SIKANDER AILAWADHI: Good afternoon. Thank you for joining us for the webinar today titled CAR-T cell therapy, current uses and future possibilities. I'm Dr. Sikander Ailawadhi, 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 Dr. Mohamed Kharfan-Dabaja, Vice Chair of Hematology and Director of Blood Marrow Transplant and Cellular Therapies in Mayo Clinic Florida. Dr. Ricardo Parrondo, a hematologist oncologist with Mayo Clinic in Florida. And Dr. Hemant 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.

CAR-T cell therapy does require a lot of claudication and a multidisciplinary team including, for example, CAR-T oncology, infectious diseases, neurology, ICU team, social work, coordinators, in addition to the hematologists who administer and manage the CAR-T cell therapy.

Because it requires a lot of coordination, 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 Dr. Kharfan, 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 selection or any other conditions that you look for while offering CAR-T cell treatment to the patient?

MOHAMED KHARFAN-DABAJA: So thank you and good afternoon, everyone. That's a great question. In fact, when we look at all the studies that have led to the approval of this CAR-T products in various hematologic cancers, there was not really a preset age limit.

So I would say that for diseases like diffuse large b-cell lymphoma, mantle cell lymphoma, or follicular lymphoma, as a matter of fact, in those cases, the limitation was more on the meeting the adult age group. So basically, 18 or older. But there was no preset limits for age.

So for us, what's more important is looking at the performance status of the patient, the organ function, and so on. We don't really disqualify patients purely based on chronological age.

SIKANDER AILAWADHI: Excellent. And are there any other patient conditions that would limit them from receiving CAR-T cell therapy in any general health conditions that you're looking for when you are considering a patient for this treatment?

MOHAMED KHARFAN-DABAJA: So yeah, that's another great question, Dr. Ailawadhi. I think what is important if one is to look at this is really looking at organ function. So for instance, does the patient have an adequate heart function?

We look at the minimum 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 situation like a decompensation of their heart condition and so on.

Also, we focus on the lung function of these patients to make sure that these patients are fit to move forward. And we also look at other functions such as the liver function, the kidney function. So we do really a very methodical and extensive workup to make sure that the patient is fit from that particular standpoint.

SIKANDER AILAWADHI: Excellent. Thanks for that comprehensive answer. Maybe I'll pose another question to you then. We hear that CAR-T cell treatment is a very complex process. 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?

MOHAMED KHARFAN-DABAJA: So definitely. First of all, the procedure can only be performed at centers that are certified to perform these procedures. And then, when the patient is deemed to be eligible for the procedure, there is a process what is called leukapheresis, which basically is procuring those lymphocytes in order to be able to manufacture the CAR-T.

That is a procedure which, basically, requires the patient to be connected to a machine called an apheresis or leukapheresis machine, typically, taking somewhere between 4 and 1/2 to 5 hours. And then, at the completion of that, those cells are shipped to the manufacturing facility that will certainly be manufactured in these products.

This process may take some time between 17 and up to 25 or 28 days at the latest. Then, the product is transferred back or shipped back to, in this case, Mayo Clinic Florida. And the patient will, at that time, be initiated with what we call lymphodepletion where we need to give a combination of chemotherapies to try to, in a way, open a space for these CAR-T cells to go and home and be able to exert the function that is asked of them.

So that is the step of the process. The lymphodepletion depending 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, the patient will go through a couple of days of rest. And the cells are infused on the subsequent days.

And this patient will be followed very closely in the hospital setting to make sure that the side effects that are anticipated are dealt with in a prompt manner.

SIKANDER AILAWADHI: Excellent. Thank you for that. Next, maybe I'll ask a question from Dr. Parrondo. Dr. Parrondo, you focus on multiple myeloma. What are the currently available CAR-T cell therapies for multiple myeloma?

RICARDO PARRONDO: Yes. Thank you, Dr. Ailawadhi. So there are currently two FDA approved autologous CAR-T cell therapies for multiple myeloma, and they both target a protein called BCMA on the myeloma cell surface. And one of those products is IDE Cell or Abecma, which is manufactured by Bristol Myers Squibb.

And the other product is cilta-cel or CARVYKTI, which is manufactured by Janssen. 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 CAR-T products.

So BCMA, 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 CAR-T, essentially, is we're phoresing the patient's T cells as Dr. Kharfan described earlier. And we're manufacturing them to express an anti-BCMA antibody on the surface of the T cell so that it can specifically target that BCMA protein on the myeloma cell surface.

And IDE Cell is a second generation CAR-T product, and cilta-cel is also a second-generation CAR-T product. But it binds to two distinct epitopes on the BCMA giving it more avidity or more ability to bind to the malignant plasma cell.

And these therapies, they continue to evolve. Right now, they're approved for four or more prior lines of therapy. But there is emerging data that we may-- it's also effective if you use it in earlier lines of therapy. So very exciting time for CAR-T and multiple myeloma and other diseases as well.

SIKANDER AILAWADHI: Excellent. Thanks for explaining that in detail. Dr. Kharfan, I'll go back to you with a question around lymphomas and CAR-T. So there are several different types of lymphomas. Can you touch upon which lymphoma types and what indications within each lymphoma type are CAR-T cell therapies available for?

MOHAMED KHARFAN-DABAJA: Sure. So there are several types of what we call B-cell lymphomas. Now, you may be familiar with, certainly, the B or the T cell type of lymphomas. In this particular case, all the lymphoma approved products target a cluster of differentiation called CD19, which is a B-cell marker. So that is pretty much what all these available products are targeting at the present time.

So for diffuse large B-cell lymphoma, there are three commercial approved products. And those were approved in the third line setting or beyond. So this patient must have failed two prior lines of therapy. And then, they basically were treated in that particular setting.

The first product that got approved for diffuse large B-cell lymphoma is called axicabtagene ciloleucel. And this product was approved based on a study known at the time as the ZUMA-1 study. The second product that was approved is tisagenlecleucel. And this product again, with similar indications, diffuse large B-cell lymphoma, whether transformed or what we call de novo, or original-- started as a large cell lymphoma.

And the third product is known as lisocabtagene maraleucel. And that also is another product. Now, based on that success, and to give you a little bit of assessing the dimension of this success is, typically, patients who have failed two or more lines of therapy with diffuse large B-cell 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, axicabtagene ciloleucel was able to yield a complete remission rate, which exceeded seven or eight-fold above that. So I would say before CAR-T, maybe 7% complete remission rate. After CAR-T, we are seeing in the ranges of 50 up to 55% or so complete remission rate. And that eventually translated into an improvement in what we call the overall survival.

Based on that success, then the second question was, well, can we use them at an earlier stage? And there were three randomized studies for diffuse large B-cell lymphoma one was known as the ZUMA-7. Another one was known as TRANSFORM. And the third one was known as the BELINDA study.

And ZUMA-7 showed a superiority to what is considered standard of care, which is a combination of a chemotherapy followed by autologous transplant versus the CAR-T. So axicabtagene versus standard of care was superior, and that led to the approval of axicabtagene ciloleucel in the second line setting.

And that was for patients who have failed to respond to the first line therapy or relapse after-- within a period of less than 12 months. So those are the patients that traditionally are known to have a very poor prognosis. And clearly, the CAR-T was superior for axicabtagene ciloleucel. And the same case was for lisocabtagene maraleucel based on the TRANSFORM study.

So these two products, axicabtagene ciloleucel and lisocabtagene maraleucel made it to that second indication. The third study known as BELINDA did not show a benefit for tisagenlecleucel, in this case, and 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 setting, which basically, as I mentioned, patients who have failed to respond to frontline therapy or have relapsed within less than 12 months.

There are the other disease for which there is an indication is called mantle cell lymphoma. And this, basically, is where patients who have relapsed disease or have refractory disease, meaning they have not responded to prior therapies. And the product here is known as brexucabtagene autoleucel, again, targeting CD19, showing impressive responses in those patients who have failed all therapies before.

The third indication in lymphomas is follicular lymphoma. And for this particular one, there are two products that are currently approved. One is axicabtagene ciloleucel. This was based on a ZUMA study, at the time known as the ZUMA-5 study, showing that patients who have failed the two or more lines of therapy for follicular lymphoma, those patients showed impressive response rate-- overall response rates of close to 90%. And certainly, durability of those responses three years later, more than 70% of these patients continue to be alive.

And certainly, the most impressive, I would say, is there is a group of patients with follicular lymphoma that tend to relapse within 24 months of initial treatment. It's called a POD24, or 24, and those patients actually-- the product demonstrated that it is effective even in that group of patients with-- has an aggressive-- more aggressive biology, perhaps.

The other product is tisagenlecleucel, which is also approved based on a study known as the ELARA study. Again, so we have those two products there. So those are the products that we have for a patient with the various types of b-cell lymphomas.

SIKANDER AILAWADHI: So thanks for pointing out all of those. And I do want our audience to know that, at Mayo Clinic, we are able to offer all of these products and all of the respective indications where they are approved.

Dr. Kharfan, you have talked quite nicely and extensively about lymphomas where these multiple products are available across various different diagnoses or lymphoma types. But a third disease area where CAR-T cell therapy is currently approved is acute lymphoblastic leukemia.

Can you tell a little bit about what specific indications for using CAR-T cell therapy in acute lymphoblastic leukemia?

MOHAMED KHARFAN-DABAJA: Sure. So the first product that was approved, again, for keeping in mind that same prior theme of CD19. So this same product axicabtagene-- sorry, brexucabtagene autoleucel, and the tisagenlecleucel have been approved for patient with acute lymphoblastic leukemia of the B-cell type. So obviously, the B-cell is-- those cells are the ones that tend to express that CD19 antigen on them.

So the first product approval actually, tisagenlecleucel, this was based on a-- the ELIANA study is what the name of the study was. And this particular study was geared towards a patient in the pediatric and young adolescent age group. So this product demonstrated that it was effective in patients who have relapsed or refractory B-cell acute lymphoblastic leukemia.

And that product, tisagenlecleucel, is currently approved for patients up to 25 years of age. So 25 years of age interpretation is really 25 year, 11 month, and 29 days. But subsequently, brexucabtagene autoleucel, based on the study known as the ZUMA-3 study, was also-- had proven 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.

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 or a very-- patient with very poor prognosis. So this is how, in my opinion, how effective and impressive these products are on those indications.

SIKANDER AILAWADHI: Excellent. Thanks a lot for pointing that out. Because as we started in the beginning or mentioned that CAR-T cell therapy has revolutionized our 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.

Dr. Murthy, I'll come to you for the next question. As Dr. Kharfan nicely laid out the importance of CAR-T cell therapy in ALL, we also know that Acute Lymphoblastic Leukemia, or ALL, is seen more frequently in the pediatric population.

Now, the more common acute leukemia seen in adults is acute myeloid leukemia. So what is the status of CAR-T cell therapy in this diagnosis?

HEMANT MURTHY: Thank you. It's an excellent question, Dr. Ailawadhi, and good evening, everyone. So in terms of acute myeloid leukemia, we have-- there are a couple of things that lend itself to be a little more difficult than the current indications that we have for other diseases, like lymphoma myeloma.

One being finding the right target for leukemia, 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 your abnormal blood stem cells, which are responsible for your normal healthy blood count. So finding a target has been a little bit difficult. But the second thing is that with the manufacturing time needed for CAR-T, many times, leukemia patients, especially with relapsed 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? And I think there are still other factors like the actual microenvironment that may contribute to the difficulty. Now, there are trials that are ongoing. 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 similar in style like the lymphoma, but they target a marker called CD33. And these are autologous or your own T cell that are being collected and then manufactured very similar to our commercially approved products.

Other options that are being-- other targets, CLL1 is another target that has-- that there are 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 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 we collected from donors or we don't need somebody's own natural killer cells.

This allows for us to be able to apply treatment faster when we-- and when we can still determine the appropriate target to harness-- to encode these NK cells and target leukemia cells. So I think there has been a significant amount of progress. Maybe still a little behind lymphoma, myeloma, and ALL. But I think there's certainly cause for optimism in the near future.

SIKANDER AILAWADHI: Excellent. Thanks for explaining all of those options that are coming on the horizon, especially in this diagnosis of AML that can be quite devastating in the relapse setting.

Dr. Kharfan, we mentioned in the beginning also that car-t cell therapy requires a lot of coordination between a community referring physician and the academic CAR-T administering center. And that's why we frequently 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 coordination planning, you mentioned the manufacturing times, et cetera.

But on the other end of the spectrum is when the patient has received the treatment and is now ready to go back, assimilate in their life. They're 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?

MOHAMED KHARFAN-DABAJA: Yes, so certainly, these patients after they have completed that process, and normally, we would like to keep them in the neighborhood 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 instruction that are coordinated between our center and that referring physician. So these patients, for instance, there is a restriction in terms of driving. They cannot be behind the wheel for at least eight weeks.

So that is, basically, one of the requirements. Second, during that process, a proportion of these patient may be requiring frequent blood testing to make sure that their blood parameters are within desirable range. So this patient could have what we call pancytopenia, requiring sometimes blood or platelet transfusions, and in some cases, also what we call growth factor to increase their 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 patient developing infection. So it's very important that the patient continue on what we call prophylactic antimicrobials. So they will have to be on certain antibiotics or antivirals for a particular amount of time.

Also, this patient will require looking at some 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 the referring physician back and forth.

And there will be also the process of assessing for response of these treatments. So we'll have to, after a certain time, for instance, in our center we like to do the radiologic evaluation at one month and then at-- subsequently to make sure that there is a response.

Typically, the prognosis of these patients or the future outcomes, I would say, is very important that there is a demonstration of a complete remission as early in the post CAR-T phase as possible. So if a patient, for instance, did not achieve a complete remission on the first 30 days, that is a group of patients that we would like to repeat another PET scan within four weeks of that. So what I call day 60 to make sure 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 patients do not achieve these early responses, they will be more likely than others who do to have, eventually, relapse or progression of the disease. So it's very important because we need to act and we need to act immediately if that's the case.

So there is, as you can imagine, a lot of coordination between our center and those referring centers to make sure that all of those things are performed in a prompt manner.

SIKANDER AILAWADHI: Excellent. And we do provide a lot of that information back to the referring physicians at the time of the patient's transfer. So we really want those referring physicians to be a partner in managing that patient because it's extremely important.

Dr. Parrondo, Dr. Kharfan mentioned about what criteria are-- typically need to be met before a patient can be sent back to their referring physician and to where they came from.

But when we are getting the patient through CAR-T cell therapy and its treatment, 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 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 that is needed?

RICARDO PARRONDO: Yeah, so those are very good questions. The main toxicities of the currently FDA approved BCMA CAR-T cell therapies for multiple myeloma include cytopenias, infections, and then, the main one that we watch out for-- one of the main ones is a cytokine release syndrome, which is an acute systemic 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. When those T cells start to expand, they release other inflammatory proteins known as cytokines, which further activate the CAR-T cells, expand the CAR-T cells. It activates other T cells, macrophages, endothelial cells. So it's sort of like an inflammatory chain reaction that can happen when you infuse the CAR-T cells that we monitor for.

Another toxicity is neurologic toxicity, known as ICANS, or Immune effector Cell-Associated Neurotoxicity Syndrome, which can manifest as headaches, confusion, language impairment, fine motor impairment, and even seizures. Patients can have any of those symptoms. And it's due to the expansion of the CAR-T cells and the release of these cytokines, which disrupt the blood-brain barrier, allowing inflammation into the central nervous system.

And with a CRA, Cytokine Release Syndrome and IECANS, 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, we use a drug called tocilizumab which neutralizes a cytokine known as IL6, which is a key cytokine leading to the inflammation that causes CRS. It's basically an antibody that will neutralize IL6.

And then, for the IECANS, or the neurologic toxicity, we have anakinra, which is an IL1, another cytokine receptor antagonist. And we also have corticosteroids, which help-- lead to the resolution of this toxicity in patients with multiple myeloma.

I mean, 95% of patients who receive CAR-T cell therapy anti-BCMA CAR-T cell therapy will have low grade cytokine release syndrome and IECANS. Only a small percentage will have severe toxicity. But it is very manageable and treatable.

And then, regarding when we send the patient back to the community oncologist, what do we do? Dr. Kharfan mentioned a lot of it. And I'd like to say it's similar to the stem cell transplant algorithm-- the autologous stem cell transplant algorithm for multiple myeloma patients.

So one of the things to monitor for is the cytopenias. The patient may be cytopenic for some time after the CAR-T due to the CAR-T itself and the lymphodepleting chemotherapy they receive. They may need transfusion support, so you have to check labs multiple times a week.

We may have to use growth factors, like G-CSF or erythropoietin stimulating agents. And if the cytopenias are persistent after 100 days, luckily, 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 replenish the bone marrow and lead to the resolution of cytopenias.

And then, another toxicity to monitor for are infections. The patients have to continue on viral prophylaxis for at least a year. PCP prophylaxis until day 100. The CAR-T causes B-cell and plasma cell aplasia. And the patients will have hypogammaglobulinemia. They're going to need IV/IG 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-- to be revaccinated again because the lymphodepleting chemotherapy may have wiped out some of their immunity to diphtheria, hepatitis B, for example.

SIKANDER AILAWADHI: That's excellent. Thanks for pointing out all these side effects that can happen. But as you rightly mentioned, it's important for our patients and our physician partners to keep in mind that, in majority of the cases, the side effects are low 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 majority of the cases, these side effects do not become advanced grade. So thanks for pointing that out.

I'll ask you another follow-up question regarding multiple myeloma and CAR-T cell therapy. So we've heard about, obviously, these excellent treatment options. They require coordination 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 the CAR-T cell therapy improved the outcomes or clinical outcomes of patients with multiple myeloma?

RICARDO PARRONDO: Yeah, so that is a key question. CAR-T has tremendously improved the clinical outcomes of multiple myeloma patients. So in the space that CAR-T is approved, after four or more prior lines of therapy, patients are what's called triple class refractory. Refractory to a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.

Or their pentarefractory, meaning they're refractory to the five main myeloma agents that we use, lenalidomide, and pomalidomide, which are immunomodulatory drugs, bortezomib, and carfilzomib, which are proteasome inhibitors, and daratumumab or isatuximab, which are anti-CD38 monoclonal antibodies.

So that group of patients, which by the time you get to four or more prior lines of therapy, almost all of them have had all of those drugs and have progressed after receiving those drugs. They had quite a dismal prognosis rate in the range of six to nine months.

But in that patient population, the patients treated with ide-cel or cilta-cel CAR-T, the median progression free survival ranges anywhere from 11 months with ide-cel to almost 35 months with cilta-cel. And the overall survival is even longer than that.

So in this pentarefractory 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 tremendously improved the survival outcomes of these patients.

SIKANDER AILAWADHI: Excellent. And I think, in a lot of cases, CAR-T cell therapy for 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 FDA approved for subsequent therapy.

Now, we've talked a lot about the hematologic malignancies, lymphoma, B-cell lymphomas, B-cell ALL, and multiple myeloma where CAR-T cell therapy is available. But frankly, solid tumor malignancies are, overall, much, much more common than these hematologic malignancy diagnoses.

So Dr. Murthy, I'll pose this question to you. What is the current or future role of CAR-T cell therapy in solid tumor malignancies?

HEMANT MURTHY: I think it's a great question. And I think we're still learning about that. Similar to the AML 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. It is a different environment for a CAR-T to navigate from a microenvironment standpoint than, say, multiple myeloma or lymphoma.

So there are some novel techniques that are being studied and investigated. We know that there are some trials that are actually looking at HLA heterozygosity, basically, to make sure that there is a difference between normal tissue and the tumor tissue.

And this way, then making a stronger car that will selectively not touch the normal tissue. So that is an interesting concept that is being investigated in different solid tumors. Other techniques is to use interleukin therapy and different encoding of the CAR-T in order to allow it to fight-- to persist long enough to have more effect on the metastatic disease.

We've seen early trials that are ongoing for breast cancer. We see trials that are ongoing for colon, colorectal, lung. So I think there is certainly some opportunity-- there is certainly some excitement there. I'd like to also add that another thing similar to AML when we talked about using natural killer cells, there are trials that are using other immune cells, such as monocytes and macrophages, which may traffic into the tumor site.

So trying to encode and 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 preclinically or very early in clinical trials.

And I think there have been some promising early results. I'd say, renal cell carcinoma has been one that has had some promising early results. And I think there's still more to come down-- in the coming future.

SIKANDER AILAWADHI: Excellent. Thanks a lot for pointing that out because that tells us that the future horizon is much brighter. And frankly, patients across the spectrum of different cancer diagnoses can hope to benefit from these advancements and the CAR-T cell therapy has to offer.

Dr. Murthy, I will ask another question of you, the next one. Being that we have heard that at least with the currently available CAR-T cell therapy, some of the barriers can be-- the CAR-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 educate us. Is there anything on the horizon to help overcome some of these barriers?

HEMANT MURTHY: It's a great question and something that we have struggled with sometimes diseases that are rapidly growing. Sometimes, these are barriers to getting people to CAR-T therapy. So I think two approaches have really been looked at. I think the first approach was seeing, do we need to manufacture our own cells? Can we use someone else's T cells?

And with the advent of gene editing-- or gene editing processes, we were able to actually edit T cells in order for the CAR-T to come from a donor but not give the toxicity that may come from introducing a donor cell such as something we encounter in bone marrow transplant called graft versus host disease.

So that is one option that has been and being studied in a number of trials. Some of the drawbacks have been that we have not seen these cells maybe last as long as some of the autologous cells. So I think there is still work to be done in this space to try to get even comparable-- even if we are able to get similar results to autologous, the difference in the time makes a difference.

Now, more recently, we've seen that many of these CAR-T manufacturers have developed faster manufacturing. One that was recently published by Michael Dickerson from Australia was about T charge, from-- and with a very rapid manufacturing of the Novartis product. And in that case, the manufacturing was as short as 48 hours and the CAR-T product was available in about five days.

Now, the importance of this is that also seeing how long the T cells from collection to manufacturing, these T cells had increased stemness and may make them more potent than if it takes a long time 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 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.

SIKANDER AILAWADHI: Excellent. Thanks a lot for pointing out. Dr. Parrondo, I'll ask you the next question. So what are some of the barriers that patients seeking CAR-T cell therapy can face generally. I mean, we know that Dr. Kharfan laid out that there are certain centers that are able to provide this treatment and the centers have to be appropriately certified.

So I can imagine patients across the country would have some barriers that they may face. So if you want to mention some of those barriers that patients seeking CAR-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?

RICARDO PARRONDO: Yes, so the main barrier that exist for CAR-T cell therapy is the limited availability of the product, right? It's not available on the spot. It's an off-the-shelf product. And there's only a certain amount of slots allotted to a medical center for CAR-T per month.

So due to that limited availability, it can lead-- that's one of the biggest barriers that patients have to overcome to get CAR-T. And 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.

And then, when you actually get through the door, you have to evaluate the patient, do vital organ testing, you have to stage the disease with the bone marrow biopsy, you have to do the T cell collection and pheresis. And then, the manufacturing process is a little bit longer for the myeloma CAR-Ts. It can take between four weeks for ide-cel and up to eight weeks for cilta-cel.

And sometimes, patients are relapsing if they've exhausted all therapies and they have very aggressive disease like extramedullary disease or rapidly progressive disease. They may not survive long enough to get the CAR-T. So those are some of the main barriers that patients face when they are looking to get CAR-T.

But Mayo clinic is doing many things to overcome these barriers so we-- and so are the companies that manufacture the CAR-T products. So we've recently increased our pheresis capacity. So we're able to pheres more patients per month to get more patients to CAR-T.

We're able to expedite the workup, the vital organ testing, the restaging of the disease. Most of the time, between one to two weeks, we can get all of this testing done for the patients. And then, as Dr. Murthy mentioned, the science of CAR-T manufacturing is improving, right? The manufacturing capacity is increasing. They're developing faster ways to develop-- to manufacture the CAR-T product.

They're devising ways to increase the persistence of the CAR-T, right? Because as of now, with the currently available products, over time, the CAR-T product may dwindle, it may not persist. And you want that CAR-T product to persist to continue to attack the disease of interest.

And then, what I always recommend to community oncologists and even myself with my own patients is early referral for CAR-T. In myeloma, by the time the patient is reaching that third-- starts third line of therapy, start referring the patient to CAR-T so we can start future planning. The patient is already in the door. We know the patient. And we start thinking of bridging therapies, right?

If the patient has very aggressive disease or is relapsing, you need a treatment to keep the disease at bay while the CAR-T is being manufactured, right? So all of that takes a little bit of time and thinking, right? So we want to get ahead of it and do it early.

So those are the main things that-- the barriers to CAR-T and the things that Mayo Clinic and the CAR-T companies are doing to help overcome these barriers.

SIKANDER AILAWADHI: Excellent. And think I mentioned in the very beginning that a multidisciplinary team comes together at Mayo Clinic to help that patient 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 frankly, if any of those side effects occur, all of those facilities, all of those team members are available to take care of the patient. And I think I should also point out that the role that our navigators or coordinators or our social workers play in overcoming some of those non-clinical barriers that the patients may have, sometimes helping them out with-- figuring out their caregiver support, 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 burdened with during the treatment

I'll pose another question to Dr. Murthy. So Dr. Murthy, Dr. Parrondo 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 provide them with all the support. Can you talk to us about some of the other characteristics or some of the other 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?

HEMANT MURTHY: Yeah, so I think this is something that we are-- we've been-- at Mayo Clinic, we've been very much on the front foot about trying to change the model of cancer care. And this is something that is not just unique to Florida, but unique to all Mayo Clinic.

And some of the things we're trying to do is, as we have become more comfortable with managing the cellular therapy, the question comes, do we need to hospitalize people so much? And maybe moving these treatments into the outpatient setting.

And so that's something that we have embarked on for-- not for CAR-T as well as other immunotherapies. We are now giving the CAR-T-- we would infuse it in the hospital. But then, very early, we will let the patient leave the hospital. And we use remote-- a program for remote patient monitoring where we monitor a patient's vital signs, we monitor them for toxicities in the comfort of their home.

Imagine now a patient doesn't have to sit-- have to be hospitalized for 10 to 14 days. And 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 treatment into a new treatment paradigm where we can-- and I think there is some implications for this.

I think patient satisfaction, quality of care, quality of life, and potentially, cost benefit to overall by reducing the amount of time that patients have to remain in the hospital. So far, this has been done in all three Mayo sites and has proven to be safe and still maintain efficacy.

So I see this expanding for the majority of our cellular therapy products and as an integral part of our cellular therapy program going forward.

SIKANDER AILAWADHI: Excellent. Thanks a lot for pointing that out. Because certainly, our patients who are receiving their CAR-T cell therapy or 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 eases the burden on their caregivers.

The next question, which is coming from one of our audience. And actually, I would remind everybody to please pose your questions in the Q&A box so that we can ask our panel to give their opinion about these questions.

So with that, one of the questions that has come, which actually, I'm going to pose to both Dr. Kharfan and Dr. Parrondo. This is 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 Dr. Kharfan, 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 you keep in mind?

MOHAMED KHARFAN-DABAJA: So that is really an amazing question to which probably there is not 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 and the center with that particular product.

Second, and very important in my judgment when I make this decision, is really, reliability of manufacturing. Which product has the most reliable track record of manufacturing, meaning 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 administration to the patient.

Among them would be things like viability, sterility, and so on and so forth of the product. And obviously, that all these products are subject to that type of quality control. But I would say that one important factor-- and I'm speaking from the lymphoma perspective-- is really the predictability of manufacturing. What product has the lowest rate of manufacturing failure. That plays a lot. And also, the predictability 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 when a patient has failed several lines of therapy and you are waiting out there for these manufacturing, every day counts. This could actually make it into the patient eventually receiving or not receiving the product at all. Just to remind those in the audience who may be familiar with this data, in probably most of the studies, there is around 10% of the patients who were intended to receive the product but never did because of the delays in manufacturing that eventually led to progression of the disease being one of the main reasons.