CAR-T Cell Therapy: Current Uses and Future Possibilities
Chimeric antigen receptor (CAR)-T cell therapy is a promising new immunotherapy for certain cancers of the blood, providing long-lasting responses for some patients. It genetically modifies T cells to make them specific for cancer cell markers and activates the immune system to destroy cancer cells. Physicians with the CAR-T cell therapy program at Mayo Clinic in Jacksonville, Florida, will discuss current uses and potential future applications. Mayo Clinic’s program includes an in-house cell manufacturing facility for developing new cutting-edge trials.
Webinar is open to physicians, physician assistants, nurses, nurse practitioners, residents, fellows, pharmacists, social workers, scientists, students, and allied health professionals. Also for medical directors or others from contracted organizations.
Understand how CAR-T cell therapy is provided.
Learn about its current use in treating lymphoma and multiple myeloma.
Learn about potential future indications, including for cancers for which there is no treatment.
Mohamed A. Kharfan-Dabaja, M.D., M.B.A., Vice Chair of Hematology and Director of Blood Marrow and Transplantation and Cellular Therapies, Mayo Clinic in Florida
Ricardo D. Parrondo, M.D., Hematology/Oncology, Mayo Clinic in Florida
Hemant S. Murthy, M.D., Hematology/Oncology, Mayo Clinic in Florida Good afternoon. Thank you for joining us for the webinar today titled Car T Cell Therapy. Current uses and future possibilities. I'm Doctor Sikander Alwadi, a hematologist oncologist with Mayo Clinic in Florida Comprehensive Cancer Center. I will be serving as the moderator for today's program. We are very glad to have you with us today and look forward to a great discussion and now I'm pleased to introduce the speakers for today's webinar. Please join me in welcoming Doctor Mohammed Karan de Baja, Vice Chair of Hematology and Director of B blood marrow transplant and cellular therapies in Mayo Clinic, Florida. Doctor uh Ricardo Perano, a hematologist oncologist with Mayo Clinic in Florida and Doctor Hamed Murthy, also a hematologist oncologist with Mayo Clinic in Florida. Today, we will be discussing how car T cell therapy is provided. Talk about its current uses in treating lymphoma and multiple myeloma and acute lymphoblastic leukemia and then discuss potential future indications including for cancers for which there is no treatment. So let's get started. Car T cell therapy is a new modality of treatment for several hematologic cancers. Today, there are some broad benefits. For example, patients can actually stop the treatment after receiving it, if they achieve success from it, there have been some excellent success stories in patients with different kinds of lymphoma with multiple myeloma and also with acute lymphoblastic leukemia. While in some cancers, we are talking about curing the disease in others, there is significant benefit that we are achieving even in situations where no options were available prior to the introduction of car T cell therapy, card T cell therapy does require a lot of co-ordination and a multidisciplinary team including for example, cardio oncology, infectious diseases, neurology, IC U teams, social work coordinators. In addition to the hematologists who administer and manage the card T cell therapy, because it requires a lot of co ordination. It is extremely important for the patients to be referred to the appropriate car T cell centers in a timely manner so that we can provide the right treatment to the right patient at the right time. With that, I'll start posing some questions to our panel over here. And um Doctor Caran, I'll start with the first question for you. I've mentioned that patient selection is important to identify the patients who can get any treatment safely for car T. Is there any age limit for patient uh selection or any other conditions that you look for while offering car T cell treatment to the patient? So thank you and uh good afternoon, everyone. Uh That's a great question. In fact, when, when we look at all the studies that have led to the approval of this uh uh cardi products uh in various hematologic cancers. Uh there was not really a preset age limit. So I would say that uh for diseases like uh diffused with cell lymphoma, man, cell lymphoma or follicular lymphoma. As a matter of fact, uh in those cases, the limitation was most on the meeting the adult age group. So basically 18 or older, but there was no preset limit for, for age. So for us, what's more important is looking at the uh performance status of the patient, the organ function and so on. So, but we don't really uh disqualify patients purely based on chronological age. Excellent. Um And are there any other uh patient conditions that would uh limit them from receiving card T cell therapy and any general health conditions that you're looking for when you are considering a patient for this treatment? So yeah, that, that's another uh great question. Doctor Lava I think what is important? Uh If one is to look at this is really looking at organ function. So for instance, uh does the patient have an adequate heart function? Uh we look at the minimum uh requirements in terms of the adequacy of that particular organ function, we look at something called the ejection fraction of the left ventricle. We have to make sure that the patient is not having any uh situation like a decompensation of their heart condition and so on also we focus on the lung function of these patients uh to make sure that these patients are fit to, to move forward. And we also look at other functions such as the liver function, the kidney function. And so, so we do really a very methodical and extensive work up to make sure that the patient is fit from that particular standpoint. Excellent. Thanks for that comprehensive answer. Uh Maybe I'll pose another question to you then um we hear that car T cell uh treatment is a very complex process. Uh Can you briefly explain for our audience, what are the different steps involved in this treatment after the patient has been considered appropriate for car T cell therapy? So definitely, uh first of all, uh the procedure can only be performed at centers that are certified to, to perform these procedures. So, uh and then when the patient is deemed to be eligible for the procedure, there is a process uh what is called uh leukopheresis, which basically is procuring those uh lymphocytes uh in order to be able to manufacture the, the car T that is a procedure which basically requires uh the patient to be connected to a machine called the Aares or L Fores machine typically uh taking somewhere between 4.5 to 5 hours. Uh And then at the completion of that, uh those cells are shipped to the manufacturing facility, uh that will certainly uh be manufacturing these products. Uh this process may take sometimes between uh 17 and up to 25 or 28 days uh at the, at the latest uh then the product is uh transferred back or, or uh shipped back to, to, in this case, Mayo Clinic Florida, and the patient will uh at that time be uh initiated with what we call lympho depletion where we need to give a combination of chemotherapy to try to in a way open a space uh for this card T cells to go on and home and be able to, to exert the function that is asked of them. So that is kind of the step of the process. The the lympho depletion depending on, on the regimen that is used and depending on what disease or product we use could take somewhere between 2 to 3 days and then uh the patient will go through a couple of days of rest and the cells are infused uh on the subsequent days. Uh And this patient will be uh followed very closely uh in the hospital setting uh to make sure that that the side effects that are anticipated are dealt with in a prompt manner. Excellent. Thank you for that. Um Next, maybe I'll ask a question from Doctor Perano. Uh Doctor Perano. Uh you focus on multiple myeloma. Uh What are the currently available car T cell therapies for multiple myeloma? Yes. Uh Thank you, Doctor Alari. So there, there are currently two FDA approved autologous uh car T cell therapies for multiple myeloma. And they both target a protein called BC MA on the myeloma cell surface. Um And one of those products is IDA Cell or Abema, which is manufactured by Bristol Myers Squib. And the other product is SIL to cell or Carvi, which is manufactured by Jansen. And both of these car T products are approved for multiple myeloma patients who have had four or more prior lines of therapy. So quite heavily pretreated patients and just to go into a little bit of detail about these uh car T products. So BC MA or B cell maturation antigen, it's a protein that's universally expressed on the myeloma cells. And it's essential for the myeloma cell proliferation differentiation and survival of the plasma cells. And what we're doing with the car T essentially is we're facing the patient's T cells as Dr Kan I described earlier and we're manufacturing them to express an anti BC ma antibody on the surface of the T cell so that it can specifically target that BC MA protein on the myeloma cell surface. And IDA cell is a second generation car T product and silt cells also a second generation car T product, but uh it binds to two distinct epito on the BC MA, uh you know, giving in more avidity or more more ability to bind to the malignant plasma cell. And you know, these therapies, you know, they continue to evolve Uh Right now, they're approved for four more prior lines of therapy. But there's uh emerging data that we may, you know, it's also effective if you use it in earlier lines of therapy. So, very exciting time for card T and multiple myeloma and o and other diseases as well. Excellent. Thanks for explaining that in detail. Um Doctor uh Caran, I'll go back to you with the question around lymphomas uh and Car T. So there are several different types of lymphomas. Uh can you uh touch upon which lymphoma types and what indications within each lymphoma type are car T cell therapies available for sure. Uh So there are uh several types of uh uh what we call B cell lymphoma. Now, uh you may be familiar with the certainly the B or the T cell uh type of lymphomas. In this particular case, all the lymphoma approved product target uh uh cluster of differentiation called CD 19, which is A B cell marker. So that that is pretty much what all these available products uh are targeting uh at the present time. So, for diffusive B cell lymphoma, uh there are three commercial approved products uh and those were approved uh in the third line setting or beyond. So, this patient must have failed two prior lines of therapy and then they basically were treated uh in that particular setting. The first product that got approved for diffuser lymphoma is called AYTA and cell. And uh this product was uh approved based on a study uh known at the time as the Zuma. One study. The second product that was approved is uh t a cruel. Uh And this product again with similar indications uh diffus al the cell lymphoma, whether transformed or what we call the no or original uh started as a large cell lymphoma. And the third product uh is known as lysogen Maral lel, Mara lel. And uh that also is another product now based on that success and to give you a little bit of, of uh uh assessing the, the, the dimension of this success is uh uh typically patients who have failed to or more lines of therapy with diffuser with a lymphoma, the probability of attaining a complete remission to the third line of therapy or beyond is less than 10% in general. And in this particular setting, for instance, Ai capa and cus was able to yield a complete remission rate which exceeded seven or eight fold above that. So, uh uh I would say before KT maybe 7% complete remission rate. After Kat, we're seeing in the ranges of 50 up to 55% or so complete remission rate. So, and that eventually translated into uh improvement in, in what we called overall survival based on that success. Then the, the second question wa was well, can we use them at an earlier stage? And there were three randomized studies for diffused, be in formal one was known as the Zuma seven. Another one was known as Transform. And the third one was known as the Belinda study. And Zuma seven showed uh superiority to what is considered standard of care, which is a combination of a chemotherapy followed by autologous transplant uh versus the car t. So axius standard of care was superior and that led to the approval of Axicabtagene cus in the second light setting. And that was for patients to have failed to respond to the first line therapy or relapse after uh within the period of less than 12 months. So, those are the patients that traditionally are uh known to have a very poor prognosis and clearly the cardi was superior for aic capta cus and the same case was for Lysogen Maral based on the transform study. So these two products uh Ay capta cus and, and the Lysol Capac Maral made it to that second indication. The third study known as Belinda did not show a benefit for for TCLER in this case. And uh that was not approved for that indication. So we have three products approved for third line or beyond. We have two products approved for second line uh uh setting, which basically as I mentioned, patients who have failed to respond to front line therapy or uh have relapsed within less than 12 months. The the other disease for which there is an indication is called mantle cell lymphoma. And this basically is for patients who have relapse disease or have refractory disease, meaning they have not responded to prior therapies. And the product here is known as Brex capta oil. Again, targeting CD 19, showing impressive responses uh in those patients who have failed all all therapies. Uh before the third indication in lymphomas is uh follicular lymphoma. And for this particular one, there are two products that are currently approved. Uh One is uh icap the cus uh This was based on a Zuma study uh at that time known as the Zuma Five study, uh showing that uh the patient who have failed uh two or more lines of therapy for follicular lymphoma. Uh Those patients showed impressive response rate, overall response rates of close to 90% and uh certainly durability of those responses. Three years later, more than 70% of this patient uh continued to be alive. And uh certainly, uh the most impressive I would say is is there is a group of patient uh with uh follicular lymphoma that tend to relapse within uh 24 months of initial treatment, uh is called the pod 24 or 24. And those patients actually demo uh the product demonstrated that it is effective even in that group of patients is uh has an aggressive uh more aggressive biology. Perhaps the other product is this a loel, which is also approved based on a study known as the uh elara study again. So we have those two products there. So those are the products that we have for uh patients with, with the various types of folic of uh A B cell lymphoma. So, thanks for pointing out all of those. And I do want our audience to know that uh at Mayo Clinic, we are able to offer all of these products and all of the respective uh indications where they are approved. Uh Doctor Kon, you have talked uh uh quite nicely and extensively about lymphomas where um these multiple products are available across various different uh diagnoses or lymphoma types. But a third uh disease area where card T cell therapy is currently appro approved is acute lymphoblastic leukemia. Uh Can you tell a little bit about uh what specific indications for using car T cell therapy in acute lymphoblastic leukemia? Sure. So the the first product that was approved again for keeping in mind that uh same prior theme uh of CD 19. So the this same product uh uh Ayara uh sorry, uh Brex capta Notus and uh this agen cell have been approved for patient with uh acute lymphoblastic leukemia of the B cell type. So obviously, the B cell is is those cells are the ones that tend to express that CD 19 antigen on them. So, the first product approval actually uh this agenda plus, this was based on uh the Eliana study is what the name of the study was. And this particular study uh was geared towards uh patient in the pediatric and uh young adolescent age group. So, uh this product demonstrated that it was uh effective in patients who have relapsed or refractory B cell, acute lymphoblastic leukemia. And the that product is a cruel is currently approved uh for patients up to 25 years of age. So 25 years of age uh interpretation is really 25 year, 11 month and 29 days. And but uh subsequently, uh Brex Capta oil based on the uh study known as the Zuma uh three study was uh also uh had proven uh efficacy in the adult age group. And that product is approved for patients with B cell, acute lymphoblastic leukemia who are 18 years of age or older. Uh And those two products demonstrated that they are able to induce a complete remission even in patients who have failed a prior allogeneic transplant, which tends to be a very aggressive uh uh uh or a very uh patient with very poor prognosis. So this is how, how, in my opinion, how uh effective and impressive these products are on those indications? Excellent. Thanks a lot for pointing that out because as we started um in the beginning or, or mentioned that uh card T cell therapy has revolutionized our uh treatment options because patients are seeing unprecedented benefit even in settings where the prognosis was very poor. And importantly, we did not have any standard of care treatment options available. Uh Doctor Murthy, I'll come to you for the next question as uh Doctor KFA nicely laid out the importance of car T cell therapy in A LL. We also know that acute lymphoblastic leukemia or A LL is seen more frequently in the pediatric population. Now, the more common uh uh acute leukemia seen in adults is acute myeloid leukemia. So what is the status of cardi cell therapy in this diagnosis? And thank you or thank you. It's an excellent question, Doctor Awai and uh good evening everyone. So in terms of acute myeloid leukemia, you know, we have, there are be, there are a couple of uh there are a coup, there are a couple of things that have that um lend itself to be a little more difficult than, than the current indications that we have for other diseases like lymphoma, myeloma. One being finding the right target for leukemia mean, meaning when we look for a target, we want to make sure that it is a target that is expressed by the tumor cells but not expressed by normal tissue where you may have undue toxicity because of that where most of the times with the leukemia, these are part these are your abnormal blood stem cells which are responsible for your normal healthy blood count. So finding a pro finding a target has been is is has been a little bit difficult. Uh The second thing is that with the manufacturing time or needed for car t many times. Leukemia patients, especially with relapse, leukemia may not have that time. So is there a way to get a product faster or are we do we need to consider using a different immune cell? So I and I think there are still other uh factors like the actual microenvironment that may contribute to, to the difficulty. Now, there, the trials, there are trials that are ongoing. There are they are still relatively in early phase trials, mostly determining safety and trying to see early signs of efficacy. We do see car T cells uh similar in style like the lymphoma that they target see is a marker called CD 33. And these are, these are ors or you know your your own T cells that are being collected and then manufactured very similar to our commercially approved products. Other options that are being other targets. Uh CLL one is another target that is that there are a few clinical trials very early or in development for. And that I think is a promising target because we do see less expression of that outside of leukemia cells. Other trials that are that are ongoing are actually taking advantage of using different types of immune cells. One particular immune cell is called a natural killer cell. And one of the benefits of a natural killer cell is that it, we we collect it from donors or we don't need somebody's somebody's own natural killer cells. This allows for us to be able to apply treatment faster when we and and when we can still determine the appropriate target to, to harness, to encode these NK cells and target the leukemia cells. So I think there is, there's been a significant amount of progress, maybe, maybe still a little behind lymphoma, myeloma and A LL. But I think there's, there's certainly a cause for optimism in the near future. Excellent. Thanks for explaining all of those options that are coming on the horizon, especially in this uh diagnosis of AM L that can be quite devastating in the relapse setting. Um Doctor Kan, we mentioned in the beginning also that car T cell therapy requires a lot of coordinations between a community, referring physician and the academic car T administering center. And that's why we um uh frequently um uh uh suggest that the patient should be referred at an earlier time than when they may actually even need the car t right away because we need all of this coordinate planning. You mentioned the manufacturing times et cetera. But on the other end of the spectrum is when the patient has received uh the treatment and is now ready to go back assimilate in uh their life, their um back, going back home or going back from the car T cell center to the community. So what dictates when the patient can actually return to his or her primary oncologist to wherever they got referred from. Yes. So certainly, uh uh these patients after they are, they have completed that process and uh normally we would like to keep them in the neighborhood of, of our center here for another couple of weeks and then these patients will be transferred back to the referring physician. Now, it's very important that there are certain uh instructions that are uh coordinate uh between the, the our center and that referring physician. So these patients, for instance, uh there is a restriction in terms of driving. They cannot be uh behind the wheel for at least eight weeks. So that is basically one of the requirements. Second, uh during that process, a proportion of of this patient may be requiring frequent blood testing to make sure that uh their uh uh blood parameters are within the zir range. So this patient uh could have what we call pancytopenia uh requiring sometimes blood or platelet transfusions. And in some cases also what we call growth factor to increase the white blood cell count. So it's very important to keep an eye on those to certainly make sure that the patients are closely followed in the community. Obviously, with low counts, there is a risk of uh patient developing infections. So it's very important that the patient continue under what we call prophylactic antimicrobials. There will have to be uncertain antibiotics or antivirus for a particular amount of time. Also, this patient will require uh looking at at some uh markers of immunity, what we call immunoglobulins to make sure that those are within a certain range to try to reduce that risk of developing infection. So there is a lot of communication with, with the references back and forth and there will be also the the process of assessing for response of this treatment. So we'll have to, after a certain uh time, for instance, in our center, we like to do the radiologic evaluation at one month and then at the subsequently to make sure that there is a response. Uh typically the prognosis of these patients or the future outcomes, I would say is very important that that there is a demonstration of a complete remission as early in the postcard uh phase as possible. So if a patient, for instance, uh did not achieve a complete remission on the 1st 30 days, that is a group of patients that we would like to repeat another uh pet scan uh within four weeks of that. So what I called day 60 to make sure that, that, that that patient have moved into a complete remission if didn't have that type of response earlier and so on and so forth. And this is important because if, if patients do not achieve uh these early responses, they will be more likely uh than others who do to have uh eventually relapse or progression of the disease. So, it's very important because uh we need to act and we need to act immediately if, if that's the case. So there is that you can imagine a lot of coordinations between our center and those referring centers to make sure that all of those things are, are performed in a prompt manner. Excellent. And, and we do provide a lot of that information back to the referring physicians at the time of the patient's transfer. So, uh we really want those um referring physicians to be um a partner in managing that uh patient because um it, it's, it's extremely important. Uh Doctor Perano, uh Doctor Haran mentioned about uh what criteria are typically uh need to be met before a patient can be sent back to their uh referring physician and, and to where they came from. But when we are uh getting the patient through car T cell therapy and its treatment, uh what are the main side effects of car T cell therapy that you keep in mind while treating your patients? And also what is the um group of side effects that you keep in mind when you're handing the patient back to the community hematologist so that they can monitor and maybe even reach back to you for guidance if it uh if that is needed. Yes. So those are, you know, very good questions. Um You know, the, the main toxicities of the currently FDA approved uh BC MA car T cell therapies for multiple myeloma include uh cytopenias infections. Uh And then you know, the main one that we watch out for. One of the main ones is uh cytokine release syndrome, which is an acute systemic uh inflammatory syndrome characterized by fever, multiple organ dysfunction. And that's caused by the expansion of the car T cells. Once they're infused into the patient, uh you know, when those T cells start to expand, they release uh other inflammatory proteins known as cytokines, which further activate the card T cells, expand the car T cells, it activates uh uh you know, other T cells, macrophages, endo endothelial cells. So it's sort of like an inflammatory chain reaction that can happen when you infuse the card T cells. Um that we monitor for. Uh another toxicity is uh neurologic toxicity known as cans or immune effector cell associated neurotoxicity syndrome, which can manifest as headaches, confusion, language impairment, uh fine motor impairment and even seizures. Uh patients can have any of those symptoms and it's due to the expansion of the card T cells and the release of these cytokines which disrupt the blood brain barrier, allowing inflammation uh into the central nervous system. And you know, with uh uh CRS cytokine release syndrome and cans, you know, uh death has been reported due to these side effects. But luckily, most of the times these toxicities are low grade and they're manageable with supportive care. So, for example, for CRS, you know, we use a drug called Toli zab which neutralizes a cytokine known as il six, which is a key cytokine leading to the inflammation that causes CRS. Um it's basically an antibody that will neutralize IO six. And then for the Ians or the neurologic toxicity, we have Anakinra, which is an IO one another cytokine uh receptor antagonist. And we also have cortical steroids uh which help, you know, the uh the lead to the resolution of uh this toxicity uh in patients with multiple myeloma. I mean, 90 95% of patients who receive card T cell therapy and T BC ma car T cell therapy will have low grade uh Croon release syndrome. And Ians only a small percentage will have a severe toxicity but it is uh very manageable and treatable. And then, you know, regarding, you know, when, when we send the patient back to the community oncologist, uh what do we do? You know Dr Khan mentioned a lot of it and I like to say it's, it's it's similar to the stem cell transplant algorithm. Um The autologous stem cell transplant algorithm for multiple myeloma patients. So, one of the things to monitor for is the cytopenias. You know, the patient may be cytopenia for some time after the car t due to the car T itself and the lympho depleting chemotherapy they receive, they may need transfusion support. So you have to check labs multiple times a week. Uh We may have to use growth factors like G CS F or uh erythropoietin stimulating agents. And if the cytopenias are persistent after 100 days, you know, luckily in, in myeloma patients, because we've collected for two stem cell transplants, a lot of patients have leftover stem cells that we can use to give them what's called a stem cell boost to sort of replenish the bone marrow and lead to the resolution of cytopenias. And then another uh toxicity to monitor for our infections. Um You know, the patients have to continue on viral prophylaxis for at least a year. PC P prophylaxis till day 100. The car T causes uh B cell and plasma cell aplasia. Uh and the patients will have hypogamma globulin anemia. They, they're gonna need ivig support to prevent infections. They need COVID and flu vaccinations. And then we do check the titers for the childhood vaccinations. They may need some uh to be vaccinated again because the lympho depleting chemotherapy may have, you know, uh uh wiped out some other immunity to, you know, uh diphtheria hepatitis B, for example. So, well, that's ex uh excellent. Thanks for uh pointing out all these um side effects that can happen. But as you rightly mentioned, uh it's important for our patients and our um physician partners to keep in mind that in majority of the cases, the side effects are lower grade. There's only a small proportion of patients where any high grade side effects can happen and frankly our management or handling of these side effects has also evolved over time. So we are able to predict them faster, we are able to act on them sooner. So that in the majority of the cases, these side effects do not become advanced grade. So thanks for pointing that out, I'll, I'll ask you another follow up question regarding um multiple myeloma car T cell therapy. So, um we've, we've heard about obviously these um excellent treatment options. They are uh require coordinations and we want the patient to be seen at the right time so that we can arrange for it. But in your opinion, how has car T cell therapy improved the outcomes or clinical outcomes of patients with multiple myeloma? Yes. So that uh is a key question, you know, car T has tremendously improved the clinical outcomes of uh multiple myeloma patients. So, you know, in, in the sort of space that car T is approved, you know, after four or more uh prior lines of therapy, you know, patients are what's called triple class refractory uh refractory to a Protess inhibitor, an immunomodulatory drug and an anti CD 38 monoclonal antibody or their Penta refractory, meaning they're refracture to the five main uh myeloma agents that we use. Uh lenalidomide pomalidomide, which are immunomodulatory drugs. Bortezomib and Carfilzomib, which are prosom inhibitors and Derra tab or isatuximab, which are anti CD 38 monoclonal antibodies. So that group of patients which you know, by the time you get to four more prior lines of therapy, almost all of them have had all of those drugs and have progressed uh a after receiving those drugs, you know, they had quite a dismal prognosis, you know, in the range of 6 to 9 months. But in that patient population, you know, the patients treated with um IDA or silo car t uh the, the median progression free survival, you know, ranges anywhere from 11 months uh with uh IDA to uh almost 35 months with sil to cell. Uh and the overall survival is even longer than that. Um So in this, you know, pta refractory or triple class refractory patient population, there were prior to the advent of car T, there were very limited treatment options and car T has really uh tremendously improved the the survival outcomes of these patients. Excellent. And I think in a lot of cases, uh cardi cell therapy for uh patients with all of these diagnoses is either curing them or controlling the disease very well. So that the patient can actually be able to get benefit from subsequent therapies that may come down the road or may become available if D approved um for subsequent therapy. Now, we've talked a lot about the hematologic malignancies. Um uh lymphomas, B, cell lymphomas, um B cell A LL and uh multiple myeloma car T cell therapies available, but frankly solid tumor, uh malignancies are overall much, much more common than these hematological malignancy diagnoses. So, um Doctor Murthy, I'll pose this question to you. What is the current or future role of car T cell therapy in solid tumor malignancies? I think it's a, it's a great question and I think we're, we're still learning about that. We're, you know, kind of similar to the AM L story is about having a car that is that finding the right target is one but also making sure that the car is actually well equipped to fight a solid tumor malignancy. I it's it is a different environment for uh for car t can navigate from a micro environment standpoint than say multiple myeloma or or uh or lymphoma. So there there are some novel techniques that are being studied and investigated. Uh you know, we see we have, we know that there are some trials that are actually looking at uh at, at uh looking at HL a heterozygosity basically to make sure that there is a difference between normal tissue and and the tumor tissue. And this way the the then making a stronger car that will selectively not clutch the normal tissue. So that is an interesting concept that is being investigated in in different uh solid tumors. Other techniques is to use uh use interleukin therapy and different encoding of the car key. And in order to allow it to, to fight uh to persist long enough to have more effect on the metastatic disease, we've seen we've seen early trial that are ongoing for breast cancer. Uh We see trials that are ongoing for colon colorectal lung. So I think there is certainly some, some op opportunity. There's certainly some excitement there. I'd like to also add that another thing similar to AM L. When we talked about using natural killer cells, there are trials that are using other immune cells such as mod sites and macrophages which may traffic into the tumor site. So trying to encode the encode and uh create cars that or car macrophages that may have a predilection of going after these tumors. So there's a lot of different strategies, a lot of different concepts that are being investigated either pre clinically or very early in clinical trials. Uh I and I think there is some, there have been some promising uh early results. I'd say renal cell carcinoma has been one of one that has had some promising early results. And I think there's still more to come uh down uh in the, in the coming uh in the coming uh future. Excellent. Thanks a lot for pointing that out because that tells us that the uh future horizon is much brighter and and frankly, patients across the spectrum of different cancer diagnoses can hope to benefit from these uh advancements in the car T cell therapy has to offer. Um Doctor Murthy, I will ask another uh question of you. The next one being that we have heard that at least with the currently available card T cell therapy, some of the barriers can be uh that card T cell, um card T cells themselves can take a longer time to manufacture, which means that the patients can sometimes need some bridging chemotherapy in between. Sometimes the disease may be too rapidly growing. And so we don't have the opportunity for the patient to wait for the T cells to manufacture, et cetera. So uh uh educate us, is there anything on the horizon to help overcome some of these barriers? That's a, it's a, it's a great question and something that we, we have struggled with, uh you know, with, with some sometimes diseases that are, that are rapidly growing. And we, you know, this is a sometimes these are barriers to getting people to car key therapy. So I think two approaches have really been looked at, I think the first approach R was, was seeing, do we need to manufacture our own cells? Can we use someone else's T cell? And with the advent of gene editing the uh gene editing uh processes, we were we were able to actually edit the T cells in order to not in order for the T for the car T to come from a donor but not give the toxicity that may come from introducing a donor cell such as such as something we encounter in bone marrow transplant called graft versus host disease. So that was that is one option that has been that has been in being studied in a number of trials. Some of the some of the uh drawbacks have been that we have not seen these cells maybe last as long as some of the, as some of the oncologist cells. So I think there is still work to be done in this space to try to get even comparable. You know, if, even if we are able to get similar results to Ortho IOUs the the difference in the time makes a difference. Now, more recently, we've seen that many of the uh many of these uh car key uh manufacturers have developed faster manufacturing. Uh you know, one that it was uh that was uh recently published by Michael Dickerson and from Australia was was about p charge for uh from uh and with a very rapid manufacturing of uh of the Novartis product. And in, in th in that case, the manufacturing was as short as 48 hours and car T product was available in, in about five days. Now, the I the importance of this is that also seeing how long the T cells from collection to manufacturing, these T cells had increased stems and may make them more potent than if it takes a long time for the for the T cells to manufacture. Now, these studies were very early, they were done conducted mostly to demonstrate safety. So longer term studies are necessary to see if the how effective these are and more importantly how effective they are compared to the standard of care. But I think there is definitely progress in trying to shorten that time and get these therapies to patients faster. Excellent. Thanks a lot for pointing out um uh Doctor Brando, I'll ask you uh the next question. So um what are some of the barriers that patients seeking car t cell therapy can face generally? I mean, we know that Doctor Kan laid out that there are um certain centers that are able to provide this treatment and the centers have to be appropriately certified. So I can and patients across the country would have some barriers um that they may face. So, uh if you want to mention some of those barriers that patients seeking card T cell therapy can face and what is mayo clinic doing currently to try and overcome those barriers? So that again the patients can get the treatment at the right time. Yes. So um you know, the the main barrier that exists, uh you know, for car T cell therapy is, you know, that sort of the limited availability of the product, right? Uh it's not available, you know, on the spot, it's on an off the shelf product. Um and there's only a certain amount of slots allotted to an uh a medical center, right, for car T per month. So, you know, due to that limited availability, uh it can lead to, you know, that's one of the biggest barriers that patients have to overcome uh to get car T. Uh and you know, if the patient lives far away from a car T cell center getting into the door, right, for the initial evaluation can be another barrier. Um And then, you know, when you actually get through the door, right, you have to evaluate the patient do vital organ testing. You have to stage the disease with a bone marrow biopsy. You have to do the T cell collection and PSIS. Uh and then the manufacturing process is a little bit longer for the myeloma cartes. It can take uh you know, between four weeks for IDA and uh up to eight weeks for Silas cell and sometimes patients are relapsing, right? If they have uh if they've exhausted all therapies and they have very aggressive disease like extra medullary disease or rapidly progressive disease, uh you know, they may not make survive long enough to get the car T. Uh So those are some of the main barriers that uh patients face when they uh are looking to get car T, but Mayo Clinic is doing many things to, to overcome these barriers. So we and so are the companies that manufacture the car T products. Uh So we've recently increased our fares capacity. So we're able to uh you know, uh fre more patients uh per month to get more patients to car T. Uh we're able to expedite the work up, write the vital organ testing, the restaging of the disease. You know, most of the time between 1 to 2 weeks, we can get all of this testing done for the patients. Uh And then as Dr Murthy mentioned, you know, the the science of car T manufacturing is improving, right? The manufacturing capacity is increasing, they're developing faster ways to develop uh to manufacture the car T product. Uh They're uh devising ways to increase the persistence of the car T, right? Because as of now, with the currently available products, you know, over time, the car T product may dwindle, it may not persist, right? And you want that car T product to persist, to continue to, to attack the the the disease of interest. Um And then you know what I always recommend to community oncologists and even, you know, myself with my own patients is, you know, early referral for car T, right? By the time in myeloma, by the time the patient is reaching that third starts third line of therapy, you know, start referring the patient to KT. So we can start future planning, the patient is already in the door, we know the patient. Um and you know, we start thinking of uh uh bridging therapies, right? If the patient has very aggressive disease or is relapsing, right, you need a treatment to keep the disease at bay while the car T is being manufactured, right? So all of that uh takes a little bit of time and thinking, right? So we want to get ahead of it and do it early. Um So those are the main things that uh you know, the barriers to car T and the things at Mayo Clinic and uh the car T companies are doing to help overcome uh these barriers. Excellent. And I think I um mentioned in the very beginning that a multidisciplinary team comes together at Mayo Clinic to help that patient um get appropriately assessed, to be able to make sure that the patient is the right candidate and is likely to benefit with hopefully less amount of side effects. And, and frankly, if any of those side effects occur, all of those facilities, all of those uh uh team members are available to uh take care of the patient. Um And I think I should, I should also point out that uh the role that our uh navigators, our coordinators or our uh social workers play in overcoming some of those uh non CIN uh barriers that the patients may have sometimes helping about with uh figuring out uh caregivers board, et cetera. All of those are also extremely helpful so that the patient can really focus on their disease and the recovery path rather than all of these other factors that they get uh burdened with uh during the treatment. Um I'll pose another question to Doctor Murphy. Um So, Doctor Murthy, Doctor uh Perano, uh laid out some of the ways in which we are overcoming the barrier and our teams are coming together to take care of the patients and um and provide them with all the support. Um Can you talk to us about some of the other uh characteristics or some of the other um methods that Mayo Clinic is instituting? So that we are providing a differentiated care for patients who are receiving car t cell therapy with us. Yeah. So I think this is something that we are. We've been as at Mayo Clinic, we've been very much uh on the front foot about trying to, trying to, to change the model of cancer care. And I, and this is something that is not just unique to Florida, but unique to all Mayo Clinic and, and, and some of the things we're trying to do is, you know, as we have become more comfortable with uh with the, with managing the cellular therapy, the the question comes, do we need to do, we need to hospitalize people so much and you know, maybe moving these treatments into the outpatient setting. And so that's something that we have, we have embarked on for not for car T as well as other immunotherapies. We, we are now a minute, we are now giving the, the car t we will infuse it in the, in the in the hospital. But then very early we will let the patient uh leave the hospital and we use remote with a program called remote patient monitoring where we monitor a patient's vital signs, we monitor them for toxicities in the comfort of their home. Now, imagine now a patient doesn't have to sit, they have to be hospitalized for, for 10 to 14 days and they can, you know, they can be managed while eating their own food, home, cooked food and sleeping in their own bed. So these are ways how we are trying to move this move uh treatment into a new, into a new uh into a new treatment paradigm where we can and and I think there is some implications for this. I think not patient satisfaction, quality of quality of care, quality of life and potentially uh cost uh cost uh benefit overall by, by reducing the amount of time that patients have to remain in the hospital. So far. They, we've this is this has been done in all three mayo sites and has proven to be safe and still maintain uh efficacy. So I see this expanding uh for, for the majority of our uh of our cellular therapy products and as an integral part of our cellular therapy program going forward. Excellent. Thanks a lot for pointing that out because certainly um our patients who are receiving their um uh car T cell therapy or um stem cell transplant, et cetera in their home setting and being monitored there, that's a huge quality of life improvement for them. And of course, also very significantly uh eases the burden on their caregivers. Um uh The, the next question uh which is coming from uh one of our audience. And actually, I would remind everybody to please pose your questions in the uh Q and A uh box so that we can ask our um panel to give their opinion about these questions. So uh with that, the uh one of the questions that has come, which actually, I'm going to pose to both Doctor Kan and Doctor Perano. Um There's an excellent question that when there are more than one and I'm going to paraphrase the question. So it's applicable both to myeloma and lymphoma. So uh Doctor Caravan first for you, when there are more than one products that are available for the same indication and the diagnosis, how do you help select, which should be the preferred agent for that patient at that time? What are the criteria keep in mind? So that is really an amazing question to which probably there is not uh 100% right answer. In my opinion, I think that there are many factors that play into this. Number one is the familiarity of the treating physician at the center with that particular product. Second, and and very important in, in, in my uh judgment, when I make this decision is really reliability of manufacturing, uh which product has the most reliable track record of manufacturing. Meaning uh when these products were approved for commercial use there is a set of requirements that the product has to meet before it can be released for, for administration uh to the patient. Uh among them would be things like viability, sterility and so on and so forth of the product. And, and obviously that all these products are subject to that type of quality control. But I would say that one important factor. Uh and I speaking from the lymphoma perspective is really the predictability of manufacturing. Uh what product has the lowest uh uh rate of of manufacturing failure that plays a lot. And also the predictability in terms in terms of timeliness of manufacturing, which product tends to have a much more sustainable track record of having timely manufacturing. And this is important because uh when a patient has failed several lines of therapy and you are waiting out there uh for this manufacturing uh every day counts. And uh there this could actually make it into the patient eventually receiving or not receiving the product at all. Just to remind uh those in the audience who may be familiar with this data. Uh In only most of the studies, there is around 10% of the patient who were intended to receive the product but never did because of the delays in manufacturing that eventually led to progression of the disease. Uh being one of the main reasons obviously in other reasons like patients changing their mind or so on, but but certainly progression of the disease is very important. Th this is a disease that is so uh difficult and refractory that every day counts. And, and I think that those are the criteria that I look at when, when I try to uh others are really the incidence of, of side effects. Uh some products have uh a little bit of higher incidence of neurotoxicity or uh uh cytokine release syndrome. And those uh I would say with time we have learned and become much better at and dealing with them. So, but it's kind of an interplay of all of those factors that really you make uh you eventually final decision on that. So um I'll ask you doctor Parada to maybe give us a little bit about how you select one of the two products in multiple myeloma. Yes. So it's a, you know, similar to what Dr Ken was saying, you know, in myeloma, we have two products, right? And if you look at the separate trials, right? Uh the uh Karma one trial and the cart one trial, you know, the the sil cell from the data from cart one of sil cell, you know, that appears to be a better car t right? But we cannot make that conclusion because the two products haven't been compared head to head, right? So what I what I use is, you know, the manufacturing times, right? Silt cell takes about eight weeks to manufacture IDA cell takes about four weeks, you know, it depends on the pa the pace of the patient's disease. You know, can they wait eight weeks for uh sil cell manufacturing, you know, if they're rapidly progressing, progressing and they cannot wait, you know, I will go with the IDA cell product because every patient deserves to get at least, you know, one type of BC MA directive therapy. So getting them to car T regardless of which one is the goal. So you use right? The the manufacturer as Dr Ken was saying the manufacturing times a side effect profile to tailor it to the specific patient. Excellent. Thanks both of you for giving us a good summary of that. Uh The other question that we're getting from the audience again, a very uh interesting question, Dr Murthy, I'm gonna uh hand this over to you. So you mentioned about how car T cell therapy is being developed and and um targets are being identified for solid tumors. But other kind of um uh convenience or an availability or a possibility for solid tumors is they're solid, can card T cells be injected locally for these solid tumors? So, more like an intralesional um administration uh is there data? What are your thoughts? So it is a it is a ve it's a very good question and one that is being looked at in clinical trials, I think one of the, one of the examples we know is that uh I believe mesothelioma they have done they have done this with direct injection of the car, of the car products uh into the plural space. But I think, you know, I think the question becomes, uh you know, most of the trials when we have these four car t have gone beyond single lesion. And, and that's where I think we're still trying to get a handle on metastatic disease. We need to show that these are truly effective in that setting. But there are certainly some aspects where people are looking at indirect injection. I would say mesothelioma is one. neuro neurologic is the other uh like such as GB M anything to inject directly into the, into the uh CNS area. But I think really um the major focus right now is uh 11 not only identifying the target but getting a handle on why on metastatic disease. And, and I do think, but there are studies that are looking at uh particularly, I think there is even one about uh using car key in a, in an application uh post, post op for on an on it. So the to, to for margin. So there's definitely uh a lot of innovation that is being thought of and out there. But I think right now in terms of major trials, the focus really is on metastatic disease right now. Excellent. Well, thanks a lot for that. Uh very well uh kind of summarized uh and, and a future looking um thought about car T cell therapy. So that will come to the end of this uh webinar. And I would really like to thank our panelists for participating in this very interesting and timely discussion and also to all our audience for uh tuning in listening and also sending some of their questions to be answered. Clearly, it has uh stirred an interest and obviously for our patients standpoint, all we want is to provide the right therapy and, and serve the needs of our patients at the right time. Uh I thank everybody and um uh I really appreciate uh your attending this.