CAR-T cell therapy: The Australian patient experience

Chapters

[0:00] Introduction & Speaker Background
[0:53] Presentation Overview: The CAR T Patient Journey
[2:28] Step 1: Screening & Pre-Treatment Workup
[4:29] Step 2: T-Cell Collection (Apheresis)
[6:24] Step 3: Manufacturing & Bridging Therapy
[8:24] Step 4: Lymphodepleting Chemotherapy
[10:29] Step 5: CAR T Infusion Day
[11:30] Neurological Assessments (ICE)
[12:29] How CAR T Cells Work (The “Pac-Man” Analogy)
[13:39] Side Effect: Cytokine Release Syndrome (CRS)
[15:05] Side Effect: Neurotoxicity (ICANS)
[16:33] Differentiating CRS from Infection
[17:59] The Acute Inpatient Period (Days 0-28)
[20:21] The Crucial Role of the Carer
[21:18] The Role of the Patient Post-Infusion
[22:05] The Day 28 Response Assessment
[23:37] Long-Term Follow-Up Schedule
[24:38] Life After CAR T: Ongoing Care & Monitoring
[25:54] Conclusion
[26:03] Q&A: Collecting Stem Cells & T-Cells Simultaneously?
[27:20] Q&A: Are Side Effects Less Severe Now?
[28:14] Closing Remarks & Seminar Information

Transcript

[0:00] Welcome back everybody. It’s my pleasure to introduce our third presentation. Tai Simpson is the CAR T clinical nurse consultant for clinical trials at the Alfred Hospital in Melbourne. He coordinates care for clinical trial patients from the early stages of pre-screening, acute inpatient admission and through to long-term follow-up. Tai manages patients with a variety of haematological malignancies receiving novel CAR T therapies. He will also oversee the introduction of NK CAR cells for solid tumour in medical oncology. Tai began his career working in intensive care before following his passion into haematology. Tai’s other interests include the patient experience, improving patient outcomes and holistic care. Tai’s presentation today is titled ‘CAR T: The Australian Patient Experience’. Thanks for being with us, Tai.

[0:53] Thanks, Kath. And thanks to everyone from Myeloma Australia for asking me to present today. It’s really exciting to be able to talk directly to patients. Usually when we’re giving chats, it’s to colleagues and to referring specialists. So it’s really great to be able to talk to patients and families and their carers today.

[1:15] So as Kath said, I’m the CAR T nurse from the Alfred. I work in clinical trials mostly looking into novel CAR Ts. So CAR Ts that haven’t been given to humans before, but also looking at CAR Ts that we know work in a certain population of people but trying them in different populations.

[1:38] So my talk today hopefully runs for just over 20 minutes. I’m going to cover what was previously mentioned before—that there’s quite intensive screening for CAR T-cell therapy. So what workup and investigations you’ll go through, how we collect the T-cells, what chemotherapy we give prior to the CAR T infusion, the CAR T infusion itself and the common side effects that you may experience when you’re admitted or in the long-term follow-up period. The role of the carer and the role of the patient during follow-up. What we do at 28 days after the infusion to see if there’s been any movement from the CAR T cells. What’s involved in long-term follow-up and what life looks like after CAR T-cell therapy.

[2:28] So as mentioned before, there’s screening and workup involved in CAR T-cell therapy that usually is done over a couple of days but I’ll break that down in a little moment. The screening and workup investigations. Once you meet all those criteria, we proceed with the CAR T-cell collection or the T-cell collection prior to having them genetically reprogrammed to become killer T-cells, the chemotherapy before the CAR T infusion, the CAR T infusion itself, and then follow up.

[3:06] So screening investigations, they’re usually completed over one to two days. Different hospitals will vary depending on the capacity and the majority of the time patients have this completed as an outpatient. So you won’t need to be admitted for this. We look at the myeloma protein and inflammatory markers of the blood. We also check for different types of organ function. We perform a bone marrow biopsy looking for myeloma cells in the bone marrow. We look for myeloma protein in the 24-hour urine collection. We do cardiac scans to make sure the heart’s okay for chemotherapy and some of the side effects that you may experience. And we perform imaging either via CT or a PET scan.

We look at dental history and we assess the veins to plan for the T-cell collection. And at that time if your veins have been exposed to chemotherapy before you may not have good access. So it’s just about planning for how we’re going to collect those T-cells which I’ll go through in a moment. One of the common side effects—well not common side effects but one of the side effects—of CAR T-cell therapy is neurotoxicity. So understanding what the brain looks like before we give CAR T-cell therapy. And part of that’s with a neurology review either via a neuropsychologist or a neurologist.

[4:29] So apheresis is how we collect the T-cells. It’s also called leukapheresis and is the process of collecting the T-cells from the peripheral blood. Patients that have had a stem cell transplant before would be familiar with a stem cell collection. It’s done either peripherally or via central line catheter. As I mentioned before, the thing with this is that it’s called a non-mobilized collection. So when we’re collecting the stem cells, we have to give a medication to get the stem cells out of the bone marrow and into the blood. But with the T-cells, they’re already circulating.

When you’re on the machine, there can be some changes to your blood pressure and you have to remember we’re removing part of the blood. So, you can experience tingling of the lips or tingling in the hand. It’s completely normal. We run transfusions during the collection. And you’re observed by a specialist nurse. And it’s one-on-one. The procedure itself takes four to six hours. It’s again done as an outpatient. It’s very boring, so please bring something to entertain yourself.

[5:42] So, you can see here this patient’s having an apheresis product taken out. There’s a draw line from one of her arms. It goes into this high-tech what I call washing machine over there with the lines on top of it. And so what happens is the blood comes into the machine, it spins very very fast and it separates all the different blood components. And from that we can isolate and take the T-cells. The blood is then mixed back together and reinfused to the patient on the other side. So it’s usually either done in a chair or it can be done in a bed over that 4 to 6 hour period.

[6:24] So down at step number one it’s leukapheresis. So collecting the T-cells. The T-cells usually this process is over one day. Some products do require a two-day collection if we haven’t collected enough cells. And then the cells in Australia, because the manufacturing site for these cells are overseas, either in Europe or America, the cells are then frozen here and sent off for manufacture. And that’s where the programming of the cell is hijacked and they are reprogrammed with specific in this case for myeloma BCMA antigen which is the attraction that they will have on the myeloma cell.

Once they’ve done this process the CAR T-cells are then expanded and then they go through conditioning before they’re sent back to us. And this process generally because we’re so far away from where it happens takes about four to 5 weeks. Because four to 5 weeks or even sometimes 6 weeks can be quite a while for someone to go without treatment. We sometimes look at something called bridging chemotherapy which is basically us giving you some chemotherapy while the cells are being made to keep everything at bay. It can be if you’re referred as previously mentioned from a regional or a remote centre where you normally have chemotherapy, if you get sent to us for CAR T-cell therapy you can have this bridging chemotherapy done at home. It can include not only chemotherapy of tablets and intravenous or subcutaneous injection, it could be radiotherapy. And at the conclusion of the bridging chemotherapy we do all those re-staging assessments and that’s so that we have established a new baseline and at 28 days after the infusion we can check that the response that you’ve had is actually from the CAR T-cells and not from the bridging chemotherapy.

[8:24] So the cells are back and we’re ready to go. They’ve passed all their tests and we’ve got a product that we’re ready to infuse. Depending on where you have CAR T-cell therapy. At the Alfred we give the what we call lymphodepleting chemotherapy. So lymphocytes are the T-cells that we collect to turn into CAR T-cells. And what we do is we lower the lymphocyte count to allow for the CAR T infusion because what happens is when we take the T-cells out, your body replaces them quite quickly and so we lower the T-cell count. But by doing that we can also lower some of the red cells and some of the platelets. So it’s given over three days. It’s given we like to do it over a Wednesday, Thursday and Friday. So we refer that as day minus five before the infusion to day minus 3. So 3 days and it’s given by a central line. So through a PICC line or a Hickman’s and we use fludarabine and cyclophosphamide which is generic; it’s used for most lymphodepletion for CAR T products.

Again it’s done as an outpatient. It’s a 2-hour appointment and because we’re giving chemotherapy we need to make sure that all your counts are robust. So we’re looking at doing blood tests daily and if there’s anything low we’re replacing that while you’re here. So by lowering your lymphocyte count, the T-cells, they’re part of the inflammatory immune response, you’re at risk of infection. And one of the other white cells that we watch very very closely, which everyone would be familiar with, is the neutrophils. And patients can become neutropenic during this phase. So there’s three days of chemotherapy followed by the weekend. And during the weekend, the patients get to go back home. If you’re referred to us, you would stay close by in local accommodation. Or if you live in Melbourne, for example, near the Alfred, you get to go home for the weekend and you represent on the Monday for the CAR T infusion.

[10:29] So the CAR T infusion is either done as an inpatient or an outpatient. We do it as an outpatient at the Alfred. We get you in nice and early. We do blood tests to make sure that everything’s on track. We do what we call a baseline ICE assessment which I’m going to go through shortly. We also do other complex neurological assessments. Now the infusion itself is very very quick. It only lasts about 15 to 30 minutes. Some of the products in clinical trials can be given over minutes. It’s infused again through the central line. So no need for constant blood tests and cannulas. You get the line in prior to the chemotherapy and that stays with you right until day 28.

We observe you very very closely. It’s very anticlimactic. Patients are sort of waiting for this big bang but it’s just as simple as sometimes for CAR Ts for myeloma they’re pushed through a syringe and other times they go through a small bag through the drip.

[11:30] So the ICE neurological assessment, there’s its breakdown. You don’t have to remember that. It is an assessment that we do to test for neurotoxicity. So we ask you if you can tell us the year, month, and city. If you can tell us where you are, we get you to follow a command. It’s a very simple command as easy as touch your right ear with your left thumb. We point to three objects and get you to name them. Something as simple as a cup, a pen, and a name tag. We get you to count back from 100 by 10 all the way to zero. And then we ask you to write a sentence. The sentence, we are looking for changes in the handwriting. It’s very very interesting. These questions and the assessment seem very very basic, but these basic questions were able to pick up small changes in cognitive function and handwriting.

[12:29] Okay, so we all know Pac-Man. So you can see in the second graphic there’s some myeloma cells. There’s a blue one, a pink one, a yellow one, and a red one. And Pac-Man’s down the bottom. So these are charged CAR T-cells. And I explain to my patients, it’s like we’ve just put in 10 million Pac-Man. And they know exactly what they’re doing. They’re going to find the myeloma. They’re going to munch it down and hopefully get rid of it.

At a closer look, you can see this is a very fancy picture, but how I’m going to explain it is the top yellow cell is a T-cell and this purple cell to the left hand side is myeloma or BCMA we’ll call it. And what you can see here is that the CAR T-cell is attracted to the myeloma and initiates the immune response. So the body’s own inflammatory immune reaction to the myeloma cell. You can see there’s the small white specks which I’ll refer to as cytokines and the cytokines are then released into the blood which is kind of the sort of ready set go of the immune system.

[13:39] So cytokine release syndrome as I said is the release of cytokines from the CAR Ts doing their job. It’s experienced by about 95% of patients. It’s very common; most patients experience it in the more what we would call grade one CRS which is just an isolated fever on its own. Patients may also experience low blood pressure which we give fluids for or temporary low oxygen concentration which we give oxygen for. So we watch you very closely and at the first sign of fever, we initiate aggressive treatment straight away. We know that the harder we treat these things from the beginning, the less severe they get and for reduced duration. So some patients may only get a fever, some may get fever and low blood pressure, some may get fever, low blood pressure and low oxygen and may need a trip to ICU for blood pressure monitoring.

We use, as I said before, it’s an inflammatory response. We use anti-inflammatory medications, things like dexamethasone, but also we’re able to slow down the immune system by giving special antidote medications. And the one for cytokine release syndrome that we use most commonly is called tocilizumab, which you don’t need to remember.

[15:05] So neurotoxicity we refer to as ICANS. Everything’s abbreviated in medicine as you probably know. It stands for immune effector cell-associated neurotoxicity syndrome. And so this is less common but can be more severe. So we get you to do the handwriting test at minimum once a day. And as things start to change, we increase the frequency. So when we’re watching you write the sentence, we may notice a tremor in the handwriting or the words may be misspelled. There may be some mild confusion. So you’re alert and orientated but may not be able to recall the exact date or the day of the week or the year or exactly where you are. There could be some fluctuation in mood and in the more severe and very rare side effects things like seizures and loss of consciousness.

The way I think about it is that those cytokines from that picture before, the little specks that looked like they were being released from the T-cell, some of those inflammatory markers can cross into the brain and it causes inflammation of the brain or swelling and like CRS we treat very aggressively from the moment we pick it up again with anti-inflammatory medications and anakinra is an injection that we give which is a very fancy antidote that is quite effective at reversing neurotoxicity or at least slowing it down.

[16:33] So what does this all mean? You’ll be admitted on the ward by this stage. And when patients have a fever, how do we know if it’s cytokine release syndrome or an infection? Because the cardinal sign of infection in a haematology patient is a fever and the cardinal sign for CRS in a CAR T patient is fever. So we’ve got some investigations to do. So just because you’ve had CAR T and you get a fever doesn’t necessarily mean it’s CRS. We do what we call a septic screen. So we’re looking for bacterial organisms all through the body by the blood, urine. We might get you to cough up some sputum if you can. And we wait for these to come back. During that time, we treat you for both. So we’ve got a process of elimination. We treat you on what we call empirical cover for infection, but also treat you pretty aggressively for cytokine release syndrome at the same time. That’s so that if in 3 days there’s a bug there that we’ve picked up on one of the cultures, we’re not three days behind because as I said, part of the lymphodepleting chemotherapy is about lowering those white cells. So you are at risk of infection. And once this is all happening, we monitor your temperature much closer. We increase our neurological assessments and increase the review by not only the CAR T team but our neurology colleagues as well.

[17:59] So we refer to the acute period as from the day of infusion all the way until day 28. The lymphodepleting chemotherapy is given as an outpatient from day minus 5 until day zero. It’s only given over those three days, but we’ll just count those days in over the weekend just to timeline things a little bit easier. As I said, it’s as an outpatient and the most common side effects are either the low blood counts, some nausea, lack of appetite, and low blood counts requiring some top-up.

The inpatient monitoring stays from the day of infusion or some centres will admit the patient a couple of days after the infusion. It is in the inpatient setting. Inpatient setting is very very busy. It’s noisy. And I think talking to patients after they’ve had therapy, I think this is the most stressful time because you’re away from your family. You’re away from your support people. You get us coming up to you and being like, “Oh, you’ve got a fever and we need to do all these tests.” So, it’s very very overwhelming. The most common side effect during this time is the CRS and the ICANS, low blood counts, and of course review by all the haematology teams, but also the neurology teams as well.

From about day 14 is when you’ve passed your highest risk period. And from there, we plan discharge education not only with the patient, but the person that will be caring for them for those two weeks after discharge. And we call that a discharge education session. And during that two week period, you’re required to stay within one to two hours of the hospital. We see you twice a week as an outpatient for relevant blood tests. We do those handwriting assessments and then we obviously care for your central line as well. But one of the most important things is that we teach your carer how to do that neurological ICE assessment. So they are the person that’s going to be responsible for giving us a call and saying, you know, my loved ones dropped a point on their assessment or I have concerns for their cognition. What should we do? And that’s what we go through in the education session.

[20:21] So the role of the carer is very very important. We know that when we’re considering patients for CAR T-cell therapy, one of the things particularly that we look for is that they have a carer that can be with them from day 14 until day 28. We teach you how to do the daily ICE assessment. We do temperature monitoring. So before each meal and before bedtime, we look out for the signs and symptoms of what to look for. So, escalating to the medical team if you have any concerns or deterioration in handwriting. And then we have a transfer to hospital plan. So, if your loved one has a fever at home or you’re concerned about them, what that looks like, what’s appropriate to be transferred in a car versus what’s appropriate to be transferred by ambulance. And of course, you’re responsible for being in the same I say house now. I used to say room, but you do not have to be in the same room together 24/7.

[21:18] So the role of the patient, we know that the highest risk period is in the first two weeks, but the risk for neurotoxicity can be up to eight weeks. So there’s no driving for eight weeks. Please do not drink alcohol for the first 28 days after the infusion. It can be hard to differentiate between what’s intoxication versus what’s neurotoxicity in our assessments. So we just have that as an exclusion rule. Come to your outpatient appointments with your carer. And bring all the documentation with you. And the important thing about bringing the documentation and your carer with you is that there’s some small check-in and a bit of a handover as to how everything’s going at home.

[22:05] So, you’ve made it through to day 28 now. So, it’s 28 days after the infusion. We’re going to retest for everything and check if there’s been a response to the CAR T-cells. So looking at the myeloma markers in the blood, urine and bone marrow. Repeat imaging. We look for ongoing CAR T persistence which we can do via a blood test to see if there’s any circulating CAR Ts. The big thing that I want to make clear here is that in other types of cancer that we use CAR Ts for there’s a big emphasis on the day 28 response because the thought is for those cancers that if there’s minimal or no response at day 28 that’s the maximum response that’s going to be experienced. In myeloma we know that the day 28 assessment is not everything and I’ve had patients that have had partial response or a reduction in their paraprotein by 50% which is pretty significant at day 28 and then at month two that comes down further and they don’t reach remission until month six but I just caught up with that patient 18 months ago and she’s still remission free so it doesn’t mean everything the day 28 assessment.

From day 28 obviously you’ve had we’ve played with your immune system we’ve given you some low-dose chemotherapy you may require supportive care so regular blood tests, neutrophil stimulating medication and maybe a blood transfusion.

[23:37] We follow you up very very closely. So on day 28 if you’re stable all patients are referred back to their primary haematology team. So if you come from the country we refer you back if it’s appropriate. If you come from interstate we refer you back to your home team to follow you up really closely and the primary care team then takes over. The follow-up that we have may be different to other hospitals. So, I’ve just included what we do. We see you face to face every 28 days for the first six months. So, it’s every month you come and see us. And then after that 6 months, we see you every 3 months. So, the frequency is reduced. So, we see you every 3 months for one year and then we follow you up via phone call or telehealth or the equivalent every 6 months for 15 years as a mandated requirement for follow-up after these sort of medications that play around with your immune system.

[24:38] So life after treatment as previously covered you know we don’t really talk about the need for immunoglobulin replacement but I think it’s important to note when we target BCMA, BCMA is not only present on the myeloma cells. So regular immunoglobulin replacement either in the hospital or at home. During the first sort of 6 to 12 months we put you on prophylaxis. So thinking things like valaciclovir and Bactrim. We revaccinate you against COVID and all your childhood immunizations. There’s quite a robust plan around that. And then we would like to see some blood tests every couple of months either from us here or from your referring centre depending on where you are referred to us from. And so when CAR T is approved through the PBS we will follow you up a little bit differently to clinical trials but as said before the clinical trials like to watch their patients a little bit closer.

[25:54] And so that’s that’s it from me. Thank you. And I was just I’ll leave this slide here just if there’s any questions.

[26:03] Excellent. Thank you, Tai. That was so informative. I’m sure our audience got a lot out of that as I did as well as as a nurse in this area too. We do have a couple of questions for you. I hope that’s okay. The first one that came through says can you collect stem cells and T-cells at the same time?

[26:21] It’s a good question. The short answer is no. So when we plan for collecting let’s talk about T-cells first. The T-cells are already in the blood. So that’s the collection what we call non-mobilized collection. And to collect the stem cells we need to mobilize them using G-CSF. So filgrastim is the medication that we use. So if we tried to do both, we’d get a little bit of T-cells, a little bit of neutrophils, and a little bit of stem cells. So it’s a little bit hard. If you’re on a clinical trial, say for example, where some patients get transplant and some patients get CAR T, we would collect stem cells after cycle 2 as per most hospitals in Australia and we would also collect the CAR T-cells usually a little bit later so around cycle four.

[27:20] Right. Okay. Thank you. And the other question just relating to the side effects in your experience, do you see less severe reactions now with the better surveillance like we’ve learned along the way?

[27:33] Yeah, definitely. I think the CAR T landscape has changed dramatically in the last I’ve been doing it for two years now in myeloma and looking at what changes we use in treatment and how aggressively we treat our patients now compared to two years ago is incredible. So I suspect the reduction in significant side effects is probably because we’re treating everything very seriously from the beginning and learning each time as we go.

[28:03] Absolutely. Absolutely. Thank you Tai. Thank you so so much for being here today. We really appreciate your time and your slides. It was fantastic. Really appreciate it.

[28:12] Thanks for having me.

[28:14] Thank you. And that concludes our seminar for today. We hope you found this session informative and uplifting. A reminder, you are still welcome to send through any questions for any of our speakers today via our nurses email which is nurses@myeloma.org.au.

We would really appreciate your feedback as we’ve mentioned. So before you log off, if you would take just a couple more minutes to complete the evaluation via the link below the video on our web page. Our second seminar this month is coming up on Thursday the 28th of March and the theme is self-empowerment. We’ve got more great presentations to share with you then, including a panel discussing patient and carer experiences.

Before we say a final goodbye, I’d just like to express a heartfelt thanks to all of our presenters today and throughout the month and to the seminar organizing team at Myeloma Australia who have coordinated a fabulous program. A very big thanks also to Patrick and the team at CVP for their hard work and skill in production. Thanks so much for joining us. Have a wonderful day.