Ask the CAR T-cell Experts

Transcript:

(00:00:01) Moderator: Good evening. Welcome to BMT InfoNet's Ask the CAR T-cell Experts webinar. My name is Michala O’Brien, and I will be your moderator this evening.

(00:00:45): It's now my pleasure to introduce our panelists. Dr. Diana Cirstea is a hematologist-oncologist at the Mass General Brigham Cancer Institute, a faculty member at Harvard Medical School, and part of the MGB Cancer Institute Multiple Myeloma Program. She's an expert in CAR T-cell therapy for patients with multiple myeloma.

(00:01:08): Dr. Jay Spiegel is an assistant professor at Miami Miller School of Medicine and a hematologist in the Transplant and Cellular Therapy Division of the University of Miami Sylvester Comprehensive Cancer Center. He's an expert in CAR T-cell therapy for patients with B-cell malignancies such as lymphoma.

(00:01:28): Margaret Franzetti is a licensed clinical social worker specializing in supporting individuals and families affected by blood cancers, with a focus on survivors of CAR T-cell therapy. She currently facilitates BMT InfoNet's CAR T-cell therapy online support groups.

(00:01:45): Let's begin with questions we've received about what's involved in undergoing CAR T-cell therapy. Please describe the steps involved in undergoing CAR T-cell therapy.

(00:02:04) Dr. Spiegel: Sure. To begin, I'll provide an example of a patient with lymphoma. So, if your lymphoma physician determines that your lymphoma has relapsed after one or several lines of therapy, depending on the type, and that you qualify for CAR T therapy, if that physician can give CAR T therapy, they will initiate the process. However, sometimes they will refer you to either an academic center or a colleague in the transplant or cellular therapy division to begin the CAR T process. So, there might be some time before you see a physician who's able to prescribe the CAR T therapy.

(00:02:45): Once you meet that physician, that physician will have to submit for insurance approval before we're able to go forward with CAR T. Depending on the center that you're at, that can take a short time or a long time. I would say about two to four weeks.

(00:03:03): If there's some lag time before you see the initial physician, some insurance lag time, it might be close to a month before you undergo the first step to make the CAR T-cells.

(00:03:20): CAR T-cell therapy requires taking your own T-cells from your body with a procedure called leukapheresis, using a machine that looks like a dialysis machine. The patient will need placement of either two peripheral IVs or a central line, which is done as an outpatient procedure.

(00:03:43): It takes four to six hours to collect the cells, which are then sent to a company that will then make the T-cells into CAR T-cells. It can take three to five weeks to manufacture CAR T-cells, depending on whether they are for lymphoma or myeloma. During that time, if you have a disease that needs therapy, your physician will give you either chemotherapy or perhaps some targeted therapy.

(00:04:11): When the CAR T-cells are ready, your center will bring you back for lymphodepleting chemotherapy, which is done in the outpatient setting. This is to prepare your body for the infusion of CAR T-cells. It typically involves three days of chemotherapy, usually consisting of fludarabine and cyclophosphamide, which are administered approximately five days before the CAR-Ts are infused.

(00:04:38): When the lymphodepleting chemotherapy is done, you will have the CAR T-cells infused into you either in the inpatient or outpatient setting. So, all in all, from the time someone decides you need CAR T therapy until infusion, it's about two months, give or take.

(00:04:59) Moderator: What are the most frequent side effects of CAR T-cell therapy? And how long do they last?

(00:05:07) Dr. Spiegel: I'll focus on the more acute toxicities. The first is cytokine release syndrome (CRS). When you have the flu, for example, you typically feel pretty terrible, with fever, chills, and muscle aches. That's actually your immune system working to eliminate the virus. Similarly, when we infuse CAR T-cells into a patient, they target the disease and release the same chemicals that your body releases when fighting the flu. Those are called cytokines, and they can cause fever and make you feel quite sick.

(00:05:44): Cytokine release syndrome typically manifests as a fever, but can also present with other symptoms, such as low blood pressure. In really severe cases, which are rare, some lung damage can occur, requiring patients to go on a breathing machine. That happens less than 5% of the time, maybe about 1% to 2% of the time, typically within the first two to five days after the cells are infused.

(00:06:10): Those same cytokines can also go to the brain and cause neurotoxicity. When people read about CAR T-cell therapy, it's the neurotoxicity that worries them the most. This typically occurs several days after the onset of cytokine release syndrome. It can happen concurrently, but usually several days after, so maybe a week after the cells are infused.

(00:06:34): Neurotoxicity can manifest in a variety of ways. Grade 1 neurotoxicity is just some confusion. We will ask you several questions repeatedly, and if you miss some of those answers, such as what today’s date is, you may be experiencing grade 1 neurotoxicity.

(00:06:54): Grade 2 neurotoxicity is usually difficulty talking. It may appear to be a stroke, but it is not a stroke. It's a difficulty with attention or word-finding.

(00:07:05): Higher grade 3 neurotoxicity can cause difficulty staying awake, what I like to call, "Lights on, nobody home." The patient is awake and in bed, but not tracking or interacting with the outside world. It can also cause a seizure.

(00:07:23): Grade 4 neurotoxicity can be either multiple seizures or a coma.

(00:07:28): The incidence of these toxicities depends on the disease you're treating as well as what type of CAR T product is selected. In general, the rate of cytokine release syndrome is in the 50% to 90% range, while neurotoxicity for the axi-cel type of CAR T-cell therapy is in the 20% to 25% range, and 10% for the 4-1BB CARs in lymphoma. With the myeloma CARs, there is much less severe neurotoxicity.

(00:08:16) Moderator: How long is a patient hospitalized for CAR T therapy? And can it be done as an outpatient procedure?

(00:08:24) Dr. Spiegel: I'll answer that backwards. Yes, it can be done as an outpatient procedure. It really depends on the center. For example, here at my center, we do most of our CARs inpatient. Given where our patients are coming from and their caregiver status, it is often easier for us to admit them.

(00:08:47): I think most centers are trying to move to an outpatient model. Patients like it better if you're at home and not stuck in the hospital. That said, patients can start off in the outpatient setting, but if they get cytokine release syndrome, they will often be admitted to the hospital. So, even if you start outpatient, you oftentimes will end up inpatient.

(00:09:14): Inpatient typically used to be for a minimum of seven days. If you're starting outpatient, that might be a tad less, but on the whole, it's a minimum of seven days and typically about 10 days, at least at my institution.

(00:09:33) Moderator: Dr. Cirstea, how long do CAR T-cells survive in the body?

(00:09:56) Dr. Cirstea: In multiple myeloma, the duration of CAR T-cells in the body varies by product and by patient. Generally, it ranges between a few months and several years.

(00:10:10): We have two CAR T products that are FDA approved for multiple myeloma: cilta-cel (CARVYKTI) and ide-cel (ABECMA). Cilta-cel CAR T-cells can be detected up to two to three years in some patients. Ide-cel CAR T-cells are usually detected for a shorter period of time, typically around three to 12 months.

(00:10:34): I know that we will be talking later about the new product, anito-cel. This is a new BCMA CAR T product for myeloma patients. It has also demonstrated persistence beyond one year.

(00:10:55): The efficacy of CAR T for myeloma does not always depend on how long the CAR T cells persist in the patient’s body. We have patients in whom CAR T-cells are not detectable after a few months, yet the patients are in a deep, sustained response.

(00:11:18): So, one of the main factors in multiple myeloma, in terms of CAR T efficacy, is the deep response achieved early on with CAR T treatment, rather than persistence.

(00:11:37) Moderator: How many times can a patient get CAR T-cell therapy if they go out of remission?

(00:11:43) Dr. Cirstea: That's a wonderful question, and I know my answer may not be relevant in even a few months from now. Currently, you can only have one of the two CAR T products that we have commercially available for myeloma: cilta-cel (CARVYKTI) or ide-cel (ABECMA).

(00:12:16): However, the rule doesn't necessarily apply to investigational CAR T-cell products. For example, some patients received cilta-cel or ide-cel as part of a clinical trial, before it was approved for commercial use. If a patient relapsed after those products became commercially available, they could get either cilta-cel or ide-cel, depending on what they received before, and have a response to that.

(00:13:02): I have a patient who received ide-cel as part of a clinical trial. The patient was in remission for about a year or so before they relapsed. And by the time they relapsed, cilta-cel was approved, so they were able to get cilta-cel and went on to have another remission of over a year.

(00:13:23): The other scenario is that after relapsing, you may be offered an investigational CAR T product on a clinical trial. That usually happens when clinical trials are available, testing a CAR T that targets a different receptor, a different protein on the myeloma cells.

(00:13:50): For example, let's say you received one of the BCMA products, ide-cel or cilta-cel, had some response, and later relapsed, and there is a clinical trial testing a GPRC5D-targeting CAR T product, such as arlo-cel. We have that available here at Massachusetts General Hospital So, patients who relapsed after ide-cel or cilta-cel can now be on this trial with the GPRC5D-targeting CAR T. While it's not a standard practice at the moment to have a second CAR T-cell therapy, I do think that in the future we'll have that option.

(00:14:39) Moderator: Is it safe to get vaccinated for COVID, flu, and RSV after CAR T? What else can I do to avoid infection?

(00:14:50) Dr. Cirstea: Yeah, wonderful question. It is generally safe to get vaccinated and is actually strongly recommended, even though the immune response to the vaccine may be suboptimal after CAR T. A study found that 31% of infections after BCMA CAR Ts were preventable. That highlights the importance of getting vaccinated.

(00:15:19): We usually recommend vaccination for COVID and flu about one month following CAR T-cell therapy. The International Myeloma Society has created guidelines for the prevention of infection, and those include pre-infusion screening for various viral infections, like HIV, hepatitis, and often COVID. Once you get the CAR T, you have to be on antivirals to prevent herpes simplex or zoster and on prophylaxis for pneumocystis pneumonia.

(00:16:12):  Many of you are probably familiar with intravenous immunoglobulin (IVIG), which plays an important role in supplementing your immune system after CAR T.

(00:16:23): A very common complication of CAR T-cell therapy is hypogammaglobulinemia [low levels of immunoglobulins in your body to fight infection]. So, an important part of supportive care is supplementing your immune system with IVIG, which we often do every month, sometimes, regardless of the IGG level. It depends on what your insurance covers.

(00:16:51): And then, the basic things: minimize your exposure to infections, follow good hygiene, avoid sick people, and consider prophylactic antimicrobials if your neutrophils are low.

(00:17:07) Moderator: Next question is for Ms. Franzetti: How long does a patient need a 24/7 caregiver after CAR T-cell therapy? And what specifically are caregivers expected to do?

(00:17:21) Ms. Franzetti: Great question. It depends on where you are being treated. For a long time, the FDA had a program called REMS, which established a national guideline for what they considered safe. It used to be very strict in terms of the monitoring and in terms of how long you needed a caregiver and couldn't drive. Those guidelines changed and were relaxed in June of 2025.

(00:17:55): There are also official instructions determined by the pharmaceutical company for each product, which may vary from the federal guidelines. Those instructions may require patients to be closely monitored for two weeks or four weeks.

(00:18:14): In the end, regardless of what the pharmaceutical company requires and the federal guidelines say, it's a matter of what your institution says. Depending on where you receive your care, the hospital has its own set of policies. Some institutions may say, "You need a full-time caregiver for 28 days after the infusion of your CAR T-cells." Others might say, "No, you only need one for two weeks." Therefore, speak with your healthcare team and understand that the recovery time can vary between two and four weeks.

(00:18:49): When it comes to what a caregiver actually does, they are really your safety partner in the process. Their job is not to provide you with medical care, but to be your eyes and ears to notice if you develop any confusion, trouble speaking, or fevers. If they notice any of these or other symptoms, they need to contact your healthcare team on your behalf.

(00:19:34): Caregivers also assist with transportation for as long as you're unable to drive after treatment. They're also there to remind you to stay hydrated and to engage you in things that bring you joy, whether it's watching a TV show or reading a book. They're there to engage, support, and encourage you.

(00:20:03) Moderator: I live alone and lack social support. I may not be able to find a caregiver. How have others dealt with this situation?

(00:20:12) Ms. Franzetti: You're definitely not alone. Many patients face this. Not everyone has a spouse, partner, or family member nearby who can fly in and step into that role. I've seen many patients get creative. At most CAR T centers, you will have a social worker, like me, available to you. They're there to help you get creative. If you don't have a social worker available, a nurse navigator will be available to assist you⠀.

(00:20:47): So getting creative may be leaning on a family member who can give you a handful of hours per week, and then leaning on a neighbor who can give you another handful of hours. Of course, we want you to minimize your exposure to different people while you are in that vulnerable state after treatment. However, it is sometimes like putting pieces of a puzzle together.

(00:21:14): Some individuals hire a home health aide for a specified period of time. Depending on the type of insurance you have, home health care may be covered by your insurance. However, that is usually very limited and typically only available through state insurance programs. Even then, it's not a full-time caregiver. 

(00:21:46): The most important piece of advice is to reach out to your social worker or your team and ask, "Are there different ways to problem-solve here?" They can help you lean on community-based organizations and volunteer organizations. These options are limited, but some are available depending on your location.

(00:22:10) Moderator: The next question concerns resources. At BMT InfoNet, we have a Caring Connections program that provides peer support. What other resources are available to help CAR T-cell therapy patients and caregivers with expenses?

(00:22:26) Ms. Franzetti: I'm a big fan of peer support resources. BMT InfoNet's Caring Connections program, as well as similar programs at Blood Cancer United (formerly known as Leukemia & Lymphoma Society), Cancer Hope Network, and a bunch of different community-based programs can help connect you with another patient who's been through CAR T. It could be someone around the same age, who had the same diagnosis, and had the same CAR T product. You can ask, "Hey, how did you feel after treatment? What were the guidelines from your institution? Did you have trouble finding a caregiver? And how did you find financial assistance?" Learning from those peer connections can be really helpful.

(00:23:17): Financial assistance resources for caregiving support are limited.  In some cases, you may need to think about them as robbing Peter to pay Pau.  There are lots of organizations that will provide general financial assistance, such as Blood Cancer United. They have a patient aid program. It's available one time only. It's $100, which isn't much, I understand that. But you could put that money towards the home health agency and pay for a caregiver or just help offset the overall financial burden of treatment.

(00:24:08): Some states have a program called Family Leave Insurance. I believe there are only 12 states with that. You can Google to find out if your state has Family Leave Insurance. If your caregiver is working and needs to take time off to be your caregiver, they may be eligible for Family Leave Insurance. It would be only a portion of their typical salary, but that could help with the cost of being out of work for some time.

(00:24:44): Additionally, your institution may offer some level of support. And, of course, BMT InfoNet has a really great financial assistance program that, depending on available funding, you can apply for. The only thing with that program is that you won't be able to apply until the day that you receive your cells. So, it would essentially be a reimbursement you could use for money you spent out of pocket for things like a caregiver.

(00:25:22): And then, the last thing to know is that the pharmaceutical companies have support resources. The programs offered by pharmaceutical companies do not provide financial assistance for the cost of a caregiver. However, they can help with the cost of transportation, meals, and lodging. It varies based on your eligibility.

(00:25:47): The best thing to do would be to reach out to your care team and ask, "Hey, are there any resources available to me?" Reach out to bigger organizations like BMT InfoNet, the American Cancer Society, and Blood Cancer United, and ask, "Do you know of any resources available?

(00:26:03) Moderator: Are there support groups for CAR T-cell patients?

(00:26:12) Ms. Franzetti: Currently, BMT InfoNet offers an online support group for CAR T patients. It is the only one in the country that's advertised, which is really, really exciting. I've been the facilitator for that group. We've done four six-week groups, and it is the most engaging and warm network. I'm sure we will do another group soon.

(00:26:54): I recommend contacting your oncology social worker or your nurse navigator to see if they're aware of any CAR T support groups in your area. If there aren't, you could also do individual peer support through BMT InfoNet’s Caring Connections program, or through Blood Cancer United's Patti R. Kaufmann peer support program. 

(00:27:29): There are also some online forums. I always caution people to be careful with those forums. You want to ensure that you search for a support forum sponsored by a reputable organization that includes a moderator, rather than just a Facebook group. I've heard stories from patients about problems with Facebook groups that lack any monitoring.

(00:27:57): The best part of having a support group is that you're able to share and find encouragement as well. So, having some level of structure around that is what helps to make the group thrive.

(00:28:30) Moderator: Our next questions are about CAR T-cell therapy for patients with multiple myeloma. I have multiple myeloma, and I'm on maintenance therapy. Should I consider CAR T-cell therapy now, or wait for new developments in CAR T-cell therapy?

(00:28:45) Dr. Cirstea: I don't think there is a one-size-fits-all answer here. It's essential to review the labels for the two CAR T products we have approved for multiple myeloma: cilta-cel and ide-cel. Why? Because initially, both were approved for myeloma patients who relapsed after four lines of treatment. But now, based on two phase 3 trials called KarMMa-3 and CARTITUDE-4, ide-cel and cilta-cel are approved for patients who relapse earlier in the course of treatment. So, patients who relapse on lenalidomide after one line of treatment may receive cilta-cel. Ide-cel has been approved after two lines of treatment for patients who received daratumumab, Velcade, and Revlimid.

(00:29:43): None of these labels include maintenance. So, you'd have to have some sign of relapse. It doesn't have to be a clinical relapse, meaning it could be just a biochemical relapse, such as when the M protein starts going up, or light chains start going up. That would be a reason to consider CAR T.

(00:30:07): So, should you consider CAR T in early relapse as opposed to later on? Should you consider some other standard of care options? I believe that, based on clinical trials and real-world data, we now have substantial evidence suggesting that it's better to use CAR T therapy earlier in the course of the disease. And it's not just because of the encouraging efficacy that was seen in those CARTITUDE-4 and KarMMa-3 trials, but because early on, your T-cells are fitter and more robust, and there is a greater chance that you'll get a healthier, more robust CAR T product.

(00:30:55): Another factor to consider is that you have a little bit more bone marrow reserve at the beginning of treatment. Once you are through a few lines of treatment, one of the complications is persistent bone marrow suppression.

(00:31:12): However, there is always a caveat: based on our cumulative experience, we have learned that there are certain side effects, specifically with cilta-cel, such as delayed neurotoxicity and second primary malignancies. That's a question that often arises. Are you ready to take that risk?

(00:31:38): And this is why it's so important to sit down with your oncologist and think about the risks and benefits, and decide for yourself how much risk you are ready to take. Obviously, the success rate with either cilta-cel or ide-cel is significant and could offer a remission for many years. We know that in the CARTITUDE-1 study, at least a third of patients were in remission for over five years, which is pretty amazing.

(00:32:18) Moderator: I had a stem cell transplant for myeloma, which wasn't successful. I didn't achieve remission. Is CAR T therapy likely to get me into remission?

(00:32:28) Dr. Cirstea: So, when I see patients who had a suboptimal response to transplant or an early relapse after transplant - within a few months, six months, even 18 months - those are considered features of high-risk disease. And what we've learned so far is that both cilta-cel and ide-cel have a pretty strong potential to induce deep responses in patients with high-risk disease when compared to standard of care regimens at the same stage of myeloma.

(00:33:09): Another trial, called the KarMMa-2 trial, looked at whether having ide-cel after transplant in patients who had a suboptimal response would bring those patients into remission and keep them in remission. What we learned is that those patients who didn't respond well to transplant actually achieved an 87% overall response with ide-cel, and 77% were complete responses, which is pretty amazing in patients with high-risk disease. The median progression-free survival, which is the period during which you remain free of disease, was not even reached after nearly three years of follow-up. So, that's pretty encouraging. Basically that tells us that yes, ide-cel for patients who either had a suboptimal response or a biochemical relapse after transplant is a very solid therapeutic option.

(00:34:36): With cilta-cel, we didn't have a similar trial, but we do know, based on CARTITUDE-4 and real-world experience, that cilta-cel is capable of achieving a response in patients with high-risk disease.

(00:34:52): So, the answer is yes. CAR T is definitely an option for patients who are relapsing after transplant. And again, the question is, how much risk is the patient willing to take when thinking about safety and long-term toxicities?

(00:35:12) Moderator: How successful is CAR T-cell therapy for high-risk myeloma patients?

(00:35:24) Dr. Cirstea: When we think about high-risk disease, early relapse after transplant is one category of patients. Another category is patients with high-risk cytogenetics, for example, 17p deletion or gain of 1q or 1p deletion. And then, another category of high-risk patients in myeloma is those who have extramedullary disease.

(00:35:48): The good news is that in earlier trials, like CARTITUDE-1 and KarMMa, which evaluated CAR T in patients who were heavily pre-treated, and in other trials that evaluated CAR T for patients in early lines of treatment who had high-risk features, both CAR T products were successful. The problem with high-risk disease is that while you achieve a response, it's not durable.

(00:36:29): So, what we've learned is that patients with high-risk disease relapse faster. They may respond, but they relapse faster. However, that gives us a window where we can control the disease and can think about the subsequent therapy to deepen the response.

(00:36:52) Moderator: Does CAR T therapy work for patients with AL amyloidosis?

(00:36:58) Dr. Cirstea: I love this question because patients with amyloidosis and myeloma are like siblings. About 5% to 20% of patients have both myeloma and amyloidosis. We have emerging data that suggest it's a very promising therapeutic option.

(00:37:24): There is a phase 1 trial that was done at Memorial Sloan Kettering Cancer Center that looked at a BCMA-targeted CAR T therapy in patients with amyloidosis. It was a fairly small, early-phase trial. However, eight out of nine patients who were tested for residual disease showed no presence of disease, meaning no clonal plasma cells were detected, which is very encouraging. Additionally, CAR T was well-tolerated.

(00:38:07): In those patients who had coexistent myeloma and amyloidosis and received CAR T, we learned that it's relatively safe. Obviously, it depends on the degree of renal involvement and cardiac involvement, and it would probably be tougher for patients with extensive cardiac and kidney involvement. Otherwise, it's pretty efficacious.

(00:38:42): We have to remember that in amyloidosis, there is a very small population of clonal plasma cells. So, the disease burden is very low. It's all about the extent of organ damage and whether we can get our patient safely through CAR T. So, yes, the data that we have so far are promising.

(00:39:04) Moderator: I have multiple myeloma and had CAR T cell therapy in July of 2025. I'm experiencing severe weakness, fatigue, poor coordination, and low red blood cell counts. Although I have trouble staying awake, I also can't sleep for long periods of time. Will these problems subside at some point?

(00:39:27) Dr. Cirstea: Many patients experience lingering side effects after CAR T therapy. Low blood counts can cause fatigue. There's also this phenomenon of chemobrain, where a patient is a little bit foggy and doesn't feel like they can focus well. There are some neurological subtle issues, and I'm not referring to delayed neurotoxicity. Also, sleep issues.

(00:39:52): All of these symptoms should improve within three to four months. If they don't, I think the question is whether those are symptoms of delayed neurotoxicity. Delayed neurotoxicity is a phenomenon seen mostly in cilta-cel patients, and less often in ide-cel patients. Patients have Parkinson-like symptoms, which a neurologist can diagnose. The treatment would be steroids and certain agents that reverse the inflammatory process.

(00:40:50): So, if these symptoms persist beyond three to four months and you don't have persistent anemia or recurrent infections that could be causing them, I would suggest discussing this with your oncologist and seeking a neurological evaluation.

(00:41:19) Moderator: Our next set of questions pertains to CAR T-cell therapy for lymphoma. I have mantle cell lymphoma. When I relapse again, I will be looking at either CAR T therapy or bispecific antibody treatment. What are the pros and cons of each?

(00:41:42) Dr. Spiegel: That's a very relevant question. I think the field will be discussing this for the next several years. Currently, in mantle cell lymphoma, the paradigm is CAR T, and then bispecific afterward, although that might change.

(00:42:06): There are two CAR Ts that are approved for mantle cell lymphoma. One is called brexu-cel (TECARTUS). It's a CD28-based CAR T therapy. It's a little more of a wild ride than liso-cel (BREYANZI), which has recently been approved for mantle cell lymphoma. Liso-cel is a little gentler and is typically associated with less toxicity.

(00:42:30): We have more follow-up with brexu-cel (TECARTUS), so I think that until very recently, most people would have defaulted to that. But it tends to have a high rate of neurotoxicity, and some real-world data have shown that there is a higher mortality, due to causes other than relapse, associated with brexu-cel.

(00:42:49): That said, based on the clinical trials that we have, which are very hard to compare because there are slight differences in the patient populations studied, it appears that patients who receive brexu-cel. might be in remission and survive longer than patients who receive liso-cel. It's a bit challenging to determine whether that's relevant for each individual patient.

(00:43:10): So, comparing CAR T to the bispecific for mantle cell lymphoma, CAR T requires time to collect the patient's T-cells and convert them into CAR T-cells. The bispecific uses the immune system as it is. The bispecific has two arms: one that latches onto the lymphoma, the other that latches onto the T-cell, and brings them close to each other. So, think of it as the best way of putting the immune therapy where it needs to be.

(00:43:51): Now, in mantle cell lymphoma, the main bispecific used is called glofitamab (COLUMVI). In patients with mantle cell lymphoma, and not in patients with other subsets of lymphoma, it has a higher rate of toxicities, particularly cytokine-release syndrome (CRS) and high-grade CRS.

(00:44:16): Patients are admitted to the hospital for at least the ramp-up phase of glofitamab treatment. In the trials, the rate of high-grade CRS - so that's low blood pressure requiring special supporting medicines - is close to 10%. Many centers are moving towards using preventive medicines to reduce the rates of toxicity, and I think we'll see real-world data that shows those steps are effective. I think that might be less of an issue going forward. Keep in mind that the toxicity profile from the cytokine release syndrome is  higher with bispecifics in mantle cell lymphoma than in other diseases.

(00:44:56): The rate of neurologic toxicity is less with the bispecific than CAR T products. With mantle cell lymphoma, that can be significant, particularly when compared with brexu-cel, where patients may remain hospitalized for longer periods of time. I think the neurotoxicity is related to the type of disease that people have when they enter CAR T therapy.

(00:45:18): Across all diseases, acute lymphoblastic leukemia (ALL), myeloma, and lymphomas, a higher disease burden is associated with less efficacy and higher toxicity. Mantle cell lymphoma, which often has a bone marrow component circulating in the peripheral blood, can be associated with these toxicities.

(00:45:41): Another thing to think about when you're considering either of these therapies is where the disease is and what the burden of disease is. That will really dictate what type of toxicity you may be at risk of experiencing.

(00:45:56): As far as other differences, bispecifics are given in an ongoing fashion. Outside of that initial hospitalization, they are typically administered in the outpatient setting. Both CAR T and bispecifics have risks of infection, but the risk with CAR T may be a little higher.

(00:46:15): Some of it comes down to the order in which you give these two treatments. We don't believe that mantle cell lymphoma is a curable disease, but rather a condition that will require multiple lines of therapy. Ultimately, many patients will receive both types of treatments, and it may simply be a matter of which one is administered first.

(00:46:37) Moderator: If I undergo CAR T-cell therapy to treat my lymphoma, what will my quality of life be like? I am worried about having a suppressed immune system. I have preschool-age grandchildren who are often sick with cold and flu illnesses.

(00:46:54) Dr. Spiegel: That's certainly a very relevant question. There have been some outcome studies in lymphoma patients after CAR T-cell therapy, and there is certainly an impaired quality of life for about 28 days, followed by more recovery over the next several months.

(00:47:16): A lot of that depends on how much toxicity you experience. If you have a slight fever and minimal neurotoxicity, you can return to a fairly normal life by the end of the first month. If you have grade 3 neurotoxicity, end up in bed for a week, and are getting steroids, your recovery will take longer. 

(00:47:42): I have patients who are back to work within a week after getting out of the hospital. One gentleman went right back to work even though I told him not to, and he's totally fine.

(00:47:57): And then, I have a patient who had significant neurotoxicity that lasted a long time, and he's still getting back on his feet, and had to go to rehab. So, there is a wide range of what patients experience, and it really depends on the extent of your disease and what toxicities you experience.

(00:48:15): As far as the infection-related question goes, you will have a suppressed immune system. As Dr. Cirstea mentioned, patients will have fewer B-cells to produce antibodies, so they will have fewer antibodies.

(00:48:33): Sometimes, we supplement the antibodies. I tend to supplement only if a patient develops an infection and has low IgG levels. But that really varies by center. Even the vaccinations that Dr. Cirstea mentioned really vary by center.

(00:48:56): The school-age grandchildren are really, I think, a risk-benefit consideration, like everything in life. During the first month, I tell people to be very careful. And then, depending on how they're doing, they can slowly expand the circle of whom they're willing to bring into their lives and what they are willing to do.

(00:49:17): So, for example, in Miami, it's a little easier. When it's winter, I tell patients to meet people outdoors. Meeting outdoors significantly reduces the risk of transmitting infectious diseases. Obviously, in the northern United States, that wouldn't be as possible during the winter months.

(00:49:35): So, you have to consider a group of people that you trust. If they're sick, stay away. But I always tell people, "You go through this therapy so that you can enjoy your life." So, to tell someone, "Don't see your grandchildren for six months," to me, that's difficult.

(00:49:55): Certainly, within the first month, I tell people to be very careful. Then, for every person, I gauge what their infection process has been and whether we can loosen that up little by little. But I think you also have to consider the patient's quality of life. From a patient's perspective, seeing your grandchildren, I think, would be very important.

(00:50:20) Moderator: What is the longest remission that's been seen for mantle cell lymphoma patients who undergo CAR T-cell therapy?

(00:50:28) Dr. Spiegel: That's a good question. The initial brexu-cel study, which is called ZUMA-2, has the longest reported follow-up, with remissions lasting just under five years. We don't have more data than that. The overall study showed that the median time patients remained in remission was two years. Median means that 50% were in remission for longer than two years, and 50% were in remission for a shorter period of time. Overall survival was about four years.

(00:50:59): With the liso-cel study, the median time patients remained in remission was about 15 months, and the overall survival was closer to two years. But because of differences in the patient populations studied, it's hard to directly compare these results with brexu-cel.

(00:51:15) Moderator: I have relapsed mantle cell lymphoma. I also have a new onset of ITP and was told I could not get CAR T-cell therapy. My platelets are stable on Promacta. Is CAR T therapy still a treatment option for me?

(00:51:29) Dr. Spiegel: The short answer is yes, but it's obviously a little more complicated than that. With mantle cell lymphoma being a bone marrow-based disease, in many cases, I would first want a bone marrow biopsy to rule out involvement by mantle cell lymphoma. I would also look for other types of diseases that can be in the bone marrow.

(00:51:48): For me, ITP (Idiopathic Thrombocytopenic Purpura) would be a diagnosis of exclusion. Mantle cell lymphoma can cause an enlarged spleen. There are several possible causes of low platelets that need to be investigated, primarily mantle cell lymphoma, but also second cancers in patients who received chemotherapy for their initial treatment of mantle cell lymphoma. 

(00:52:11): Dr. Cirstea mentioned that low blood counts are a significant issue after CAR T. I think probably a little more with myeloma than with lymphoma. There is a score called the CAR-HEMATOTOX score, developed by Dr. Kai Rejeski, that calculates a score based on clinically obtained blood tests. It can actually give you a projection of what your low blood counts might look like after CAR T therapy. It is based on how you come into CAR T therapy. 

(00:52:47): Most lymphoma patients’ low blood counts resolve within two to three months after CAR T-cell therapy. Approximately one-quarter of patients will require a blood or platelet transfusion, but the majority do not.

 (00:53:07): If you have low platelets, I think it really depends on what that level is. Being on Promacta is great. There are some data for using Promacta for low platelets in the post-CAR T setting, but it really depends on the level of platelets. And then, looking at how you'll manage the Promacta after CAR therapy.

(00:53:37) Moderator: Our final set of questions will address what to expect after CAR T-cell therapy and what the future holds for this treatment. Dr. Cirstea, are there other diseases that may be treated with CAR T-cell therapy in the future?

(00:53:54) Dr. Cirstea: I'm looking forward to what's coming up. Beyond myeloma, we are learning how CAR T can be used in amyloidosis, and I think this field will keep moving forward.

(00:54:11): And then, there are other hematological malignancies, apart from lymphoma, that Dr. Spiegel nicely outlined, that may be candidates for CAR T-cell therapy. CAR T has been used in chronic lymphocytic leukemia and also in acute myeloid leukemia (AML). But these applications are still being studied in clinical trials.

(00:54:37): There are also clinical trials looking at CAR T for solid tumors, but this is a little more challenging because of the difficulty CAR T cells have penetrating the solid tumors. That could be an issue that we'll have to overcome.

(00:55:00): There are also CAR-NK cells [natural killer cells] that are being tested in solid cancers, where you use NK cells instead of T-cells to make CARs.

(00:55:11): And then there are non-cancer diagnoses, such as autoimmune diseases, where CAR-like cells may delete specific immune clones. For example, CARs targeting CD19 could be used in the autoimmune disorders that are driven by B-cells producing the antibodies that attack your own tissues. I think this field will keep evolving and growing.

(00:55:48): So, there is a lot of hope, as long as we have courageous patients who are willing to participate in trials and trust us. I am deeply thankful to them, their families, and their caregivers. I think we'll be able to push the field forward.

(00:56:15) Moderator: Dr. Spiegel, what are the pros and cons of using donor T-cells rather than a patient's own T-cells to make CAR T-cells for a patient?

(00:56:26) Dr. Spiegel: This was a very exciting frontier in the field several years ago. I think there are multiple pros. We've talked about patients' T-cell fitness after several lines of therapy. We use T-cell exhaustion as a medical term, but I think it's very evocative. You've been through lots of therapy, the T-cells have been trying to fight the cancer, and maybe they're not able to keep up the fight anymore if we try to supercharge them as CAR T-cells.

(00:57:02): Donor CAR Ts don't require time waiting for CAR Ts to be manufactured. You can just reach them off the shelf and have a very effective therapy.

(00:57:20): However, what we've found out, through multiple trials, is that these donor cells don't really stick around very long. As such, I don't think the data currently supports their use as a replacement for T-cells collected from the patient.

(00:57:42): So, your immune system isn't strong enough to fight the cancer, but it's still strong enough to fight off donor CAR T-cells. Many trials are investigating various methods to modify the donor CAR T-cells so that the patient's immune system does not reject them. I think, at the moment, this approach is not ready for prime time, and I suspect that without significant changes, it won't be.

(00:58:11) Moderator: This is a question for Dr. Cirstea. How does cilta-cel (CARVYKTI) compare to anito-cel to treat multiple myeloma? When will anito-cel be approved by the FDA?

(00:58:32) Dr. Cirstea: I'm also looking forward to approval because I love anito-cel. It's important to remember that both cilta-cel and anito-cel target the same receptor - BCMA. Cilta-cel has essentially two warheads which attach to two BCMA epitopes on the myeloma cells. So, it has kind of a dual attachment.

(00:58:59): Anito-cel has an engineered synthetic D-domain that makes it a little bit more persistent and avoids the production of antibodies by the patient against the CAR T-cells, which can happen with other products. So, it's just a better design in terms of the persistence and the attachment to the myeloma cells.

(00:59:35): So what data do we have so far? We have a lot of data on cilta-cel. We know it works. We also know that there is some toxicity with it, and we're always very careful when we decide to deploy it.

(00:59:54): In a Phase 1 clinical trial, the response rate with anito-cel was 100%. The median progression-free survival - the period where you are disease-free - was almost three years. So, very comparable to cilta-cel.

(01:00:15): The beauty of anito-cel is that we haven't really seen any delayed neurotoxicity. So, that's a big plus. We now have a phase 3 clinical trial that's comparing anito-cel to standard of care regimens in myeloma patients early in the course of their myeloma, after one to three lines of treatment. The hope is that, maybe in 2026, we'll see FDA approval of anito-cel.

(01:00:51) Moderator: This is a question for Dr. Spiegel. What is in-vivo CAR T-cell therapy? Is it safer than the current type of CAR T-cell therapy?

(01:01:08) Dr. Spiegel: That's a great question. In-vivo CAR T relies on some of the mRNA-based technologies that we leveraged for some of the COVID vaccines. Instead of manufacturing CAR T cells outside the body in a manufacturing facility, we can inject genetic DNA into a patient and produce CAR T cells directly within the patient's body.

(01:01:52): The question is about persistence. It may also avoid some concerns about generating T-cell cancers with the CARs, which isn't really a massive problem, but it is a small problem that we have noticed.

(01:02:31): That said, it is still in a very early phase of clinical trials. We don't know whether the cytokine release syndrome or neurotoxicity will be less. I think that's really going to play out over the next two to five years. It might be the next frontier, rather than the donor cells, but it is still at a very early stage of research.

(01:02:53) Moderator: Well, I'm afraid we're out of time this evening. Thank you to all our expert panelists for sharing your knowledge, your expertise, and your time with us tonight.