Congress to Clinic: Clinic Advances Journal Club on Emerging CAR T‑Cell Therapy Data From Summer Conferences ASCO, EHA, and ICML

Welcome, everybody, as I take us through the updates in CAR T‑cell therapy for lymphoma from the summer congress.

[00:14:49]

FDA‑Approved CAR T‑Cell Therapies in HCL

Here are the current FDA‑approved CAR T‑cell indications in lymphoma. We have axicabtagene‑ciloleucel, which has indications for relapsed large cell after failure of 2 lines of therapy. It can also be administered to people who are primary refractory. Axi‑cel is also approved for relapsed/refractory follicular lymphoma after 2 lines of therapy.

Brexucabtagene‑autoleucel is approved for relapsed mantle cell lymphoma.

Lisocabtagene‑maraleucel has the most indications; approved in diffuse large B‑cell lymphoma in people who are primary refractory, patients who have failed 2 prior lines of therapy, or people who have failed just 1 line of therapy but are not suitable for autologous stem cell transplant. Liso‑cel is also now approved in relapsed/refractory CLL if they have had at least 2 lines of therapy, including BTKi and BCL‑2; relapsed follicular lymphoma, with at least 2 prior lines of therapy; and relapsed mantle cell lymphoma with at least 2 prior lines of therapy, including a BTKi.

And then we have tisagenlecleucel, which is approved in relapsed diffuse large B‑cell lymphoma after 2 prior lines, or follicular after 2 prior lines.

A lot of approvals in the space. What is new?

[00:16:18]

FDA Eliminates REMS for CAR T‑Cell Therapy

One of the things that is new is the elimination of the REMS program, which will make it a little bit easier for patients and caregivers. That was welcome news this summer.

[00:16:29]

Large B‑Cell Lymphoma (LBCL)

Let us talk about what we learned at the conferences this summer in diffuse large B‑cell lymphoma.

[00:16:37]

ZUMA‑7: Axicabtagene Ciloleucel in R/R LBCL

Here is the original data from ZUMA‑7. This was the trial that led to the approval of axi‑cel in primary refractory diffuse large B‑cell lymphoma. You see the big event‑free survival benefit compared to immunochemotherapy with the intent to do a stem cell transplant.

[00:16:54]

Real‑world Outcomes for 2L Axi‑Cel for R/R LBCL: Safety

One of the interesting abstracts at the congresses was this real‑world look at second‑line axi‑cel for relapsed/refractory large B‑cell lymphoma. You can see that the toxicity data looks pretty comparable to what we are used to, a low rate of high‑grade CRS, but there is about a 20% chance for grade 3 ICANS. The largest cause of death is still relapse of the disease.

[00:17:26]

Real‑world Outcomes for 2L Axi‑Cel for R/R LBCL

Here is the outcome data for second line axi‑cel. You can see that the event‑free survival curve in this real‑world experience from CIBMTR with over 400 patients, the results look very similar to ZUMA‑7, which is very reassuring that the clinical trial data is translating to the real‑world population.

[00:18:05]

Retrospective CAR TVs Auto‑HSCT From EBMT Group

One of the ongoing dilemmas in the CAR T world is what do you do if you have a patient who is primary refractory and you are thinking, I need to go to CAR T‑cell therapy. But they need some salvage because of disease control or symptoms, so you give them R‑ICE, DAP, or something like that. All of a sudden, you get them into CR. Do you still go to CAR, or does that bring autologous transplant back into the equation? This was a really interesting retrospective look from the European Bone Marrow Transplant Group, which looked at these patients in CR and looked at outcomes. What you can see is, if the patient does get into CR, the autologous transplant still performs about as well as the CAR T‑cell strategy for overall survival and progression‑free survival.

[00:18:57]

Retrospective CAR TVs Auto‑HSCT From EBMT Group: Relapse and Nonrelapse Mortality (NRM)

Here we see the relapse incidence. The relapse rate is actually a little higher with CAR T‑cell therapy, although the non‑relapse mortality is a little higher for transplant. The net result is comparable overall survival.

[00:19:15]

Phase I Study of KITE‑363: Anti‑CD19/CD20 CAR T‑Cell Therapy for R/R B‑Cell Lymphoma

What about new CAR products for diffuse large B‑cell lymphoma? One of the big areas of interest is CARs that have dual targets because loss of antigens sometimes is a mechanism of failure. Here is an example of this KITE‑363 molecule, which targets both CD19 and CD20. This is some data from their phase I study.

[00:19:45]

Phase I Study of KITE‑363: Baseline Characteristics

The patient characteristics are quite typical for this kind of patient population. Most patients were positive for both antigens, although 13% just had 1 of the antigens.

[00:20:00]

Phase I Study of KITE‑363: Prior Therapy

Some of the patients, about 20% had failed prior CAR T, and about 15% had failed prior autologous stem cell transplant.

[00:20:13]

Phase I Study of KITE‑363: CRS and ICANS

What about toxicity? I will focus on dose level 3. You can see the risk for grade 3 CRS was only 4%. For grade 3 ICANS was only 8%. Looking pretty good from a safety standpoint.

[00:20:31]

Phase I Study of KITE‑363: Safety

The other toxicities were what we would expect after CAR T cell therapy, namely, cytopenias and infections, but there were no new or worrisome toxicities noted with this novel compound.

[00:20:44]

Phase I Study of KITE‑363: Response

The efficacy looks quite good. You can see in the CAR‑naive patients that received dose level 3, 23 patients, the overall response rate is 87%, with 78% of the patients achieving complete remission. Very impressive. We do not really have long‑term data, but at 6 months, 71% of the CR patients remain in CR. Early days for this compound, but promising data and something to keep your eye on going forward.

[00:21:17]

Follicular Lymphoma (FL)

What about follicular lymphoma?

[00:21:22]

ELARA: Tisagenlecleucel in R/R FL

Tisa‑cel, as I mentioned earlier, is already approved for relapsed/refractory follicular based upon this single‑arm trial. A lot of us who treat follicular lymphoma have been very anxious to see longer‑term data for the CAR products. How are these remissions holding up at 3 years, 4 years, 5 years?

[00:21:42]

ELARA: >4 Yr Updated Efficacy

Now, we are starting to get some of that data. I would say the data is looking impressive. Here is the progression‑free survival with a median follow‑up of 53 months. The blue curve is all patients. At 4 years, over half the patients are still holding remission. If your patient does achieve CR, the 4‑year remission rate is closer to 66%. Personally, I am very impressed with the longer‑term follow‑up from this particular CAR product and others. It is making me even more excited about the use of CAR T‑cells in follicular lymphoma than I was a few years ago.

[00:22:28]

ELARA: No New Safety Signals

No new safety signals with longer‑term follow‑up.

[00:22:31]

ZUMA‑5: Axicabtagene Ciloleucel in FL and MZL

Here is, again, a longer‑term follow‑up from the axi‑cel product, looking at its outcomes in follicular. Now, we are adding in marginal zone lymphoma. Marginal zone is a lymphoma subtype that has no CAR T indication at this time. We are anxious to see some CAR T data in marginal zone lymphoma.

[00:22:54]

ZUMA‑5: 5‑Yr Updated Responses, DoR, TTNT

What you can see here, with longer‑term follow‑up, just like we saw with tisa‑cel, the progression‑free survival is looking very impressive at 3 years and 4 years, with some patients getting out to 5 years now.

[00:23:11]

ZUMA‑5: 5‑Yr Updated PFS and Cumulative Incidence of Progression and Lymphoma‑Specific Death

When we first saw this data, the marginal curves did not look as good. We thought it was going to be a bust. But with longer‑term follow‑up, the marginal zone lymphoma outcomes look to be just as good as the follicular lymphoma long‑term outcome. Again, this makes me encouraged and optimistic about using CAR T‑cell therapy for patients with follicular and marginal zone lymphoma.

[00:23:41]

Marginal Zone Lymphoma (MZL)

[00:23:42]

TRANSCEND FL: MZL Cohort of Lisocabtagene Maraleucel

Specifically in marginal zone lymphoma, we have the liso‑cel product being studied in the TRANSCEND follicular. A separate cohort in this study. They have even better numbers of patients, 67 patients with marginal zone lymphoma receiving liso‑cel.

[00:24:00]

TRANSCEND FL: MZL Cohort CRS and Neurological Events

What you can see is the risk for grade 3 CRS or neurologic events is very low, less than 5%, so that is reassuring.

[00:24:16]

TRANSCEND FL: MZL Cohort ORR and PFS

The response rates are impressive. The overall response rate in marginal zone lymphoma is over 95%, with 62% of those being complete remission. If you look at the 2‑year progression‑free survival, it is holding at 85%. Just like with axi‑cel, liso‑cel is looking highly promising in relapsed/refractory marginal zone lymphoma.

[00:24:45]

Mantle Cell Lymphoma (MCL)

What about mantle cell lymphoma?

[00:24:49]

ZUMA‑2: Brexucabtagene Autoleucel in MCL

We have brexucabtagene‑autoleucel approved in this space from the ZUMA‑2 trial.

[00:24:57]

ZUMA‑2 Cohorts 1 and 2: ORR and DoR

Here is some longer‑term follow‑up from the original cohorts in the ZUMA‑2 study. Overall response rate 93% with the majority of these being complete remission. It should be 64% complete remission, and good durability at 3 and 4 years, close to 50%.

[00:25:18]

ZUMA‑2 Cohort 3: ORR and ORR in Key Subgroups

Presented at ASH this past year was the ZUMA‑2 Cohort 3, which are patients who had no prior BTKi. They are less heavily pretreated. A lot of these were high‑risk patients because they had TP53 mutations or some other adverse feature. If you look at the bar plots here, the overall response rate is 91%. There is a typo here; it is complete response in orange. So 73% of the patients achieved a complete response, 17% of the patients partial response. Brexu‑cel is looking very promising in Cohort 3 of the ZUMA‑2 trial.

[00:26:09]

ZUMA‑2 Cohort 3: PFS and OS

Here is the Kaplan‑Meier curves. You can see that for patients who achieve a complete remission, follow‑up is short. But at 12 months and 18 months, the majority of patients are holding their remissions.

[00:26:22]

ZUMA‑2 Cohort 3: Safety

What about safety? With brexu‑cel, we always have to be a little concerned about safety. Fortunately, the grade 3 CRS was not high, although the grade 3 ICANS is still approaching 20%. That is definitely a consideration when you are considering your mantle cell lymphoma patients for CAR T‑cell therapy. There is some risk there.

[00:26:53]

Post‑Brexu‑Cel Outcomes for MCL: A Descar‑T‑Study

This was a sobering analysis that came out of the ICML meeting, looking at post brexu‑cel outcomes. This was a French consortium looking at outcomes after CAR T failure in mantle cell lymphoma. What we have learned there is this is a huge unmet need. You can see the response rates to most attempts at salvage are very disappointing. R squared only 18%. Immunochemotherapy 23%. BTK inhibitors 0%. Probably the most promising would be bispecifics at 42%, although there were only 7 patients. There is definitely a huge unmet need for how to manage mantle cell lymphoma patients who relapse after CAR.

[00:27:40]

Chronic Lymphocytic Leukemia (CLL)

What about chronic lymphocytic leukemia?

[00:27:45]

TRANSCEND CLL 004: Lisocabtagene Maraleucel in Relapsed/Refractory CLL/SLL

We now have liso‑cel approved in this space from the TRANSCEND CLL 004 study, and we are interested in seeing longer‑term follow‑up.

[00:27:58]

TRANSCEND CLL 004: Efficacy Outcomes in DL2

I draw your attention to the response rates here. Notice that the complete response rate is only about 20%. CAR T in CLL has not looked as promising as CAR T looks in mantle cell or diffuse large B‑cell lymphoma or follicular lymphoma.

[00:28:20]

TRANSCEND CLL 004: DoR and PFS in DL2

Here we see the time‑to‑event curves. You can see that if your patient is in that lucky 20% who derive a complete response, those can be durable. I think if you have a young CLL patient who is refractory to both BTK and BCL‑2 inhibitors, this is a perfectly reasonable thing to consider. But you can see that if your patient only achieves partial remission, they tend not to be terribly durable.

[00:28:49]

TRANSCEND CLL 004: Safety in Full Study Population

There is some risk. You can see the grade 3 cytokine release syndrome at 8% and the grade 3 neurotoxicity at 18%. I do not think I would send a CLL patient to this therapy unless they had failed all available oral agents.

[00:29:10]

Summary of T‑Cell Therapy Data in Lymphomas

Let me summarize what we learned from the summer congresses. New CAR T data in lymphoma.

In diffuse large B‑cell lymphoma, we learned that the real‑world axi‑cel cell data look very similar to ZUMA‑7, which is reassuring. We saw retrospective data suggesting that if you are planning on CAR T‑cell therapy, but your patient achieves CR to salvage, you then can reconsider. You could have that patient undergo an auto transplant and save the CAR T‑cell for later, giving you 2 bites at the apple. That is a reasonable strategy to consider. And then, we have this brand new CAR product, dual targeting agents CD19, CD20, with a very high overall response rate, an agent to keep your eye on going forward.

In follicular lymphoma, we are seeing longer‑term follow‑up for tisa‑cel and axi‑cel, with the majority of patients still holding the remissions at 4 years, which I think is outstanding.

Now we have promising data in marginal zone lymphoma with the TRANSCEND follicular study enrolling some marginal zone patients. Overall response rate of 95% with good durability. That is now undergoing priority FDA review.

In mantle cell lymphoma we have now seen ZUMA‑2 outcomes for patients who have not been BTK‑exposed. They look very promising as well. We saw the very poor outcomes post brexu‑cel failure, and it proves to be a large unmet need in the field.

Finally, we now know that liso‑cel is an option and FDA‑approved in relapsed CLL. Complete response rate of only 20%. But if your patient is in that lucky 20%, they can achieve durable remission.

[00:31:12]

Let’s Revisit a Question

We are going to revisit our question.

[00:31:17]

Posttest 1

What was the primary result of liso‑cel cell for marginal zone lymphoma in the phase II TRANSCEND follicular study? Is it:

1. An incidence of all grade ICANS greater than 50%
2. Median duration response of about 18 months
3. No grade 3 or higher CRS events
4. The overall response rate of 95%

Here we go. It is the overall response rate of greater than 95%. I am happy to see most of our participants got that answer correct.

[00:32:14]

Question and Answer Session

In the interest of time, I am going to put the lymphoma Q&A towards the end, and I will turn it over to DrRaje.

[00:32:20]

Multiple Myeloma

DrNoopur Raje (Massachusetts General Hospital Cancer Center): Great. Thank you so much, Brad. That was a quick overview of all of the lymphomas. Now, in the next 15, 20 minutes, we are going to focus on multiple myeloma. We are going to really focus on some of the older data, but also some of the new data which was presented at this year's summer meetings, ASCO, and EHA.

[00:32:47]

FDA‑Approved Autologous CAR T Therapy for R/R MM

We all know that we have 2 FDA‑approved autologous CAR T‑cell products in the context of myeloma. We have idecabtagene vicleucel, or ide‑cel, and ciltacabtagene autoleucel, or cilta‑cel. Both of them are targeting BCMA. Both of them have the 4‑1BB construct as the secondary activator. Both of them have been approved in earlier lines of treatment. Slight difference in the indications. With ide‑cel, you have to have had 2 prior lines of treatment, including an IMiD, a PI, and an anti‑CD38 monoclonal antibody based on the KarMMa‑3 data. You can actually give patients cilta‑cel after just 1 prior line of treatment. All they have had to have is a PI and IMiD. They have to be refractory to lenalidomide to be able to get cilta‑cel based on the CARTITUDE‑4 trials.

[00:33:50]

CARTITUDE‑1: Ciltacabtagene Autoleucel for R/R MM

We saw very recently the long‑term data on CARTITUDE‑1. This was the old trial, which was used in patients who were refractory to every possible treatment.

[00:33:08]

CARTITUDE‑1: Updated PFS and OS at ASCO 2025

What we saw here was updated PFS and overall survival. You saw at a median follow‑up of a little over 5 years, the progression‑free survival of these patients was 33%. The overall survival was also pretty close. This actually got a lot of press. This is where people think these are patients who were potentially cured of their myeloma because they have been off of all treatment for more than 5 years now.

[00:33:42]

CARTITUDE‑1: Long‑term Safety and Future Directions

This is the long‑term safety data with this as well. There is really no new safety signal. There were 2 new cases of secondary primary malignancies, and the neurological events were the same, which had been reported previously in the CARTITUDE‑1 trial. There are ongoing trials now with cilta‑cel in the up‑front space, both with CARTITUDE‑5 as well as CARTITUDE‑6. It is going to be a couple of years before we see results for CARTITUDE‑5 and 6.

[00:35:16]

Arlocabtagene Autoleucel for R/R MM: Study Design

What about other targets? This is a brand new CAR T‑cell. This is arlocabtagene autoleucel. This is a CAR T cell which is targeting GPRC5D. This CAR T cell has gone through a phase I dose escalation study.

[00:35:37]

Arlo‑cel for R/R MM: Extended Follow‑up

If you look at the data with this dose escalation study, you see very high response rates with arlo‑cel close to 90% overall in this patient population. In general, extremely well tolerated.

[00:36:04]

Arlo‑cel for R/R MM: TEAES (≥ 30% of Treated Patients)

This translated into typical CRS and neurotoxicity, which is seen. The ICANS and CRS grades are low, very few, if any, high‑grade toxicities noted with this CAR T‑cell product.

[00:36:15]

Arlo‑cel for R/R MM: Select TRAEs

If you start looking at specific toxicities, there were some other neurotoxicities seen with arlo‑cel, which is very typical of targeting GPRC5D. That was mainly cerebellar toxicities but that was seen in a minority of patients, about 7% or so. A subset of patients also saw HLH in this patient population. Some of the on‑target, off‑tumor toxicities, which we are used to seeing with a drug product such as talquetamab, were seen, but the incidence of nail toxicities, dysarthria, as well as skin toxicities, is a lot less with arlo‑cel as compared with talquetamab.

[00:37:03]

Arlo‑cel: Actively Recruiting Studies

Arlo‑cel is actively recruiting. Right now, there's a phase II QUINTESSENTIAL trial wherein arlo‑cel is being used in triple‑class and quad‑class exposed patients with relapsed/refractory patients who have had at least 2 prior lines of treatment. There is also an ongoing phase III confirmatory trial. It is called the QUINTESSENTIAL‑2 trial. That is looking at arlo‑cel vs standard of care. This is the registration trial in patients who have had 1 to 3 prior lines of treatment.

[00:37:41]

iMMagine‑1: Phase II Study of Anitocabtagene Autoleucel in R/R MM

There are other CAR products as well. This is data with anitocabtagene autoleucel. You have already seen the first in‑human trials with that. High response rates with a median PFS close to about 30 months. iMMagine‑1 was a phase II trial which recruited about 120 patients, which were relapsed/refractory patients.

[00:38:05]

iMMagine‑1: Updated Efficacy Results

These patients ended up at a median follow‑up. Their overall response rate was incredibly high. 97% of these patients responded, with a complete response rate of 68%. The median PFS at 6 months was 91%, and at 12 months, 79%. So still fairly early data, but at least very promising data that we are seeing with anito‑cel in the space of relapsed/refractory myeloma.

[00:38:38]

iMMagine‑1: CRS and ICANS

Again, if you look at the toxicities of anito‑cel, we did not see anything which was new. Nausea. The CRS and ICANS rates are very similar to what we are used to seeing with ide‑cel, as well as cilta‑cel. To date, at least, we have not seen any delayed neurotoxicity with anito‑cel. Again, an interesting product with a lot of efficacy in patients with relapsed/refractory multiple myeloma.

[00:39:08]

iMMagine‑1: Treatment‑Emergent AEs

Other treatment‑emergent toxicities from anito‑cel, not quite different. The typical cytopenias. Infection rate was also not specifically higher than what we are used to seeing in the context of CAR T cells.

[00:39:25]

ESO‑TO1: In Vivo B‑Cell Maturation Antigen CAR T‑Cell Therapy for Relapsed or Refractory Multiple Myeloma

What has really been exciting is this new in vivo BCMA‑directed CAR T‑cell therapy using ESO‑T01. This is a nanobody‑targeted, immune‑shielded lentiviral vector, which is injected into patients. Obviously, this is very early data. This was just a case series which has been presented and now published in The Lancet by the Chinese investigators.

[00:39:58]

ESO‑TO1: Early Safety and Efficacy in 4 Patients

What they showed pretty remarkably in 4 patients is, as soon as you infuse this viral vector, you see a surge of cytokines, you see patients becoming febrile. And then, as these become CAR T‑cells in vivo, you see a second expansion. This was associated with a very high response rate. Obviously, early data. If we can get off the shelf CAR T‑cells such as this ESO‑T01, this is going to be a game changer, because you are not going to have to wait the 4 to 6 weeks for actual manufacturing of CAR T‑cells.

[00:40:38]

GC012F: Dual‑Targeting BCMA/CD19 CAR T‑Cell Therapy

Other CAR products which were presented at this year's meetings. This is another exciting one. This is GC012F. This is a dual‑targeting CAR T‑cell. It targets BCMA as well as CD19. The reason for CD19 is, there's some belief that CD19 is expressed on the stem cells or the precursor myeloma cells and trying to address both CD19 as well as BCMA will have better efficacy.

[00:41:07]

GCO12F: Phase I Study in R/R MM

If you look at the data of a phase I study in the relapsed/refractory state, very high response rates with this GC012F, as well as very good progression‑free survival at 12 months and at 3 years. Really quite remarkable data with this.

[00:41:28]

GCO12F: Phase I Study in Newly Diagnosed MM

This has also been studied in the newly diagnosed space. In the newly diagnosed space, again, 100% response rate with MRD negativity in the majority of these patients, suggesting that these patients are going to have a remarkable progression‑free survival.

[00:41:48]

GCO12F: Safety

Again, the good news is that the safety is very comparable to what we have seen with ide‑cel and cilta‑cel. No new safety signals with any of these. We certainly have not seen any delayed neurotoxicity with these novel new drug products as well.

[00:42:08]

BMS‑986453: Dual Targeting BCMAxGPRC5D CAR T‑Cells

BMS is also using a new CAR T‑cell, which is a dual‑targeting CAR T‑cell. In this case, it is targeting GPRC5D like the arlo‑cel, as well as BCMA. Ide‑cel, arlo‑cel combined together. Dual‑targeting CAR is already accruing in a phase I first in‑human study. This is going to be looking at safety of this dual targeting. There are a lot of good, interesting things going on in the myeloma space with the potential of remarkable efficacy and hopefully, long‑term disease control with some of these novel approaches.

[00:42:52]

TriPRIL: Trimeric APRIL‑Based XAR T‑Cells Dual‑Targeting BCMA and TACI

We, at MGH, also have our own homegrown CAR T‑cell. This is the triPRIL CAR T‑cell. What it does is it is a trimer against APRIL, which is a ligand which targets or signals through TACI and BCMA. This is an ongoing first in‑human trial, and I think the first data we will be presenting at this year's International Myeloma Society meeting later in September.

[00:43:32]

Let’s Revisit a Question

With that, I think I have gone through all of what we already have and what we are looking forward to. So, let us just revisit our poll question again. This was the first.

[00:43:40

Posttest 2

Which of the following patients may be a candidate for treatment with this ongoing arlocabtagene‑autoleucel study, the phase III QUINTESSENTIAL‑2 trial?

1. Is it a patient with CLL after 3 prior lines of treatment, including a BTK inhibitor and venetoclax?
2. Is it patients with diffuse large B‑cell lymphoma arising from follicular lymphoma after 2 prior lines of systemic treatment?
3. Or would it be a multiple myeloma patient up to 2 prior lines of treatment, including lenalidomide exposure, a PI and and an IMiD?
4. Or is it somebody with marginal zone lymphoma?

Let us see what folks have to say. All right. You are listening. This is a myeloma, a CAR T‑cell lecture, so that is great. QUINTESSENTIAL will be the confirmatory registration trial for arlo‑cel. We had another question, I believe.

[00:44:50]

Patient Case: 62‑Yr‑Old Woman With R/R MM

This is a case, a 62‑year‑old woman with relapsed/refractory myeloma. She was previously newly diagnosed, was treated with a quad treatment that included a CD38 monoclonal antibody, a proteasome inhibitor and an immunomodulatory agent. She is now experiencing a relapse while on lenalidomide maintenance.

[00:45:13]

Posttest 3

Based on the current indications of the approved CAR products that we have, what would be the most appropriate therapy for this?

1. Is it axicabtagene ciloleucel?
2. Is it ciltacabtagene autoleucel?
3. Is it idecabtagene vicleucel?
4. Or is it lisocabtagene maraleucel?

I am still waiting for the responses, I guess. This is all over the place a little bit. This is a patient with myeloma. All these names can be tongue twisters. Cilta‑cel is approved after 1 line of treatment and the indication is really in lenalidomide refractory patients. Somebody who has had a quadruplet cilta‑cel, as close to 40% of you have highlighted, would be the treatment of choice in this particular patient. As far as idecabtagene vicleucel or ide‑cel is concerned, you have to have had more than 2 prior lines of treatment. Cilta‑cel would be the right answer out there.

[00:46:45]

Question and Answer Session

With that, we have a few minutes for questions and answers. Brad is here as well. Both of us are happy to answer questions as they come along.

Amber Williams: There are a couple of questions in the chat.

DrKahl: I am looking at the first question in the chat. For a CLL patient who progressed on a BTK inhibitor and venetoclax, do you wait for them to progress on pirtobrutinib prior to collecting cells for CAR?

That is a great question. If you look at the pirtobrutinib data in these double refractory patients, the response rate is about 80%. So that is good. But the median progression‑free survival is only about a year and a half, so the responses are not super durable. If I have a young patient who I think is fit enough for CAR T therapy, I will definitely get the CAR T option lined up. I will also look carefully at the quality of the response to pirtobrutinib. If someone seems like they are going into a complete remission or a really good partial remission, I will probably stay on pirtobrutinib as long as I can. But sometimes you get these really mediocre quality remissions, and then I know they are not going to be very durable, and then I would start getting my CAR T strategy lined up.

DrRaje: Great. The next question, Brad, I think, is more myeloma‑wise. Is anito‑cel expected to work differently from other BCMA targeting CAR T‑cells?

I think that is a great question as well. I do think, although all of these CARs target BCMA, they all work a little bit differently. The way anito‑cel is manufactured, it synthetically binds to BCMA. The binding is tighter. The binding site is smaller. With that, the tonic signaling is a lot less. That may be the reason why persistence is different. The high response rates may be because of the tight binding. The durability may be because of the decrease in the tonic signaling. This is the hypothesis. This truly needs to be tested, and we need to look at longer follow‑up with these studies and make sure that what we are saying is actually accurate.

Any clinical trials with allogeneic CAR T‑cells? I will let Brad answer, and then I will answer my piece there as well.

DrKahl: There are allogeneic CARs being studied in lymphoma. We have a trial ongoing at our site. It is early days. We certainly have seen nice responses in our patients who have received the allo CAR products. I do think there is a lot of potential here. It obviously helps eliminate the manufacturing time and delays. This is a whole other line of CAR research that I think is really important. We will probably learn a lot in the next 2 to 3 years about the potential of these products in lymphoma.

DrRaje: I think for myeloma, we have struggled with the allogeneic CAR T‑cells a little bit. But I do think we are getting better ways of getting rid of the T‑cell receptor piece so that we do not have to give very immunosuppressive treatments. The rate of infections with the early allo CAR T‑cells was very high because of us having to give them Campath‑like regimens, et cetera. Hopefully, it will get better. But I just showed you some data with in vivo CARs as well. This field is moving forward very fast, and we really have to see if we can find a safe allo CAR. Whether it is an allo CAR or an in vivo CAR, I think the jury is out there. We will have to wait and see which one wins in this situation.