Omar Nadeem, MD
Clinical Director, Myeloma Cellular Therapies Program
Dana Farber Cancer Institute Boston, MA
Omar Nadeem, MD: Good afternoon, everyone. My name is Omar Nadeem, I’m a member of the myeloma division at the Dana-Farber Cancer Institute in Boston, Massachusetts. I also serve as the Clinical Director for the Myeloma Cellular Therapies program. It is my pleasure today to give you guys an overview of The Journey Through CAR-T Cell Therapy. We’ll be discussing topics such as design, manufacturing, and considerations for both physicians and patients as we treat more and more patients with this exciting novel therapy.
These are the program disclosures. This program is funded by Janssen.
So as mentioned, today we will spend some time giving a broad general overview of CAR-T cell therapy, including the CAR-T cell design construct and the rationale for why we’re all so excited about using this therapy in our patients. We will also spend some time discussing the CAR-T cell manufacturing process, and some of the logistical barriers that come with that process itself as it relates to patients and having them be treated with this particular product.
We will then talk about the CAR-T cell journey from both the patient perspective in terms of their expectations, but also a critical component of coordinating from a healthcare practitioner perspective the care for these patients as they go from community sites into the academic centers and then back to the community sites. And it’s critical to have that channel of communication be as seamless as possible as patients go through this complex therapy.
So we will start first by talking about just a broad overview of CAR-T cell therapy in terms of what it is and how it works.
So CAR-T cell therapy essentially is a way for our own immune system to recognize a specific antigen on the tumor cells, and this is done by essentially utilizing the immune system using a specificity of antibodies and then combining it with the cytotoxicity of T cells.
So as depicted in the picture here below, the process involves T cell apheresis or collection from the patient, and once the cells are collected the cells are then sent over to a manufacturing facility where they’re actually genetically modified. And the way this works is using this viral vector code which then expresses the CAR-T cell receptor on the surface, and then these cells are again manufactured at the facility, proliferated there, and then sent back to us to have patients be treated with this particular modality so they are then infused into the patient. And basically what this is doing is essentially creating an army of T cells that are then going to go and attack the specific tumor cell that needs treatment.
So digging a little bit deeper about what this CAR-T cell actually looks like. So it has several domains; it has an extracellular domain and an intracellular domain connected via hinge mechanism, as you can see here, across the T cell membrane. So the extracellular domain is actually a single-chain variable fragment, and this is the portion of the antibody that is very specific to the tumor that this T cell receptor is targeting. So CD19, for example, in the lymphoma CARs and BCMA now in the myeloma CAR, and many more targets that are currently in development which we’ll touch upon shortly.
So once the target and the receptor is engaged, it actually leads to activation of the intracellular domain, and then this contains again important signaling domains that cause T cell receptor to then become activated and proliferate and really generate a robust, enhanced immune response against the tumor cell itself leading to enhanced activity of this particular product in various different oncologic conditions.
So once this T-cell receptor engages with the tumor cell, as you can see here depicted in this diagram, it really leads to very direct effects onto the tumor cell itself, because it is targeted to that particular antigen. But this binding really leads to this T cell proliferation that releases lots of molecules that actually trigger lysis of the tumor cell. And this activity in itself leads to further augmentation of the immune response to antigen-presenting cells and other mechanisms, so it really sort of feeds upon itself in terms of the potency of this particular therapy once the genetically modified T cell interacts with the tumor cell itself.
So as mentioned, the reason why the whole field of oncology is so excited about this particular form of therapy is that it is one now approved for various hematologic malignancies, as you can see listed here, including ALL, diffuse large B cell lymphoma, mantle cell lymphoma, and more recently multiple myeloma which is the first approval of its kind in this particular disease itself.
And as you can see here on this table, the research is ongoing for use of CAR-T cells in many other diseases. This includes various targets for solid tumors, as depicted here, including GBM, colorectal cancer, pancreatic cancer, and various other cancers in terms of solid tumors that you can see listed here as well.
Other hematologic malignancies including other non-Hodgkin’s lymphomas where it has gained some recent approvals, as we just mentioned, T cell malignancies, and multiple myeloma using targets such as BCMA but also other novel targets that are currently in development as well. And a study of this is also underway looking at certain infectious diseases, so to really highlight the power of the immune system and then targeting it essentially to cancers and other diseases.
So I expect this area to continue to proliferate very, very fast, as it already is, with lots of different approvals, and hopefully a lot more indications for patients not specifically with the disease itself, but also in different lines of therapy where this is now being studied quite extensively in myeloma and other diseases itself.
So let’s now talk a bit about CAR-T cell manufacturing process itself.
So the T cells are harvested during leukapheresis. And then as you can imagine, the quality of the T cells collected at the time of leukapheresis is very important to create the target number of T cells necessary in them and in the labeled manufactured product, but also the health of those T cells is also equally as important to have a viable treatment option for these patients.
So we do look at certain medications that we would want patients to not be exposed to in the time right before apheresis. Some of those are listed already here in this table. So immunosuppressants, we prefer the patients are off of them in the context of ALL therapy PEG asparaginase 4 weeks is recommended prior to the apheresis session. For most of the chemoimmunotherapy that we think about in myeloma and lymphoma, we usually recommend at least 2 weeks prior to apheresis that the patients are off any of these therapies to allow for the best T cell yield. For steroids about 72 hours or more, and then for anticoagulants for obvious reasons it’s about 12 hours so patients can undergo the apheresis procedure safely.
I will say in our early experience with myeloma because the products were just approved earlier this year, this is extremely important because we have a lot of patients that are heavily pretreated and they’re on many, many different combination therapies over a very long period of time. And I think this issue of having adequate T cells collected and manufactured really kind of goes back to making sure that the apheresis goes smoothly. So this is again a point of discussion between the referring side and also the center that’s going to be carrying out the apheresis and the CAR-T cell therapy as a whole to make sure that these channels of communication are open so that way you can be up to speed with what the patient is receiving at their local center.
So once the patient’s T cells are collected, they may be frozen, or they are sometimes shipped fresh to the manufacturing facility. And then when they get to the manufacturing facility, the cells are then thawed if they’re frozen and the T cells are then isolated. Once those T cells are isolated, they’re then again genetically engineered with the viral vector to express the actual CAR-T cell construct that we talked about before on the surface, and once that’s achieved the T cells are then grown and expanded.
And this process of manufacturing can take up to 4 weeks, and in some instances it has been even a bit longer. But the general consensus is that it’s about 2 to 4 weeks depending on the manufacturer. So it is critical for us to time this properly which we’ll get into in a second in terms of choosing the right patient for this type of treatment modality, because it is a bit of a delay from when they actually are identified to when they actually can be treated.
For example, if you have a patient with multiple myeloma that you think will benefit from this therapy, early identification of that patient is critical because, one, we have to then get them a slot for the apheresis itself at the center, but also be able to keep their disease in check while their cells are being manufactured via various bridging mechanisms which we’ll touch upon in a second. But this really highlights identifying the right patient that can actually wait for the T cell product to then come back, which again can take up to 4 weeks. And once it’s back the patients that undergo lymphodepletion chemotherapy can have their cell infusion at the infusion center itself.
And there’s various quality control measures, as you can imagine, and this is really designed to make sure that the product that’s sent back is viable and meets the product label indication in terms of just the T cell health, and also the amount of cells present in the actual product.
So let’s now talk a little bit about the patient’s experience through undergoing CAR-T cell therapy.
So as we just briefly touched upon, patient identification is the first step to happen, and key to identify the right patient that meets the indication and also is fit enough to undergo this sort of therapy. We then think about some of those eligibility considerations in terms of their organ health, and again the labeled indication, etc., and the disease that we’re considering for CAR-T cell therapy.
At this time, the patient is referred to the treatment facility which really kind of verifies a lot of those eligibility considerations. And then it’s again key to have the seamless transition back to the community centers after T-cell therapy because patients are hospitalized for this therapy as it currently stands, although the outpatient focus of this particular therapy is also increasing. So hopefully we’ll be able to offer this to patients without significant need for hospitalization in the absence of management of toxicity, but right now as it currently stands, at least at our center, patients are admitted for CAR-T cell therapy for the duration of their follow-up.
But after they’re discharged, they do have to then have a very seamless transition back to their local center for supportive care which can go on sometimes for a few months after CAR-T cell therapy such as transfusion support, growth factor support, management of any kind of infections or other complications that may arise a bit later after their post-infusion course.
So we touched upon the first three items on this particular list here. So again, when you have the patient identification you have the referral to the specific center. We will then look at the patient’s eligibility in detail, and this includes not only their disease eligibility, their performance status, their organ function, but also equally as important now in the world that we in is financial constraints and which insurance they have, and whether the patient will be approved by their insurer. So we work a lot with the payers to identify, make sure that they’re up to speed with the labeled indications, and that this process as more and more people get treated with this particular therapy hopefully will become more and more seamless as time goes on.
But once all those first steps are conducted, the patient will then be set up for a leukapheresis state, which we try to get done as efficiently as possible because that’s the first step in getting the manufacturing process started, and then frequently at this time the patients will then undergo bridging therapy. And this bridging therapy is very unique to the disease that we’re talking about, but also to the patient’s ability to tolerate therapy.
As you know, these patients are progressing, hence they’re going on this particular therapy, so choosing the bridging therapy is sometimes a bit of a challenge. Particularly as I can speak to in myeloma, we have a lot of patients, right now the labeled indication for the approved product, IDE-cel, is 4 prior lines of therapy, and that usually encompasses most of our available myeloma therapies.
So if patients have progressed on that previously, we have to be a bit creative in choosing that therapy for a few weeks in between their manufacturing and their cell infusion to make sure that the patient’s disease stays in check for them to be able to be eligible for T cell infusion when the product arrives.
And then prior to the T-cell infusion, we give 3 days of lymphodepletion chemotherapy, this usually includes cyclophosphamide and fludarabine, and again this is designed to enhance the T cell product’s activity and expansion essentially in the post-infusion period, and then this will then allow the patient to hopefully respond to that therapy for a reasonable duration.
And then after that the patient again remains in the proximity of the treatment center for about 4 weeks, and this is per the FDA REMS guidelines in terms of what they need to be. So if a patient is coming from very far away, we usually have a system in place to have a place for them to stay even post-hospitalization that’s local, and a lot of this involves frequent check-ins with labs and other supportive care therapies at our center. And then after that 28-day window, patients are then usually sent to their local facility where they’ll have the routine follow-up there, and then we will still check in with them, obviously, periodically at our center for follow-up and monitoring of their disease status.
So now just talking a bit more specifically about which patient is generally eligible for CAR-T cell therapy. So as mentioned again, I can speak more to the myeloma world since that’s what I do. You have to identify again identify these patients a bit earlier than that fourth prior line of therapy, because at that point the benefit that patients get from what’s available is relatively short, and in that window their disease progresses very rapidly even if we think they’re an ideal candidate for CAR-T cells, sometimes it’s just reality, unfortunately.
By the time we identify them, they go through the apheresis, their disease can be progressing, their counts get worse, their renal function may get worse, and it really makes T cell infusion not a reality, unfortunately, for a lot of these patients. So it’s really critical to identify these patients a little bit before that, refer them to the center so that we can prepare to be able to offer this treatment to them in real time.
We will obviously make sure that they meet the criteria per the label, and again a lot of this goes back to the payers and what they will approve for CAR-T cell therapy for a particular patient, as well, and so we will start that process a bit early at that time.
And then general expectations the patient’s in good health, they have an ECOG performance status of 0 to 1. And equally as important is that they have a good support system for undergoing this entire process, because if they’re coming from a different site they have to stay somewhere else for up to a month, they really need caregivers and other members of their family and friends to help out in that context to get them through this phase of therapy.
The good news is once patients usually recover from the toxicities and other side effects that may come from this particular form of therapy, we don’t really see too many downstream effects with CAR-T cell therapy, similar to what we may see, let’s say, with an autologous stem cell transplant where the patients may take several months to really bounce back into their previous state. In CAR-T cell therapy, although the toxicities are unique, they are short-lived at least in that several week window when they’re monitored very, very closely.
So again, in terms of talking to patients about this, you have to just think about is CAR-T cell therapy a viable treatment option based on what we just talked about. Is the patient at risk for disease progression? And again, if they are then I think a lot of times it just becomes very challenging for them to actually receive this particular product.
Is the patient well enough for treatment and immunosuppressive therapy? Because again, this will because of lymphodepletion chemotherapy they do get cytopenic, sometimes those cytopenias do take a while to recover, so is the patient able to handle that nadir from therapy and all the toxicity that may come from the T-cell product itself.
And again, importantly, does the patient fit the product indication, and does the patient have a support system in place, as we just touched upon.
Speaking of that again, we do have again some assistance from our entire team and other centers’ teams that do this, so guiding them via nurse navigators that help from the identification process to coordinating a lot of the pretesting that goes, and the post-care after cell infusion once they leave the hospital. So we have our support system in place to help patients navigate through this complex treatment.
But again, I think we see particularly with some products more so in lymphoma where patients may get neurological toxicity with CAR-T cells, and perhaps they’re not as robust as they were at least for the short duration post-T-cell therapy where they may need some extra help. So we want to just make sure that transportation from the treatment center and other appointments is in place, caregivers can remain with the patient for an extended period of time even when they’re home or at the treatment facility.
There are some complex medication management issues that may come up post-T-cell therapy, whether it’s antibiotics or other things that we have the patient on. Help with just household and general care. This is not unique to T-cell therapy, but still making sure that they’re able to care for themselves when they get home is critically important.
And then having really an additional point of contact for the medical team. As I alluded to earlier, as we’re considering moving some of these therapies to the outpatient world, we’re really thinking about how can we do this safely. If the patient is developing some toxicity and they’re not necessarily able to communicate that to us, well that’s a big problem, and obviously we’re going to need somebody from their caregiver team to help us monitor the patients for these adverse events that may occur.
In terms of logistical considerations from the referring center perspective, how far is the closest treatment center and what CAR-T products do they offer? I think some of the challenges that we’ve faced in the myeloma rollout so far for CAR-T cell therapy is just the availability, so not only do we have the approved available products but also several clinical trials obviously that include CAR-T cell therapies that could potentially be an option for the patient.
So you have to think about which center is close, but also which center has the capability of offering this sort of treatment to your patient at the time of referral. And can the patient actually stay there for 4 weeks or an extended period of time, or if they fall within the general window that we’d consider to be an acceptable range even within post-discharge, is that going to be too much of a barrier to getting in and out of the city, for example, where we are?
And again, has the patient and the treatment team investigated the financial impact of treatment, and then where can the patient make these arrangements for leukapheresis? For us it’s done at our site where the patient is actually being treated, but a lot of this again requires a fair bit of coordination.
Now jumping to the actual infusion itself. So it’s actually relatively uneventful, so when the cells actually come back and they get their lymphodepletion chemotherapy, a few days after that they get their cell infusion. We give some pre-medications to prevent allergic reaction, but most of the time this particular process of the cell infusion isn’t very eventful. And the T cells are usually frozen, and they do have a short window in which they must be used after thawing, and then once the cells are inserted that’s where all the action happens in terms of toxicities.
So this is where it’s quite variable amongst different products both in lymphoma and in myeloma, so obviously we talk about cytokine release syndrome shortly, but the timing of that really is quite different. And then some products will have perhaps a higher incidence of neurological toxicity compared to the others, so when we think about choosing the right product for the right patient we’re looking at all these considerations in terms of timing and severity of CRS, incidence of neurotoxicity, and all these things.
As we get more and more products available in the clinic, and they don’t usually have a lot of head-to-head comparisons within the disease, we’re using some of these toxicity considerations when choosing the right therapy for the right patient.
So again, I think we’ve touched upon this a bit. The patient will be closely monitored in the short term for adverse events and long term for relapse and delayed toxicities. So the adverse events again can occur either immediately or delayed. Most of the CAR-specific adverse events do happen within the window where they are under the care of the tertiary care center where their T cell infusions are being administered. And then again, usually we have a team of providers that manage this day in and day out, so recognition of the early signs of these toxicities is extremely important.
And then from 4 weeks onward you have to monitor obviously for disease progression and signs of relapse. Again, this requires a lot of coordination between the treatment center and the referring physician. And then we do recommend that the patient return to the treatment center at regular intervals for the first few years so we can monitor their disease status and any delayed toxicities that may occur for some of these patients, but at that point most of the post-CAR management is in the hands of the referring team.
And right now as things currently stand, although we are looking at several things in the myeloma world about what to do post-CAR T cells, right now it’s nothing. Patients are actually essentially on observation, so that really leads mainly to supportive care in terms of requirements for post-CAR T cell therapy follow-up.
So now just talking specifically about some of the toxicities we see with CAR-T cell therapy. So CRS, or cytokine release syndrome, is very, very common and almost universally seen across all these CAR-T products, and this is basically a constellation of symptoms that really represent immune activation. So they can lead to fever, blood pressure changes, people can develop low oxygen levels, can lead to arrhythmias or some organ dysfunction as a result.
These can be very mild ranging from just a fever, and we have a grading system that we use to identify which grade they are, which then ties into what we do about it. But essentially we talk about fever as Grade 1, and then if they’re starting to have any other compromise such as hypotension or hypoxia, then they move up the grading scale and that’s where we up some of our supportive care therapies.
So initially it’s just management of fever usually with just measures like Tylenol, and then if patients are getting sicker we are now very quick to use drugs such as tocilizumab which is an IL-6 blocker or what steroids depending on the severity of these particular symptoms. And then it can escalate all the way up to ICU level care with vasopressors or a need for high-flow oxygen and things like that.
So we have a stepwise approach as to how we manage this. We have had some challenges recently because there is a tocilizumab shortage, so these are some of the things to think about now as we’re treating a lot of these patients with CAR-T cell therapy about how we allocate some of these resources. Thankfully we’ve been okay so far, we haven’t run into any trouble with that specifically, but it’s something to watch out for as time goes on.
The next big toxicity with CAR-T cell therapy is neurological toxicities, terms ICANS which is immune effector cell-associated neurotoxicity syndrome. And this can have again a varying range of symptoms ranging from just mild cognition and confusion, problems with attention, all the way to seizures, cerebral edema, and then much more serious impairment of motor function, etc.
For the most part, the management of this is supportive care initially, but steroids are really the backbone of management with this particular toxicity. In the CAR products that carry a higher incidence of neurological toxicity, we do prophylactic measures such as seizure prophylaxis, and we’re very quick to intervene again with corticosteroids at any signs of neurological toxicity along with obviously neurological monitoring with imaging as appropriate.
We are seeing differences in terms of the incidence of this amongst different products, and in the multiple myeloma world we’re not necessarily seeing too much of the neurological toxicity to go with the CRS which we are seeing very, very frequently.
So just to summarize points that we raised today. Again, early identification of the right patient is key, and referral to the center prior to perhaps the exact labeled indication is probably important so that we can make sure that the patient will be eligible for that therapy at the time that they need the therapy. And then we’ll talk again about insurance coverage, transportation, the labeled indication, the disease they have matching it with the right product that we have; all those things will happen at that time at our center.
When we feel the patient is appropriate for treatment, they’ll undergo leukapheresis and then have everything coordinated here in terms of hospitalization, etc. And then immediate post-infusion follow-up will occur at the referring center for at least a month or so, and then the patient will go back to the referring site for further therapy.
And again to just summarize the T-cell therapy itself. Again, these are genetically modified T cells that express an antibody receptor against these tumor antigens, and again that exact antigen pool is increasing very rapidly amongst different diseases and even within diseases as we’re identifying new targets. Again, this is now approved for several hematologic malignancies and is under investigation across a variety of other diseases such as solid tumors, and again this is the greatest form of immunotherapy, in my opinion, because it is really using your own immune cells and directing them to the tumor cell that’s in need of therapy. And then again, using coordination between referring physician and a certified center is key to make sure that we take care of these patients properly.
And then in the final few minutes, we’ll just quickly touch upon the differences between stem cell transplant and T cell therapy. So this is a question that we get asked quite commonly, and now we’re starting to see some data with which is the better approach. Right now we don’t think of these as replacing one another, we think of them as separate from each other at least up until now in terms of what we have seen with different products, but even though both require collection of a patient’s cells, whether it’s stem cells or T cells, the intent of therapy is totally different.
So in autologous transplantation that we do for multiple myeloma, the goal of that essentially is to deliver high-dose melphalan or high-dose chemotherapy which is really disease-targeting in terms of targeting with chemotherapy as opposed to with immunotherapy, whereas with CAR-T cells you’re really taking the T cells, modifying them to recognize BCMA or other targets, and then growing them and infusing them in the patient really to allow the cells to do all the work. So really the chemotherapy component in CAR-T cell therapy is really designed as a form of lymphodepletion which will just allow the T cells to essentially work and do what they’re designed to do.
Some of the other differences then come into recovery, as we talked about. Recovering from high-dose melphalan is very different than recovering from the T cell-mediated toxicities that may occur in that short window such as CRS and neurological toxicity that we talked about. They are both in myeloma a form of autologous therapies, so they are from patient’s own products, although we are now looking at various other allogeneic forms of off-the-shelf therapies when it comes to T-cell therapies and other therapies that are currently under investigation.
And while stem cell transplant doesn’t have some of the unique toxicities such as CRS or neurotoxicity, it is more likely to have delayed toxicities that we see not uncommonly in patients that receive high-dose therapy, etc. So although there are a lot of similarities, they’re equally as important in terms of differences.
So with that I think that was the last slide, and I will take a few questions that I think have come up in the chat.
The first question is could you explain the 4-week stay after therapy? What level of support do patients tend to need at this stage?
Basically, what happens is the patient gets admitted for their cell therapy. So a lot of times we do the lymphodepletion piece as an outpatient, and then when the date is due for their cell therapy, the day before they get admitted and they get their cells. At that point there’s quite differences amongst different products in terms of when the CRS occurs. In some products it occurs almost immediately within the first day or two, and other products it doesn’t appear for a week or so.
Right now we’ve kept everybody in-house mostly, we’ve tried to have sort of an outpatient hybrid-type system where they may come out for a few days, but they’ll still be in proximity at a local hotel or a center near us. They’re followed daily, essentially, as an outpatient with assessments, and if they’re starting to have signs of CRS or neurotoxicity, etc., they will get readmitted, and we’re trying to make sure that that process is quite seamless. So basically looking at that particular piece is happening in the first two-ish weeks of their first 4-week stay where they’re mostly in the hospital during that time frame.
After that, a lot of it is just essentially outpatient care where they may come in and get assessed a couple times a week. If they need blood products or if they need growth factor support, if they have specific infections or toxicities that may have occurred, that’s really what’s happening in that particular time point. So usually by the time they’re leaving the initial stay, the patients should be feeling pretty close to baseline post-CAR-T-cell therapy.
So I think this is highlighting the next question that I see here. In terms of outpatient administration, I think the key really is to make sure that that seamless transition from inpatient to outpatient is key, because what we see is if the patient’s getting a fever and we know it’s CRS, we don’t want to wait until they go to the ER, and then they wait there for several hours and they finally get their medication that they need immediately.
That’s what we’re trying to avoid. And some of this is challenging because we have bed constraints, and as you know everything is so busy. So we want to make sure that that process is seamless. We’re looking at wearables and having monitoring of vital signs, etc., and we’re going to be building the outpatient program more and more going forward as some of these differences occur between different products.
I think that’s all the time we had. I appreciate everybody joining and hope you all have a great day. Thank you so much.
*Provide an overview of chimeric antigen receptor T cell (CAR-T) therapy
*Explain the CAR-T manufacturing process
*Understand the CAR-T journey for both patients and healthcare practitioners (HCPs)