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Amelia Langston, MD: Hello. I'm Dr Amelia Langston from Emory University. Welcome to Medscape's InDiscussion series on chimeric antigen receptor (CAR) T-cell therapy. Today we're going to be discussing CAR T-cell therapy for B-cell acute lymphoblastic leukemia (ALL) with Dr Bijal Shah. Dr Shah is an associate member in the department of malignant hematology at Moffitt Cancer Center in Tampa, Florida. Dr Shah's primary clinical interests are non-Hodgkin lymphoma and ALL. Dr Shah is both an internist and a pediatrician and has a special interest in adolescent and young adult malignant hematology. In previous episodes, we talked about CAR T-cell therapy to reprogram a patient's own T cells to become targeted killers aimed at tumor-specific cell surface proteins. Today, we're going to focus on the applicability of these therapies to B-cell ALL using CAR T cells targeting CD19. Dr Shah, pediatric ALL was one of the first dramatic success stories for CAR T-cell therapy. Maybe we can start by talking about some of the early studies that established the promise of CD19-directed CAR T-cell therapy in this setting.
Bijal Shah, MD: We wouldn't be talking about CAR T-cell therapy were it not for the early experiences with tisagenlecleucel. These data were published in a couple of studies — a global study as well as a phase 2 study out of the University of Pennsylvania showing that relapsed/refractory ALL patients could achieve extraordinarily high response rates upward of 80% and were minimal residual disease (MRD) negative. Starting from that pivotal point, we saw children with multiply relapsed disease achieving deep responses. Classically, we were taking these patients to bone marrow transplant, and if there was a recurrence after the bone marrow transplant, we tried a number of different approaches such as chemotherapy, novel agents, targeting a specific enzymatic pathway, or a combination of a few of these in hopes of achieving something. The mortality rates were extraordinarily high, as you can imagine, with successive myelosuppressive therapy. We weren't just losing patients to their disease — we were losing them to treatment-related toxicities as well. Tisagenlecleucel coming on to the scene changed that paradigm. We took patients with relapsed/refractory ALL and achieved these very high response rates. What was unexpected was that these response rates were sustained. Fast forwarding, we have published data out to 3 years. We also have data that were presented at the European Hematology Association meeting last year, with 5-year follow-up data showing the curve plateaus when we talk about event-free survival. These patients continue to do extraordinarily well. That has also been extremely encouraging. It was with that background that we started asking how we can do it differently for adults. We have similar challenges in adults. We've been a bit more lucky to get approvals and drugs like blinatumomab, a CD19/CD3 bispecific antibody, and inotuzumab, the CD22-targeted antibody drug conjugate, but CAR T-cell therapy had eluded us — in large part due to concerns about treatment-related toxicity in adults and whether we could deliver it safely. There's no question going back to that tisagenlecleucel data that we did see neurotoxicity. We did see considerable cytokine release syndrome, an inflammatory syndrome that presents almost like a sepsis or a systemic inflammatory response syndrome-like picture. We were worried. The first attempt to do this occurred with the company Juno. For those who don't remember, they came to the scene building off the same platform that Memorial Sloan Kettering had developed. This was a CD28-based CAR T-cell therapy that similarly had shown very, very high response rates in the patients treated in an earlier phase 1 study. Five patients in that trial ended up with lethal cerebral edema, and that ended up shutting down the study. Again, it begged the question, can we do this in grown-ups? This is when Kite and the ZUMA-3 trial that ultimately led to the FDA approval of CAR T cells in adults started phase 1 testing. It's delightful to see it now at the end of this journey, post-FDA approval. We now have a 2-year follow-up we've presented on that study and a 3-year follow-up we're looking forward to sharing this year. To be able to see deep remissions and durable remissions has been exciting, especially acknowledging that a lot of these patients are coming to us much later, even after the blinatumomab and inotuzumab. It's been a journey and one I'm glad to be a part of.
Langston: We continue to debate, certainly at our center, on the question of durability, particularly in our adult patients. That leads us to a logical question. Do we transplant or do we use CAR T-cell therapy? Do we need use transplant for a patient who's gotten CAR T-cell therapy and particularly patients who have advanced disease?
Shah: I'm going to cut to the chase and say I don't know. Transplants weren't performed commonly in the ZUMA-3 clinical trial, and that's largely because a lot of the patients came to us already having had a prior allogeneic transplant. It was about 40% or so of the patients. Certainly no one in the trial had received a second transplant, and only about 10 or 11 or so folks had gone on to transplant. We can look at the data in a simple fashion and ask what the survival looks like if we transplant or if we don't. It suggests that there's a benefit to the transplant following CAR T-cell therapy. The hard part is that our best responders went to transplant. When you set it up a little differently to do landmark analyses to answer the same question, you no longer see this. The truth is that I don't know. My practice for patients who have very high disease burden going into CAR T-cell therapy and for individuals who have burned through the current menu of options — the blinatumomab, inotuzumab and such — is that I don't hesitate. I think transplant makes a lot of good sense if you don't have a good salvage option if the disease comes back after CAR T-cell therapy. In terms of the durability piece of ZUMA-3, it's important to understand that 35% of the patients in the phase 2 study had over 75% blasts going into CAR T-cell therapy. When you talk about extraordinarily high disease burden, you can expect that CAR T-cell therapy is not going to (a) have the same response rate and (b) carry with it the same duration of response you would want to see in those very advanced settings. We've seen that pattern across pediatric studies. We've seen that also in lymphoma studies where patients with the highest tumor burdens didn't do as well. On the flip side, when it comes to a safety standpoint, patients with high tumor burdens seem to accentuate the worst of what we want to see. It's where we're going to see a higher tendency for high-grade cytokine release syndrome and higher tendency for high-grade neurotoxicity. I try really hard now to get patients to CAR T-cell therapy who have a lower disease burden. If they haven't burned their bridges, meaning that they haven't seen all these other relapse options, I feel very comfortable watching them and following them closely for MRD. We now have better tools like the clonoSEQ platform that gets us down to about one in 1 million or one in 10 million cells. We also have the ability to follow-up closely for B-cell aplasia. I'll say very quickly here that when we talk about ZUMA-3, we don't really know whether B-cell aplasia has any meaningful role in terms of predicting the durability of the CAR T cell and its activity over time. We do have the ability to track these things in real time and use those tools to inform what we do next. In a study by Mike Pulsipher and colleagues — and I believe it was real-world experience, I don't think these patients came from a clinical trial — they looked for that same MRD approach, the same B-cell aplasia approach after getting tisagenlecleucel in kids. They showed that the time points of both day 28 and day 90 are highly predictive for what comes next. This means that if a patient has any MRD — like I said, even down to one in 10 million cells — that patient is extraordinarily high risk. The B-cell aplasia seems to follow that same curve, so those same patients also tended to either never develop B-cell aplasia or lose it very, very quickly. It's really interesting how those two parameters align for the tisagenlecleucel data. In the ZUMA-3 data and in the real world, we're also looking very closely at those same parameters. I'm excited to say we'll see our first real-world abstract that we submitted for the American Society of Clinical Oncology meeting. Hopefully, we'll see that presented this year and start to see how it looks in the real-world setting addressing some of the same issues.
Langston: One of the things about ALL that poses a real challenge is that the disease is often progressing while the manufacturing period is going on. How do we manage patients during that gap? In lymphoma, we often don't need to use bridging therapy between cell collection. We often need to do that in in B-cell ALL. Has that also been your experience?
Shah: It has. Whether we look at ZUMA-3, the ELIANA study that tisagenlecleucel approval was based on, or other clinical trials of CAR T-cell therapy in ALL, we're finding a roughly 20%-25% dropout during that period of manufacturing, largely due to infection. This tells us a very, very important story, which you just pointed out, that we're going to have to start thinking about how we integrate CAR T-cell therapy quite literally from day one. What are our triggers postinduction when we're measuring that MRD assessment, or what are the triggers based on the underlying biology? Do patients have a TP53 mutation or MLL rearranged ALL? Are there other risk factors they're bringing to the table where we can anticipate, if we fast forward 6 months, we're going to be in a world of hurt continuing down this plan? It was the same thing we ran into, by the way, with allogeneic stem cell transplant. It follows the same sort of risk features, and we ask ourselves, "At what point do we start thinking about it?" My hope is that we can start to change this paradigm a little bit. We can say if a patient has low-end MRD postinduction, we are fine continuing with consolidation. I'm already beginning the process of saying, "Let's have you seen in our CAR T-cell therapy clinic because if we're still seeing that MRD postconsolidation, we know where we're going to land, right?" Very seldom do we actually convert a patient to a durable MRD-negative state, or at least one that's deep enough to facilitate bone marrow transplant. Let's begin the process of trying to understand how we integrate CAR T-cell therapy, but do it early. That's certainly the approach we're taking at Moffit. Since the approval, one of the nice things is that less than 10% of our patients we're treating are coming to CAR T-cell therapy at our center with high disease burdens over 75%. The overall majority are getting there with low disease burden because we've been proactive. We've avoided that dropout during bridging therapy because we can keep the patients stable. You don't have to worry about blasting. In terms of what I did in the trial, back then, we had the approval for liposomal vincristine, which was my most common bridging strategy. I was not trying to completely knock out the leukemic cells. I was just trying to keep them stable, keep them steady, and keep their counts at a reasonable range so we could get patients through the therapy. Again, I took them to CAR T-cell therapy with high tumor burdens — keep that in mind with the bridging approach — but at the same time, it was more successful in getting patients to that point. Where are we now that we don't have liposomal vincristine? I love the idea of inotuzumab bridging for patients who are sensitive and trying to come up with a lower-dose approach. Instead of the standard fractionation that's approved, we'll use 0.3 mg/m2 dosing on day one and day eight. We may combine it with a little bit of vincristine/dexamethasone. We're trying to chip away a little bit at the disease as patients go into CAR T-cell immunotherapy without making them neutropenic or thrombocytopenic or significantly at risk of infection.
Langston: I think that's an incredibly important point — not beating them up out of the gate because then then they fall off.
Shah: On that note, I will say that Jae Park and colleagues looked at this and did it in two centers, I think. I know that the intensity of bridging therapy did not correlate with an improved outcome. In fact, it was associated with a higher likelihood of falling off, and that ultimately compromised the trial.
Langston: The technology is changing rapidly, and there are lots of new things out there. Let's talk a little bit about some of the newer approaches to make big, bigger, and better CAR T cells and to improve outcomes and reduce complications.
Shah: One of the things we're trying to do is integrate CAR T-cell therapy much earlier. We have the approval for relapsed and refractory disease. As we pointed out, because of that setting, you're going to take on the worst of the worst. What we want to do is integrate the CAR T cells postinduction and take an approach not terribly dissimilar from ECOG-ACRIN E1910 where they integrated blinatumomab for MRD-negative disease and demonstrated an improvement in outcomes. Here at Moffitt, we'll say we want patients to be MRD-positive to justify the use of the CAR T cells, but we want to use it with lower burdens. We're willing to take on disease that is below that 10-4 threshold and use that as our trigger. Patients can come in with higher disease burden, up to the 5% typical of MRD, but we want to allow them to come in with a much lower disease burden and integrate the CAR T-cell therapy early as an opportunity to address the risk associated with that postinduction MRD positivity. At the same time, it will hopefully allow us to take away all the aggressive components that follow that are associated with treatment-related toxicity and mortality. I'm hopeful that trial will be open in June or so. We're still going through all the regulatory pieces right now. That is a major important step in trying to figure out how we get CAR T cells into adults in a safe manner that has the potential to improve outcomes. In terms of novel CAR design, there are things that I'm excited about. I'll talk about some of the dual-specific CAR T cells. By and large, we've been focused on CD19 and CD22. There are data from the Stanford Group doing this. There are data from the UPenn group doing this. Those are interesting approaches. I should also say that the National Cancer Institute's Nirali Shah is doing some work in this space. The hard part is that I don't know yet if it's better than CD19 CAR T-cell therapy by itself. That's going to be the tough part as these approaches evolve where we can target more than one antigen and potentially avoid the antigen downregulation or antigen loss. How do we ultimately decide it's better than what came before? I don't see a world in which we're going to be doing randomized clinical trials with different CAR T cells. Maybe I'm wrong. Maybe there will be that that opportunity as the science evolves. But it seems really challenging to do now. We're going to be stuck with all of the challenges that come with different populations of people enrolled to different trials and trying to compare across trials to ask if one is better than the other. That's the challenge I see in terms of trying to understand where we land in the end. In terms of the biology we're seeing under the hood, there are some pretty cool things to be excited about. I love the trial out of UPenn because it did something I've not seen happen before. These were CAR T cells targeting CD19 given together with CAR T cells targeting CD22. Some of the cells had both the 19 and the 22. What they saw was what we typically see. The CD19-positive CAR T cells expanded quickly and then resolved quickly, and you see the typical cytokine release syndrome associated with that. What was really fascinating is that there was a late rise and late expansion in the CD22 CAR T cells. I think that's really cool because that's postlymphodepletion. You're talking about being weeks out from lymphodepletion where that effect is gone, and somehow these CD22 CAR T cells are able to expand, presumably because they're targeting CD22 antigen–positive cells. Hopefully that correlates to an improved outcome from an ALL perspective. Again, that kind of biology really excites me because it's the kind of thing you shouldn't see. When you see it, you scratch your head and say, "Oh, this is so cool."
That's a little bit different than the Stanford trials where you have both 19 and 22 on the same cell, so you're not really trying to hit this mixed population. Stanford had some very intriguing data with their 19/22 CAR T cells. Again, we have the same caveat trying to understand if this really puts us in a better position. They're doing the phase 2 trials now. I'm really excited to see where they land. Are we going to be at a place where we've got a better CAR than what we have now? Is it due to addressing the risks of antigen loss or allowing for better persistence of the CAR because there's more than one antigen that could stimulate it? I'm not really sure, but I'm excited about it. I want to say a little bit about allogeneic CAR T cells because I am excited about them. We worked with a company, Precision BioSciences, during the phase 1 part of that program treating patients with relapsed/refractory ALL. The patients included those for whom prior autologous CAR T-cell therapy had failed. These are patients who had really beat-up immune systems who had often seen one or even two allogeneic stem cell transplants, and there was no opportunity for us to come in with another autologous CAR T cell product. They didn't have the immune system to support it. We gave them allogeneic CAR T cells and it worked. It not only worked to put them in remission, but we were seeing remissions that were extraordinarily prolonged. The remission was a year and sometimes even longer before we were seeing recurrence of the ALL. For an allogeneic product to do that I think is really, really interesting. For company-related reasons — all the things that happen when you have a startup — they've chosen to focus on lymphoma for now. I am absolutely hopeful and have encouraged them to think about how to pivot back to the ALL space. Because again, that signature was real and robust, and it also tells us we can start to think about how those allogeneic CAR T cells may work in other contexts. T-cell ALL is where we're seeing it advance most quickly. That's the allogeneic CAR T-cell product from Wugen that is CD7-directed and generating deep molecular remissions. Right now, the expectation is to follow-up with bone marrow transplant. Following the Wugen CAR T-cell product trial, this recipe may actually be brilliant. Think about the allogeneic CAR T cells almost as a component of conditioning to deepen your molecular remission far as you can go, capitalizing on it with the bone marrow transplant to remove the stem cell source, and then, again, allowing for some graft-vs-leukemia effect to occur after. That trial is ongoing. I think the early data have been presented.
Langston: Today we've had Dr Bijal Shah discussing CAR T-cell therapy for ALL. Thank you so much, Dr Shah, and thank you to the audience for joining us. This is Dr Amelia Langston for InDiscussion.
Resources
Cancer Immunotherapy With Chimeric Antigen Receptor (CAR) T Cells
Acute Lymphoblastic Leukemia (ALL) Treatment & Management
Tisagenlecleucel in Children and Young Adults With B-Cell Lymphoblastic Leukemia
Clinical Significance and Management of MRD in Adults With Acute Lymphoblastic Leukemia
FDA Approves Inotuzumab for Adults With B-Cell Acute Lymphoblastic Leukemia
Immune Effector Cell Associated Neurotoxicity Syndrome in Chimeric Antigen Receptor-T Cell Therapy
Systemic Inflammatory Response Syndrome
CAR T-Cell Therapy Approved for Some Children and Young Adults With Leukemia
Allogeneic Stem Cell Transplant
Management of Hypogammaglobulinaemia and B-Cell Aplasia
Therapeutic Targeting of Mutated p53 in Acute Lymphoblastic Leukemia
MLL-Rearranged Acute Lymphoblastic Leukemia
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Cite this: CAR T-Cell Therapy for B-Cell Acute Lymphoblastic Leukemia - Medscape - Jun 13, 2023.
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