CAR T-Cell Therapy: Its Role after Transplant

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CAR T-Cell Therapy: Its Role after Transplant

Thursday, April 22, 2021

Presenter: Dr. Matt Lunning DO, FACP, Associate Professor, Division of Hematology/Oncology, Nebraska Medicine

Presentation is 35 minutes long with 23 minutes of Q & A.

Summary: CAR T-cell therapy is new treatment option for patients with certain types of non-Hodgkin lymphoma, acute lymphoblastic leukemia and multiple myeloma who relapsed or did not respond to other treatments. This presentation discusses who is eligible to receive CAR T-cell therapy, what the procedure entails and potential side effects.

Highlights:

• CAR T-cells are created in a laboratory, using the patient’s own T-cells, and are programmed to attack the patient’s cancer.
• The Food and Drug Administration (FDA) has approved CAR T-cell therapies to treat patients with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, follicular lymphoma, multiple myeloma and acute lymphoblastic leukemia (ALL).
• Two serious side effects can occur after CAR T-cell therapy: cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS).

Key Points:

(03:43) T-cells are like the general of the immune system and play an important role in fighting cancer.

(06:25) CAR T-cells are created using the patient’s own T-cells. The T-cells are engineered in a laboratory to become more effective in fighting cancer

(11:08) Four different CAR T-cell therapies have been approved by the Food and Drug Administration (FDA):  Yescarta®, Kymriah®, Breyanzi® and Abecma®.

(13:38) Eligibility for CAR T-cell therapy depends on the disease type, prior therapy the patient received, how well prior therapy was tolerated, how often and how soon after prior therapy the patient relapsed, and the patient’s general health.

(20:28) Getting insurance approval can take time and may delay getting to CAR T-cell therapy.

(25:09) Patients receive chemotherapy prior to the infusion of CAR T-cells.

(26:43) A side effect called cytokine release syndrome (CRS) often occurs after CAR T-cell therapy. It can cause fever, fatigue, nausea, vomiting, low blood pressure, low levels of oxygen and, in severe cases, organ dysfunction. It can usually be managed with a drug called tocilizumab.

(28:17) A second common side effect of CAR T-cell therapy is a neurological problem called ICANS. Symptoms include tremors, agitation, difficulty finding words, weakness and seizures. It usually resolves after treatment with steroids.

(30:47) CAR T-cell recipients need a 24/7 caregiver and will remain close to the hospital for the first few weeks.

(32:53) CAR T-cell recipients cannot drive or operate heavy machinery until eight weeks after treatment.

Transcript of Presentation:

(00:01) [Michala O'Brien]   Introduction.  Good afternoon, my name is Michala O'Brien. Welcome to the workshop, CAR T-cell Therapy: Its Role After Transplant. Today, it's my pleasure to introduce our speaker, Dr. Matthew Lunning. Dr. Lunning is an Associate Professor in the Division of Hematology Oncology, and Medical Director of the Clinical Research Center at the University of Nebraska. His research focuses on lymphoma and CAR T-cell therapy. Dr. Lunning has served on several national committees on immunotherapy and lymphoma, and is a member of the American Society for Clinical Oncology's Cancer Education Committees on Non-Hodgkin's Lymphoma. Please join me in welcoming Dr. Lunning

(00:50) [Dr. Matthew Lunning]   Overview of talk. Thank you for that kind introduction and welcome, everybody, this evening. I'd like to thank the organizers for giving me the time to give this talk: CAR T-cell Therapy: Its Role After Transplant. Here are my disclosures.

(01:12) The objectives that I'd like to cover today are multiple, but to start off I'd like to discuss how the immune system and CAR T-cells share a common theme, discuss where CAR T-cell therapy plays a role in the treatment of patients with blood disorders, discuss the evaluation process for candidacy for CAR T-cell therapy, discuss the CAR T-cell journey for both patients and their families before, during, and after the procedure, and discuss the potential toxicities and impact on quality of life, both in the short-term, as well as in the long-term.

(01:49)  Stem cells are the cells collected for an autologous or allogeneic stem cell transplant. So, this cartoon here is meant to sort out just how complex our immune system is. And many of you have heard that transplants, or have gone through transplants or have had family members who went through transplants, and you've heard a lot of reference back to the stem cell. So, it's the stem cell that we often harvest prior to undergoing an autologous stem cell transplant. Or it can be a certain areas or parts of the immune system that we're collecting, including stem cells, as part of an allogeneic stem cell transplant. So, when I speak to auto transplant, I'm talking about bone marrow or stem cells from the patient who, then, they're re-infused, versus an allogeneic transplant, which is cells or stem cells taken from a donor that are matched [to the patient] in the best possible way.

(02:46) Stem cells can evolve into  myeloid blood cells that include neutrophils, red blood cells and platelets.And you can see here, those stem cells then become committed progenitors and they may become parts of your myeloid system. So, you've heard about neutrophils, red blood cells and platelets which make up our myeloid mature cells. So, platelets stop clotting. So if the patient were to bleed, red blood cells carry oxygen throughout the body and white blood cells are infection-fighting cells, or are parts of our infection-fighting cells, typically neutrophils, basophils, eosinophils from that standpoint.

(03:20) Lymphoid stem cells can evolve in B-cells or T-cells. On the top here, you see the lymphoid progenitor which can evolve into either B-cells, which may mature over time in circulation as well as in lymph nodes, and then the oldest B-cell is the plasma cell, and many of you have heard of plasma cells because those are the bad guys in the realm of multiple myeloma.

(03:43) T-cells are like a general that signals the immune system when bacteria or a virus enters the body. We see here at the top is T-Lymphocytes, and this is a part of the immune system and they're very much like the general of the immune system, where there may be very few of them, but they are helping signal to the rest of the immune system when an invader, whether or not that's a bacteria or a virus enters the body to fight it off, but it also could play an important part in fighting off cancer.

(04:14) T-cells can control cancer. So, how does T-cells fight cancer? Here is another schematic of seeing the tumor there at the bottom. And if you follow the step-wise, you can see that the tumor will often outgrow its blood supply and you will get auto-necrosis of the tumor, which will release cancer cell antigen. Those cancer cells antigens are presented to a part of the immune system called dendritic cells, or antigen-presenting cells as highlighted by those red dots on the arms of the antigen-presenting cell. These antigen-presenting cells interact with T-cells and prime and activate those T-cells. They then traffic back potentially to the lymph node and create cytotoxic T-lymphocytes. Through further signaling, those T-cells then infiltrate into the tumor. They recognize those cancer cells by engaging the cell surface of those cancer cells and work to kill a cancer cell through a process similar to boring holes or degrading the cell or eating it via different mechanisms. And so, T-cells can be incredibly important in the fight against cancer.

(05:37) T-cells need two “signals” to respond to cancer cells. We knew this for a long time that T-cells can interact and control cancer. And one of the processes that the... as we further learned about T-cell biology, is we learned over time that there was the T-cells engaging a receptor on a cancer cell and that first signal of engagement may lead to T-cell anergy or the T-cell just doesn't respond. And over time, we learned that actually, the T-cell needed two signals in order to activate effectively to kill off another cell. So really, T-cell biology requires a signal one, of T-cell engagement, and a second signal, more of a regulator signal to further activate the T-cell.

(06:25) CAR T-cells are created by taking the the patient's T-cells and converting them to cells that can more effectively fight cancer. We use this understanding then to take T-cells and re-engineer them into CAR T-cells. And you can see here the Model T car on the far left with our first generation car, which incorporated an anti-tumor associated antigen to a small arm on the outside of the T-cell surface. And we're able to generate just that signal one process called the CD3 zeta or the FCR gamma receptor. So, this was just that first signal one. And really, this first generation CAR T-cell didn't really work very well. At best, it could keep cancer in a Petri dish under control for a certain period of time.

(07:07) That led to further understanding of the T-cell interplay between signal one and signal two. And what led to the second generation cars, where you have an anti-tumor associated antigen. So, that can be any cancer antigen that's basically a flag that's flown on the outside of the cancer cell. But here, we understood that we needed to incorporate signal two. And that signal two would subsequently activate the T-cells and allow them to further divide as well as kill the cancer. You can see here that there have been two signal two co-stimulatory molecules incorporated into a CAR T-cell product. Namely, CD28 and 4-1BB, so these are the signal two. And the signal one is hanging out at the end there.

(7:58) Second generation CAR T-cells have improved upon earlier versions of CAR T-cells. And so with this signal one and signal two, came about a new generation of CAR T-cells called the second generation CAR T-cells, which really has shown significant amount of efficacy in blood cancers, depending upon the anti-tumor associated antigen. And we'll go through what those antigens are. Beyond the scope of this talk as further generation of CAR T-cells where you're creating different certain loops and expanding the capabilities of these CAR T-cells. And those are in the third generation and beyond CAR T-cells. But for the discussion today, we'll be talking about CAR T-cells that live in the second generation.

(08:41) So, that's some really complex biology that I tried to discuss on this simplified slide. But to simplify it even further, how do we discuss with patients and patients' families, something incredibly complex and get it to a level that potentially they could understand what's exactly going to happen or near exactly what's going to happen in their body? So, I'll have often used the yellow corn to multicolored corn analogy when discussing CAR T-cell therapy with my patients, just based upon the location or the geography that I live in. We do serve some farmers or families who know farmers, and so corn and soybeans is not too far from anybody's mind in Nebraska.

(09:29) T-cells are sent to a special laboratory to be converted into CAR T-cells. So, how do I speak to this? So, I use the yellow corn analogy. Think about all those kernels of yellow corn. Each individual kernel is a T-cell. And what we're going to do is, we're going to take that ear of corn which harbors hundreds if not thousands of kernels of T-cells and we're going to send it off to a company that takes those kernels of corn and re-engineers them to put CAR T-cells on top of that ear of corn and then send it back. And when it gets sent back, it is multi-colored corn. So, each individual color may represent just the density of CAR T-cell receptors on that individual kernel or T-cell that we then give back to that person. So no longer is it all yellow corn, but it is multicolored corn. So, there may be some yellow corn that didn't take, but there may be some black kernels that just have a significant amount of CAR T-cell receptors available to engage that cancer cell that we inject back into the person's body.

(10:34) CAR T-cells can kill cancer but they can also cause serious side effects. I often use then the popcorn analogy is what often happen when that kernel of corn meets that cancer cell and it causes cell death and that popcorn, if you've ever opened microwave popcorn, you want to keep it away from your face because steam will come out. Well, that energy that comes out after that kernel is popped or that CAR T-cell has popped that cancer cell can lead to toxicities that we attribute to CAR T-cell therapy, which I'm going to speak to later on in this talk.

(11:08) So, where does CAR T-cell currently fit in hematologic malignancies? So, we're going to go through on one simple slide here four different CAR T-cells that are now FDA approved in their different indications.

(11:25) Yescarta® is FDA-approved for management of relapsed/refractory large B-cell lymphoma. So as you can see here, axicabtagene ciloleucel, otherwise known as Yescarta®, is approved for the management of relapsed/refractory large B-cell lymphoma. It is also recently approved for mantle cell lymphoma and follicular lymphoma.

(11:40) CAR T cells can attack both cancer and normal cells. So when I talk about a tumor-associated antigen or that flag that these CAR T-cells attack, they're attacking the CD19 antigen on the tumor cell surface. Now, CD19 is expressed broadly across normal B-cells too. And so, with engagement of CD19 to CAR T-cells, CAR T-cells don't know if they're attacking a lymphoma cell or a normal B-cell. So, it can deplete both good cells while it depletes the cancer cells itself.

(12:13) Kymriah® is FDA-approved for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL).  The same thing can happen with tisagenlecleucel, otherwise known as Kymriah®. This is also approved in large relapsed/refractory diffuse large B-cell lymphoma, but it is also approved in relapsed/refractory ALL up to individuals by age of 25. So, in second relapse or later. This also engages CD19 as its target.

(12:41) Breyanzi® is FDA-approved for the treatment of diffuse large B-cell lymphoma (DLBCL) The most recent CAR T-cell that has been approved by the FDA is lisocabtagene maraleucel or Breyanzi®. This is currently approved just for diffuse large B-cell lymphoma and continues the theme of targeting CD19.

(13:00) Abecma® is FDA-approved for treatment of multiple myeloma. Most recently, and the first approval in multiple myeloma was Ide-cel or Abecma®. And so, this targets a different target because this targets a plasma cell disorder. And so, this targets a BCMA or B-cell maturation antigen. And in myeloma, you can see here the indication is after four prior lines of therapy. And you have specific drugs that the patients must have had exposure to before they can become available to receive this CAR T-cell therapy.

(13:38) Eligibility for CAR T-cell therapy depends on the disease type and prior therapy the patient received. So, what about the journey to CAR T-cell? Well, I think it really starts with consultation with a CAR T-cell therapist, which may be an individual who sees only lymphoma or only sees myeloma or it may be an individual who does auto transplants and allogeneic transplants and CAR T-cell therapy. So, each institution is unique in who does cellular therapy or CAR T-cell therapy, depending upon the location where you're being referred to. What may occur is, the consultation with the individual may differ, depending upon the disease type that the individual has, whether or not it's large B-cell lymphoma, mantle cell lymphoma, ALL, follicular lymphoma or multiple myeloma. At the time of the consultation, the physician or their team will look at what prior therapies the individual has had before considering CAR T-cell because there may be a situation where they have not received enough lines of therapy for it to be appropriate to undergo commercial CAR T-cell therapy. However, also at that time, clinical trials related to CAR T-cell therapy and other clinical trials may be discussed.

(14:59) How well a patient tolerated prior therapies is considered when determining eligibility for CAR T-cell therapy. One of the other caveats that we may look at is CAR T-cell can be a very intensive therapy. Just like transplant is a very intensive therapy, CAR T-cell therapy can be very intensive and can come with some significant toxicities. And so, we will see what the tolerance of prior therapies have been and also, what was the intensity of the prior therapies? Did an individual get full doses of chemotherapy? Was there dose reductions that were required? Was therapy stopped early because of unforeseen complications or toxicities? Also, has the individual undergone a transplant? And that transplant can include autologous transplant, again, transplants from the patient's bone marrow or stem cells or an allogeneic stem cell transplant. And if an allogeneic stem cell transplant has occurred, what have been the complications, if any, that have occurred post-transplant, whether it be infections, graft-versus-host disease, and what is the pace of the relapse post an allogeneic transplant?

(16:07) Whether the patient relapsed or never responded to prior therapy is considered when determining eligibility for CAR T-cell therapy. That leads to lastly, talking about the disease status. Is this a person that has had a relapse of their disease? And how long was the duration of remission and what is also the pace of the relapse? So, is this a relapse that has been occurring or been evident over months or weeks, or is this tumor growing by the day? Other statuses are if the patient is refractory or has previously received a therapy that now is growing through and the patient can be having symptoms in this condition because not only are they having the toxicity potentially from the treatment, but they may be having toxicity from the disease concurrently.

(16:56) I would say the most concerning disease status to get an individual to CAR T-cell are those individuals who I call never in remission. So, these are people who often have aggressive biology, whether or not it's diffuse large B-cell lymphoma, ALL, more rarely, people with follicular lymphoma or mantle cell lymphoma but can occur, where they've received multiple lines of therapy and they've never achieved a remission. So, their lymphoma grew or was primary progressive or refractory to lines of therapy, whether or not they'd be one, two or three lines of therapy, whether or not that's been to your kind of classic chemotherapy, or your other more targeted oral therapies or immunotherapies.

(17:52) Prior to CAR T-cell therapy patients will undergo a series of tests to determine the extent of their cancer and health of their organs. So, what workup is done during this time? So, we will assess the disease burden. This may be done purely by physical exam, but often, imaging via CAT scan or PET CT depending upon the appropriate use of imaging may help discern what is the disease burden and what is the pace, and whether or not that disease burden is impending or about to cause difficulty with organ function. So, is there a mass next to the kidney, a mass next to liver, airway, so on and so forth?

(18:30) We will also commonly do a cardiac function. Most commonly with an echocardiogram to look at the strengths of the function of the heart. We often will also do infectious disease workup to include but not limited to HIV, Hepatitis B, Hepatitis C. Other laboratory assessments that we may consider is doing a complete blood count or a CBC. This can be helpful in establishing what the bone marrow reserve is as many people have undergone multiple lines of therapy before coming to CAR T-cell and we also have to think about whether or not there's a second potential cancer in the bone marrow called myelodysplastic syndrome, which is where the bone marrow myeloid cells just don't... aren't produced appropriately, which is a cancer and can lead to other acute leukemias over time. We also will look at hepatic reserves, so people will may have received chemotherapy which may have caused some toxicity to the liver and you can monitor those by liver function tests as well as bilirubin.

(19:41) We'll also often draw blood to look at the creatinine which can give an idea of the renal reserve and that's often in creatinine clearance and this is something that is dependent not only on gender but also on age and weight. Sometimes, if the creatinine clearance is low enough and a patient is going towards CAR T-cell therapy, the lympho-depleting chemotherapy dosing may need to be altered.

(20:07) And lastly, looking at pulmonary reserve, and this is often done, at least in the clinical trial setting and often in the clinical commercial setting, looking at pulse oximetry such as putting that pulse oximeter on your finger and checking the level of oxygenation of the body.

(20:28) Getting insurance approval can take time and may delay CAR T-cell therapy.  So, what's next after you, your care team and your physician or your CAR T-cell therapy team decide that they'd like to go towards treatment? I call this period of time the brain to vein time. So, when you and your physician want to go towards CAR T-cell and what happens before the CAR T-cells are infused? And so, this is a period of time which I think is currently one of the most crucial periods of time in CAR T-cell therapy because you want to do CAR T-cell, but there's a delay or a gap in time to get to CAR T-cell therapy. And that goes beyond the manufacturing of the CAR T-cells itself, which can take days to weeks in order to manufacture.

(21:17) And so, what are some of the aspects of the brain to vein time that I think about and I discuss with my patients? It is, what is their insurance? Is it public versus private? And so, public insurance meaning Medicare or Medicaid, private meaning your third party payers. Often, patients with Medicare can get to apheresis for CAR T-cells potentially quicker than patients with private insurance. And this may affect what you would do in this pre-apheresis timeframe.

(21:54) Then, is often a prior authorization where it is determined whether or not this been on label or appropriate time to do CAR T-cell. After prior authorization is in place, then pre-determination and single case agreements may be completed if necessary. And single case agreements are negotiations about the payment for the product, so these products do have a dollar sign to them, and they're also discuss payment for the care post infusion of the CAR T-cell.

(22:31) Treatment to stabilize the disease may be required while waiting for insurance approval of CAR T-cell therapy. So, why do I discuss this? Because this period of time can take weeks in order to take place and this is before you're taking out the T-cells and sending them off to be manufactured. So during this time, you have to think about the pre-apheresis treatment and what's the disease burden? What's the disease velocity or how is the disease changing over time? And really, you have to anticipate the time to T-cell removal or apheresis because you may need to treat them during this time and really, what you're trying to treat them with is what I would call a disease stabilizing agent, but something that is not going to or you think is going to impact in their performance status. So, keeping the performance status stable but at least impacting their disease to stabilize it.

(23:25) While patients waits for their T-cells to be converted into CAR T-cells, they will be monitored for infection and may receive drugs to control their disease. Now, jumping into the vein to vein time, so vein to vein time is after you pull the T-cells out. So, we often do this similar to a collection for an autologous stem cell transplant on a very similar machine where we do apheresis and then send them away for manufacturing until they're re-inserted. And so, what are you doing during the post-apheresis phase? Well, you're monitoring for fitness. You may have given chemotherapy in the pre-apheresis timeframe, but then you're monitoring to see if you need to give more of that chemotherapy post-apheresis. You're also monitoring for infection and you may be considering even further bridging therapy in the vein to vein time. And often, we use steroids, bolus or pulse steroids to help control the disease. If it's a distance from the infusion, we may use radiation to problem locations at fault or threatening locations to organs. We may also use low dose chemotherapy again if there's an appropriate distance from the lympho-depleting chemotherapy.

(24:37) So again, looking at the timeline, it's apheresis, it's transported, it's sent to the manufacturing facility. You can see there then once it's manufactured, it goes through a quality assurance process to make sure the CAR T-cells what are in specification allowed for release by the FDA. It is then released. We often get a phone call saying that they're ready for transport and that they will arrive on a specific day. Once they come on site, then you will start lympho-depleting chemotherapy.

(25:09) Patients receive chemotherapy before the CAR T-cells are infused. Lympho-depleting chemotherapy most commonly is with fludarabine and cyclophosphamide. This is the most common lympho-depleting chemotherapy. The doses may differ depending up on the CAR T-cell construct that is chosen to be used. It is often three days of treatment and then at least two days of rest before infusion of the CAR T-cell. There are some CAR T-cells, mainly tisagenlecleucel, which has used bendamustine given over two days of treatment as part of lympho-depleting chemotherapy. Tisagenlecleucel is the only CAR T-cell that has data looking at if you are not to use lympho-depleting chemotherapy.

(25:55) So, the infusion is often done in the patient's room or in the infusion center if being administered as an outpatient. It usually lasts for minutes, but again depends on the product. Some products are in a single bag or may come in multiple bags, and some products may come in vials like Liso-cel, which is a two-dose vial of CD4 T-cells and CD8 T-cells.

(26:20) What does it feel like? Well, the infusions should be painless, but often people have PIC lines or central lines in place. There can be an odor which is from the DMSO. You may have heard about that odor if you had a prior autologous transplant. And that odor is often smelled by the family but not necessarily by the patient, which is an interesting phenomenon.

(26:43) After CAR T-cells are infused into the patient, two serious side effects often occur: cytokine release syndrome (CRS) and a neurological disorder called ICANS. So, to wrap up my talk, I'm going to speak to a little bit of the toxicities of CAR T-cells and we'll open it up for questions. So, what can I say about CAR T-cells in general is that the management of the toxicity, I really think that experience matters because there is a broad spectrum to the toxicity profile of CAR T-cells and really, the management of the toxicity of cytokine release syndrome and neurotoxicity has had quite the pendulum shift over time as we've gotten more experience with CAR T-cell therapies and more experience with the treatments for CAR T-cell therapies.

(27:25) Symptoms of cytokine release syndrome are fever, fatigue, nausea, vomiting, low blood pressure and low oxygen levels. So, I'll speak to two major toxicities, the first being cytokine release syndrome (CRS) And as you can see here, often, it's pathognomonic, or the first feature of CRS is fever but can be concurrent with fatigue, nausea and vomiting and as the grades increase, patients may have low blood pressure, low levels of oxygenation of the blood and may lead, in severe cases, to organ dysfunction. Often, we're treating early grade CRS with a drug called tocilizumab, which is an IL-6 receptor monoclonal antibody. And so, different constructs may have different treatment paradigms and different treatment thresholds, depending on the grade of CRS.

(28:17) ICANS is a neurological side effect. Symptoms include tremors, agitation, difficulty finding words, weakness and seizures. The next is the management of ICANS, or some people call it neurotoxicity. ICANS stands for immune effector cell associated neurotoxicity syndrome, or neurotox. I call it the shake of the hand. When I'm seeing a CAR T-cell patient in their plus stage, in the pre-pandemic and even in the post-pandemic phase when I'm checking their neurologic function, I shake their hand and I hold their hand out to see if there's any evidence of tremor. Tremor in my opinion can be one of the earliest signs of coming neurotoxicity. Also, you can see agitation, word-finding difficulties, weakness, and as it progresses to higher grades, you can see people have comas, seizures and also may, in the severe cases, have brain swelling. This is often treated with systemic steroids and not necessarily treated with tocilizumab, unless there is concurrent CRS.

(29:23) Tocilizumab is used to treat cytokine release syndrome, and steroids are used to treat ICANS. So, what about post-infusion monitoring? So days one to 14, you're monitoring for CRS and ICANS. You have to have the ability of two doses of tocilizumab per CAR T-cell patient. So if you have five CAR T-cell patients in your hospital, you have to have at least 10 doses of tocilizumab available. Steroids commonly are dexamethasone that can be used and the dose depends upon the severity of the ICANS, but it may go to higher doses of dexamethasone as well as methylprednisolone.

(29:53) CAR T-cell patients are given medications to prevent infections, and may require red blood cell and/or platelet transfusions. Infections can be an issue. And so, we do use prophylactic medications in the short-term including prophylactic antibiotics and anti-fungals, but in the long-term, we concurrently use anti-virals and anti-PJP (p jiroveci pneumonia) medicines. Red cell transfusions can be common given the previous treatment as well as the lympho-depleting chemotherapies that we're seeing. And so, it's not uncommon that patients early post-CAR T-cell require red blood cell transfusion and platelet transfusions.

(30:26) We also work very hard with the replacement of electrolytes, looking at things like potassium, magnesium as well as phosphorous in the replacement during these times. And then, IV fluids based upon whether or not the patient is eating and drinking well.

(30:47) CAR T-cell recipients need a 24/7 caregiver and will remain close to the hospital for the first few weeks. In the days 15-20, what I call the post-discharge, often, depending upon the degree of complications from the CAR T-cell, patients may be out of the hospital at this point, they're remaining in close proximity of the CAR T-cell center. They have a 24/7 care giver and we're monitoring for recurrence or emergence, less commonly a CRS and ICANS. And you may be seeing your post-CAR T-cell team multiple times per week. You should be off of or having less red blood cell transfusions. And this concept I call the double dip where as you can see early recovery from the lympho-depleting chemotherapy, but you may see a subsequent drop in the absolute neutrophil count and people can require sporadic use of growth factor for neutropenia. This can potentially be more common if you experience a CRS or neurotoxicity during your CAR T-cell therapy.

(31:50) CAR T-cell recipients can usually return home a month after treatment. In days 29 and beyond are when you're returning home. Often if you're traveling a distance and referred by your local oncologist, there will be discussion with the CAR T-cell oncologist and the local oncologist letting them know how the CAR T-cell went, what are some special things that you need to consider and medicines that should be continued. Cytopenias [low blood cell counts] may persist, but transfusions are hopefully less frequent in this time frame as well as sporadic neutropenia [low white blood cell count] may recur, requiring growth factor use.

 (32:24) And slowly, patients are returning to work. We again are monitoring for recurrent infections because as I alluded to, the CD19 CAR T-cells and potentially with BCMA CAR T-cells, you can have B-cell aplasia and that leads to low immunoglobulins and people may require IVIG or IV immunoglobulin use if recurrent infections are seen and you have low IgG count.

(32:53) CAR T-cell recipients cannot drive or operate heavy machinery for eight weeks after treatment. Nebraska, we do our initial response evaluation around day 100. We may do it earlier if there is potential concern for progression. And with each of these products, there is no driving for eight weeks. This includes heavy machinery, light combine and what my recommendation is, is at that eight-week time point when you're ready to drive, return to the side streets or the rural roads first before hopping on things like the interstate or highways and just get comfortable behind the wheel again because you're in a new post-CAR T-cell environment.

(33:27) CAR T-cell therapy has prolonged disease-free survival in patients with difficult-to-treat disease. And this is my last slide before I will take and have time for questions here. So in summary, use of CAR T-cell has been effective in difficult to treat situations with the prospect of prolonged disease-free survival. So, that really sums up the majority of our CAR T-cell experience despite no head to head comparison of any CAR T-cell product. Just alluding to, there's no head to head trial for large B-cell lymphoma to determine the safest or most effective CAR T-cell, and so it often is an individual decision with the CAR T-cell team on what CAR T construct to move forward with or whether to move forward with CAR T-cell versus other available therapies at that time. CAR T access may be limited by the brain to vein time, and so this can be often a frustrating time point for your CAR T-cell team as well as the care team as you're waiting to apheresis and some of the things like treatment that may need to occur during this time.

(34:35) Half the battle is the time it takes to get insurance approval for CAR T-cell therapy. I think really, because of the brain to vein time, half the battle is getting to CAR T-cell, whereas dealing with often very refractory situations and diseases that are growing very quickly and threatening to take people's lives. And so, trying to control the disease while getting to CAR T-cell can be difficult.

(34:59) Management of toxic side effects of CAR T-cell therapy has greatly improved. And I will say that the toxicity management has significantly improved and we've learned a lot over the years within clinical trials with some of the different iterations of clinical trials to help us better understand how to treat toxicity and lessen that toxicity without potentially affecting efficacy or how well the CAR T-cell works in these lymphomas and leukemias and myelomas.

(35:27) And with that, I will end and I think we have time for questions.

Question & Answer Session

(35:35) [Michala O'Brien]     Q & A. Thank you, Dr. Lunning, for this excellent presentation. As a reminder, if you have a question, please type it into the chat box on the lower left hand corner of your screen.

(35:47) Our first question is, "If a patient has a CAR T treatment and does not respond or relapses afterwards, would they be eligible for a different CAR T or perhaps a clinical trial?"

(36:01) [Dr. Matthew Lunning]      Yes. You may be eligible for a clinical trial or a different CAR T-cell if at that time point it engages a different antigen. I think there have been data of using the same construct where a patient initially is treated with, let's say a CD19 CAR T-cell. The patient has a response and some durability and then the disease comes back that they have been re-treated and have responded with a second infusion of the same CAR T-cell. There may be examples of using a different construct. In general, let's say you got an experimental CAR T-cell first and then receive a commercial CAR T-cell second. That is a possibility.

(36:43) I didn't go into because it's beyond the scope of this talk, but you're alluding to, there are some other CAR T-cells that just don't hit one antigen, but they hit more than one antigen. So, there are CAR T-cells that are hitting CD19 as well CD20 or CD19 as well as CD22. And so, trying to reduce the escape mechanisms, by which the cancer stops flying that CD19 flag or it was never flying, and we just didn't know it, and so hitting two different targets at the same time. So, yes. That is a possibility. And those CD19, 20, 19, 22 CAR T-cells are still in the clinical trial realm. I've often encouraged makers of CAR T-cells to not exclude people who have prior exposure to CD19 CAR T-cells or CD19 engaging medications that are now approved on the market, drugs like tafasitamab is a monoclonal antibody against CD19 that is out in commercial use.

(37:54) [Michala O'Brien]      Great. Thank you. Next question: "Is a CAR T therapy a less invasive treatment than transplant?"

(38:05) [Dr. Matthew Lunning]     Well, that's a tough one to answer because I've had people... people can die due to a transplant and people can die due to a CAR T-cell. So, I think that they both have the potential for significant toxicities. Often, the toxicities are different. We don't commonly see... we can't see engraftment syndromes with fevers and people can have difficulty breathing at certain graphing post auto or allogeneic transplants. So, it's hard to say that one has more consequences. I think we had a longer period of time where we've understood autologous and allogeneic stem cell transplants versus CAR T-cell, but they're all each unique, and I would say that each has the potential to have their severe toxicities, so I wouldn't say one is less intense than the other from that standpoint.

(39:05) Now that being said, there may be patients who we would consider not doing a transplant for or what we would consider transplant ineligible, that may still be able to go towards a CAR T-cell therapy. But really in that transplant ineligible population, you really have to look to what was making them not transplant-eligible or what made them not a transplant candidate. And most commonly, I think it is their disease not being amenable to getting a transplant, meaning not being under good enough control to go towards an autologous or an allogeneic stem cell transplant. And remember, that can be the difference because we don't do consolidated CAR T-cells meaning that you don't do a CAR T-cell in a person who has often no evidence of disease. We are doing CAR T-cell in patients who have evidence of disease, active disease and progressing disease. So, it can be different scenarios.

(40:00) [Michala O'Brien]      Okay. This question kind of piggy backs on that question. "Can an allogeneic transplant patient later receive the CAR T-cells from the allogeneic donor, and how does CAR T therapy compare to an allogeneic donor lymphocyte therapy?"

(40:15) [Dr. Matthew Lunning]      Sure. So, that's a good question. So if a person who's had an allogeneic transplant has full donor chimerism, meaning that all their T-cells are donor, and if that individual goes to a CAR T-cell therapy, those by nature would be an allogeneic CAR T. There are examples in the clinical trial realm where we're doing allogeneic CAR T-cell trials. Which it may not be the donor from whom the person had an allogeneic stem cell transplant that CAR T-cells would be made... it is a CAR T-cells of somebody else that looks enough like them, and maybe with some alterations in the CAR T-cells themselves, to hopefully prevent graft-versus-host disease. I don't know of a test case of where we've had a donor get apheresed, manufacture cells and then given that back to their original donor, however. So it would be possible, but I don't know that I've seen it done.

(41:29) [Dr. Matthew Lunning]     ... I think DLI or donor lymphocyte infusions and CAR T-cells, DLI can be used as a means to try to treat a relapse post allogeneic transplant. They've never been head to head compared, and so it's hard to comment on the outcome.

(41:51) [Michala O'Brien]        Okay. "Can donor-derived CAR T-cells seven years following an allogeneic SCT help severe chronic GVHD seven years post-transplant?"

(42:01) [Dr. Matthew Lunning]      Can donor-derived CAR T-cells seven years following-

(42:11) [Michala O'Brien]      Seven years following a stem cell transplant.

(42:14) [Dr. Matthew Lunning]     ... So, I don't know that you would give CAR T-cells with the pure intent to treat graft-versus-host disease in a person that doesn't have any evidence of active lymphoma or leukemia or what the underlying disease is using. And I think that what the person asking the question is asking a question which may be trying to answered in the research realm rather than what's commercially available right now.

(42:47) [Michala O'Brien]      Okay. "What age group has the highest success at CAR T-cell therapy?"

(42:54) [Dr. Matthew Lunning]      Well, we haven't really sorted that out because multiple different CAR T-cell constructs have looked at differing at age, let's say, greater than or less than 60 or greater than or less than 65. To say that there is a clear cut age that says that this is best age group to get CAR T-cells, I think really having the discussion as an individual that they have the right organ function, they have the right disease state in order to proceed to CAR T-cells, but I personally don't think that there's an age limit to CAR T-cells an upper age limits to CAR T-cells, in regards to if it's the right disease, the right patient with the right organ function and performance status. So, I would argue we aren't differentiating people by their decades of life in CAR T-cell therapy.

(43:53) [Michala O'Brien]      Okay. The next patient wants to know, "What's the life of a CAR T-cell? I'm post-80 days out and I've been told mine is no longer helping. I'm also six years post-all bone marrow transplant, A-L-L bone marrow transplant."

(44:11) [Dr. Matthew Lunning]      So, what are the CAR T-cells doing if they're not working?

(44:17) [Michala O'Brien]      What's the life of a CAR T-cell is the first part.

(44:21) [Dr. Matthew Lunning]      Okay.

(44:22) [Michala O'Brien]      And they've been told that it isn't helping.

(44:25) [Dr. Matthew Lunning]      So, depending upon the constructs, whether or not it's the CD28 or for 1DB, perhaps that can comment to the longevity or the persistence of the CAR T-cells. But with both post-stimulatory molecules, you can see CAR T-cells persist for a very long time. If the disease has come back after CAR T-cell therapy, it could have been that the antigen that the CAR T-cells was targeting, it may no longer be expressed or expressed to the degree that the CAR T-cells can recognize it and gauge it. Or the CAR T-cells may have went into an exhaustive state, meaning that they just didn't have the capabilities because of the T-cell, innate T-cell features was unable to kill the cancer cell. So, there's multiple reasons that we're just starting to elucidate on why people relapse after CAR T-cell.

(45:31) [Michala O'Brien]      "Which is more effective treatment for multiple myeloma: CAR T therapy or auto transplant?"

(45:39) [Dr. Matthew Lunning]      That's a research question that may get answered in future clinical trials. Remember, often we're using CAR T-cells for people with very active disease. And often in myeloma, we're using autologous transplant as a form of consolidation. So, people in the majority of the timeframes, we're using autologous transplants, given the highly effective frontline therapy in myeloma, we're using melphalan-based auto transplant to consolidate. They're trying to improve upon... people can be in stringent complete remissions and still get auto transplant where there isn't going to be significant improvement in their serologic disease and they have negative bone marrows going into it.

(46:30) So really, I think you're comparing apples and oranges when you ask that question, at least in 2021. May we do in the future an auto versus CAR T-cell consolidated trial in multiple myeloma? Potentially, that may occur. But I think we have to wait and see how CAR T-cell and myeloma perform in the post-commercial setting.

(46:59) [Michala O'Brien]      "What are the specific reasons for not driving after transplant?" I think you talked about that a little bit during the show.

(47:06) [Dr. Matthew Lunning]      Yes. I think this is something that came in the early days of post-CAR T-cell. We knew there was neurotoxicity and we didn't understand what was the long-term neurologic effects, and I think it just became one of those recommendations that was handed down by the agency and an eight-week time frame. I don't know that there was any clear cut data to say that eight weeks is safe and six weeks isn't, or maybe we should go to 12 weeks. It's just been an adopted standard. I can tell you that I am one in the pre-COVID era, I was ready to study this question, had a clinical trial all set and ready to go, and it got COVID-ed because we were going to try and study people and see how their driving efficiency was pre- and post-CAR T-cell. I hope that that trial will get resurrected so I can answer that question the next time I give this talk and the next time somebody asks me that question.

(48:18) [Michala O'Brien]      All right. The next question is, "I had a scary reaction to the DMSO during auto transplant. It made me severely anxious and I had trouble breathing. Is DMSO the only preservative they can use?"

(48:35) [Dr. Matthew Lunning]      That is a very good question, one that I've not been asked before, but I believe DMSO is the only one that I know of, but I would discuss that specifically with your care team if you're considering a CAR T-cell therapy so that they can engage the manufacturer early on to see if there is any capability or any possibility of substitution as well as how confident the care team is, is that the reaction is related to DMSO. So, I think that those are two things that I would give as advice to that question.

(49:21) [Michala O'Brien]      "Myeloproliferative disorders and CAR T-cell therapy: where does this stand?"

(49:29) [Dr. Matthew Lunning]      So, MPM lives on that spectrum of myeloproliferative neoplasms, myelodysplastic syndrome and then acute myelogenous leukemia. So really, CAR T-cell needs a specific target in order to engage. I'm sure that there are researchers that are trying to go after certain targets against myeloproliferative neoplasms, but you have to remember whether there are effective therapies for myeloproliferative neoplasms. And so, you have to really find the right risk benefit ratio to do therapies like CAR T-cell therapy in certain diseases.

(50:15) [Michala O'Brien]        "What's the mortality of CAR T-cell therapy?"

(50:20) [Dr. Matthew Lunning]      So, if you're speaking towards people dying related to the CAR T-cell therapy and not related to the disease, that has occurred. It has gotten better over time. For instance, the most recent Zooma-5 data, which was data from follicular lymphoma, again an indolent lymphoma with people who have previously seen two prior lines of therapy. So again, a disease that you may consider indolent, but is not being indolent in this population. I believe there was one death related to a grade five cytokine release syndrome. There were other deaths early on, potentially due to neurotoxicity. But if people are dying post-CAR T-cell, the vast majority of the reason is due to disease coming back and not necessarily due to the CAR T-cell causing death. But it has occurred.

(51:33) [Michala O'Brien]     "If you have one CAR T-cell therapy, can you do a second treatment?"

(51:39) [Dr. Matthew Lunning]      Yes. So, we kind of commented on that question a little bit earlier, so there is data from Axi-cel where people have received treatment and then had a response and then had the disease come back and be re-treated. Often, I think the summary of that data is that the response may be equivalent in duration or potentially a little bit less. I think that if you're going to do a second CAR T-cell, you should have that of the same antigen. So if only engaging CD19, you should have a plan potentially like an allogeneic transplant to consolidate if the patient goes into a remission acceptable to go to an allogeneic transplant. Also, could get a clinical trial that may allow prior treatment with CAR T-cells that may engage not only CD19 but a different antigen like CD20 or CD22 and in that case, CAR T-cells may be able to be done a second time.

(52:53) [Michala O'Brien]      "Would a 74 year old man treated with CHOP in 2016 and an autologous transplant in 2019 for diffuse large B-cell NHL [non-Hodgkin lymphoma] be considered for a CAR T-cell therapy? He's currently undergoing bi-monthly treatments of rituxin for a planned two year period for follicular NHL."

(53:20) [Dr. Matthew Lunning]      So being that he's had two prior lines of therapy, but it sounds like this individual had what I call a retrograde transformation, so meaning that he had a diffuse large B-cell lymphoma, which is an aggressive non-Hodgkin's lymphoma and then when it relapsed, it relapsed as a follicular non-Hodgkin's lymphoma. But this is a matter of counting from that standpoint. Being that he had two prior lines for diffuse large B-cell lymphoma, had it come back as a diffuse large B-cell lymphoma, then the patient would have been eligible for CAR T-cell therapy. But being that it came back as a follicular non-Hodgkin's lymphoma or [inaudible] lymphoma, often, those patients can be treated differently than diffuse large B-cell lymphoma and I think that if it stays follicular lymphoma, then that individual could get CAR T-cells after two further lines of having had exposed to two lines of therapy for follicular lymphoma, given their history. If it transforms back to large cell lymphoma, let's say it progresses, then I think you could argue that he's seen two prior lines of therapy for his large cell lymphoma. And CAR T-cell therapy may be an option at that point. Good question. I mean, complicated question.

(54:48) [Michala O'Brien]      The next question: "Does exposure to a bi-specific like blinatumomab decrease one's chance to a CAR T success?"

(55:01) [Dr. Matthew Lunning]      So, yeah. So, blinatumomab is an agent that has been tested and is approved in ALL and it's a drug that engages CD19 but also bring the native T-cells, so it's a bi-specific engager where it recruits CD3 positive T-cells and engages CD19 positive B-cells and that should hopefully lead to death of the tumor. I think that in people who have seen prior Blin exposure and then are potential candidates for CAR T-cell therapy for ALL, if it meets the right label indication, can proceed to CAR T-cell with the hopes of efficacy. I think there is some discussion still in ALL. I'm not an ALL doctor, but I still think there is some discussion in ALL in this situation whether or not if a response is seen post CAR T-cell whether or not you would take that person to an allogeneic transplant if available.

(56:16) [Michala O'Brien]      "Can CAR T-cell therapy be used for relapse of T-cell CLL after Campath and a stem cell transplant?"

(56:26) [Dr. Matthew Lunning]      So remember, it's all about the antigen that you're attacking, right? And so, these are T-cells that are going after a target that's a B-cell marker. And so, if you had a CAR T-cell that attacked a T-cell marker, there is a concern about this concept which is called fratricide, whereas the CAR T-cells are going after each other. So, you have to find a unique enough target for the T-cells to go after and not attack themselves in this situation. So really, treatments for, if there's cellular therapies out there for CLL, this would live in the clinical trial realm.

(57:14) [Michala O'Brien]      Okay. This one says, "I was treated for non-Hodgkin's lymphoma via autologous stem cell transplant. I'm three years and three months post-transplant. I feel great, but always wonder as I progress, will I ever need a CAR T-cell transplant? I am 71."

(57:37) [Dr. Matthew Lunning]      I'm glad that you feel great and I'm glad that you're in remission at three years and three months post-autologous transplant for your non-Hodgkin's lymphoma. I think it depends if your lymphoma were to return. I think it depends upon what type of lymphoma returns and how well you feel and how good your organs and your body is functioning at that time and you would make that decision if you need to, and I hope you don't need to in the future and at that time, but I think that CAR T-cell again, and we do, I'm not sure of the CAR T-cell has an upper age limit to its therapy and I think it can be part of the discussion.

(58:23) [Michala O'Brien]      Closing. Great. Thank you. On behalf of BMT InfoNet and our partners, thank you Dr. Lunning for your very helpful remarks. And thank you, the audience for your excellent questions. This was a great workshop.

(58:37) [Dr. Matthew Lunning]      Yes. Great questions. Thank you for your time.