment with CAR T-cell? For those of you that have had a transplant in the past, it's very much the same. The requirements are a little different depending on what product is given, and really depending on whether the treatment is given on a clinical trial or not. If the treatment is given on a clinical trial, it is likely that the clinical trial will have specific enrollment criteria in order for the patient to be able to receive that treatment.
In general what we need to do as physicians is to make sure that the patient is healthy enough to receive the treatment. Just like we do for transplant, we evaluate the heart, the lungs, the kidneys, the liver, and the entire body, to make sure the patient is healthy enough. Also, we need to make sure that the disease that the patient has, that it makes sense to treat the patient with CAR T-cells.
00:24:48 Is CAR T therapy given in the hospital or outpatient clinic? Another common question is, is CAR T-cell therapy given inpatient or outpatient? The answer is, it depends. It depends on the CAR T-cell product. When we first began this journey of CAR T-cell therapy, the majority of all of the treatment was done inpatient. Patients would be in the hospital, similar to what we do with our stem cell transplants. We watch them for a couple of weeks, maybe several weeks, depending on whether there were any side effects, and then the patients will be discharged.
What's happened over the last few years is that more centers are moving this to the outpatient setting. Patients are receiving the infusion of the cells in the outpatient setting and they're being monitored from home. There are clinical trials that are ongoing right now to determine how safe this is to do, but so far the signal has been very good. We think that with selected patients depending on the status of the disease, we'll be able to perform this in the outpatient setting with the goal of only bringing the patient into the hospital if the patient has any complications or any side effects from the treatment.
00:25:58 Is chemotherapy given with CAR-T therapy? Another question is, is chemotherapy given with CAR T-cell therapy, and the answer is yes. A low dose of chemotherapy is given within three days or 72 hours before receiving the CAR T-cells. Why do we do that? We call this therapy lymphodepletion chemotherapy, and the object here is to make a little bit of room inside the patient, a little bit of room inside the immune system, so that these cells have a chance to grow inside the patient so that they can go and kill the tumor. It's really a low dose chemotherapy, low intensity, compared to what a patient would normally get for the treatment of lymphoma, treatment of leukemia, treatment of myeloma, and much less aggressive than the chemotherapy that patients get before a stem cell transplant.
00:26:50 How long does the CAR-T cell therapy take? How long does the CAR T-cell therapy process take? It takes anywhere between 2-4 weeks to make the CAR T-cells, perhaps closer to the four week mark than the two week mark. Once the cells are collected from the patient, they get sent to the manufacturing facility, 2-4 weeks to make the cells. Then the cells get infused into the patient. The first 2-4 weeks are the period within which the more side effects can happen, so we watch patients very closely, whether the treatment is done in a clinical trial. There may be some mandated time in the hospital. If the treatment is done as one of the FDA approved therapies, then there it's likely going to be done in the hospital most of the time, with some of the patients being done outside of the hospital. I think the process is close to two months, 2-4 weeks to get the cells done and probably another four weeks after the infusion of the cells is given.
00:28:00 What other side effects can happen besides cytokine release syndrome and neurotoxicity? Those two, like I mentioned, are the most common ones, but other things that can happen are things that you associate with cancer, with chemotherapy. Low counts are going to happen because of the therapy, because of lymphodepletion chemotherapy and the CAR-T cells. You could have GI symptoms, like vomiting, like diarrhea. Muscle or joint pain has also been reported. Very much like what you'd expect with receiving chemo before transplant, receiving chemo for lymphoma or myeloma or leukemia.
If there are any questions I didn't cover in this frequently asked questions, please do ask those and we'll address those after we finish the formal presentation. I want to take a little bit of time to talk about some of the research that's being done in CAR T-cell, because although we have some products that have been approved, we are really moving at a very fast pace, as far as the research goes.
00:29:05 Can CAR T therapy help patients with multiple myeloma? One of the most exciting things, besides the lymphoma and the ALL, has been the treatment of multiple myeloma with CAR T-cells. There are several clinical trials that are being looked at right now where patients have been treated. We have some very good preliminary data. We're trying to understand how long the effect of the CAR T-cells last in these patients. It is possible that this could be one of the next FDA-approved indications. We don't know the final verdict yet, but there's some very good research going on in multiple myeloma and CAR T-cells.
00:29:43 Can CAR T therapy help patients with follicular lymphoma, mantle cell lymphoma or chronic lymphocytic leukemia (CLL)? CAR T-cells for the treatment of other types of non-Hodgkin lymphoma besides the ones that we mentioned earlier, for example, treatments for follicular lymphoma, treatment of mantle cell, treatment of CLL. Those treatments are being investigated right now in clinical trials. The data is very promising. It is possible that we will have approval for some of these cancers very soon. Mantle cell could possibly be the next one that will be approved, but stay tuned, because I think within the next year we're going to have several other types of non-Hodgkin's lymphoma that's going to be treated with CAR T-cells.
00:30:21 Can CAR T therapy help patients with acute myeloid leukemia (AML)? As a leukemia doctor, the majority of my patients with acute leukemia have AML, and one of the questions that we get again is do we have any CAR T-cells for AML? In the beginning ,finding a target on the AML cells was a little more difficult than finding a target in the ALL cells or in the myeloma or lymphoma cells. Now, more recently, we have found some targets that we believe will be good, will be safe. There are several clinical trials again that are open right now and enrolling, studying the role of CAR T-cells in the treatment of acute myeloid leukemia. There's a great amount of interest in the field to develop this treatment for this specific type of disease.
00:31:08 CAR T therapy using cells from a donor to treat relapse after a transplant using donor cells (allogeneic transplant): This is an interesting one. We know as a community of physicians and as a community of blood cancer patients that one of the biggest reasons why patients don't do well after an allogeneic transplant is because the disease relapses, because the disease comes back. In order to address this issue, there are some researchers right now that are looking at this CAR-T therapy after an allogeneic transplant, treating patients with relapsed blood cancers. Right now we're looking at lymphoma, acute lymphoblastic leukemia, and CLL that has relapsed after an allogeneic transplant.
Now what's different about these trials? The difference is that as opposed to getting the T-cells that are going to be modified from the patient, what these guys are doing is they're going to the donor of the stem cell transplant, they're getting the T-cells from the donor of the stem cell transplant, they're modifying those T-cells and they're giving them back to the patient. So they are an allogeneic CAR T-cell product. I think that that is a very exciting modality. I think that that's the next frontier in the treatment using CAR T-cells is using an allogeneic source of T-cells, and we're all looking forward to the result of these clinical trials.
00:32:27 How many clinical trials are testing CAR T therapy? This is a little bit of an old statistic. It's now five months old, but as of March of 2019 there were 378 active clinical trials of CAR T-cell therapy in the world, and 145 of those were here in the United States. That's really an astonishing number considering that less than 10 years ago we had a handful. We didn't have that many. This therapy has really exploded and I think it really has changed the way that we treat blood cancers, and that we are going to treat blood cancers in the future. If you guys don't know this, there is this website clinicaltrials.gov that has a listing of all the clinical trials that are available for patients, so that's a good reference to have.
So that's the information about CAR T-cells, about the immune system, about tumor immunology. I hope that we've covered the topics that are of interest to you. If there are any questions that you have, please ask them now, and we'll be glad to answer those questions.
00:33:29 Summary of presentation on CAR T therapy: Just a quick summary of what we covered today. We talked about how our immune system is able to recognize and destroy cancer cells. We mentioned that there are methods that the tumors have developed to evade this immune control, but by learning how these tumors evade the immune system we have developed therapies that are enabling us to cure cancer in some cases. CAR-T cells are one of those new treatments, one of those immunotherapies that have been developed. CAR T-cells are a viable option for patients that have relapsed after an autologous transplant or an allogeneic transplant, so it is a therapy that can be given after transplant. Most importantly, I think, is that we've made great progress so far with this therapy, but I think what's to come is going to be extremely exciting. We're going to have so many more chances, so many more options for patients that sorely need these therapies, and I think CAR T-cells are going to bring us a lot of novel therapies that are going to be very, very successful in treating patients with blood cancers.
I just want to leave you with an image. I found this many years ago and I thought it was a perfect description of what a CAR T-cell is. Here we have a normal T-cell, and her we have Mr. CAR T-cell. With that, I'll close, and we'll take any questions that you guys may have.
Question and Answer Period
00:34:53 [moderator] Thank you very much, Dr. Varela. That was a great and very clear explanation of what CAR-T is, and I think has answered a lot of the questions that folks have. We do have a number of questions, and, again, if you have a question, please type it in the chat box on the lower left corner of your screen, and Dr. Varela will answer as many of those as we can get done in the amount of time that's left.
00:35:17 How many times can you do CAR T therapy? Let me start with a question from Meritza. She wants to know how many times you can do a CAR-T therapy.
Initially the plan is to do one treatment with CAR T-cell therapy. There have been some clinical trials with some patients that have been retreated with CAR T-cells depending on the situation, but in general we plan to do one treatment with CAR T-cells, and we wait and see what the response is. Depending on the situation, depending on whether we have enough cells to do a second treatment, we have done second treatments in the past.
00:36:04 CAR T therapy for Richter's transformation: We actually have looked at that. Many of the clinical trials that have been done had Richter transformation patients in those trials. Although the subset analysis, meaning that specifically looking at Richter transformation, we don't have specific data on that, the patients with Richter transformation have been involved in these trials, and they're actually eligible for the treatment, so it is a possibility. It is an option for patients with Richter transformation. The final verdict on how effective it is is still coming, and we'll find out soon as far as percentages of response, but it's definitely something that we used in this population of patients.
00:37:04 Is there a way to verify that CD19, CD20 or CD22 exists on the surface of the tumor cells prior to infusing CAR-T cells? Absolutely. We have very sensitive methods. We can easily tell whether this protein is expressed on the surface, and that's a great question because as a community of physicians we ask that and we say, okay, of course we need to have the target noted for the therapy to be effective. There are some trials that are looking at whether or not the CD19 negative cells are killed as well, but in general, yes, the answer is yes. We have a way to look at it. Yes, you have to have the expression of that protein noted for the therapy to be effective.
00:37:47 Average lifespan of a CAR T patient: It varies from the disease. It varies on the response to therapy. I think the best example of this has been the first ALL pediatric CAR T-cell patient, her name is Emily, she was treated at the Children's Hospital of Philadelphia. I believe she is now in her late teens. She was treated when she was much younger than that. You can have prolonged survival. It all really depends on the patient. It's different in every case. Like we mentioned before, we are thinking that in some of the lymphoma patients this may be a cure. We're not quite ready as a community to say that, but it is possible. In the leukemia patients, we're still having some discussions about that, but there are some very long-term survival in pediatric patients that have been treated with CAR T-cell therapy.
00:38:53 Can autologous stem cells stored for transplant be used for CAR T therapy? The stem cells that were collected for an autologous transplant cannot be used as a CAR T-cell therapy. We have to collect T-cells if the patient was to undergo that treatment again. Can those stem cells be used for anything else besides transplant? They could be used for research purposes. Sometimes there are things that specific centers do in investigating new treatments for blood cancers or understanding some of the processes that happen, but typically once we have those cells for a patient, they are there for a patient. In some cases, for example a multiple myeloma, we do more than one transplant, so those cells will be used for a second transplant is possible.
00:39:45 Is there an age limit for CAR T therapy? There isn't a hard limit. I think what we look at is at the condition of the patient. I think that in certain clinical trials there will be a limit, but just like there isn't a specific limit for a stem cell transplant, we evaluate the patient and if we believe that they are healthy enough to undergo the procedure, we do it.
00:40:24 Does the emotional health of the patient affect outcome after CAR T therapy? think that this is ... And again I keep referring to this, but I think that this is very similar to the transplant process. I think that cancer patients are tough patients. They're special patients, and they deal with a lot. If you're able to tolerate therapy and have good support and have been successful with a transplant or with strong chemotherapy in the past, I think that you will do just fine with this process. This is tough. Having a cancer diagnosis is tough. Having a diagnosis of a blood cancer can really bring you down, but I think it's all about the patient, the support. You've got to make sure that you have a team that you trust, a doctor that you trust, that can get you through the process, but there isn't a specific type. I think all of patients are special. All of our patients can do this if they put their mind to it.
00:41:33 Is CAR T therapy offered to patients who are in remission? No. Right now the CAR T-cell therapy is only offered if a patient has relapsed disease.
00:41:50 How long is progression-free survival for myeloma patients who have had CAR T therapy? That's a very good question, and that's a question that the myeloma community is dealing with right now. The latest data shows that the progression free survival from these therapies is about 12 months. It's about 11-12 months. That's been a little bit disappointing to us in the field, and that's what we're trying to understand. Do we need to hit a different target? Do we need to change something about the process?
00:42:29 Are there CAR T trials for patients with chronic lymphocytic leukemia (CLL)? There are trials that are targeting CD22. I will refer you to clinicaltrials.gov. You can put in CD22 CLL, and you'll find a listing of the trials that are available, but there has been some research done in looking at that target. It's a common target in lymphocytes, in B lymphocytes. It's also used for leukemia, for ALL, so there are trials that are looking at CD22 as a target right now.
00:43:29 Do you need a catheter to have CAR T cells infused into the patient? Okay. That depends on the center. Some centers have created pathways and some of them say we're going to put in a catheter, whether it is a transfusion catheter similar to what we do for transplant or a PICC line or something else to go through the process. I think the majority of centers do that. Some centers don't. Some centers, if the patient has good veins, we can do all this with peripheral IVs, but it depends on the center and on the patient.
00:44:06 How much does CAR T therapy cost? That is a fantastic question, and as a community of oncologist and cellular therapists, we have been dealing with that over the last couple of years since this treatment came out. I know that it's no secret that it is a very expensive treatment, and we are working with insurers, with Medicare, to get this paid. We have had experience that private insurance has been reasonably good at paying for this treatment, and now Medicare has some new rules where they're going to increase the coverage of this treatment, but it's still something that hospitals and providers and insurers are dealing with. I think that if a patient needs to have this treatment there are ways that this can be figured out. Each center is going to have a different process for making sure that the patient can receive this treatment.
00:45:13 How many patients have died due to CAR T therapy? Yeah. There have been some deaths that happened in the clinical trials, but they have been really minimal. I think that some trials had two people die in the same trial from cerebral edema in the past. There have been some new data with a couple of other patients have died, but of the hundreds of patients that I've been treating with CAR T-cells, the mortality related to CAR T-cell has been very, very low. I would estimate that the CAR T-cell death related specifically to the CAR T-cells have been probably less than 5%. Now mortality can happen from the disease, from a complication, from an infection or something else that happens. Whether or not we consider that as part of the CAR T-cell process, I guess it will depend on the timing, but from the medication itself, from the drug itself, from the T-cells itself, the mortality is very low, although the side effects can happen in 30% of folks, 40% of folks. The majority of the folks recover from those side effects.
00:46:52 At what point in CAR T therapy is chemotherapy given? I'll give that a try. The lymphodepletion, the chemotherapy, the low dose chemotherapy is given right before the cells are being infused, so the patient undergoes collection of the T-cells, the T-cells get manufactured. Once we know that the T-cells have been made, we bring the patient into the infusion center or hospital. We give them the low dose lymphodepletion, the low dose chemotherapy, and then after that the patient gets the CAR T-cells.
00:47:33 Can CAR T therapy help patients with myelodysplastic syndrome (MDS): We have not looked at that quite yet. There are some trials that we've mentioned before that are looking at AML. Some of those trials may also allow folks with high grade MDS. I think that that's probably something that we will do in the future because folks with MDS sometimes need transplants, sometimes need more aggressive therapies, and in my view MDS tends to have a slower progression than some of the acute leukemias, which will give us more time so that therapies like this will have it's maximum effect. My prediction is that it will probably become something that's used in the near future.
00:48:36 Can CAR T therapy be given to patients with CNS disease? Yes. Now CAR T-cells are being used with patients that have secondary CNS lymphoma and also with patients that have CNS disease. At the beginning some of the trials would exclude patients that have CNS leukemia, but now we're starting to understand that it's safe to give CAR T-cells. Most of that right now is being done in the CNS lymphoma field, not in the ALL with CNS involvement, though.
00:49:22 How long after CAR T therapy does it take to know if it worked? We normally monitor the patients, and it's different in every patient. In some patients we know whether it's working right away. If it's a patient with leukemia we can see that the leukemic burden is going down. If it's a patient with lymphoma, we can image and see if there's been a result. A month is a period in which we can take a look and see if the masses are getting smaller. It's also dictated a little bit by whether the patient is in a clinical trial or not. Clinical trials will have a specific timing as to when you look and see whether the treatment has responded or not. If you're getting an FDA approved product that's going to be a discussion that has to be had with your provider, with your doctor, as to when the time to look will be, but I would say in the range of weeks after therapy you can take a look and see if the CAR-Ts have worked.
00:50:36 Can CAR T therapy be used for patients with T-cell lymphoma? The answer is yes, theoretically it can. There are some CAR-T cells that are being developed to target, for example, CD30. CD30 is a common protein on angioimmunoblastic T-cell lymphoma. So, yes, it can. It's not something that's one of the approved indications for these T-cells yet, but in clinical trials in the future it's something that can be done.
00:51:12 Can you do BITE therapy if T-cell is not successful? It depends on the situation. I think right now, as far as the timing of different therapies, for example, there is a BITE therapy for ALL. I think most folks would receive BITE therapy before CAR T-cell therapy, at least that's been my experience, but mainly because BITE came along before CAR T-cells. Will we use CAR T-cells or will we use BITE after CAR T-cells? It's possible if the patient hasn't seen it or hasn't been treated with that yet, but typically BITE comes before CAR-T.
00:52:02 Are trials being done to test CAR T therapy in combination with other therapies? Yeah, there's some work is being done exploring molecules we call checkpoint inhibitors, things like pembrolizumab or nivolumab, which are molecules that take the brakes off the immune system. We think combining these with the CAR T-cells would enhance the treatment. I think that in solid tumors there's going to be some interest in developing combination therapies like what you suggest.
00:52:42 Is CAR T therapy as dangerous as an allogeneic stem cell transplant? That's a good question. Personally, I believe that the risk of CAR T-cell therapy falls somewhere between an autologous transplant and an allogeneic transplant. It's also going to depend on the patient, but in general it's perhaps not as intense. The side effects are not going to be as intense as what you have with an allogeneic transplant. Probably not as severe as an allogeneic transplant.
00:53:25 Do CAR T patients develop graft-versus-host disease? That's the reason that we're doing the clinical trials, and especially the clinical trial where we are generating CAR T-cells from the donor. I think that's one of the main interests is we want to see can we do this safely without causing GVHD. That's going to be something that we're all going to be looking forward to as far as hopefully that's not the case, but we're in the middle of studying that right now.
00:53:59 Why is CAR T therapy not being used as a first-line treatment for myeloma patients? Yeah, that's a great question, and I think that it's the same thing with a lot of therapies. Whenever we're doing clinical trials, the patients that are enrolled in these clinical trials are typically the patient that have failed multiple treatments. Once we show that our therapy is effective, we start moving it further and further forward in the treatment. I agree. I think that someday we may have a trial where we're doing CAR-T as first line for some of these diseases like multiple myeloma lymphoma. Right now there are some clinical trials that are looking at moving the treatment of diffuse large B cell lymphoma with CAR-Ts a little bit further up. There are trials that are comparing whether an autologous transplant is better or whether CAR-T cell is better. We have to slowly move things towards the front of the line when it comes to novel therapies, but I believe that someday we may be seeing this as the first line treatment.
00:55:14 Is there a correlation between no side effects after CAR T therapy and success of the treatment? People have looked at that, whether or not there's correlation in between whether a patient gets CRS or not and whether the therapy works. There's no clear data that's the case, so we can't tell you. That's not going to be a relationship between those two. I think we just have to see whether the treatment works or not at the appropriate time. There's no correlation between side effects and effectiveness right now.
00:55:45 Is any maintenance therapy required after CAR T therapy? No. There is not. As of now, CAR T-cells are a destination treatment in some cases or a bridging therapy if we do it before an allogeneic transplant, but we typically don't give maintenance therapy after giving CAR T-cell therapy. That may change in the past. Maybe if we have an immunomodulatory molecule that we think may enhance or prolong the effective of CAR T-cell, it may be something that we do in the future, but right now that's not something that's done.
00:56:30 CAR T clinical trials outside the U.S.: I think that there are some clinical trials that are being done internationally. China is actually a very large site for clinical trials in CAR-T. I think that a clinical trial in the United States for someone that doesn't live here is going to be a little more difficult because some of the insurance challenges. Even though a patient is in a clinical trial, there are still things that are paid by the insurance, so if there's no insurance, it's going to be very hard to enroll in the clinical trial, but I would say that there are international places, China, close to the Philippines that have this available, and I hope that this becomes available worldwide at some point.
00:57:20 Does CAR T therapy help patients with graft-versus-host disease (GVHD)? At this time, we don't believe that's the case. These cells don't have an inhibitory capacity, meaning that they can block the effect of graft-versus-host disease. There are other cellular therapies that are not CAR T-cells that are being used and are in clinical trials to treat graft-versus-host disease. The immune system has cells that are both killers, like T-cells, and have cells that are more inhibitory, so we're trying to take some of those inhibitory cells and use them in the setting of graft versus host disease to see if we can get some results and help patients with that disease.
00:58:09 How long does it take to recover from CAR T therapy? Typically I would say it's somewhere between 45-60 days of very close monitoring. Obviously, when you get the collection to the time that you get the cells it's going to be 3-4 weeks. Then it's about a month until after you get the CAR T-cells. I think it depends on what type of work you do. It's going to be, like we've said before, similar to autologous transplants, perhaps a little longer. I would say probably after 90 days would probably be the best case scenario, but it depends on the patient. It depends on what type of job or work you do.
00:58:57 Is CAR T possible for high risk myeloma with 1Q gain? I'm guessing that that is going to be a 1Q in myeloma. If that's the case, then, yes, we're looking at treatment of multiple myeloma with CAR T-cells. Right now the mutations, this type of genetic changes, all those are being looked at. We don't have a subgroup analysis to see whether it works better for translocation 11-14 or deletion 1Q or 1P. Right now we're taking all multiple myeloma patients and looking at whether this treatment works for those patients. But, yes, it's available for multiple myeloma patients.
00:59:43 Does CAR T work for patients with myelofibrorsis? Right now we don't have any trials looking at CAR T-cells for myelofibrosis. Myelofibrosis is a disease for which we really don't have a lot of cell therapy protocols for trials that are being looked at. Myelofibrosis is treated with stem cell transplant now more than it was before, so I think that eventually we may get there, but right now it's not something that's being done.
01:00:19 Can CAR T therapy prevent B-cell lymphoma in patients with Wiskott-Aldrich syndrome? We haven't looked at this as a therapy for prevention. We've looked at it as a therapy for treatment. Can it prevent it? I think it would be difficult because of the way that the therapy works. We need some sort of ... more of a vaccine platform or a vaccine therapy in that case to prevent lymphoma from happening. This therapy is mostly about treating lymphoma that's already there.
01:01:07 Can a 67-year-old patient with cardiovascular disease undergo CAR-T? We would have to do an evaluation with the center that can provide that treatment. Just from the age and the comorbidities that I'm hearing, I don't see a reason why not, but we'd have to do a full evaluation as to whether the patient is able to get this treatment, but it sounds like it's a possibility.
01:01:34 Can CAR-T help patients with prolymphocytic leukemia? Prolymphocytic leukemia is one of the rare blood cancers. Right now I'm not aware of any trials that are looking at targeting PLL. Now PLL does have some of the same markers that lymphomas have, that leukemias have, so eventually I think we'll get there, but there's no specific trial for PLL, but it's a therapy that in theory that should work for PLL once we prove it safe.
01:02:11 What other immunotherapies, besides CAR T, are available for patients? Depending on the type of cancer that you have, there are multiple types of immunotherapies. We've talked about CAR T-cell therapy, which is cellular therapy. There are different kinds of cellular therapies that are available.
There are antibodies that are available to treat cancer. That's something that we've been using for many years in lymphoma, for many years in breast cancer. There are checkpoint inhibitors, which are those guys that we talked about that can take the brakes of the immune system. Checkpoint inhibitors in combination with CAR T-cell therapy have really revolutionized the treatment of cancer. Checkpoint inhibitors are used in many cellular cancers, melanoma, renal cell, lung cancer, with very good results. BITEs are another type of immunotherapy that we use. BITE stands for Bispecific T-Cell Engager. It's a way to redirect your body's T-cells to target a tumor. The one BITE that's FDA approved is a BITE to treat ALL. We've been using immunotherapy for several years in melanoma and renal cell.
Sometimes we use cytokines, just like we talked about cytokine release syndrome as being one of the side effects of CAR T-cell therapy. In the past for many years we have used cytokines themselves to treat cancer, because they are an inflammatory molecule. Of course, an allogeneic bone marrow transplant is the most widely used immunotherapy. We depend on the graft versus leukemia effect, the graft versus lymphoma effect to cure cancer. Although it doesn't seem like it, we have been using immunotherapy for some time, but it wasn't until the last decade that it really just became a major tool that we could use.
01:04:16 Can multiple expressions on myeloma cells such as CD19, CD38, etc be treated with one CAR T therapy? That's a very good question, because one of the reasons that we think that CAR T-cells fail is because they target a single protein. There are studies and there are researchers that are looking at generating CAR T-cells that can target more than one protein at the same time. Right now that's not available yet, but I think it will be in the future. That might be the next generation CAR T-cell therapy. I believe that we'll move forward with it and targeting multiple [inaudible 01:04:45] at the same time, multiple proteins, will be part of the future of CAR T-cell therapy.
01:05:05 Can you do a second CAR T therapy if the first one fails? Sure. It's going to be dependent on the patient. We plan on doing only one CAR T-cell therapy. In some patients we do multiple depending on whether there is enough product available and whether we've had a response initially, and also on what we're trying to do with that patient. That has to be considered on a patient by patient basis. It is possible to give more than one treatment of CAR T-cells. It is not something that's commonly done. We typically just plan on one treatment with CAR T-cells.
01:05:50 What is the average cost of CAR T therapy and are there resources to help pay for it? Yeah. I think the price of CAR T-cells are out there for the treatment of ALL. The cost of the therapy itself, just the drug, is somewhere around $475,000. For the treatment of lymphoma it's somewhere in the $370,000-$380,000 range. There are other costs that are associated with it, the hospital cost, the medication cost. There has been a lot of discussion between providers, insurances, Medicare, to try to bring some of those costs down, to come up with an agreement of how can we get this treatment to patients. Each center is going to have a different set of resources that can be used to help the patient financially, and I know that, Sue, you probably have some things, some other avenues to find some support.
Yes. You can contact BMT InfoNet. Although we don't pay for the cost of treatment, there are funds available to help with some of the things like travel, lodging, food while you're undergoing treatment, and there are some other organizations that provide some help as well. So you can contact BMT InfoNet and we can try to put you in touch with organizations that can be of help.
01:07:28 Should patients in remission consider CAR T therapy? At this time, no. At this time I say that because the way that the cells are made, they're made to recognize tumor cells that are there. The question is do we think there are tumor cells that are hiding somewhere if somebody's in remission? It's possible. I think at some point this may be looked at as a treatment for consolidation for somebody that had a good response to therapy. Right now it's not being looked at that way. It's possible, but right now it's not something that's considered for patients that are in remission.
01:08:02 With that, I think we will wrap it up. Dr. Varela I want to thank you for an excellent presentation. If you have questions, do not hesitate to contact BMT InfoNet at 888-597-7674 or, again, at help@bmtinfonet.org, and we will reach out to help you. Thank you very much for a great presentation and evening folks. Be well and goodnight.
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