Shaping the Future of ALL: Advancing Novel Immune-Targeted Therapies to Address Unmet Clinical Needs

Immune therapy has led to consider the success in the treatment of B-cell ALL. Today, we have several effective immune-based therapy that target a range of surface antigen on B-cells, including monoclonal antibody, bispecific antibody, T-cell engagers, as well as CAR T-cell therapy. The most prominent and used targeted antigen in B-cell ALL is CD19, which is uniformly expressed on the surface of B-cell ALL.

[00:19:28]

Bispecific T-Cell Engager Blinatumomab in ALL

Blinatumomab is a bispecific T-cell engager for CD3 and CD19. It is currently the only approved bispecific in B-cell ALL. It is comprised of 2 single-chain variable fragments with no Fc region. Therefore, activity is independent of major histocompatibility complex presentation, and this leads to overcome common mechanisms of resistance. Blinatumomab brings T-cells in close proximity to B-cell ALL. This will mediate T-cell activation and their killing of B-cell ALL.

Currently, blinatumomab is FDA-approved for different indications in B-cell ALL. It is approved for adult and pediatric patients as young as 1 months old with MRD-positive B-cell ALL either in CR1 or CR2, as well as in patients with relapsed/refractory CD19-positive B-cell ALL that include both Ph-positive and Ph-negative ALL. The most recent approval is as a consolidation therapy in combination with multi-phase chemotherapy consolidations in patients who achieve MRD-negative CR1.

[00:20:54]

Key Historical Clinical Trials with Blinatumomab in Adults With B-ALL

The TOWER study is what led to the blinatumomab approval in relapsed/refractory disease. This was a phase III study, around more than 400 adult patients with relapsed/refractory Ph-negative B-cell ALL. Patients were randomized to either blinatumomab as single agent or physician's choice of salvage multi-agent chemotherapy. Blinatumomab led to an improved in CR, as well as CR, CRi, CRh, and led to superior median overall survival, which was 7.7 compared to 4 months in patients who received chemotherapy.

The BLAST study is what has led to the approval of blinatumomab for MRD-positive disease, where it was a phase II study, around more than 100 patients who had at least 3 prior lines of chemotherapy and had persistent MRD in morphological remission and single-agent blinatumomab led to complete molecular remission in close to 80% of patients, with a median overall survival close to 37 months.

[00:22:02]

ECOG-ACRIN E1910: Blinatumomab + Chemotherapy vs Chemotherapy in BCR::ABL1-Negative B-ALL

The most recent approval for blinatumomab as a consolidation MRD-negative CR1, this was based on the ECOG 1910 study in addition to the COG study. However, in the ECOG 1910 study, adult patient aged between 30 and 70 years old with Ph-negative ALL new diagnosis, they received an induction for 2 cycles then intensification. For those who achieve MRD negativity, defined as less than 0.01%, they were randomized to either receive consolidation cycles of chemotherapy or the same consolidation cycles in combination with 4 cycles of blinatumomab given between consolidation chemotherapy. The primary endpoint was overall survival. Key secondary endpoints were MRD status and RFS. You see, there 488 patients were enrolled and were randomized in MRD negativity to chemo ± blin in 224 patients.

[00:23:10]

ECOG-ACRIN E1910: Overall Survival in MRD-Negative Patients (Primary Endpoint)

After initial induction, 81% achieved CR. When patients completed intensification, 78% of these patients achieved MRD negativity, and they were eligible for randomization. The inclusion of blinatumomab as part of the consolidation was to improve overall survival compared to chemotherapy. The 3-year overall survival in the blinatumomab arm was 85%, compared to 68% in patients who received only chemotherapy.

[00:23:44]

ECOG-ACRIN E1910: Safety During Consolidation

Overall, the inclusion of blinatumomab in consolidation was well-tolerated. If anything, you can see that the grade 3/4 cytopenias were less when the patient received blinatumomab with chemotherapy compared to chemotherapy. However, blinatumomab led to more neurological and psychiatric events compared to chemotherapy, 23% vs 5%. In the blinatumomab arm, 17 deaths were recorded, compared to 40 deaths in the chemotherapy group. You can see that death due to non-relapsed mortality was comparable between the 2 arms. What led to improved overall survival in the blinatumomab arm is the reduction in relapse and death due to leukemia.

[00:24:36]

ECOG-ACRIN E1910: Efficacy of Blinatumomab in MRD-Negative Patients Aged <55 Yr

When data analyzed based on the patient age, remember the patient age was between 30 and 70 years, most of the benefits were seen in younger patients where the 3-year overall survival for those less than 55 was 92% in the blinatumomab arm, compared to 67%. In the patients 55 and above, there was no statistical significant benefit. However, again, the number of the patients was small.

[00:25:11]

SC Blinatumomab in R/R B-ALL: Efficacy

There is a new version blinatumomab, which is sub-Q blinatumomab, which delivers a higher dose of blinatumomab with a more convenient one than continuous infusion. It is given as sub-Q rather as a continuous infusion for 28 days. There was a phase I, this trial. Most recently, Dr Jabbour presented the optimization cohort on the sub-Q blinatumomab study. I think it was just published in JCO.

In the 2 doses that were tested in the optimization, sub-Q blinatumomab is given initially daily for the first week. Then starting their second week, it is given 3 times a week. They tested 2 different doses. The initial dose was 250 μg given daily for the first week, then 500 μg given 3 times a week thereafter. There is a higher dose where they start with 500 μg, they increase to 1000 μg 3 times a week after the first week.

The study allowed patients who failed prior blinatumomab as well as CAR T-cell therapy, inotuzumab, and transplant. The treatment was effective. You can see that the overall response CR/CRh was 77%. If you include patient who achieved CRi, it was as high as 91%. The majority of responders achieve MRD negativity with no significant difference in efficacy, at least between the higher and lower dose. Responses were seen in patients who even failed prior blinatumomab, CAR T-cell therapy, transplant, and inotuzumab.

As we have learned from IV blinatumomab where we see there is a difference in response based on the disease burden pretreatment where patients with higher disease burden, defined as 50% or more, they have lower response. In sub-Q blinatumomab, the difference was insignificant. 85% CR/CRi rate and patients with less disease burden compared to 72%.

[00:27:23]

SC Blinatumomab in R/R B-ALL: Safety

Now toxicity. You can see that the majority of patients develop treatment-related adverse events. Treatment-related adverse events leading to treatment interruption were recorded in more than half of the patients in both cohorts. However, leading to discontinuation was reported in 17% with a lower dose and 12% with a higher dose.

Looking at CRS, you see that any-grade CRS was very common, 83% vs 94%. However, for grade 3 and higher, was 17% in the lower dose and 23% in the higher dose. Any-grade neurologic events were also common, over half of the patient with the low dose and 77% in patients who received the higher dose. For grade 3 or higher, neurotoxicity was reported as 28% in the lower dose and 27% in the higher dose. However, they reported that most of the CRS neurological events resolved with dose modification and supportive care and not requiring blinatumomab discontinuation.

[00:28:37]

Medical Need for New and Innovative Immune-Targeted Therapies

With this progress, there is still a medical need to improve more on the treatment we have currently for patients with B-cell ALL. Cure rates and survival outcomes, although, has significantly improved, you can see that it is still not reaching children with ALL. For AYA patient, the 5-year overall survival is in the range of 60%. We are having more challenge with older and middle age adult patients where the survival outcome is in the range of 20-40%. Even in some high-risk subtypes like in children and infants less than 1 years old, where we have seen actually lower overall survival, there is some room to improve actually their outcomes. They have seen some progress with the early introduction of blinatumomab with chemotherapy. However, we will have to see how these patients do with longer follow-up.

As more patient develop resistance to current immunotherapy, as we introduced this immune therapy early on, I think we will have challenges when the patient relapse after CR1 because we need more novel therapies that can salvage these patients.

[00:29:54]

Poll 3: What do you feel is the most important unmet need in ALL?  

This is a poll. What do you think is the most important unmet need in ALL?

1. Improving survival in older patients;
2. Access to cutting-edge treatments;
3. Lack of awareness about newer immune therapy;
4. Immune therapy adverse events mitigation;
5. Lengthy treatment duration and difficulty maintaining compliance.

If you can, please answer. Again, I think these are all important points. I do not think we can just identify one. I think these are all challenges in ALL treatment.

Most people answer either improving survival in older adult patients or lack of awareness about newer immune therapy.

[00:30:51]

Discussion Points  

This is just briefly about discussion points. I have Dr Park, maybe I can ask him a question. Clearly, Jae, these are some of the current challenges of integrating blinatumomab in frontline therapy with chemotherapy. Part of it is usually not very common outside academic centers, people having challenges with the continuous infusion, toxicity still happening, even we are using it in MRD-negative, and ALL regimen is already very long, and we are adding 4 cycles of blinatumomab. Jae, can you please comment on your experience and your practice, how you incorporate? Are you incorporating blinatumomab first with the frontline chemotherapy? How do you do it?

Dr Jae Park (Memorial Sloan Kettering Cancer Center): Sure. As you suggested, I think E1910 data was practice-changing in a way, for the first time, that we have seen the data that blinatumomab improves survival even when using MRD-negative CR setting and consolidation. Based on the data that we are incorporating at our institution, blinatumomab to Ph-negative B-ALL patients in combination with the chemotherapy, we are not using the E1910 backbone of a chemotherapy, however. We have been using a different regimen for our younger patients, 18 to 40, for example, than we do use pediatric regimen such as CALGB 10403.

40 to 60, that group that we are using a pediatric-inspired chemotherapy regimen with some asparaginase, however, dose-reduced and modified with the chemotherapy. That has been our standard regimen. It is similar to E2993 which was a backbone chemo of E1910. We are using blinatumomab added to those, the chemotherapy regimen.

What is a little bit unclear with E1910 is how many cycles blinatumomab still is necessary, because patients were receiving either anywhere between 2 to 4 cycles. Not everybody received 4. It is unclear whether you need all 4. Is it too good enough? We have internally discussed how many we should be adding. There are mixed opinions even within our group. However, we have agreed that a minimum of 2. There is some COG data, they only did 2 cycles of blinatumomab, improved the outcome. At least a minimum of 2 cycles of blinatumomab. Blinatumomab should be added in the frontline chemotherapy-based regimen.

The second change that we did is that we are using blina earlier than what was used in E1910, because I think about 30-35% of the patients actually did not make it to randomization, meaning the patients either relapsed early or never achieved the deepening of remission to be randomized. We are using blinatumomab after 2 cycles of a chemotherapy or around the month 3 mark, as opposed to after intensification, which is after a third block of a chemotherapy in E1910. We are using a little bit earlier. Then we are incorporating blinatumomab, although we do struggle a little bit as to how many cycles. As you said, we are not yet replacing the chemotherapy block. However, I think that will be the next step, to see whether with the incorporation of this effective immunotherapy, blinatumomab and others we will talk about, whether we should be ready at some point to ask the questions about replacing chemotherapy.

Dr Aldoss: Thank you, Jae. That is very informative. We do the same. We try to incorporate with the CALGB 10403. We aim to not actually to give 4. However, typically, we aim for 4 cycles. We reduce the pump maintenance to keep it not that lengthy. We start counting from the first cycle of blinatumomab 2 years.

Jae, another related topic is now we are using blinatumomab frontline. Can you comment about what is the challenge with can a patient relapse after failing blinatumomab? Would you go back to blinatumomab, or you try something else in these cases?

Dr Park: That is a good question. It is a real-life issue that we do deal with. Luckily, most of the patients actually do quite well. However, in those cases when they do relapse, I think the first thing is the timing of relapse after blinatumomab or the chemotherapy for that matter, it is important to see whether they might still retain sensitivity to the agent they receive before.

We have learned that, with the chemotherapy, the patients who have a late relapse after chemo could respond again to chemotherapy. I have seen similar things with blinatumomab or other similarly immunotherapy-based approaches targeting the same antigen if they are late relapse. You got in early exposure, respond very well. Then the time has passed, I think those patients, it is reasonable to retry. What we must do is to examine the target expression for CD19, just making sure, because we do know it can happen, the target loss. We have to verify the CD19 expression before we think about what immunotherapy might be best. I think that is a must. However, I think recycling of blinatumomab is an option.

I used to do good amount of those. However, now that we actually have a different immunotherapeutic options and potentially different mechanisms of action, maybe targeting the same antigen, now we have more options. Rather than going back to the same one, even though we could, I think if I have some other therapies of different mechanisms of action where we think it is going to work better, reaching for those to use even when they had it. However, just because they failed blinatumomab, though, I do not think it means that we cannot try, or they are not going to do well with the other BiTE or CAR T-cells for that matter.

Dr Aldoss: Thank you, Jae.

Novel and Emerging T-Cell Engagers in ALL

[00:36:50]

Moving to novel and emerging T-cell engagers in ALL. Surprisingly, we are seeing actually some advances even in this not very common disease. Actually, we are seeing that we are having some new bispecific T-cells. Before we talk about the newer ones, let us maybe answer some of those polls.

Pretest 1: In discussing the rationale for investigational T-cell engagers in the treatment of B-ALL with a colleague, which of the following statements would you say is true?  

In discussing the rationale for investigational T-cell engagers in the treatment of B-cell ALL with a colleague, which of the following statements would you say is true?

1. They do not cause CRS;
2. They have a similar structure to blinatumomab;
3. They have a lower risk of infection;
4. They have a more convenient dosing schedule.

Can you please answer?

Some answer B, others answer C, others answer D.

[00:38:04]

Pretest 2: How does a silent Fc domain affect safety and efficacy  

How does silent Fc domain affect safety and efficacy of investigational bispecific T-cell engager?

1. Does it prolong half-life?
2. Does it enhance CD3-binding affinity?
3. Does it enhance antibody-dependent cellular cytotoxicity?
4. Does it increase cytokine release?

We will ask these questions after we discuss the recent data.

[00:38:45]

Pretest 3: Which of the following findings was recently reported from the phase I/II SYRUS trial of surovatamig (AZD0486) in patients with R/R B-ALL?

Then let us move to the next one. Which of the following findings was recently reported from the phase I/II SYRUS trial of surovatamig in patients with relapsed/refractory B-cell ALL?

1. A majority of patients experienced a response;
2. Dose limiting toxicities were infection and sepsis;
3. Rate of any-grade CRS was dose dependent;
4. Response was not associated with MRD negativity.

[00:39:22]

Pretest 4: How confident are you in your ability to identify patients who may be eligible for ongoing clinical trials of novel immune-targeted therapies in ALL?

Maybe we can move to the next question. How confident are you in your ability to identify patients who may be eligible for ongoing clinical trials of novel immune-targeted therapies in ALL?

1. Not confident;
2. Low confidence;
3. Modest confidence;
4. Confident;
5. Very confident.

The majority answer "modest confidence." Maybe we will discuss this after we discuss some of the recent data.

[00:40:11]

Surovatamig (AZD0486): Novel CD3xCD19 Bispecific T-Cell Engager  

Surovatamig, previously called AZD0486, is a novel CD3/CD19 bispecific T-cell engager. It is a fully human CD3/CD 19 IgG4 bispecific T-cell engager. It is different than blinatumomab, in that it has a low affinity CD3-binding site. This results in decreasing the release of cytokines and potential release of CRS. Also, it has a silenced Fc tail that prolongs the half-life. It is estimated in the range of 8-12 days. This was tested in non-Hodgkin lymphoma initially and show promising activity as well as actually encouraging safety profile.

That is what led to the design of the SYRUS study.

[00:41:00]

SYRUS: Phase I/II Trial of Surovatamig (AZD0486) in R/R B-ALL  

This is a phase I/II study for patients with relapsed/refractory B-cell ALL. It is a global open-label study. It has 3 phases. They have phase IA. In phase IA, it is a dose escalation study. Then part B, which is dose optimization, we select 2 doses from the part A, and we compare the efficacy and safety so we can declare the recommended phase II dosing. Part C is dose expansion, where the recommended phase II dosing is tested to evaluate for activity.

In EHA 2025, that was a couple weeks ago, we presented the data from the dose escalation part A, where we actually reported on the first dose levels in the study. The SYRUS study eligibility included patients 16-80 years old. Again, once we move to Part B, which is optimization, the age will be dropped to 12. Included patients with the relapsed/refractory B-cell ALL, that can be pH‑positive/pH-negative. They have to have the CD19 expression. However, there is no limit to how much the expression of CD19, and it is reported locally. The study allows prior anti-CD19 therapy patients could have received prior blinatumomab or CAR T-cell therapy.

The treatment included 3 steps of dosing, where the starting dose is, on Day 1, a low dose, then increase on Day 4, then again on Day 8. The target dose will be given on Day 15. It is given every 2 weeks. In the dose level 1, there was a lower step-up dosing was used. The target dose was 2.4 mg where we give it Day 15, then every 2 weeks. Dose level 2 and 3 have the same higher step-up dosing, which was higher than the dose level 1. However, the target dose for dose level 2 was 7.2 mg and for dose level 3 was 15 mg.

[00:43:18]

SYRUS: Response  

Patients enrolled on the SYRUS study were heavily pretreated. The median prior lines of therapy was around 3 frequently. I would say 60% of patients had prior blinatumomab and maybe a third of the patient had prior CAR T-cell therapy. Many patients had both blinatumomab and CAR T-cell therapy before enrollment to the study.

You can see here these are the 3 dose levels. There was actually a dose-dependent increase response with AZD0486. The CR/CRi rate was 46% with the lowest dose, increased to 58% with 7.2 mg dose level 2, and increased to 83% for dose level 3 15 mg. You can notice that the majority of patients actually achieve MRD negativity.

The responses were seen in patients who had prior CAR T-cell therapy, who had prior blinatumomab, or they had both prior blinatumomab and CAR T-cell therapy. What is different than what we have seen with blinatumomab, what we see as extra medullary failure is a common way of treatment failure in blinatumomab. They do not respond well to blina. It is a common relapse site after blinatumomab response. We have seen in the SYRUS study that AZD0486 was actually active in extra medullary disease. Four out of 5 patients who had extra medullary disease before treatment cleared the extra medullary disease. With a follow-up on the study, we only have seen 2 relapses. These were relapses occurred in patients treated in dose level 1. At 6 months, the duration of response was 86%.

[00:45:14]

SYRUS: Safety Summary  

From the safety standpoint, overall, the treatment was safe. These are grade 3 or higher AEs that occur at least in 5% of patients, which mean 2 out of the 31 patients. They are in line with what we see with the studies, including patients with relapsed/refractory ALL, being neutropenic fever, infection, some cytopenia, some transaminases as well. CRS and ICANS are not reported here because only 1 grade 3 ICANS and 1 grade 3 CRS in these patients occurred.

There were 2 DLTs in this cohort. Both of them were prolonged cytopenia during cycle 1. Both of these 2 patients who have prolonged cytopenia, they actually recovered their counts and were able to continue with the target dose with no recurrence of the severe cytopenia. One of those patients developed transient transaminitis grade 3 early during the step-up dosing, and completely resolved. They were able to continue and escalate to the full targeted dose without recurrence.

[00:46:31]

SYRUS: CRS and ICANS by STEP Up or Target Dose  

This is CRS and ICANS reported in the study. Here, during the step-up dosing. Here, after the target dose. You see, it is not dose dependent based on the target dose. At the higher dose, we have not seen any CRS or ICANS after we reach the target dose. You see most of the ICANS and CRS during the step-up dosing, more common if you start with higher step-up dosing. However, grade 3 CRS and ICANS were rare. Only 1 CRS grade 3 during the step-up dosing and 1 grade 3 ICANS after the target dose in dose level 2.

[00:47:09]

CN201: Novel CD3xCD19 Bispecific T-Cell Engager  

Another novel bispecific antibody is the CN201. This also comprised of humanized IgG4 with silence Fc domain and has this unique knob-in-hole design with IgG-like structure. This knob-in-hole design minimizes heavy chain mismatch. The silent Fc domain leads to prolonged half-life of the drug. It also has a unique thing in the CD3 arm where the CL-CH1 domain is replaced with TCR alpha-beta. This was to minimize the light chain mismatch and to modulate CD3 affinity and decrease the CRS. The median half-life is in the range of 3 to 4 days. It is given weekly once we reach the target dose.

[00:47:59]

Phase I/II Study of CN201 in Patients with R/R B-ALL  

In a phase I/II study of CN201 in patients with relapsed/refractory B-cell ALL, the study includes the patient as young as 2 years of age with relapsed/refractory B-cell ALL, can be Ph-positive, Ph-negative. They allow prior CD19 target therapy. However, different than the SYRUS study where patients cannot have prior anti-CD19 target within 3 months of the treatment. The drug is given initially with a step-up dosing where the lowest dose, priming dose, is given on Day 1. Then intermediate dose on Day 8. Then the target dose on Day 15. Then, it is given weekly afterwards.

[00:48:45]

Phase I Study of CN201: Efficacy by Dose Level in Adults  

This is some data from the phase I study that was presented in ASCO 2024. You can see there is a dose-dependent response. At higher dose, we are seeing very encouraging responses. Again, few patients. However, the 4 mg dose, 3 out of 4 responded. In the 60 mg dose, 3 out of 3 responded. The majority of responders achieve MRD negativity.

[00:49:13]

Phase I Study of CN201: Safety in Adults  

In the study, the maximum tolerated dose was not reached. Again, it is consistent with any relapsed/refractory ALL study in term of AEs, mainly cytopenia infection. You can see most of the CRS happened early on after the prime dosing. There were 2 cases of grade 3 CRS. However, they reported no ICANS with the CN201.

[00:49:44]

Trispecific Antibodies in B-ALL  

Another advancement in the field is a trispecific antibody in B-ALL. Resistance to bispecific may occur either by losing the target. You may have T-cell exhaustion, PD-1 upregulation, as well as an increased number of regulatory T-cells. There is this interesting drug PIT565. It is actually a trispecific antibody. It is IgG-like CD19, CD3, CD2. The reason for CD2 is to minimize on decreased T-cell exhaustion and to enhance the activity of this antibody. There is an ongoing multicenter phase I study for patients with B-cell non-Hodgkin lymphoma, as well as ALL. However, there is no clinical data so far. There are other trispecific antibodies that have shown promise in preclinical trials, where they include CD20 or CD22 as another receptor.

Let's Revisit Our Questions

[00:50:51]

With that, I conclude the bispecific antibody. Let us revisit our questions and we can discuss the answers.

[00:50:58]

Posttest1: In discussing the rationale for investigational T-cell engagers in the treatment of B-ALL with a colleague, which of the following statements would you say is true?  

In discussing the rationale for investigational T-cell engager in treatment of B-cell ALL with a colleague, which of the following statement would you say it is true?

1. They do not cause CRS;
2. They have similar structure to blina
3. Lower risk of infection;
4. They have more convenient dosing.

[00:51:38]

The majority have answered actually more convenient dosing. We think this is the right thing. Beside convenient dosing, we are seeing actually efficacy even for patients who failed prior blinatumomab. However, it does not seem they cause more CRS. If anything, they are actually having less CRS. They are different than blinatumomab. The risk of infection is common in any relapsed/refractory ALL when you start treating the patient.

[00:52:04]

Posttest 2: How does a silent Fc domain affect safety and efficacy of investigational bispecific T-cell engagers?  

How does silent Fc domain affect safety and efficacy of investigational bispecific T-cell?

1. Prolong half-life;
2. Enhance CD3-binding affinity;
3. Enhance antibody-dependent cellular cytotoxicity;
4. Increase cytokine release.

[00:52:40]

The majority answer it prolongs half-life. This is the right thing, silencing the Fc domain that improves and increases the half-life of the antibody.

[00:52:54]

Posttest 3: Which of the following findings was recently reported from the phase I/II SYRUS trial of surovatamig (ZD0486) in patients with R/R B-ALL?  

Which of the following findings was recently reported from the SYRUS study for AZD0486 in patients with relapsed/refractory B-cell ALL?

1. The majority of patients experienced response;
2. Dose limiting toxicity, infection and sepsis;
3. Rate of any-grade CRS was dose dependent;
4. Response was not associated with MRD.

[00:53:30]

The majority answered that a majority of patients experienced response. This is what we have seen actually, especially with higher doses.

[00:53:40]

Discussion Points  

Dr Park, you have seen some of those investigational bispecific antibody, what is your impression comparing to blinatumomab in terms of toxicity, efficacy, maybe a convenience to use?

Dr Park: I have a lot of experience with the SYRUS trials. I am curious to get your thoughts also. My initial reaction is that what we have seen with even with the sub-Q blinatumomab, when you are able to deliver a higher dose, I think it does look like that we are able to get a better and deeper response in higher-burden patients previously with IV continuous blinatumomab, which is only formulation that we have currently as an FDA-approved therapy. We can use it all. However, I think the best efficacy is limited to lower-burden patients. However, with sub-Q, with a better pharmacokinetics and the way we are able to deliver more higher doses, I think is able to overcome that.

What is also interesting is that we are not seeing that much of a higher degree of CRS and ICANS despite that, which was a limitation with a prior IV blinatumomab higher dose, because of the higher rates of these toxicities. That is the reason that we were not able to have the step-up dosing. However, the sub-Q versions of maybe slower kinetics, but a more steady state is able to accomplish. It seems like the best of the both, a higher efficacy with the comparable safety profiles too. Obviously, with an AZD, in SYRUS trial, that is also very interesting with even more convenience dosing schedule. Because the sub-Q blend, the data looks very good. However, it is still 3 times a week, depending on how it is going to be rolled out in real life, in self-administration obviously, or the centers have to administer them. Every 2 weeks is certainly much more convenient for the patient and are able to achieve the dosing. I thought that was actually quite intriguing, to still get the result.

If I can ask questions about the AZD with this kind of step-up dosing in every 2 weeks, was the cytopenia dose dependent? I know there were only major 2 dose cohorts, and I know that escalation is ongoing.

Dr Aldoss: It was not, Jae, because we saw it with the first dose in 1 patient and with the dose level 3 in 1 patient. I do not think it is dose-dependent because I think it is more related to high disease burden to treat the disease, because we were able to continue with the target dose while they still have some cytopenia. If anything, actually the platelet counts improve, and did not come down even with continuing the every-other-week dosing. I think it is more related to the disease, and the disease burden, rather than it is purely related to the bispecific antibody.

I would say, Jae, I agree with you. I think the convenience with the sub-Q blina, unless they come up with the way where the patient can give it at home, it is not very convenient. I think having every week, every other week I think is a more convenient way to give the bispecific antibody. I would say that the neurotoxicity maybe was higher with the sub-Q blina. I think they reported grade 3 close to a quarter of the patients. Again, it was self-limited, transient. However, it is something we do not see with the AZD and the CN201.

Dr Park: Correct. I actually did notice that too, because there was a sub-Q blinatumomab where the neurotoxicity is a combination of any type of neurotoxicity. However, having said that, it is a higher rate. It was interesting that you guys did not see that as much with the other 2.

Dr Aldoss: Because they call it ICANS again in the SYRUS study compared to neurotoxicity as you mentioned. It could be ICANS based other things, headaches and others.

Dr Park: The safety profile does look very promising, though. It certainly is a lot easier to give than continuously infusion pump changes or even 3 times a week injection.

Dr Aldoss: Definitely. Dr Park, you are next.

CAR T-Cell Therapies in ALL: Approved and Emerging

[00:58:10]

Dr Park: Obviously, Dr Aldoss actually has done very nice job of giving an overview of a bispecific antibody in ALL. I now have the pleasure of talking about another type of immunotherapy, but cellular immunotherapy, engineering of a cell delivery for treatment of ALL.

[00:58:32]

CAR T-Cell Structure  

You guys may already know, CAR T are already FDA-approved therapies for many years. However, just to refresh our memory that the top portion of it actually listed here as the tumor antigen binding domain, the VH and VL, is a heavy and light chain. That is actually the same component as what we are using for the BiTE. However, there is binding to CD19. Obviously, in the BiTE, you have that and this connected to another binder that connects CD3. Here, we use the same binder, or not same, but same idea of using the binder against CD19 that is derived from the antibody. That you then ligate or connect it to the body and tail of a T-cell receptor.

What these CAR T-cells are allowing us to do, as genetic engineering is allowing us to do, is that it binds like an antibody, but it acts like T-cells so that you do not need continuous either infusion or injections, because these are now living cells as opposed to that needs to rely on other drug administration to continuously activate the T-cell. Hence, the name chimera, because it is a head of an antibody and tail of a T-cell receptor. Again, the big contrast.

Even though the idea is very similar, but these are T-cell activating therapy that is targeting a tumor-specific antigen. Today, we will talk a lot about CD19, which is a universal B-cell antigen. However, the differentiating factor for cell therapy as opposed to the BiTEs, the T-cell engager is that these are supposedly a 1-time infusion for autologous cells that are living, or they proliferate initially, and then they can persist long-term to provide more continued immune surveillance with a single therapy. That is the potential benefit of any cell therapy like this one.

[01:00:29]

FDA-Approved CD19-Directed CAR T-Cell Therapies in B-ALL  

With that, we do have now 3 FDA-approved CD19-directed CAR T-cell therapies for ALL. The very first one that was approved was tisagenlecleucel. That was for pediatric and young adult patients up to the age of 25 for relapsed/refractory B-cell ALL. Subsequently, the brexucabtagene was approved targeting the same CD-19 for adult patients, 18 and older, for the relapsed/refractory B-cell ALL. Most recently, obecabtagene that was approved in November 2024 with a different binding domain. That is also approved for adult patients with the relapsed/refractory B-cell ALL. For adults, we now have 2 products that we can use, either brexucabtagene or obecabtagene. We will review that data.

[01:01:16]

ELIANA: Tisagenlecleucel in Pediatric and Young Adult Patients with B-ALL  

Very first product, again, ELIANA study: Tisagenlecleucel in pediatric and young adult patients with the B-cell ALL. This was the pivotal international study that led to approval worldwide. This was open-label, single-arm phase II. Patients aged 3 to 21 were able to be treated. You need to have a morphologically-evident disease, 5% or higher bone marrow blast, which is true for all the CAR T-cell therapy. The patients do get some type of a lymphodepleting regimen, most commonly in fludarabine and cyclophosphamide combination. Doses are slightly different between the products. However, here is a 30 mg/m² for 4 doses and cyclophosphamide 500 mg for 2 doses followed by a single infusion of the CD19 CAR T-cells. The primary endpoint of the study was overall response rate, defined by CR or CRi.

[01:02:16]

ELIANA: Efficacy  

The overall response rate on this study was 80%, which is actually listed on the far left. The duration response at 6 months was 80% where patients were in response, which at that time was one of the highest responses we were seeing. Although now, as Dr Aldoss presented, we are beginning to see with the BiTEs that high of a response of anywhere from 60-80% with the subcutaneous versions of these medications.

What is notable here is that with the initial high response rates, even though there are some relapses that occur, there is a kind of hint of a plateau of a survival curve. You can see from the event-free survival and overall survival that about 60% of the patients do appear to be cured after a single infusion of the CAR T-cell treatment. Some of these patients, these are not censured for allogeneic transplants. You can actually see they are independent of a transplant. In this particular study, less than 20%, about only 15% of the patients went to bone marrow transplant after CAR T-cell infusion. Again, this suggested for this patient population with T-cell, this may potentially be a standalone therapy for pediatric patients.

[01:03:29]

ELIANA: AEs of Special Interest  

It is a very similar side effect profile as the BiTEs that Dr Aldoss talked about. However, some of these could be more severe because, as opposed to BiTEs, you have a little bit more control that if you did get the toxicity, you can either hold the continuous infusion or decide not to give the subsequent doses of a BiTE. Here, we do not have as much of a control of the single-cell infusion. The cells will do their own thing inside the body. They can proliferate and expand greatly. What things we can do are giving some medications to suppress the immune system a bit or anti‑inflammatory agents to bring down those reactions. However, it is not as tight of a control.

With that in mind, CRS, cytokine release syndrome, was seen in about 77% of the patients. The majority of the patients get some type of fever. Infection rates were in the 43% altogether. Again, these patients do get some chemotherapy, fludarabine and cyclophosphamide. These are, again, heavily-treated patients. About 40% of the patients did have a prior bone marrow transplant before receiving CAR T-cell therapy. CRS infections, these are the symptoms to watch out for. Remarkably though, despite its rapid activity, that tumor lysis syndrome is actually rare after CD19 CAR T-cell therapy.

[01:04:52]

ZUMA-3: Brexu-cel in R/R B-ALL  

Next, we will move on to adult patients who are receiving CD-19 CAR. This is a ZUMA-3 study with brexucabtagene or brexu-cel. Again, targeting CD19 with a CD28 costi domain that is slightly different than T-cell that we just looked at. This was also an international open-label phase I and II trial for adult patients 18 and older. They needed to have a bone marrow blast greater than 5% at the time of enrollment. They did receive lymphodepleting chemotherapy, a slightly different dosing schedule. However, the same drug, fludarabine and cyclophosphamide followed by single infusion of CAR T-cells on Day 0, which was 1 million CAR T-cells per kilogram. For phase II portion of the study, the primary endpoint was the overall response rate. That was CR plus CRi combined.

[01:05:47]

ZUMA-3: Responses by Prior Treatment  

Response by prior treatment. If you look at the far left, all treated patients was 78. Overall response rate was 74%. Again, very comparable to the prior CAR T that we just looked at for pediatric patients, which was about 80%. There is 74%, 63% being CR. Now, looking at prior blinatumomab patients, there is a smaller number but no significant differences between yes or no. Maybe they hint for numerically high response rate without the prior blinatumomab. If you look at the prior inotuzumab, maybe a similar trend, meaning maybe a slightly higher response rate who did not get prior inotuzumab. These are always challenging, to be honest, with the prior treatment history because, as we talked about before, it may mean that whether they were refractory to these agents, how long ago did they receive this therapy before receiving CAR T-cells. There might have been a reason they did not get blinatumomab or inotuzumab. I think there are a lot of biases that might be introduced. However, it is nonetheless an interesting trend that we are beginning to see.

The prior transplant, however, there is not as clear differences. Both groups responded well. I think it is important that there are some thoughts that in the patients who have prior transplant should not or cannot get CAR T-cells, which is also not true. The same thing is true for bispecific T‑cell engagers that we looked at. In those cases, it may actually work better. Some thoughts are that we are actually now activating the donor T-cells that these patients do have in the case of BiTE. In the case of autologous CAR T-cells, we take the T-cells from the patient who post-transplant is a mixture, it is a mixed chimera. However, the majority of the cells end up being donor T-cells. I think there are some additional effect of a graft vs leukemia these patients may get.

[01:07:43]

ZUMA-3 5-Yr Update: Overall Survival by Response  

Now looking at the longer-term outcome in the ZUMA-3, we now have a 5-year survival update which was presented at EHA, updated just a couple of weeks ago. All patients looking at by CR, CRi, or the overall response rates. Here, we also do see some long-term responders on this therapy. If we look at the responding patients, the CR or CRi patients, that, again, roughly about 50% of the patients do appear to be in continuous remission or surviving after a single infusion of the brexucabtagene. Some of these patients did get bone marrow transplant, about quarter of the patients as a consolidation. Some patients, if they relapse after CAR T-cell therapy, they might have received salvage therapy, and they might have gone to transplant. This is not censored for those. However, this overall survival that there is still improvement compared to what we had before.

Although not shown here, they also have presented the data, the benefit for those treated with a prior blina and inotuzumab might be less pronounced, meaning less benefit for those patients. However, again, with lots of caveat. I would not take that as to the fact that just because you have prior blinatumomab or inotuzumab or other BiTEs, that does not mean that we cannot try, or we should not try the CAR T-cell therapy. However, I think we take with a grain of salt and I may be more mindful or follow these patients more closely after these agents, because their relapse rate might be higher. However, more study needs to be done. I think it is important to recognize that these are still good therapy options for those patients.

[01:09:25]

ZUMA 3: Safety Summary by Prior Treatment  

Looking at the safety, looking at the CRS and ICANS, here, they reported as a neurological event. Between prior blinatumomab, prior inotuzumab, prior transplant, there is no significant differences in terms of the rate of the CRS and ICANS. The rates are generally higher. I think roughly about 25% of the patients overall get grade 3 and higher CRS or ICANS. A quarter of the patients do receive some type of ICU level of care. I think that might have been the limitations in the past, even though the therapy works very well. They did not report any new T-cell malignancies on the long-term follow-up of this study, and no new safety signals after 5 years of a follow-up also, which is important considering there are some other cell therapies that they are beginning to see some new safety signals. With this, we did not.

[01:10:23]

Real-world Safety and Efficacy of Brexu-cel in R/R B-ALL  

After commercial therapy approval of brexu-cel in the U.S., there is publication that I know both of us participated in the real-world data. It is called ROCCA, a consortium of many different centers participating. This was a publication that was published earlier just in JCO. 189 patients who received a commercially-approved brexucabtagene. A similar population as ZUMA-3. However, about 40% would not have been eligible for ZUMA-3. The majority of the reasons actually were these patients had a lower burden of the disease or undetectable or only MRD-positive.

I think the one trend that we are now beginning to see is that the toxicity that we have seen with the CRS and ICANS, to some degree is also true for BiTE, correlates with the disease burden. Meaning the higher the disease burden, the more likely that you may get the CRS or ICANS. So the benefit might be higher, and then the risk will be lower, if we treat these patients with a lower disease burden. In the real-world setting that we are using this CAR T-cell therapy in earlier, meaning before they have a full-on relapse with 80% less or 60% less, but, rather they are beginning to relapse at a lower burden patients, I do believe that is the best time that we can deliver CAR T-cell therapy both for efficacy and safety. That is a trend that you can see in the brexucabtagene.

The CR rate was 79%. Again, it was very comparable to what we have seen before in the clinical trial. It is assuring that that same data could be replicated in the real-world setting. The adverse events were interesting. The CRS rate is indeed lower, grade 3 and higher was 11% as opposed to 25% in the clinical trial. However, the ICANS rate was so similar to what we have seen before, despite the fact that we have treated patients in a lower disease burden setting. That continues to remain one of the challenges or the side effects that we are mindful of when we are using brexucabtagene in adult patients.

[01:12:30]

FELIX: Obe-cel in R/R B-ALL  

The last CD-19 CAR product that is approved is the obe-cel or obecabtagene. The FELIX was the name of the pivotal international study that led to the approval in US, also in November 2024. Similar study design, however, there are 2 different changes or modifications from the prior trials that we just looked at.

The first is that they do have a tumor burden-based dosing. I briefly mentioned the higher disease burden is correlating with the higher toxicity. Given those years of experience that we have had in this particular study, if you had a higher disease burden here defined as bone marrow blasts greater than 20%, you first get 10 million CAR T-cells, meaning a lower dose of CAR T, which is in the red box. After 10 days, if you are doing well and no significant side effects, you receive the remaining dose of 400. Total dose is 410. However, it is the test dosing or split dosing as we did with the rituximab in a high burden patients, or obinutuzumab. It is very similar idea. That you get 10 first and then 400. If you have a lower disease burden, you actually get 100 million and then followed by 310. Total CAR T-cell dosing is the same regardless of the disease burden. However, the dose you receive as first infusions are different. Again, tumor-based dosing is a unique thing on this. The 2 different infusions on Day 1 and Day 10 are also unique factors for this study. The primary endpoint of this was also the overall response, same as before.

[01:14:09]

FELIX: Response by Cohort  

With this, if you look the phase II on the right or the total patients, probably the best column to look at is cohort 2A. In other words, 94 patients were treated. That there was 77% CR/CRi. Again, very consistent with what we have seen with both brexucabtagene and T-cells. It is pretty remarkable that we are seeing consistent result across the 3 different very similarly structured CAR T-cells.

[01:14:40]

FELIX 2-Yr Update: Event-free Survival  

What was exciting about this, and we just presented the data 2 weeks ago at EHA, was the event-free survival rate, that 43% of the patients are in ongoing remission beyond 2 years. Most of these patients did not have a bone marrow transplant. To be exact, 38% of the patients were in ongoing remission beyond 2 years without any transplant after CAR T-cell therapy.

So that was encouraging in the sense now we are, even though the follow-up is still short 2 years and reaching almost 3 years at this time of the presentation, that this suggests that this CAR T-cell therapy be potentially be a definitive treatment for that portion of the patients without needing for subsequent transplant.

[01:15:29]

FELIX 2-Yr Update: Overall Survival  

And this again is the overall survival curve that 46% of the patients are alive beyond the 2 years' mark.

[01:15:37]

FELIX: Select Safety Events With Obe-cel in Adults With B-ALL  

Now, safety is what probably distinguishes also more drastically compared to what we have seen with the other 2 CAR products before.

The CRS, the all-grade is 69%. So that might be similar, but grade 3 and higher was 2%. So this is less than 5%. Again, just put in perspective, we're seeing about roughly 20-25%, even with the real-world setting with the brexucabtagene, it was 11% grade 3 and higher. This is one of the lowest numbers that we're seeing, kind of comparable to what we're seeing with the BiTE, actually the data that we just looked at. So this is kind of remarkable that we're seeing the low rate of toxicity.

Similarly, for ICANs, for neurotoxicity, 23% all-grade. And so that is also lower. And for grade 3 and higher, 7%. Again, one of the lowest that we have seen with CAR T-cell therapy in ALL patients. So I think that is also encouraging that not only they work well and comparable in a long, durable remissions, but toxicity profiles to appear to be better than what we have seen before.

Now the infections, the problem in this patient population who have had a lot of chemotherapy before, including some patients who had a bone marrow transplant, about 40% of the patients had a transplant. So cytopenia, infections, are the complications are something that we need to be mindful of because CAR T-cells can persist longer. Their CD19-positive normal B-cells might be depleted, and therefore they also may have a more prolonged hypogammaglobulinemia and increased risk of infection. So they might need more IVIg replacements, which I've seen and have done.

I think these are a follow-up that we need to do and especially when they return to their, you know, the referring to centers and are closer to home and receiving their care as follow-up, I think this is important to monitor for. I think it's similar to be true for BiTE, but especially for CAR T-cells, it's more so important.

[01:17:40]

FELIX: Baseline Characteristics Associated With Increased Chance of Achieving CR/CRi  

I think we just reviewed that about 40% of the patients could be a long-term remission. We wanted to see is there any particular group who tend to do well?

So this is a multivariate analysis that was performed to see any factors associated with a higher rate of a CR/CRi. Some of the factors as listed here, I think probably the lower disease burden is one came out to be more significant to be associated with the better response. Not being refractory to less line of a therapy and less prior lines of a therapy was also important. And having a Ph-positive disease was also a higher likelihood of achieving a good response.

[01:18:25]

FELIX: Baseline Characteristics Associated With Better EFS  

Similar for EFS, lower disease burden again came out to be important, less prior lines of a therapy, Ph-positive disease, so same factors that were associated with a better response. In addition, the ongoing CAR T-cell persistence, meaning the longer CAR T-cells were there, these patients tend to have a longer EFS. And then having a prior bone marrow transplant was also associated with higher EFS also.

[01:18:49]

FELIX: Baseline Characteristics Associated With Better OS  

And for overall survival, again, very similar, same characteristics we looked at.

The only addition here is a prior inotuzumab. If they receive prior ino and then receive CAR T, and more work needs to be done, but at least in this data set, those patients did not do as well. They have less survival compared to patients who did not get inotuzumab.

Again, I think it doesn't mean that they cannot get CAR T-cells after inotuzumab, but I think this raises a question that are these higher-risk patients that we should do things differently in terms of the monitoring after receiving CAR T-cell therapy.

[01:19:25]

Discussion Points  

So, I know there was kind of a long overview of looking at 3 different CAR T-cells for ALL. So, these are some of the discussion points that I will get Dr Aldoss' point of view.

We used to not have these questions as much between IV blinatumomab and CAR T-cell therapy, higher disease burden. I was automatically just drawn to CAR T-cells because in IV blin didn't work. Now, we have sub-Q, these BiTEs who don't seem to mind higher disease burden and they get higher response rate.

In your mind, Ibrahim, how would you kind of choose between CAR T-cell therapy and maybe this subcutaneous or novel T-cell engagers who may actually have a similar at least initial response rates?

Dr Aldoss: Yes, I think it was easier when we only had blinatumomab. I agree with you. blinatumomab, if it is extramedullary disease, we used to choose CAR over blina. If it is more, we give it as a definitive therapy. Someone who cannot go to transplant, we usually favor CAR T-cell therapy. I think it is now, again, we don't have a long follow-up with this new novel bispecific antibody. Again, if the treatment is more a definitive treatment and no plan to go to transplant, I still favor CAR T-cell therapy over the bispecific antibody. I think enough data suggests how effective is CAR T-cell therapy for extramedullary disease, and it's very encouraging that we're seeing a response in extramedullary with the novel bispecific.

But I would say at least, I still may favor more CAR T-cell therapy over bispecific in general, especially if the novels one are not available, and only we have blinatumomab in that setting.

Dr Park: Yes. I think it's similar for me too. I think if somebody were looking for more definitive therapy and then, because I am considering the T-cell engagers as a bridge to transplant until we get a little bit longer follow-up data. So I think that currently that's how I also think about CAR T‑cells for those patients who shad a prior transplant and that I may not be excited to give a second bone marrow transplant engaging for CAR T-cells.

Logistically, is there any patients that you think they should not get CAR T-cells or you would not consider for CAR T or lean more towards BiTE?

Dr Aldoss: Yes. These cases that they have very proliferative leukemia where it's hard to collect between cycles of cytoreduction to allow time for the T-cells to recover so you can collect. It's nice that we have actually effective BiTE-specific antibody with high disease burden and maybe these are the patients who make more sense to actually go into this novel BiTE-specific antibody rather than kind of waiting until the cancer recover to collect, and you need to keep the disease control until you make the CAR T-cells before you give it.

So maybe this is one group. Another group is, again, I think if you have low disease burden and the plan is to go to transplant quickly, I think it makes sense. It's available off the shelf. You can start immediately achieving MRD-negative CR. Then, if you have a donor, you can go to transplant very quickly.

Dr Park: Got it. Thanks. So I think, and I'll move on to the next section, but I think the autologous CAR T-cell, I think the biggest benefit is that this is a single infusion and might be a definitive therapy to a subset of the patients as opposed to needing for continuous treatment. But there are some challenges which we'll talk about autologous.

[01:23:04]

Poll 4: Have you referred patients to clinical trials of investigational T-cell engagers or CAR T-cell therapies?  

Before we get there, though. There are some polling questions you guys can answer. The first one is: Have you referred patients to clinical trials of investigation T-cell engagers or CAR T-cell therapies?

Hopefully, you have, but let's see.

Okay, good. 43% yes. So hopefully, we can get more referrals for those appropriate patients. Let's see.

[01:23:42]

Poll 5: What is your greatest challenge incorporating approved CAR T-cell therapy into ALL care?

And then the next question is: What is your greatest challenge incorporating approved CAR T-cell therapy into ALL care?

1. The access or cost;
2. Adverse events;
3. Lack of knowledge about these agents; or
4. Lack of long-term data.

Okay. So access and cost, which is the real issue. But I think it's good to see the overview. Hopefully the long-term data they were getting in 5 years and the follow-up data for the other 2, and then about 3 years for the obe-cel, I think the more we get the data, the more comfortable they will get with a long-term follow-up.

The cost is it still continues to be a problem that hopefully that will come down in the future. But the adverse event profiles are getting better with the newer CAR T-cell therapy.

[01:24:42]

Poll 6: What treatment strategy do you most often recommend for patients with ALL who relapse on CAR T-cell therapy?

Next is, what treatment strategy do you most often recommend for patients with an ALL who relapse on CAR T-cell therapy, or who relapse after CAR T-cell therapy?

1. Clinical trial;
2. DLI;
3. Transplant; or
4. Chemo.

These are definitely more difficult patients if they relapse or during or after. Let's see.

Correct. I think the clinical trial in this case is because we need a novel mechanism of action for these patients. The transplant, I think, is also very valid assuming that we can also get these patients into a remission for the transplant to work better.

[01:25:27]

Autologous vs Allogeneic CAR T-Cell Therapy

As good, great as autologous CAR T-cell therapy in terms of the efficacy, durability of the remission, manageable side effect profiles is, logistically could be challenging. I think some of you raised questions about the access issue. And then Ibrahim also briefly mentioned when can we collect the CAR T-cells?

In the allogeneic CAR T-cells with off-the-shelf CAR T, therefore, it might be attractive looking at this. First, donor-originated T-cells instead of coming from the patient who already had cancers, gone through several rounds of the chemotherapy, these T-cells will be coming from healthy donors production and manufacturing can be scaled up, and many products could be available, many doses could be available. There are some risks because, these are the donor T-cells.

So, there may be potential for graft-vs-host disease where it may not last as long if they get rejected by the host. And then the cost actually will be better. So, these are some of the differences.

[01:26:24]

Autologous CAR T-Cell Therapy: Underlying Principles  

I think you guys know this, but autologous CAR T-cell therapy, the first step that needs to happen before we get there is that we have to collect the T-cells from the patients. And some of the challenges that if the disease is not well-controlled, or they need an immediate therapy, that we can't collect the T-cells in a right way because it does take time to get the financial clearance and the line placement and the collection too. So, it often cannot be done immediately.

So, that's another reason that we always like to see these patients, know about these patients earlier than later before their full-on relapse or very rapid proliferative disease so that we can actually get to the leukapheresis in time or on time. And then, even after collection, there's manufacturing that needs to happen. That time frame is actually getting shorter.

It used to be 2 or 3 weeks. Now, it's usually about a 2-week period of the time and then the cells will be shipped back to the institution frozen, and then they could be infused. So, while the manufacturing is getting shorter and better, I think that we're still dealing with the timing for the leukapheresis and infusion for different reasons.

[01:27:27]

CARPALL: Phase I Trial of CD19/CD22-Targeting CAR T-Cell Therapy AUTO1/2 in R/R B-ALL

Now, allogeneic CAR T-cells will obviate the need and the data is a little bit sparse and not as much, so I'll go through this data more quickly than the first one. So, this is one of the others in the CAR T-cell therapy that from the healthy donor T-cells that's modified to express 19 and 22 CAR, and this was pediatric patient data. Again, with a lymphodepleting chemotherapy, there are various regimens and some are a little bit more severe lymphodepletion or enhanced lymphodepletion with a higher dose of a fludarabine. The response rates are quite similar as to autologous CAR T-cell therapy. If you look at the box on the right, it's 83% response rate.

So, that is encouraging and then 12 months event-free survival was 60%. So, that looks promising. However, more relapses do happen after allogeneic CAR T, but they don't seem to last as long as auto-CAR T.

[01:28:21]

BALLI-01: Phase I/II Trial of Allogeneic CAR T-Cell Therapy UCART22 in R/R B-ALL

This is another trial, again, healthy donor derived allogeneic T-cells. Now, this time with a CD22. It's a different antigen-targeting CAR T-cell therapy. A lot of these patients actually had a prior CD19 CAR and therefore enrolled to this study and received them.

Encouragingly, they are able to rescue these patients or reach a response about 50% of the time, but response duration was actually short for some of these patients.

[01:28:52]

Phase I Trial of Allogeneic Anti-CD19 CAR T-cell Therapy RD06-03 in B-ALL

Lastly, this is one from China, looking at the other CD19 CAR T-cell therapy from the healthy donor, pediatric and adult patients.

I think the consistent theme here is that it is a much smaller study in the preliminary data. The response rates are comparable to what we are seeing with autologous CAR T-cells, but the duration is shorter because the T-cells might be rejected by the host as the immune system is recovering after lymphodepletion, so that is 1 limitation, but it might serve as a very effective bridge to transplant for some and there are different versions of allogeneic CAR T-cell therapy that is being developed to overcome this limitation. Hopefully in the future, we will see a better version of this off-the-shelf CAR T to get the better response for those.

I know it is not a lot of data yet, but I think that more work is to be done and will be done, and I hope to see this be successful because it makes it a lot easier for the patient to receive it, and we can skip the steps of collections and other things and I think with the current technology development that we can actually see that fruit in the near futures and there are other disease settings that we are already seeing that.

[01:30:06]

Posttest 4: How confident are you in your ability to identify patients who may be eligible for ongoing clinical trials of novel immune-targeted therapies in ALL?

So with that, we will do the posttest session and one more discussion after this, but how confident are you in your ability to identify patients who may be eligible for clinical trials of novel immune-targeted therapies in ALL?

1. Not confident;
2. Low;
3. Moderate;
4. Confident; or
5. Very.

Please vote.

Good. At least moderate confidence is excellent.

Then we will move on to the next.

[01:30:47]

Poll 7: Do you plan to make any changes in your clinical practice based on what you learned in today's program?

Do you plan to make changes in your clinical practice based on what you learned in today's program?

1. Yes;
2. No; or
3. Uncertain.

[01:31:15]

Poll 8: Please take a moment to enter 1 key change that you plan to make in your clinical practice based on this education.  

And then the last one. So please take a moment to enter one key change that you plan to make in your clinical practice based on this education.

Shiraz: And while the audience is answering that final poll, I think we can move on to a discussion.

[01:31:46]

Discussion Points

Dr Park: Thank you. So I know we are coming to the end, but I think there are a couple of points that I wanted to see and pick Aldoss's brain as well.

Looking at the CAR T-cell therapy, one of the things is that now in all the trials in the commercial settings they looked at relapsed/refractory patients who usually after 2 more prior lines of a therapy. Do you think we're ready now to move some of these CAR T-cell therapy to earlier lines of a setting?

Dr Aldoss: Yes, I think so, Jae. You are aware of the data from us, as well as we have a proposal together using CAR T-cell therapy in the first remission. And the idea is if you use it in someone in remission, it is always easy to achieve remission. It is a problem to maintain the remission in patients with ALL and avoid the toxicity from repeating cycles of chemotherapy. So the idea is if we give CAR T-cell therapy early on, most likely the fitness of the T-cells will be better, less exhausted, patient will be in remission, so less toxicity, and it can draw out the remission and potentially cure without additional therapy, and patients can go back to a normal life earlier than just staying on treatment.

We have tested that with our own CAR T-cell therapy at City of Hope. We have seen encouraging outcomes in older patients who achieve CR with initial therapy in terms of low rate of [inaudible] [Inaudible 01:33:15] we only have seen grade 3 [inaudible] to non-neurotoxicity, and we're seeing durability of ongoing MRD negativity in these patients. The data is still preliminary, and we are hoping we can do the same experience with one of the commercially approved products. So I think that is where the field is moving, Jae.

Dr Park: I 100% agree, I think that is the best setting to test CAR T-cell therapy as a true potential for consolidation for definitive treatment. And if successful, is probably the next game-changer in ALL, as we talked about in the frontline setting, between induction and consolidation and a couple of years of maintenance, it is several years of treatment. But if this approach works, after several months of induction or some chemo maybe, and then followed by 1 infusion of CAR T it could be it for these patients, which will dramatically reduce the treatment of the patient and hopefully an improved quality of life.

We also looked at allogeneic CAR T‑cell data, which are not that many, and we have tried in the past, what are some of the unmet needs in ALL that you think we still need to address with this type of immunotherapy?

Dr Aldoss: I think it is what is beyond CD19-targeted CAR T-cell therapy. I have now 3 products in CD19 CAR T-cell therapy, many bispecifics targeting CD19. It is the problem in patients who actually have CD19-negative disease. These patients really do not do well. The options are very limited. We have inotuzumab, but it is not a curative treatment. So, we need new targets in ALL.

The same thing applies to T-cell ALL. We are struggling of having CAR T-cell therapy for different reasons. They share the same antigen as the T-cells. There are different approaches to make it feasible with CAR T-cell therapy. Although we are seeing some responses, the issue is the durability of this response, especially as we use allogeneic CAR T-cell therapy is the persistence and durability is not the same as what we get with autologous CAR T-cell therapy.

Dr Park: Yes. I think hopefully the novel mechanism of cloaking and overcoming the immune system might overcome that. I think we're beginning to see some IL-18 CAR T-cell therapy approaches with autologous CAR T-cells that may overcome the limitation of the current CAR T‑cell therapy.

I see a question from the audience. Any thoughts on what underlies differences in CAR T agent safety profiles? It is a good question. With the obe-cel, I think we looked at significantly lower rates of CRS and ICANS. I will first share my thoughts and see what Ibrahim also thinks.

It is unclear what is driving. I think there are some good hypotheses. One is that their binder is different. They have a low affinity, which is similar to the BiTE, and they are taking a similar approach there too. So, you have a lower time to engage with an antigen and maybe because of that, you do not get as much of a rapid T-cell activation, and maybe because of that, you get a lower rate of toxicity.

And then maybe the split dosing regimen, does that really help? I am not sure. I think that might also have contributed to these. And manufacturing with these cells is different, which that we do not know, is a little bit of black box there. But it think the binder might potentially make a difference. What do you think, Ibrahim?

Dr Aldoss: I agree. These are 2 points, at least what we know about. The binder is different, lower affinity and is a split dose, which is another actual reason of toxicity compared with CAR Ts.

Dr Park: Yes. If any other questions come up from the audience, feel free to pick them on there too.

And just to finish it off, what other novel CAR T-cell therapies are you most excited about?

Dr Aldoss: As you mentioned, enhanced CAR T-cells, I think with IL-18, that seems very encouraging. Again, looking for other targets, I know there are different groups looking at the TSLP, which is for CLF2 rearrange Ph, like ALL. This is a disease with an unmet need, frequently chemo refractory.

We have the BAFF-R CAR T-cells, which is applicable for a subset of B-cell, which express the BAFF-R. We are seeing some encouraging results as well in this.

What are your thoughts, Jae, for bispecific CAR T-cells compared to CD19 CAR T-cells?

Dr Park: At least in ALL, I have not been super impressed with the data so far, to be honest, and neither is CD19/22 or CD19/20. Lymphoma might be a different disease, might be a different story, but in ALL, it has been tried. We did not present the data here, but the response rates are quite similar. It is hard to improve upon what we are seeing so far. The relapse rates are not that much different than the single-antigen-targeted. Even when they relapse, the antigen is still retained. It is not preventing the relapses or the antigen escapes as much. It may be due to the other binders. The CD22 binder may not have been as good. CD19 is exceptionally good. It is very forgiving. However, the other binders may not be. So maybe that is the issue. So far, I am not convinced, at least in ALL, that that will be the major changer.

Dr Aldoss: It seems like the persistence is less than CD19 CAR.

Dr Park: Correct. There are different ways of targeting them. CD19 always seems to be better in those cases, but not in all studies. But the persistence may also be different. We are seeing with the persistence with other studies beyond 2 years with a CD19 CAR, yes, CD19-negative relapse is a problem, but it's still not the major mechanism of resistance in ALL.

Dr Aldoss: What about CD20? Are you aware of any CD20 CAR T-cell in ALL?

Dr Park: I do not know. It has not been tried as much because CD20 expression is not as universal, although they are expressed 70-80% of the time, maybe even higher if you look hard enough. But I do not think it has been looked, certainly not as a single antigen but as even double, CD19 and CD20, which is explored extensively in lymphoma patients.

Dr Aldoss: It seems, at least with CAR T-cell therapy, how strong is the expression is the predictor.

Dr Park: Yes, true, you do need some expression. I think that's another important point after blin and the CAR T-cell is that we do have to check, but just because we have a low expression, we don't know, and we have seen with a low-expressing CD19 that CAR T-cells can work, and the same thing is true for blin there as well too. I think that should not also be a reason not to refer. If they have a zero expression, then it is. Sometimes we see that it is gone right after the blin, and they can reappear too. I think it is important to recheck after blinatumomab because the antigen can resurface.

Dr Aldoss: We have seen this in our experience. Frequently they regain the CD19, most likely emerging CD19-positive B-cell ALL, but we do not see it after CAR T-cell therapy. Once you lose it after CD19, typically they remain CD19-negative.

Dr Park: That is a good point. I think you are right there too.