Before we get into some additional presentations, we are going to start with a broad overview of chimeric antigen receptor, or CAR T-cell therapy.

 

[00:23:54]

 

Autologous CAR T-Cell Therapy: Underlying Principles

 

CAR T-cell therapy has transformed the treatment landscape for patients with hematologic malignancies, yielding durable remissions in patients who previously had poor prognoses. It is a living drug, an autologous, meaning from the patient product. It has a unique set of steps in order to administer the treatment.

 

First, patients must undergo leukapheresis, where the patient's white blood cells are collected over an approximately 3- to 4-hour period. Once these white blood cells have been successfully collected, a manufacturing step must be undergone that takes, on average, about 17 to 28 days, depending upon the product.

 

In this manufacturing process, the T-cells must be isolated and activated, and then engineered into CAR T-cells, where a CAR gene is inserted via a viral vector, yielding an engineered CAR T-cell.

 

This CAR T-cell has several elements that we will review on the next slide, but include:

 

• An element to target the cancer, an antigen on the exterior of the cancer, which is often CD19 in B-cell lymphomas;
• A spacer;
• A transmembrane domain;
• A costimulatory domain; and
• A T-cell signaling domain.

 

After the CAR T-cell has been engineered, it must be expanded to an appropriate dose based upon whatever is approved for that particular CAR T-cell product, and then it is tested to ensure that it meets the proper specifications.

 

During this process, patients may require something called bridging therapy in order to control their disease while the manufacturing process is being completed. Once the product is completed, it will be sent back to the treating center and patients will undergo lymphodepletion, most commonly with 3 days of fludarabine and cyclophosphamide.

 

Following this, patients are typically infused with a single infusion of CAR T-cell therapy, which again typically targets CD19 in the FDA approved products for B-cell lymphomas.

 

[00:25:58]

 

CAR T-Cell Construct

 

In terms of CAR T-cell constructs, there are several important components to note. CAR T-cells target an antigen on the exterior of the tumor cell, CD19 in the case of the approved B-cell lymphoma products via a single chain variable fragment domain, which is what provides that specific target recognition and affects the immunogenicity of the CAR.

 

The CAR will also include:

 

• A hinge domain, which is what helps in CAR positioning;
• A transmembrane domain, which has a primary role of stability of the CAR product; and then,
• An intracellular domain, which is what yields T-cell activation, survival, persistence, and ultimately its expansion.

 

CAR T-cells achieve their anti-tumor efficacy, partly through the secretion of cytokines, which also help with expansion.

 

[00:26:45]

 

Generations of CAR T-Cell Therapy

 

Multiple generations of CAR T-cells have been developed over time. First-generation CAR T-cells importantly did not have a costimulatory domain. The costimulatory domain is critical for the ultimate activity of CAR T-cells, and second-generation CAR T-cells are what the approved products represent, including many that we will discuss today.

 

Costimulatory domains in these products are usually either CD28 or 4-1BB. CD28 has a more rapid expansion profile, as opposed to 4-1BB, which has a more gradual expansion profile. This is important because in general, this faster expansion with CD28 costimulation yields a higher risk of toxicities in terms of CRS and neurologic toxicities.

 

We now have in development third-generation CAR T-cells, which have multiple costimulatory domains, as well as fourth-generation CAR T-cells, which are including the ability of a CAR to secrete therapies, such as a drug or potentially a cytokine inducer. We are also seeing the inclusion of kill switches into CAR T-cell design. This continues to be an exciting area of CAR development.

 

[00:27:53]

 

FDA-Approved CAR T-Cell Therapies in NHL

 

This is a very helpful slide which summarizes the FDA-approved CAR T-cell therapies in non-Hodgkin lymphoma. Those include:

 

• Axicabtagene ciloleucel, or axi-cel;
• Brexucabtagene autoleucel, or brexu-cel;
• Lisocabtagene maraleucel, or liso-cel; and
• Tisagenlecleucel, or tisa-cel.

 

I would point out that axi-cel and liso-cel are both approved for large B-cell lymphoma in the second-line or later setting. Liso-cel has the broadest set of FDA approvals, as shown on this slide. Brexu-cel is approved for mantle cell lymphoma and B-ALL. Tisa-cel has approvals in follicular lymphoma, large B-cell lymphoma, and B-ALL.

 

[00:28:37]

 

Pivotal Trials Leading to FDA Approval in NHL

 

This is a summary of some, though not all, of the pivotal trials that led to FDA approval for various non-Hodgkin lymphoma CAR products. I will note that this slide is not meant for definitive comparison of these products, but is trying to overview the different patient populations, the numbers treated and the response rates and survival rates for these different products.

 

Critically, many of these therapies have completely transformed the treatment outcomes for these particular patient populations. You will see some additional data in some of the subsequent presentations, looking at the pivotal trials as well as some real-world data.

 

[00:29:14]

 

FDA Eliminates REMS for CAR T-Cell Therapy

 

Critically, we are seeing reductions in some of the monitoring requirements and logistics in CAR T-cell therapy. Recently, the FDA has eliminated the Risk Evaluation and Mitigation Strategy, or REMS requirement, for autologous CAR T-cell therapies, which hopefully will make it easier for additional centers to onboard for CAR T-cells.

 

Moreover, the restrictions for patients have been reduced. There is now a requirement of 14 days for a 24/7 caregiver, and the driving restriction has been reduced from 8 weeks to 2 weeks. These hopefully will continue to mitigate some of the barriers for CAR T-cell therapy received.

 

[00:29:54]

 

Recent Trial Results and Updates

 

In today's presentations, we will see some updated data for recent trials. I will note that there has been 5-year updated data for tisa-cel in follicular lymphoma, for axi-cel in follicular lymphoma and marginal zone lymphoma, for liso-cel in follicular lymphoma. Importantly, we now have a recent FDA approval, the first for a CAR T-cell product of liso-cel in relapsed/refractory marginal zone lymphoma in early December. There is also updated data for brexu-cel in mantle cell lymphoma and data for liso-cel in CLL.

 

[00:30:30]

 

Ongoing Trials Moving CAR T-Cell Therapy to Earlier Lines of Treatment

 

There is continued work for trying to move CAR T-cell therapy earlier in the treatment landscape. The ZUMA-23 trial is looking at the use of axi-cel in the first-line setting for high-risk large B-cell lymphoma. Interestingly, the ALPHA3 trial looks at an allogeneic CAR T-cell, cema-cel, as a consolidation strategy in patients who, after frontline chemo immunotherapy, remain MRD positive.

 

Finally, the CARMAN trial looks at brexu-cel in high-risk mantle cell lymphoma after receiving induction therapy with ibrutinib and rituximab. We look forward to the results of these trials in the near future.

 

[00:31:09]

 

Fitting CAR T-Cell Therapy Into Current Treatment Paradigms: DLBCL

 

With that, I would like to turn it over to my colleague, Dr Jeremy Abramson.

 

Dr Jeremy Abramson (Harvard Medical School): Thanks, Dr Johnson, and thanks Decera for having me here today. It is a privilege to be with Dr Johnson and Maloney, to talk to you today about CAR T-cell therapy.

 

Let us think a little building on Dr Johnson's wonderful introduction, about where CAR T-cells currently fit, specifically in diffuse large B-cell lymphoma, which, of course, is the most common lymphoma in the United States and worldwide.

 

[00:31:43]

 

Pivotal Trials Leading to FDA Approval for LBCL

 

We know that CAR T-cells in large cell lymphoma were initially approved in the third-line and later setting, based on these 3 pivotal trials. This was the:

 

• ZUMA-1 trial of axi-cel;
• TRANSCEND trial of liso-cell; and
• JULIET trial of tisa-cel.

 

All of these studies were in adults with relapsed/refractory large B-cell lymphomas. There are some modest differences in the studies and their designs.

 

However, I would note that the response rates were quite high. Both axi-cel and liso-cel produced CR rates in just excess of 50%, and overall response rates in excess of 70% in heavily pretreated patients, with a median of 3 prior lines of therapy for large cell lymphoma.

 

These translated into a 1-year progression-free survival of just over 40%, and at 2 years, that was approximately 40% in both the ZUMA-1 and TRANSCEND trials of axi-cel and liso-cel, respectively. We have some recent 5-year data that I will highlight in a moment.

 

I will note that, as you can see from the JULIET trial here, that the overall response rate, complete response rate and progression-free survival are a bit lower with tisa-cel in the JULIET trial, and that has been borne out with real-world analyses. My general preference is for either liso-cel or axi-cel in the third-line or later DLBCL setting.

 

[00:33:23]

 

ZUMA-1 vs SCHOLAR-1: Outcomes With Axicabtagene Ciloleucel vs SoC for Refractory DLBCL

 

We also have some retrospective comparative data, because those 3 pivotal trials in third-line and later large cell lymphoma were all non-comparative single-arm studies. We do have some evidence where the population from the ZUMA-1 study was matched and compared to the SCHOLAR-1 study, which was a retrospective analysis with some pooled retrospective and prospectively collected data from clinical trials. So an analogous patient population using conventional therapies as opposed to CAR T-cells.

 

What we can see here in an overall survival analysis, a dramatically better overall survival with the ZUMA-1 trial compared to a matched population in SCHOLAR-1, 31 months of median overall survival compared to only 5 months for patients treated with conventional therapies, highlighting the improvement in the natural history of this disease.

 

[00:34:24]

 

5-Yr Results From TRANSCEND and ZUMA-1 Support Curative Potential of CAR T-Cells as 3L+ Tx

 

That is particularly striking when we look at the 5-year data for both the ZUMA-1 and the TRANSCEND trial. Here, we are looking at disease-specific survival for axi-cel and liso-cel on the left and the right. What you can see is, at 5 years, the disease-specific survival is 51% for axi-cel, 52% for liso-cell, remarkably showing that fewer than half of patients had died of lymphoma at 5 years. Reminding you this was a third-line and later population in large cell lymphoma, who previously would have predicted an overall survival of 6 months or less at a median. This is really a dramatic improvement.

 

You can see that the additional long-term follow-up data are cited below, which validate really superb ongoing results, with the overall survival median for both liso-cel and axi-cel being in excess of 25 months.

 

[00:35:31]

 

Overall Survival for CD19 CAR T in R/R 3L+ LBCL

 

If we look at the overall survival across all 3 of these pivotal trials in the third-line or later setting, now with 5 years follow up for axi-cel and liso-cel once again, a median overall survival of 26 months for axi-cel, 28 months for liso-cel, and 11 months for tisa-cell, again validating axi-cel and liso-cel, in my opinion, as the preferred CAR T-cells in the third-line and later setting for patients with large B-cell lymphomas.

 

[00:36:01]

 

Safety of CD19 CAR T in R/R 3L+ LBCL

 

We do see some clear differences in safety. If we are primarily thinking about axi-cel or liso-cel in the third-line and later setting when reaching for a CAR T-cell in large B-cell lymphoma, it is important to help discern between these products by looking at the toxicity profile, having previously showed you that the efficacy of these products appears quite overlapping.

 

We do actually see much excess toxicity with axi-cel compared to liso-cel. This likely reflects the CD28 costimulation domain with axi-cel compared to the 4-1BB costimulation domain in liso-cel. That leads to different CAR T-cell kinetic expansions with an earlier, more rapid and peak expansion with axi-cel compared to liso-cel, which is a more gradual expansion in a longer area under the curve.

 

What that produces is a higher rate of any grade and severe cytokine release syndrome. With axi-cel in the ZUMA-1 trial, you can see CRS occurred in 93% of patients, severe in 13%, as opposed to liso-cel in TRANSCEND, where any grade CRS occurred in only 42% of patients and severe in only 2%.

 

We also see a clear difference in this inflammatory cytokine-mediated neurologic syndrome. We now call immune effector cell-associated neurologic syndrome, or ICANS. Neurologic events occurred in nearly two thirds of patients with axi-cel and was severe in approximately one third of patients. Compare that to liso-cel, where any grade neurologic toxicities occurred in 30% of patients and severe in only 10%.

 

So for both CRS and axi-cel, really a much lower rate of any grade and severe CRS and neurotoxicity with liso-cell compared with axi-cel.

 

Other side effects seen with these products include cytopenias, reflecting both the lymphodepleting chemotherapy, but also an impact of the cytokine release syndrome and inflammatory marrow suppression. We do see increased risk of infections with immune suppression. That risk in the pivotal trials was higher for axi-cel than with liso-cel, and a similar rate of hypogammaglobulinemia across products.

 

[00:38:29]

 

Real-world Data Show Liso-cel Has Similar Efficacy With a More Favorable Safety Profile Compared With Axi-cel

 

We do have some real-world data using commercially supplied CAR T-cells, as opposed to the more rigorously controlled pivotal trials that I just highlighted for you a moment ago. These are data for patients receiving axi-cel, liso-cel or tisa-cel from commercial supply in the third-line or later setting.

 

What we can see in the progression-free survival curve is overlapping efficacy, as highlighted earlier between axi-cel and liso-cel with a 2-year progression-free survival of about 45% for both of those products, validating what I noted earlier, a lower progression-free survival for patients treated with tisa-cel.

 

We also see reflected what I previously showed you in the pivotal trials in terms of toxicities. Looking at axi-cel and liso-cel, we see higher rates in the commercial setting, real-world setting for severe CRS or severe ICANS.

 

Severe CRS and ICANS was reported in 13% and 16% of patients, respectively, with axi-cel, compared to 1.4% and 6% of patients treated with liso-cel. Once again, significantly lower rates of severe CRS and ICANS favoring liso-cel over axi-cel in a real-world population, and suggesting improved efficacy for both axi-cel and liso-cel compared with tisa-cel.

 

I will note, relative to the side effect profile of tisa-cel, that it is also a 4-1BB co-stimulated CAR T-cell. In this analysis, we saw a similar incidence of high-grade CRS to axi-cel, although that may reflect different grading criteria, but a significantly lower rate of high-grade ICANS compared to axi-cel that was much more similar to liso-cel.

 

[00:40:36]

 

Axi-cel Has Shortest Vein-to-Vein Time Compared With Liso-cel and Tisa-cel

 

Now, all things being equal, if you have 2 products that have overlapping efficacy and 1 of them is safer, then you would prefer the safer product. In general, I prefer liso-cell over axi-cel, all things being equal, because of the more favorable safety but the overlapping benefit in terms of efficacy.

 

But all things are not necessarily created equal. One thing I will highlight is that axi-cel is produced faster than liso-cel or tisa-cel. We typically receive axi-cel about a week earlier than we receive liso-cel.

 

Now, I would say in general, that difference is not clinically significant for the majority of patients, but for some patients, every day counts. Patients with rapidly progressive, high tumor burden, highly symptomatic disease, difficult to bridge, we may prefer a faster product to get to that patient sooner. For those patients who I really need to get that product, as quickly as humanly possible, if I think they can tolerate axi-cel, then axi-cel would be my treatment of choice for those patients based on the faster vein to vein time for axi-cel compared to liso-cel.

 

[00:41:59]

 

Phase III Trials of CAR T-Cells vs SoC: High-Risk DLBCL Refractory to or Relapsed Within 12 Mo of 1L Tx

 

If we move our attention from the third-line and later into the second-line setting, it is important to recognize that our standard of care for second-line DLBCL for decades has been high-dose chemotherapy followed by autologous stem cell transplant for patients with chemo-sensitive disease who are eligible for high-dose chemotherapy.

 

The remarkable efficacy of CAR T-cells in the third-line and later setting prompted the question of whether CAR T-cell therapy might actually be a better option compared to that historic standard of care. That question was addressed in no fewer than 3 randomized controlled trials, which all took patients with highest risk relapsed disease and the lowest likelihood of durable remission from autologous transplant.

 

Those are patients with primary refractory disease or disease that progresses or relapses within 1 year of initial chemoimmunotherapy, where we would historically predict a success rate with an auto transplant approach of less than 25%.

 

The ZUMA-7, TRANSFORM and BELINDA trials compared either axi-cel, liso-cel or tisa-cel with the historic standard of care of second-line platinum-based chemotherapy, followed by high-dose chemo and stem cell transplant for patients who were eligible for a transplant with primary refractory or early relapse disease.

 

What you can see is the pivotal randomized trials of either axi-cel or liso-cel compared to standard of care. Both met their primary end point of superior event-free survival over standard of care. You can see that the study of axi-cel compared to standard of care dramatically improved event-free survival with a 48% reduction in risk of an event.

 

The study of liso-cel compared to standard of care, the TRANSFORM trial, demonstrated a greater than 60% reduction in risk of an event, clearly showing that axi-cel and liso-cel should be preferred over the historic chemotherapy based standard in this population.

 

The BELINDA trial of tisa-cel was a stone-cold negative trial, and so this did not lead to regulatory approval and further removed some of the luster from tisa-cel and is not recommended in the second-line setting, whereas liso-cel and axi-cel are now standards of care for patients with primary refractory or early relapsed disease.

 

[00:44:38]

 

PILOT: Liso-cel in Nontransplant-Eligible Patients in 2L

 

What about patients who are actually not eligible for high-dose chemotherapy and a stem cell transplant? Can we offer those patients curative intent CAR T-cells in the second-line setting?

 

This phase II PILOT trial suggests that we can and we should. Here we see 61 patients, who had relapsed DLBCL after upfront R-CHOP or R-CHOP-like therapy. The most of these patients had diffuse large B-cell lymphoma, and just more than half of these patients had primary refractory disease, though they did not have to be relapsed or progressed within 12 months on this trial.

 

What we can see here is a complete response rate of 54%. 80% of patients responded. The median progression-free survival is 9 months. In 1.5 year, what we see is over 40% of patients remain progression-free and very likely cured, showing us that we should indeed offer this therapy.

 

Now, this is an older, frailer population of patients with a median age of 74 years old. So we naturally need to ask whether they could tolerate this CAR T-cell therapy. The answer is they could. Only 38% of patients had any grade of cytokine release syndrome, almost entirely low grade. Only a third of patients developed neurologic side effects, almost entirely low grade as well. Non-relapse mortality in this study was only 3%, and that was due to 2 cases of COVID-19.

 

[00:46:11]

 

ALYCANTE: Axi-cel in Nontransplant-Eligible Patients in 2L*

 

Now, axi-cel has also been evaluated in a noncomparative phase II ALYCANTE trial, also looking at patients with nontransplant-eligible DLBCL. The median age here a bit lower at 70 years old and nearly all patients had DLBCL NOS. Again, just more than half of patients had primary refractory disease.

 

The complete response rate was quite impressive at 82%, and at 1 year, 48% of patients remained progression-free. I will note, however, in this older frailer population, the incidence of CRS and ICANS was quite high as expected with axi-cel. Here, 94% of patients had any grade cytokine release syndrome, though it was mostly low grade. 8% of patients did have severe CRS.

 

ICANS occurred in more than half of patients and 15% had grade 3 or 4 neurologic toxicity. This higher toxicity profile reflected a higher non-relapse mortality rate of 10%. So 1 in 10 patients dying related more to toxicity than to their underlying disease.

 

This study did not lead to regulatory approval of axi-cel, and I would favor liso-cel in second-line and later non-transplant eligible patients on the basis of the PILOT trial with encouraging efficacy and a more favorable safety profile, particularly in those older frailer adults.

 

[00:47:40]

 

          Fitting CAR T-Cell Therapy Into Current Treatment Paradigms in DLBCL

 

We have put all of this together and see where these CAR T-cells fit into patients with relapsed and refractory DLBCL. The randomized TRANSFORM and ZUMA-7 trials clearly show us that axi-cel or liso-cel should be our preferred therapy for any patient with primary refractory or early relapsed DLBCL.

 

If we have patients who are transplant-ineligible, regardless of their duration of initial remission, those patients are eligible for liso-cel with curative intent based on the PILOT trial showing us we should be offering curative intent CAR T-cell therapy to any patient with relapsed and refractory DLBCL in the second-line or later setting.

 

For patients who do relapse late and are young and fit, those are the patients, though uncommon, who should still go to second-line platinum-based chemotherapy and be offered high-dose chemo and stem cell transplant for chemo-sensitive disease. But if they do not have chemo-sensitive disease or if they are relapsed/refractory after an auto transplant, then they have 3 CAR T-cells available in the third-line or later setting, though I mentioned my preference for either liso-cel or axi-cel in that context.

 

It is critically important to note that given the availability of liso-cel and axi-cel in multiple lines of therapy, that patients should be referred early for consideration of CAR T-cells. In any relapsed/refractory DLBCL patient, I would recommend referring to a CAR T-cell center for consideration of CAR T-cell eligibility. The majority of patients with relapsed DLBCL are eligible for a second-line and later CAR T-cell therapy.

 

We would ask that we avoid highly lymphodepleting therapies for those patients if they are under consideration for CAR T-cell therapy, such as, for example, avoiding bendamustine for those patients, if they might be a candidate.

 

We always consider whether a patient should have a bridging therapy or a holding therapy to control the disease while they are under consideration. This is an important thing to discuss with the CAR T-cell consultant early in the course of that patient's treatment course to optimize the sequencing of their therapies.

 

[00:49:59]

 

          Master Class Case Discussion

 

We will turn now to a case. This is a 74-year-old woman with diffuse large B-cell lymphoma not otherwise specified, GCB subtype with no MYC rearrangement by FISH. This patient is started on R-CHOP. After 3 cycles of therapy, has an interim PET scan, which shows a mixed response. You can see here this patient, with their PET scan on the right, has said some areas decrease but other new areas or progressive areas of disease.

 

This patient is then taken to biopsy of a new area to confirm primary refractory disease. That biopsy does confirm once again persistent DLBCL NOS. That said, she looks and feels well. Her organ and marrow function are normal, and her LDH is modestly elevated.

 

Let me turn to my panelists and say we have a 74-year-old patient with primary refractory disease. Dr Johnson, how would you approach this patient in your practice?

 

Dr Johnson: This is a great case, Dr Abramson, for illustrating a lot of the points that you discussed. Based upon both randomized controlled trials, we reviewed ZUMA-7 and TRANSFORM, I would be favoring anti-CD19 CAR T-cell therapy for this patient. Given the patient's age at 74, though she seems relatively fit 74, my preference would be towards liso-cel for the more favorable tolerability in terms of the product.

 

Given that this was primary refractory disease and she has GCB subtype, I would be leaning towards a systemic bridge. I would usually use polatuzumab-rituximab and would omit bendamustine, given the T-cell toxic effects of bendamustine. I do think for some patients, a radiation therapy as a bridge can be a great consideration, but she has multifocal disease without a clear dominant site. So I would really be leaning towards a polatuzumab-based bridge.

 

Dr Abramson: Dr Maloney, 1 is, would you concur with a CAR T-cell therapy here? How do you approach selecting bridging therapy for patients?

 

Dr David Maloney (Fred Hutchinson Cancer Center): Yes, it is a tricky question to consider what the best option to either intervene with more bridging or to go straight to CAR T. I would definitely try to move to CAR T and make that next plan. I would try to immediately harvest lymphocytes by apheresis. I would try to get that in the books.

 

If we can get that done, then it would depend a little bit on what the turnaround is going to be. I too would favor liso-cel in this situation due to the age, although we certainly have used axi-cel in patients of this age and they can get through it, but albeit with more toxicity, as you have elegantly pointed out.

 

I would also favor polatuzumab-rituximab approach in the setting, or if we needed to be a little more aggressive, maybe a gemcitabine-based cycle, GCB type therapy for 1 cycle and try to get to CAR T.

 

Dr Abramson: Terrific. With that then, let me turn the floor. We are seeing the cases. I will tell you is exactly what we did. That patient was bridged with Pola-R did very well with that. Got liso-cel, achieved a complete remission which continues to this day.

 

With that, as a segue from large B-cell lymphomas, it turns out there are lots of other types of lymphoma. To review those, I will turn it over to Dr Maloney.

 

[00:53:58]

 

Follicular Lymphoma (FL) and Marginal Zone Lymphoma (MZL)

 

Dr Maloney: Thank you very much. You guys have made it a lot easier for me by setting the stage with these other lymphomas. I appreciate that.

 

We are going to jump into some of the other lymphomas. I will start off with follicular lymphoma and marginal zone lymphoma.

 

[00:54:12]

 

ELARA: Tisagenlecleucel in R/R FL

 

The first data just to remind you is the ELARA trial with tisagenlecleucel in relapsed/refractory follicular lymphoma. This was a fairly large study, again, done with tisagenlecleucel. I will just remind you that the conditioning therapy in the setting is a little bit lower. It was with fludarabine of 25 mg/m² for 3 days with cyclophosphamide at 250 for 3 days or bendamustine 90 for 2 days.

 

The number of patients that actually received bendamustine is quite small, but per the outcomes, they were similar.

 

[00:55:00]

 

ELARA: 5-Yr Updated Efficacy

 

The 5-year updated efficacy results are shown here. The CR rate was 68.1%, and the 60-month overall survival rate was 74%. 16-month PFS rate was 46%, and around 60% in patients who actually had a CR.

 

Here, unlike the data you were seeing in large cell lymphoma, we see a fairly really good outcome in patients with relapsed/refractory follicular lymphoma, with a relative flattening of the curves over time. This is certainly an encouraging result.

 

[00:55:36]

 

ELARA: Safety

 

The toxicity was pretty much as expected. Most patients did have an adverse event, but only 48% had CRS, and most of that was grade 1 with relatively low amounts of grade 2 and 3, or higher grades CRS. Otherwise, this was pretty much as expected.

 

[00:56:01]

 

ZUMA-5: Axicabtagene Ciloleucel in FL and MZL

 

The other data that has also been updated and is quite exceptional data is the ZUMA-5. This is axi-cel in follicular lymphoma and marginal zone lymphoma. Again, this is the typical conditioning regimen you heard earlier, 30 mg of fludarabine, plus 500 of cyclophosphamide. So, there is a higher dose of cyclophosphamide here. This does lead to slightly greater lymphodepletion and hematologic toxicity.

 

Axi-cel is given at 2 x 10⁶/kg and with a similar design, as you saw earlier.

 

[00:56:41]

 

ZUMA-5: 5-Yr Updated Responses in R/R FL and MZL

 

The response rates were outstanding in all patients. This was 159 patients. The response rate was 90%, with 75% of people having a complete remission, again, higher than what you were seeing in large cell lymphoma. If you broke that into follicular lymphoma, it went up slightly with 79% CR rate, but again 94% overall response rate. In the marginal zone subset of only 31 patients, the response rate was 77% overall with 65% CR.

 

You can see the curves as shown here. This is again quite exciting. Both the marginal zone and the follicular lymphoma patients did very well. Again, this is an exciting result, bringing into the question is, whether you can actually cure follicular lymphoma with CAR T-cell therapy? You can see 58% of the patients with a CR maintained a CR with a median duration of over 5 years.

 

Toxicities were as expected from the study.

 

[00:57:48]

 

ZUMA-5: 5-Yr Updated PFS in R/R FL and MZL (continued)

 

This is the 5-year data updated for follicular lymphoma and marginal zone lymphoma. Again, consistent across all the risk groups. The 60-month PFS rate for CR patients was around 62% and only 9% of patients with the PR. It is important to have a CR to be in that long-term progression-free survival group.

 

Interestingly, if you look at the risk of lymphoma actually relapse or death, you can see that beyond about month 24, the risk of lymphoma actually relapsing is quite low, although as these are elderly patients, you can see there is an ongoing competing risk of mortality. Some of this due to toxicity and some of this are due to adverse events and some due to obviously natural causes.

 

[00:58:47]

 

ZUMA-5: CRS and Neurologic Events

 

The CRS and neurologic events seen with this are typical of axi-cel. You can see any grade CRS was the majority of patients, 78%, a little less than what we saw in large cell lymphoma, mostly grade 1 to 2 events. There are some grade 3 events in both cohorts, and the usual treatment with tocilizumab and corticosteroids. Again, nothing too different than what we have seen previously.

 

[00:59:21]

 

TRANSCEND FL: Lisocabtagene Maraleucel in FL and MZL

 

Now, TRANSCEND has also been used in follicular lymphoma. This again was with 30 mg of fludarabine times 3 days and 300 mg of cyclophosphamide for 3 days. So a little bit less than what was seen with the axi-cel lymphodepletion. Liso-cel was giving it a flat dose of 100 million CAR T-cells.

 

[00:59:43]

 

TRANSCEND FL: Efficacy in R/R FL

 

The results of this study again show a very good response rates. I will show you that in the next slide. The CR rate was 94%, with 97% overall response rate. This was across all the different risk groups, prior therapy groups of patients with follicular lymphoma.

 

[01:00:11]

 

TRANSCEND FL: Efficacy in R/R MZL

 

Now turning to marginal zone lymphoma. You can see that the results were a little different, but overall response rates are nearly 100%, 98.2%. The CR rate was 62%. So a little bit lower than what we saw with follicular lymphoma, but with good progression or the good overall survival in these patients, you can see shown in the curve to the right.

 

Based on this data, the FDA did approve liso-cel for patients with relapsed/refractory marginal zone lymphoma after 2 prior lines of systemic therapy. That was on December 4th of last year.

 

[01:01:03]

 

TRANSCEND FL: CRS and Neurologic Events

 

The toxicity was consistent with what we have seen with liso-cel. You can see any grade CRS was around 58%, any grade neurologic toxicity of 15% in follicular lymphoma, and fairly similar in marginal zone, although possibly a little bit higher any grade.

 

Severe disease or toxicity was rare. Most patients who did develop a significant CRS did receive treatment with tocilizumab or tocilizumab and corticosteroids.

 

[01:01:41]

 

Let's Revisit a Question

 

Let us revisit a question we had earlier.

 

[01:01:46]

 

          Posttest 1

 

After demonstrating high overall response rate and CR, liso-cel is now FDA approved for the treatment of which adult population?

 

1. Relapsed/refractory marginal zone lymphoma after 1 prior line of therapy; or
2. After 2 lines of therapy; or
3. Relapsed/refractory B-cell precursor ALL; or
4. Relapsed/refractory B-cell precursor ALL after greater than 2 prior lines of therapy.

 

Please go ahead and vote. We will move on.

 

[01:02:33]

 

          Posttest 1

 

These are the results popping up. The correct answer is B, relapsed/refractory marginal zone lymphoma after at least 2 prior lines of systemic therapy. Most folks got that right.

 

[01:02:51]

 

Mantle Cell Lymphoma

 

Next, I would like to turn my attention to mantle cell lymphoma.

 

[01:02:58]

 

ZUMA-2: Brexucabtagene Autoleucel in MCL

 

Now, mantle cell lymphoma is a quite challenging disease to treat for all of those of us who treat lymphomas. It has gone through a quite a rapid change in outcome over the past decades. The ZUMA-2 trial was the first main study in mantle cell lymphoma with brexucabtagene autoleucel now.

 

Brexu-cel is basically axi-cel but done with a slightly different manufacturing process that included B-cell depletion because many of these patients have circulating tumor cells. The structure of the treatment was essentially the same as what we have seen with other axi-cel trials, fludarabine and cyclophosphamide and then brexu-cel administration.

 

There were several cohorts studied. The first 2 cohorts were looking at patients who had had been or not been treated previously with ibrutinib. Then cohort 3 was patients who did not require treatment with prior ibrutinib. That was the main cohort going forward.

 

[01:04:10]

 

ZUMA-2 Cohort 1 and 2: ORR and DoR

 

Data is shown here. Overall response rate was very high, 93%. 64% of patients had a complete remission and 29% of PR. This is in the first 2 lead-in cohorts looking at patients who had previously been treated or not been treated with ibrutinib. You can see there was really no difference in the response rates. Patients did have CRs in multiple of these cohorts. So the study was continued to cohort 3.

 

[01:04:47]

 

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

 

This is the key data from this. Again, 91% overall response rate, 86 total patients. 73% had a complete remission, 17% had a partial remission. These are patients with no prior BTKi. This met the primary endpoint and had very high response rates. Really all of the key different subgroups, whether you had TP53 mutation or not, tumor burden, Ki67, proliferation index being over 50%, high MIPI scores, secondary MIPI scores or prior bendamustine. You can see excellent results.

 

[01:05:34]

 

ZUMA-2 Cohort 3: PFS and OS

 

What we saw also was that these results were reasonably durable, although there is less of a hint of a complete plateau on this curve. Patients with a CR did do better than obviously non-responders, but the partial remission patients also did fairly well, considering that most of these patients had relapsed or refractory disease.

 

Overall survival is shown here. Overall, the 12-month PFS rates were 75% for all patients, 84% for those with a CR.

 

[01:06:12]

 

ZUMA-2 Cohort 3: Safety

 

Now, we did see a significant toxicity from this study. 95% of patients did have cytokine release syndrome. I am really focusing on cohort 3 here, 86 patients. You can see 6% had grade 3 or greater.

 

Neurologic toxicity or ICANS, you can see almost between a quarter and a third of patients had grade 3 or higher toxicity. This is a little bit higher than what we saw in the other low-grade lymphomas, and it is something to certainly be concerned about, or at least take into account that these patients may have significant toxicity and require prolonged recovery.

 

The other CRS and ICANS data are quite consistent with what we have seen before. Early onset CRS with a median duration of 6 days. Later onset of ICANS with a median duration also of about a week.

 

[01:07:22]

 

Post–Brexu-cel Outcomes for MCL: A Descar-T Study

 

Now there has been a study, a Descar-T study, that looked at the outcome of patients who had relapsed after brexu-cel. You can see that their outcome is pretty dismal. 64% of patients died, and median time to death was 8 months. Most of these deaths were due to lymphoma, a few were due to other infections.

 

You can see a variety of other agents have been tried. The response to salvage regimen is quite low. Overall response rates of generally less than 20%. So this is an area of unmet need, and coming up with new treatments for patients or better treatments is necessary for this disease.

 

[01:08:13]

 

TRANSCEND-MCL: Lisocabtagene Maraleucel in MCL (MCL Cohort of TRANSCEND NHL 001)

 

Now, liso-cel is also been looked at in mantle cell lymphoma. This is the same scheme as a portion of the TRANSCEND NHL 001 study. Patients received fludarabine at 30 and cyclophosphamide at 300 times 3 levels. Again, the dose of CAR T-cells was around 100 million cells, flat dose for the dose level 2 which was picked as the standard treatment.

 

[01:08:47]

 

TRANSCEND-MCL: Efficacy

 

Efficacy and PFS and OS is shown here. The overall response rate was very high. This is 86% and the CR rate of 74%. Good outcomes again, but without really a hint of a complete plateau on the curve, at least with relatively early data at 24 months.

 

[01:09:15]

 

TRANSCEND-MCL: Safety

 

Toxicity was slightly different than what we had seen previously. There was a slightly higher incidence of overall CRS, but still the rates of grade 3 or higher were very low. Only 1 case. Neurologic toxicity was also slightly higher. There was 8% grade 3, 1% grade 4 toxicity. This was again slightly higher than what we had seen in follicular lymphoma.

 

A variety of other AEs of special interest are shown here. We worry always about infections. Hypogammaglobulinemia, rare cases of tumor lysis syndrome. There were no MAS or macrophage activation syndrome seen in this study, but prolonged cytopenias are again an issue that needs to be watched for.

 

[01:10:08]

 

Chronic Lymphocytic Leukemia

 

Lastly, I would like to turn briefly to chronic lymphocytic leukemia.

 

[01:10:13]

 

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

 

This is the TRANSCEND CLL 004 study of liso-cel in relapsed/refractory CLL. This took a very high-risk group of patients, most of them who had failed chemoimmunotherapy and looked at a variety of subsets of patients. The key subset was patients who had progressed on a BTKi and had venetoclax. You can see they received the standard dose of liso-cel at 100 million cells.

 

[01:10:48]

 

TRANSCEND CLL 004: Efficacy Outcomes in DL2

 

The outcomes are quite interesting in this study. Overall, the CR rate was surprisingly low in the study. It was 20% across the board with no real difference in the groups. Interestingly, a higher rate of patients had undetectable MRD4 rate in the blood for using PCR to essentially measure the tumor or flow cytometry.

 

You can see around 66% of patients had undetectable MRD, while only 20% of patients had a CR. This can be best shown that even patients with a PR, they had a very high rate of molecular remission of nearly 100% in blood and in bone marrow.

 

We have a discordant outcome here where we can easily get a CR in the blood and the bone marrow, even at molecular rates. It is a little harder to get a nodal complete remissions in this heavily treated patient population.

 

[01:11:57]

 

TRANSCEND CLL 004: DoR and PFS in DL2

 

If you could achieve a CR of those 20% of patients, they did extremely well. As shown here, the PR patients also clearly benefit compared to patients who are non-responders. This is exciting that led to the approval of liso-cel in this population.

 

[01:12:20]

 

TRANSCEND CLL 004: Safety in Full Study Population

 

Toxicity. Again, a little similar to what we saw with mantle cell. There was a higher rate of any grade CRS, but grade 3 or higher was still pretty low at 8%. There were more neurologic toxicities and grade 3 around 18% along cytopenias, also slightly longer. Again, this is fitting with the population, again heavily treated with poor marrow function coming into it.

 

We will see a gradual change in the population as chemoimmunotherapy becomes a less standard treatment option for these patients. Otherwise, no big changes there.

 

[01:13:02]

 

Let's Revisit a Question

 

Let us revisit our previous question.

 

[01:13:06]

 

          Patient Case: 68-Yr-Old Woman With R/R CLL

 

We have a 68-year-old woman with relapsed/refractory CLL, diagnosed in 2016 with high-risk cytogenetics with a deletion 17p treated with ibrutinib with a PR. After 3 years has increasing lymphocytosis and new lymphadenopathy. She then completed 24 months of venetoclax therapy, maintained a CR for a year, but then has progressed.

 

[01:13:29]

 

          Posttest 2

 

Post-test question 2. Based on current indications, which CAR T-cell therapy is the most appropriate option for this patient?

 

1. Axi-cel;
2. Brexu-cel;
3. Liso-cel; and
4. Tisagenlecleucel.

 

We can also look at our panelists. Jeremy, what would you do in this situation?

 

Dr Abramson: Yes. This patient is really high-risk CLL. They are effectively refractory to a covalent BTK inhibitor. They have progressed fairly rapidly after discontinuing time-limited venetoclax. This is a patient I would try and get to CAR T-cell therapy for really definitive disease control, with liso-cel being the only approved option in this setting.

 

I would consider pirtobrutinib as a potential bridging option, if needed. But I would consider liso-cel the most definitive option in this setting.

 

Dr Maloney: Dr Johnson, anything to add?

 

Dr Johnson: I was going to say the same thing, and I like pirtobrutinib as a bridge. The other thing I would point out is what you alluded to, is a lot of the patients in the trial had also received chemoimmunotherapy. As the population evolves, some of the toxicity profile like persistent cytopenias may be lessened by the prior exposure to mostly novel therapies instead of intensive chemotherapy.

 

Dr Maloney: Yes, that is what we were seeing. We were seeing all these patients come in with multiple chromosomal abnormalities, very complex cytogenetics, very poor counts, bad marrow reserve. It is a really tough situation. We will be seeing venetoclax failures and BTK, including pirtobrutinib failures. That is where if we can get these patients earlier, that might be a better option.

 

[01:15:39]

 

Best Practice Referrals to Authorized CAR T-Cell Treatment Centers and Coordination of Care

 

Moving forward, I want to briefly talk a little bit about best practice referrals to get these patients into CAR T therapies.

 

[01:15:49]

 

Perceptions of Community Hematologists/Oncologists on Barriers to CAR T-Cell Therapy for DLBCL

 

Now, you have heard a lot about this, but when a survey was done in 2019 of hematology/oncology providers, the 3 major problems with giving CAR T-cells were the logistics, the cost and the toxicity. This was perceived to be the biggest issues.

 

[01:16:11]

 

Perceptions of Community Hematologists/Oncologists on Barriers to CAR T-Cell Therapy for DLBCL

 

When asked about other issues, lack of communication from the CAR T-cell center, and that the patients actually deteriorated before the CAR T-cell product could even be administered were the 2 major factors.

 

Looking at these 2 issues, we need to figure out how can we provide this service to our patients in a more timely fashion to get patients into a CAR T-cell center, before they deteriorate to the point where people are essentially giving up.

 

[01:16:45]

 

CAR T-Cell Therapy Patient Journey

 

You have heard about this journey, but I will just highlight a few things. Make sure the patient meets the FDA label. There is no age cutoff. There is no requirement for CD19 or BCMA in these products. The CAR T-cell centers will have variable eligibility criteria, so it is best to actually get the patient to the CAR T-cell center and let them decide. The earlier the better.

 

Once they are there, they will be evaluated for eligibility, general health, insurance authorization, consent and education. This consent and education cannot really start too early. It is very important, even as a referring physician, to start to talk about what to expect.

 

T-cell collection is done and then patients receive their LD chemotherapy. This is usually outpatient. The CAR T-cell infusion can be inpatient or outpatient. Post-infusion monitoring involves daily labs and usually seeing the patient daily for at least 7 days. They may have required some bridging therapy to get from T-cell collection to that LD chemotherapy regimen. If that is the case, this may be coordinated with the outside physician.

 

After the chemotherapy is given and the CAR T-cells are infused, they are monitored for those acute effects. As you have heard, this can be shorter now, including up to as short as 2 weeks for patients that are doing well. But patients who obviously have a lot of toxicity, usually stay at the center for longer periods of time.

 

[01:18:27]

 

Current Review Process Gene and Cellular Therapies

 

Now, authorizations is a completely moving target. You really need to submit these requests in advance of possible. Mark as urgent. Sometimes this requires a peer to peer reviews. That is going down, thankfully, but still there is a lot of time spent in arguing, in some cases, for your patient to receive these FDA approved treatments.

 

[01:18:58]

 

Patient Education: In the Trenches — Clearance, LD Chemotherapy, and Admission

 

It is also very important that the patient understands that this clearance may take some time, that the cells are going to be sent to a manufacturer. That manufacturer can go wrong in some cases where they cannot make a product. You may have to try again. If you can get the cells back, then if the patient's status is okay, you can move to that LD therapy. Often there is a washout between when you give the prior bridging therapy and when you want to start your lymphodepletion. This is often driven by the patient clinical status as well.

 

If the treatment is done in hospital, then there obviously has to be good communication to the inpatient teams and get the patient into the clinic. Make sure that they have been adhering to the REMS program until recently. It will make it a lot easier to not have to do all the documentation required in the REMS program of training. It is gratifying to see that that has been reduced.

 

[01:20:05]

 

CAR T-Cell Treatment Schema

 

In terms of the overall timeline, the apheresis is short. It is usually a 1-session event, 4-6 hours. There may be a period of 2-4 weeks of requiring bridging therapy. The actual treatment with lymphodepletion takes about 6 days. Then the cells are infused. There is that approximate 14-day period where these toxicities of CRS, ICANS are the most frequent. That is the most urgent toxicity. But then you have to be alert, carefully identify infections, as these patients often have persistent cytopenias and may require transfusion support as they are sent home to their doctor.

 

[01:20:56]

 

Salvage and Bridging Therapy: Community and Academic Coordination of Care

 

Just a couple other issues. Coordination of care between the community and academic sites. It is really important to discuss salvage therapy. Salvage therapy is often given before patients arrive. It does require a washout period. Before apheresis, you have to recover a T-cell count to be able to collect lymphocytes to be produced into the CAR T-cells. This is usually on the order of 3 weeks, depending on what the salvage therapy is.

 

We like to avoid any kind of fludarabine or purine analogue or bendamustine in this setting. Then try to get the cells collected. After that, they may require bridging therapy to bridge that time between the collection of the cells and when they will come back from the manufacturer. As you heard from Dr Abramson, axi-cel has a shorter return time, although that is ever changing as products are refined.

 

The goals of bridging therapy are to reduce the tumor burden and palliate the symptoms and limit CRS and ICANS by debulking the patient. There is a correlation of high disease burden with toxicity, and it likely impacts CAR T-cell efficacy. Treating patients with less disease generally leads to a better outcome. This does require frequent communication between the patient, the primary oncologist and the manufacturer, and even more so now whereas treatment times are being reduced and sending patients home earlier.

 

A real life time, as we mentioned, from apheresis to infusion, is often in that 30-day range. You really need to be careful with bridging therapy, to allow the patient to be able to hopefully recover by the time of treatment. Again, avoiding immunosuppressive therapy, checkpoint inhibitors, blinatumomab. I also avoid anything targeting the same antigen that the CAR T-cell is going to target.

 

If I am using a CD19 CAR, which is what we have been talking about, I try to limit any CD19 therapy in this immediate pre-CAR T-cell therapy.

 

[01:23:22]

 

FDA Eliminates REMS for CAR T-Cell Therapy

 

As you heard, the FDA eliminates Risk Evaluation and Mitigation Strategies, or REMS. This will make it easier for centers to establish programs and also makes it easier for patients to get back to their referring physician.

 

[01:23:38]

 

Inpatient vs Outpatient CAR T-Cell Therapy

 

Now, CAR T-cells can be given inpatient or outpatient. It is really dependent on what the center experience is. If they are inpatient, they are often for about 7 days until that period of resolution of cytokine release syndrome or neurologic toxicity. They need to stay within the treatment center for a couple of weeks and avoid driving for at least 2 weeks following CAR T-cell infusion, or longer based on whether they have had any neurologic toxicity.

 

They need to be monitored for ongoing cytopenias, hydration status and first response assessment, which is usually done around 4 weeks. If it is done in outpatient, you have to have an outpatient center that is capable of providing 24/7 care. Patients need to stay near the center. They need to be in frequent contact with the center and generally seen daily for at least the first week. We admit all patients at the onset of fever or confusion. But the good news is, is that that does not seem to compromise their care, and their CRS or neurotoxicity does not change if you are using an outpatient vs inpatient approach.

 

[01:24:52]

 

Evidence for Outpatient CAR T-Cell Therapy

 

Most outpatient experiences so far using the 4-1BB CAR T-cells, as you have heard, but a slower onset of CRS and neurologic toxicity.

 

With that delayed approach, also there is a lower overall incidence of severe disease. We do not really make a big difference at the Fred Hutchinson between age. Older patients are still eligible for outpatient infusion. We do worry a little bit about patients with significant organ dysfunction before starting. If they need to be in the hospital just for that, then obviously they would require treatment to be administered while in the hospital.

 

We have talked about this already, but this is really dependent on the CAR T-cell center and how they have their system set up.

 

[01:25:52]

 

Patient Education: In the Trenches — Infusion and Postinfusion Monitoring

 

Patients need to be monitored. They need to be educated about infusions and the post-infusion monitoring period. It is really important that you have that discussion.

 

[01:26:12]

 

CAR T-Cell Therapy: Best Referral Practices

 

I am concluding on this slide. CAR T-cell therapy is really dependent on the center that we had. As we mentioned earlier, there is the transplant model where patients come in through that door. There is a disease center model where they come in through a lymphoma specialist. Either way, get the patients in early. Try to get patients in before they urgently need treatment. That gives the center more treatment options.

 

[01:26:39]

 

Considerations for Caregivers

 

Caregivers are necessary for these patients, especially if they are going to be treated in the outpatient setting. Caregiver has to be involved in the patient. They cannot just come in once a day. They really need to be with the patient, especially when they are outpatient after CAR T-cell infusion. We generally require this for at least 30 days, although the REMS requirement is going down, as you heard.

 

We try to avoid having caregivers be hired, but it is a really tough situation if you have no caregiver. Then the center is really working hard to try to figure out what the options are. It may be that the treatment has to be given in hospital.

 

[01:27:19]

 

          Master Class Case Discussion

 

Here is a discussion case. I will bring my co-presenters on. A 61-year-old man with relapsed/refractory follicular lymphoma diagnosed with follicular lymphoma 3 years ago with widespread adenopathy. Has a high FLIPI score, treated with BR, bendamustine-rituximab, 6 cycles, has a PR, developed progressive adenopathy only 6 months later, that is POD-24. He was treated with R-CHOP, had a CR and again relapsed 1 year later.

 

Now, this is probably the most complicated area of trying to figure out what to do with patients.

 

What treatment would you recommend now?

 

1. Salvage chemotherapy; go down the transplant route potentially;
2. Bispecific antibody, mosunetuzumab;
3. Tafasitamab, targeting CD19;
4. Loncastuximab; CD19 drug conjugate; or
5. Referral for CAR T-cell therapy.

 

This is a very challenging situation. All of those options are routinely used by everybody. Jeremy, what would you be doing or thinking about doing in this situation?

 

Dr Abramson: Yes. David, this is a very high-risk follicular lymphoma patient. Most patients have a nice lengthy response to initial treatment. And if they relapse, have a nice lengthy response to their second-line treatment.

 

This patient presented with high-risk disease. They had a really very brief response to upfront chemoimmunotherapy, and then a fairly brief response to second-line therapy with R-CHOP with a relapse only 1 year later.

 

A very high-risk patient like this, I would take to CAR T-cell therapy in third-line. I would be deciding between a bispecific antibody like mosunetuzumab vs a CAR T-cell. The CR rates and progression-free survival are generally better for CAR T-cells than bispecific antibodies, although they are favorable for both.

 

At the highest risk patient like this with very resistant disease, I would want the most definitive therapy possible. I would view that here as a CAR T-cell. In contrast, patients who have the very lengthy response to frontline therapy, a fairly lengthy response to second-line therapy, I am more often reading reaching for a bispecific antibody in those patients.

 

For a high-risk patient like this, I really would prioritize a CAR T-cell therapy. It is notable this patient did get bendamustine as their frontline therapy, but it has been 1.5 year since their bendamustine. I do think that with that lengthy period from bendamustine exposure, that CAR T-cell would still be appropriate and probably still have preserved T-cell health moving forward.

 

Dr Maloney: Yes. Some of our treatment options, like mosunetuzumab obviously is a CD20/CD3 bispecific, but tafasitamab and loncastuximab are targeting CD19.

 

Dr Johnson, do you try to avoid targeting the same antigen prior to CAR T-cells? Or do you think that does not matter at this point?

 

Dr Johnson: I think where I get the most nervous about it are high-risk diseases, so certainly large cell lymphoma. Though we do have data suggesting that CD19 expression is maintained after loncastuximab and tafasitamab, which is good to see, we do not have tons and tons of data. I still worry about antigen loss or even mitigating the antigen density in high-risk diseases.

 

This patient, as Dr Abramson points out, is a very high-risk patient. So I would be a little bit concerned about an anti-CD19-targeted therapy prior to CAR T-cells in this patient. In patients who have lengthy remissions, I would be less concerned and would have the full armamentarium open.

 

I would add, this is a young patient where sometimes a time-limited therapy with minimal time on treatment can be very advantageous or desirable for someone who is a young age.

 

Dr Maloney: Any other comments by the faculty? I do not see any open questions, so I think we will move on back to Dr Abramson.

 

[01:31:41]

 

Effectively Identifying and Managing CAR T-Cell–Mediated Adverse Events

 

Dr Abramson: Great. Now we will take a deep dive into actually managing the unique side effect profile with CAR T-cell therapy.

 

[01:31:52]

 

Spectrum of Clinical Toxicities Associated With CAR T-Cell Therapy

 

You have heard a lot already about these side effects, particularly CRS and neurologic toxicities. Now, CRS certainly includes a broad spectrum. The most common feature of CRS is fever. This can progress to a vasodilatory state, leading to hypotension, organ injury including kidney or liver injury, hypoxia from pulmonary injury. If arrested early, those more severe side effects can hopefully be abated.

 

We do see some neurologic side effects in context of CRS with high fevers. We know we can see a delirium type syndrome just from high fevers, but the true ICANS typically follows the cresting of a CRS. While not always most patients who develop ICANS have previously had CRS, and though that is not 100%, it is usually the case. Oftentimes with CRS reach its peak, start getting better, things are better, the patient is afebrile, and then we see neurologic changes.

 

Those neurologic changes of ICANS are typically a delirium type state, mental status changes, word finding difficulties can occur early on, confusional states. Those can progress to somnolence or even a comatose state. Certainly aphasias are very common, and in very severe cases, we can see status epilepticus, or in rare very serious cases, even cerebral edema.

 

[01:33:34]

 

CAR T-Cell Therapy: Acute Toxicities

 

If we look specifically at the timing, CRS is typically an early event. It occurs within the first week, almost always. That is why in our monitoring program for patients, we typically recommend daily evaluations within the first 7 days. Now oftentimes those patients are in the hospital. But if they are outpatient, we do daily evaluations for 7 days. We do a required total evaluation for 2 weeks, but the second week does not need to be every single day.

 

This is consistent with the current recommendation of a total of 2 weeks of monitoring. Obviously, if a patient has any evidence of CRS or ICANS, during those first 7 days of daily monitoring and then the following week of regular monitoring, we would follow them later. But for a patient who has had no toxicities within those first 2 weeks, then we can often follow them less closely thereafter.

 

Now, we are not just watching for CRS and ICANS. We know these patients get acute cytopenias, particularly in the immediate aftermath of lymphodepleting fludarabine and cyclophosphamide. These patients may have neutropenic fever when they develop CRS and we have to consider infectious causes. We do not assume every fever is CRS. We need to send cultures. We need to think about respiratory viruses. Here, it is flu season of course, and COVID-19 continues to be an issue. We are seeing cases of RSV.

 

If we are seeing LFTs on the rise, refractory fevers, low platelets, we need to think about HLH-like syndrome or macrophage activating syndrome, and of course, infectious toxicities in this immunocompromised state.

 

For CRS, we will talk a little bit more about the side effects. Certainly for just low-grade, grade 1 CRS, with something like liso-cel, that can often abate all on its own and just need to be monitored. Once patients have grade 2 CRS, we are typically adding in tocilizumab. Once patients develop high-grade CRS, like grade 3, that really does require both tocilizumab and corticosteroids. If patients have steroid-resistant disease, we will usually add in the IL-1 blocker, anakinra.

 

Neurologic side effects are typically again occurring early, usually just after the CRS. This might be happening in the 7- to 10-day period. For patients developing that, we get them quickly on seizure prophylaxis to prevent subsequent seizures, which are ultimately rare. The primary treatment for ICANS that is anything over grade 1 would be corticosteroids.

 

Tocilizumab does not have a role in the treatment of ICANS, but we do use dexamethasone in that context. For patients who are not recovering quickly with dexamethasone, we will again add in often anakinra.

 

For the immune effector cell-associated hemophagocytic syndrome or macrophage activating syndrome, this is often a later event occurring in the 2- to 3-week range. Here, traditional tocilizumab does not typically work. We will often add in steroids to be sure. There is some small data sets suggesting value to anakinra or ruxolitinib, which we will try. Etoposide has historically been used in hemophagocytic syndromes and some more recent data for emapalumab, which we also reach for, for patients with resistant IEC hemophagocytosis.

 

It is important to recognize, because of these side effects, as I have noted, patients due to be monitored for 2 weeks at minimum for CRS and ICANS, with at least daily evaluations for that first week of monitoring when the risk is highest.

 

[01:37:39]

 

Let's Revisit a Question

 

Let us revisit a polling question from the beginning.

 

[01:37:44]

 

          Posttest 3

 

At minimum, how frequently should a patient be monitored for CRS and neurologic side effects following CAR T-cell therapy? Options are:

 

1. Monitor daily for 1 week;
2. Monitor for a total of 2 weeks, but at least daily for the first week;
3. Monitor daily for all 2 weeks; or
4. Monitor for 3 weeks, and at least daily for the first week.

 

Go ahead and vote.

 

The majority of people selecting the correct answer. It is a minimum of 2 weeks of monitoring and at least daily evaluations for the very first week following CAR T-cell infusion. Good work.

 

[01:38:48]

 

CAR T-Cell Therapy: Late Toxicities

 

If we turn our attention to late side effects, it is important to recognize that once patients are out of the woods for CRS and ICANS, it does not mean they are out of the woods entirely. We do see significant late toxicities. About a third of patients will have prolonged cytopenias, all patients with a B-cell aplasia. Remember, CD19-directed CAR T-cells are not magically deleting just CD19 positive lymphoma cells, are also deleting all healthy CD9-positive B-cells. So all patients are left B-cell aplastic with hypogammaglobulinemia.

 

We can see this start to recover often in the 6- to 9-month range. But prolonged hypogammaglobulinemia may be seen particularly in heavily pretreated patients.

 

We also see prolonged T-cell lymphopenia, again, particularly in heavily pretreated patients who then get fludarabine-based lymphodepletion. CD4 counts remain quite low for some time. It is important to think about prophylaxis and attention to infection risk, not only based on B-cell depletion and hypogammaglobulinemia, but also the potential for prolonged CD4 T-cell lymphopenia.

 

We think about prolonged infections. We think about prolonged cytopenias, which often patients may still have a grade 3 or 4 cytopenias at a month and about a third to 40% of patients, depending on the study and the population. That drops down dramatically. Most of these patients have recovered to grade 1 or 2 within day 60.

 

There are potential for long-term neurologic side effects, particularly patients can have some prolonged neurocognitive defects, attention difficulty or prolonged tremors, minor movement disorders. I will note that specifically with BCMA-directed CAR T-cell, particularly the cilta-cel product, we are not talking about that today, but there is a Parkinson-like syndrome that can be seen late in those patients. We have not, however, observed those with CD19-directed CAR T-cells.

 

There can be transient cardiac toxicities, including arrhythmias that is worth noting, and secondary malignancies, which we will talk about, particularly secondary myeloid leukemias or MDS, largely reflecting the impact of multiple prior lines of chemotherapy in a heavily pretreated patient.

 

In terms of management of prolonged cytopenias, early on it is simply growth factor support along with transfusion support, as needed. I will note, particularly for patients who reach day 60 and still have grade 3 or 4 cytopenias, it is important to do a bone marrow biopsy. These patients are at risk for myelodysplasia. They may have their underlying disease affecting marrow function as well.

 

Sometimes they just have empty marrows and aplasia observed. It is very important to do a bone marrow evaluation to help elucidate the cause of cytopenias, particularly those that are prolonged, and I would say, have not recovered by day 60 or even requiring ongoing transfusion support outside of beyond a month, I would have consider a bone marrow evaluation.

 

For patients who are myeloma patients who might have had stem cells stored, then stem cell boosts have been used to good result, although that is rarely a possibility in lymphoma patients. We do not typically store stem cells for those patients, so do not have them available for a boost.

 

For patient, who is 3 months out still with prolonged cytopenias, transfusion requiring not responding to growth factor support, there are rare patients will actually consider an allogeneic stem cell transplant. Thankfully, that is quite rare.

 

For patients with hypogammaglobulinemia, I typically do not give most patients routine prophylactic IVIG unless they have recurrent or severe infections, and an IgG level of less than 400. If it is a single infectious event, or if they have no infections and a low IgG level, I do not routinely give IVIG. That is different in the myeloma population getting BCMA CARs. Those patients are even more immunocompromised.

 

Oftentimes for a BCMA-directed CAR patient with myeloma, they are going to get routine IVIG repletion. But certainly for lymphoma patients, if they have an IgG level less than 400 and they are having a severe or recurrent infections, prophylactic IVIG replacement monthly intervals is recommended.

 

We do pay attention to infectious prophylaxis. All of our patients go on HSV prophylaxis with acyclovir or an equivalent and pneumocystis prophylaxis with Bactrim or an equivalent. Those should continue at least for several months. Because patients can have prolonged CD4 lymphopenia, my practice is to check CD4 counts and not to discontinue if their CD4 count is less than 200. Others use 6 months for Bactrim or equivalent 1 year for antiviral prophylaxis. There are varying strategies.

 

It is also important to think about revaccination strategies once you are more than really 3 months out of CAR T-cell therapy. That is particularly important for the viral respiratory pathogens, which are the most common pathogens that occur in these patients. So revaccination against the annual influenza, COVID-19 and RSV.

 

[01:44:50]

 

Timeline for Delayed Toxicities With CAR T-Cells

 

We think about the types of infections. It does evolve over time. Early on, patients are certainly at risk for all types of infections, including bacterial infections, viral infections. Fungal infections are not common. If you have a patient who is heavily immunocompromised going in, or they receive a lot of doses of corticosteroids for management of CRS and ICANS, those are patients with high-risk for fungal infections, including mold infections, and should be considered even for prophylactic antifungal therapy, although we do not use that routinely.

 

We do routinely administer pneumocystis prophylaxis, typically for a minimum of 6 months. Again, I check CD4 counts to ensure it is safe to discontinue.

 

We talked about monitoring IgG levels and repleting with IVIG, as indicated, and the prolonged potential for T-cell recovery. The prolonged cytopenias we already alluded to with using growth factor support and transfusion support and potential extreme rescue measures such as stem cell boost or transplant, if needed.

 

Then those late neurologic complications can really be quite late, along with late immune-related adverse events, which can even occur beyond 6-12 months. In the late population, we are also thinking about subsequent secondary malignancies. Again, secondary leukemia as an MDS, being the most common, in this population who have been heavily pretreated with chemotherapy.

 

[01:46:35]

 

Long-term Monitoring and Toxicities: Wk to Mo From Infusion

 

All patients should be monitored for cytopenias and treated accordingly, as we have talked about. The question becomes really making sure that the long-term monitoring is delineated in terms of who is taking the lead. These are often patients who have returned to the care of their local oncologist and are no longer in routine, regular or frequent contact with the CAR T-cell center.

 

It is critically important that the CAR T-cell center have a well-established care plan and monitoring plan that has been worked out and agreed to with the primary oncologist who is managing the patient after 3 months, 6 months, etc. That means monitoring cytopenias, monitoring IgG levels, being prepared to replete IVIG, if needed. Understanding that these patients may be at risk for opportunistic infections and thinking about appropriate viral respiratory evaluations, including CMV in these patients with their prolonged lymphopenias as well as pneumocystis, as well as observing for secondary malignancies.

 

We talked about anti-herpes and anti-PJP prophylaxis again, generally for a minimum of 6 months, and I would monitor a CD4 count to confirm it is safe to discontinue. We talked about routine respiratory viral revaccination. Other revaccination strategies vary. Some centers follow more of an allotransplant type approach and revaccinate against every childhood pathogen. I do not consider this a stem cell transplant and do not routinely vaccinate it against every child pathogen. These patients are not typically getting rubella or polio.

 

What I do check is serologies. I typically am revaccinating against pneumovax, pneumonia, with the most up-to-date pneumonia vaccine. I will check serologies for other vaccines. My experience is usually patients have preserved immunity against most childhood vaccines, but some may need boosting. So I do evaluate on a case by case basis. Again, this strategy varies widely center to center.

 

[01:48:53]

 

Overview of CRS and Neurologic Events After CAR T-Cell Therapy

 

Here is a more close overview of CRS and neurotoxicity, which I think we have generally already evaluated and discussed at length, but this is available in your slide deck for further evaluation.

 

[01:49:10]

 

CRS Grading: ASTCT Recommendations

 

We do grade CRS, and I mentioned grade 1 CRS earlier as often being able to follow just with observation alone. That is an isolated fever. Blood pressure is normal. No hypoxia, particularly with a patient who is treated with a 4-1BB co-stimulated product like liso-cel.

 

Axi-cel or brexu-cel, higher rates of CRS, higher rates of progressing to high-grade CRS. Even grade 1 CRS in an axi-cel or brexu-cel patient, particularly if it is occurring within 48 hours of their initial CAR T-cell infusion, I will often treat that patient with the addition of dexamethasone and tocilizumab, while a grade 1 liso-cel CRS, I will typically observe and oftentimes that baits on its own.

 

If a patient like that is having prolonged grade 1 CRS, they are still fevering after 72 hours or 3 days, I will often give that patient a dose of tocilizumab.

 

Grade 2 CRS is fever, with maybe some hypertension that does not require vasopressors, just a fluid bolus or maybe they require low flow oxygen. This is a patient I would typically treat with tocilizumab with or without corticosteroids. Once a patient reaches grade 3, they need vasopressors or high-flow oxygen support. That is definitely a time where we are giving tocilizumab and corticosteroids with dexamethasone.

 

[01:50:41]

 

Management: CRS

 

This highlights that grade 1 is often just supportive care alone with or without tocilizumab. Again, if it is prolonged grade 1 CRS, if it is a high-risk product like axi-cel or brexu-cel, or if the patient is very frail and really cannot tolerate ongoing CRS, then tocilizumab can be considered for grade 1, but often observation alone, particularly for a low-risk patient getting liso-cel.

 

Once patients are grade 2, definitely tocilizumab with or without corticosteroid. Grade 3, these patients need vasopressors, high-flow oxygen, tocilizumab and dexamethasone is required. Certainly grade 4, these are high-dose corticosteroids and tocilizumab. And of course, these patients are being cared for in an ICU.

 

Another reminder that once patients have an isolated fever or any CRS, always think about infections as a cause. Not every fever is CRS. So you need to also think about other potential causes of these things, including infections with empiric therapy as needed in the setting of neutropenic fever, evaluating cultures and other infectious serologies. Thinking about other toxicities that can happen, including heart failure, arrhythmias, pulmonary edema, etc.

 

[01:52:01]

 

Let's Revisit a Question

 

Let us revisit 1 of our questions.

 

[01:52:03]

 

          Patient Case: AEs After CAR T-Cell Infusion

 

This is a question about a 70-year-old man who got axi-cel for large cell lymphoma. 48 hours after axi-cel, this patient developed fever, dizziness and shortness of breath. He required vasopressor support as well as high-flow nasal cannula for oxygen delivery. This patient did have an infectious evaluation, and there was no obvious source of infection on laboratory studies or acute imaging.

 

This patient developed hypotension requiring vasopressors and high-flow oxygen requirement for hypoxia within 48 hours of axi-cel.

 

[01:52:45]

 

          Posttest 4

 

In addition to supportive care, oxygen support and vasopressors, what else will you do for this patient? Will it be:

 

1. Begin treatment with anakinra;
2. Begin treatment with dexamethasone alone;
3. Begin treatment with tocilizumab alone;
4. Begin treatment with anakinra and dexamethasone; or
5. Begin treatment with tocilizumab and dexamethasone.

 

Please vote.

 

The majority of people picked the correct answer. This patient has grade 3 CRS. Absolutely the correct answer is tocilizumab plus dexamethasone.

 

[01:53:38]

 

          Management: Neurologic Toxicity and ICANS

 

We turn our attention to ICANS. Remember, tocilizumab does not work for ICANS unless that patient also has CRS, in which case the tocilizumab is a treatment for the CRS. Grade 1 neurologic toxicity, minor word finding difficulties, minor abnormalities on their so-called ICE score would typically be supportive care alone. If it is prolonged, potentially adding in corticosteroids.

 

I typically wait until grade 2 to add in corticosteroids, typically with dexamethasone. Certainly grade 2 ICANS requires corticosteroids. If they are refractory to corticosteroids alone and not getting better, we would often add in anakinra. For grade 4 ICANS, this is ICU level support. This is where we would also consider imaging for cerebral edema. High-dose methylprednisolone in that context is essential.

 

[01:54:43]

 

Infection Prophylaxis and Vaccinations

 

We have already discussed at length infectious prophylaxis and IVIG replacement and vaccines, so I would not go to this in greater detail. Remembering growth factor for neutropenia IVIG support as needed, ongoing prophylaxis as we've discussed, and vaccinations as we have also discussed as well.

 

There is no routine role for antibacterial prophylaxis, except in a patient with very prolonged neutropenia. Obviously, if a patient has febrile neutropenia, you are treating with antibiotics accordingly. Routine antifungal prophylaxis, I mentioned not recommended unless a patient is very high-risk or getting prolonged steroid exposure. But antiviral prophylaxis and anti-pneumocystis prophylaxis should be given to all patients.

 

[01:55:37]

 

Other AEs With CAR T-Cell Therapy

 

We already talked about prolonged cytopenias earlier using growth factor support. Growth factor support and transfusion support as needed. Again, a bone marrow biopsy for prolonged cytopenias, with no recovery, despite the conservative measures I highlighted.

 

[01:56:01]

 

B-Cell Aplasia/Hypogammaglobulinemia 

 

We already talked about B-cell aplasia and hypogammaglobulinemia. Again, these patients may have prolonged hypogammaglobulinemia. Some of these patients have hypogammaglobulinemia even prior to CAR T-cell therapy due to extensive prior treatments. So making sure this monitored at baseline and throughout and considering IVIG replacement as we have discussed.

 

[01:56:26]

 

Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome

 

HLH or macrophage activation syndrome, very uncommon for patients who have ongoing high fevers, typically later than CRS, think about checking. Make sure LFTs are checked. Make sure ferritin is checked here. Ferritin is typically greater than 10,000. These patients typically have transaminitis as well. Their lipid, triglycerides may be elevated and other organ function and significant thrombocytopenia.

 

This is a sepsis-like or a DIC picture. We think about certainly corticosteroids potential ruxolitinib, ipilimumab, anakinra or etoposide in these patients.

 

[01:57:10]

 

FDA Black Box Warning

 

A black box warning does exist now for secondary malignancies, particularly for this very rare risk of T-cell malignancies. I will say that the black box warning stemmed from a small number of case reports which were not even clearly directly related to the CAR T-cell product.

 

In fact, this is a very rare event. An actual integration of the CAR T-cell DNA into a T-cell lymphoma has only been very rarely reported.

 

[01:57:41]

 

Proportion of Reports of Each SPM Within Each Product Relative to the Number of AE Reports per Product

 

In fact, if we look at secondary malignancies following CAR T-cell therapy, the vast majority, as you can see here, are either secondary myeloid neoplasms, again, MDS or AML in heavily pretreated patients or non-melanoma skin cancers.

 

[01:58:00]

 

Absolute Number of Reports for Each SPM in CAR T-Cell Products

 

This is also true for the absolute number as opposed to proportion. Again, these numbers are actually overall quite low. These are a total of just over 300 cases of secondary leukemias among tens of thousands of patients who have been treated with CAR T-cell therapy to-date.

 

[01:58:22]

 

FDA Black Box Warning (continued)

 

In terms of the specifics of a T-cell lymphoma, the group at Stanford specifically looked at over 700 patients and only found a single patient who developed a new T-cell lymphoma. When they looked deeply, actually the T-cell lymphoma was actually present even before the CAR T-cell was administered. We had this experience as well as 1 of our liso-cel studies, the patient had a T-cell lymphoma diagnosed following CAR T-cell therapy. We went back and sequenced the patient's lymphoma even prior to CAR T-cell therapy, and the malignant T-cell clone was present even at baseline.

 

While it is something to know about, I would consider this a theoretical concern that can be discussed with patients. Clearly, when we are using these products, the benefit of CAR T-cell therapy clearly far outweighs the vanishingly rare theoretical risk of actually transforming a T-cell with CAR T-cell therapy.

 

[01:59:22]

 

          Master Class Case Discussion

 

Let us go back to our next masterclass case for discussion. I will invite my colleagues back on for this 66-year-old man who is treated with brexu-cel for relapsed mantle cell lymphoma after having received frontline bendamustine-rituximab and second-line BTK inhibition with zanubrutinib. On Day 2, after CAR T-cell therapy, this patient develops a fever and hypotension, which is responsive to fluid boluses.

 

This patient has grade 2 CRS. He is appropriately treated with tocilizumab and dexamethasone, leading to rapid resolution of CRS. Three days after that, this patient develops confusion, word finding difficulties and aphasia.

 

Dr Maloney, how would you characterize these symptoms and what would you do?

 

Dr Maloney: Yes. This is at least grade 3 neurologic toxicity with those symptoms. I would definitely start him back on dexamethasone, assuming it had been stopped for the CRS. I would have probably a short fuse to also starting anakinra, at least that is what we do at our center. We have some studies of variety of dose levels of anakinra in this setting. That is what I would probably start at this point.

 

Dr Abramson: Dr Johnson, let us say you start corticosteroids. How long would you wait for those corticosteroids again before starting a next line of therapy like anakinra, as Dr Maloney talked about?

 

Dr Johnson: A couple of things I will point out. Just as you discussed in your presentation, Dr Abramson, this is the typical tempo for when neurologic toxicity might occur after someone who had had CRS a few days later. I typically would start dexamethasone. If the patient is remaining stable and starting to improve, I would just continue that therapy.

 

If after 24 hours, the patient is beginning to progress, if we are seeing neurologic symptoms worsening despite corticosteroids, I would have a very low threshold to add anakinra, as Dr Maloney mentioned. I typically give anakinra in that circumstance as intravenously instead of subcutaneously.

 

[02:01:44]

 

          Master Class Case Discussion (continued) 

 

Dr Abramson: Perfect. This patient is treated with tocilizumab and dexamethasone for the CRS, then develops the neurologic symptoms for which dexamethasone is resumed. The neurologic symptoms progressed and the dexamethasone dose was increased and anakinra was added. This patient was treated per the recommendations of Drs. Johnson and Maloney. These symptoms gradually abated over 10 days. Patient was deconditioned as a result and required discharge to inpatient rehab.

 

One of the lessons here is that the neurologic side effects really can be prolonged. They do not turn around as quickly as CRS with tocilizumab. It can be more prolonged. It is this side effect that may lead to deconditioning and patients needing to go to rehab, which obviously we do try to avoid.

 

[02:02:39]

 

Future Directions in CAR T-Cell Therapy

 

Now, we have been talking about a very bright present, but as with always, the future is even brighter. Let me turn it over to Dr Johnson.

 

[02:02:47]

 

Future Directions

 

Dr Johnson: Thank you so much. We have heard some fantastic presentations about the state of the field in CAR T-cell therapy. Now it is my privilege to talk a little bit about some potential future directions.

 

One category of future directions in CAR T-cells represent novel antigen targets. We have discussed CD19, but a number of different antigens are possible with CAR T-cell therapy. Some of those mentioned are CD70, CD79b, and ROR1. I particularly would highlight BAFF-R or B-cell activating factor receptor. There was some data presented of a CAR T-cell targeting this antigen at the recent ASH meeting, which showed some encouraging early responses.

 

Another major modality of improving CAR T-cell therapy potentially is dual or even tri-targeting. The majority of the CAR T-cell therapies that are further along in clinical development are dual-targeting CD19 and CD20. These CAR T-cells seek to mitigate the risk of antigen loss as a mechanism of relapse by having multiple antigens target.

 

We talked in the very beginning about multiple generations of CAR T-cells, including CAR T-cells that are armored, meaning that they have the ability to either secrete additional cytokines as part of their anti-tumor efficacy, or even a drug such as a PD-1 inhibitor.

 

Finally, we have an entire new modality of CAR T-cell therapies that are being investigated. I mentioned a clinical trial earlier of allogeneic CAR T-cells, but also NK CAR T-cells, and even in vivo CARs, where the potential manufacturing step can be entirely omitted with the manufacturing occurring within the patient. It is early days for in vivo CAR, but this could be a very exciting way to potentially increase the availability of CAR T-cells.

 

One clinical trial looked at double dosing or an extra dose of axicabtagene ciloleucel as a strategy in a subset of patients with large B-cell lymphoma and showed some encouraging response rates. This could be an additional strategy in CAR T-cell therapy.

 

[02:05:00]

 

CD19/CD20 Dual-Targeting CARs

 

I highlighted dual-targeting CAR T-cells as 1 potential future avenue. This is a very interesting slide that summarizes the dual CD19/CD20 targeting CAR T-cell therapies that are in late phase clinical development in some cases, and earlier phase clinical development in others.

 

J&J, Kite and Lyell all have products that have shown encouraging response rates of around 90% and complete response rates close to 75% or even more in patients with multiply relapsed large B-cell lymphomas. All 3 of these clinical products are reaching the phase of being tested in randomized controlled trials against standard anti-CD19 CAR T-cell therapy. So this is a particularly exciting area to look forward to in the future.

 

[02:05:47]

 

Rapid Manufacture and Fresh CAR T-Cells

 

In addition to dual-targeting CAR T-cell therapies, there is an entire field focused on improving the manufacturing steps. Zamto-cel is a dual-targeting CAR T-cell that uses a fresh non-cryopreserved product, and by doing that has a very shortened vein to vein time. It has been investigated in clinical trials, including 1 listed on the slide here.

 

KITE-753 is a dual-targeting CAR T-cell that, in addition to being dual targeting, uses a rapid manufacturing platform.

 

Similarly, rapcabtagene autoleucel uses a rapid manufacturing platform and is an anti-CD19 CAR T-cell with the same construct as tisa-cel. Both KITE-753 and rapcabtagene autoleucel essentially shorten the step of ex vivo manufacturing, letting the manufacturing process occur more in the patient, with the goal of yielding a memory T-cell phenotype in terms of enrichment of the T-cells. This also has the added benefit of shortening the manufacturing time.

 

For rapcabtagene autoleucel, this was specifically presented recently at ASH in a cohort of patients with high-risk large B-cell lymphoma who had had less than a complete response to frontline chemoimmunotherapy and showed a complete response rate of 74%, an encouraging response rate in a group of patients with high-risk disease and suboptimal response to frontline therapy.

 

[02:07:09]

 

Let's Revisit a Question   

 

Let us revisit a question at the beginning of the presentation.

 

[02:07:15]

 

          Posttest 5

 

The new CAR T-cell therapy, KITE-753, is currently being evaluated in an ongoing phase I/II clinical trial enrolling patients with relapsed/refractory large B-cell lymphomas. Which of the following represents the novel properties of this CAR T-cell therapy? Is it:

 

1. Dual targeting only;
2. Rapid manufacturing only;
3. A fresh product only;
4. Dual targeting and rapid manufacturing; or
5. Dual targeting and a fresh product.

 

Please submit your answers.

 

Great. The vast majority of folks entered the correct answer, which is that this product represents 2 avenues for trying to improve CAR T-cell therapy, both by having a rapid manufacturing process and by having dual targeting of CD19/CD20.

 

[02:08:17]

 

          Poll 3

 

With the discontinuation of REMS for CAR T-cell therapies, will you consider referring more patients for CAR T-cell therapy eligibility screening?

 

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

 

These are some of our final poll questions that will wrap up before our question and answer session.

 

[02:08:48]

 

          Poll 4

 

Poll question 4. Do you plan to make any changes in your clinical practice based on what you learned in today's program?

 

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

 

Please submit your answers.

 

[02:09:21]

 

          Poll 5

 

Please take a moment to enter 1 key change you plan to make in your clinical practice based on today's education.

 

Amber Williams: Dr Johnson, we can actually move on to the Q&A session while the audience can fill in this.

 

[02:09:36]

 

Q&A

 

Dr Johnson: With that, I would like to invite the rest of our panel to join. We have a couple of questions that have been submitted. Great. It looks like these have both been answered, which is terrific.

 

First, I will ask Dr Maloney. You have heard a little bit in my presentation about some developments in the future of CAR T-cells. What is something within CAR T-cell therapy that you are excited about for the future?

 

Dr Maloney: That is a great question, where is the future going to be? I really appreciated your discussion of some of the options. Dual targeting will potentially have a role. Remember, CD19 is expressed more broadly than CD20. CD20 is a pretty polluted space in terms of all the CD20 antibodies that patients are hammered with in their frontline therapy.

 

I am a little concerned that CD20 may not have as big an impact on efficacy, although I cannot argue with the results that are out there. The dual targeting is going to be exciting.

 

The other thing we need to think about, we need to make better CARs, but I also think we need to make CARs more available. I do not know how we do that. We keep doing the seminar here in the United States where these things have wide access. But many of the countries do not even have access to the current CARs, and I think that easier delivery of CARs will be important.

 

I am interested in the in vivo CARs, although, again, I do not know whether they are going to be able to have the same effect. I applaud the early shorter manufacturing. Get the cells into the patient quicker and we will see how that goes.

 

Dr Johnson: Dr Abramson, what about you? Same question.

 

Dr Abramson: Yes. These newer products are really exciting in many ways. Most of them are CD19 and CD20 directed. I shared Dr Maloney’s concern that these are folks who have usually had multiple rounds of CD20-directed therapy, and may have lost CD20 or downregulated. But if we ultimately move these in second-line, then maybe that will be less of an issue.

 

Some have been looking at CD22 as part of that, though, there has been a signal of hemophagocytosis with the CD22 products that warrants ongoing careful attention.

 

I have to say, some of the benefit that we are seeing with these newer products may not have anything to do with the dual targeting, but just with better manufacturing. One thing that you saw is that these products are now being manufactured much quicker. The quicker you manufacture a CAR T-cell, the more you produce a cell with a stem memory phenotype that is less exhausted and potentially less exhaustible and ultimately making a better T-cell into a better CAR T-cell.

 

Ultimately, I am really curious to see if we can make allogeneic off-the-shelf CAR T-cells and NK cells persist long enough to induce durable remissions. Thus far, we have seen some encouraging response rates, but we know that they do not persist as long as due to earlier rejection, and that has impacted long-term durability of these responses. But would not it be great if we can take a T-cell that had not previously been exposed to chemotherapy or to the immune suppressive effects of the patient's underlying lymphoma and use a healthy donor cell off-the-shelf.

 

There is still a lot to work out there. Using those products in minimal residual disease states like the ALPHA3 trial is looking at with cemacabtagene is an exciting potential prospect in that ongoing trial of just targeting MRD clearance with an allogeneic CAR T-cell in patients with MRD detectable disease at the end of induction.

 

Faster manufacturing, better CAR T-cell phenotyping coming out of that and earlier use and potentially even allogeneic products, I am excited about.

 

Dr Johnson: Looks like we have some great questions in the chat. Dr Maloney, is there a future for CAR T-cell therapy in autoimmune diseases?

 

Dr Maloney: Yes, we are seeing an explosion right now of clinical trials of using generally CD19-directed CAR T-cells in autoimmunity. There is also exploration with BCMA or other antigen targeting as well. Some of the data coming out of the original studies in Germany are just outstanding.

 

Dr Schett’s program showed virtually all patients going into complete remission with a variety of malignancy or a variety of rheumatologic disorders that we would not even necessarily think were caused by B-cells. It seems like the B-cell may be the master orchestrator of some of the autoimmunity. If you can eliminate B-cells in a profound level, you might get the B-cells to recover after a profound depletion to a state where that autoimmunity is controlled.

 

There is a big role for it right now. Lots of companies are jumping into trying to look at activity and a lot of diseases. Lupus nephritis is 1 of the most interesting, but also multiple sclerosis, which surprisingly you might see some activity.

 

Dr Johnson: Dr Abramson, there is a question about bridging therapy, which I know we had in great case. If polatuzumab is inaccessible, what about bispecifics as a bridging therapy? What is our understanding of that, and how do you approach that or other bridging therapies when polatuzumab is not a good systemic option?

 

Dr Abramson: Yes. Polatuzumab often is not an inaccessible option. Or of course you have got a patient who is primary refractory on Pola-R-CHP, you are obviously not going to get any bang for your buck out of bridging polatuzumab.

 

This is a controversial question. Bridging therapy really needs to be personalized to the patient, to their underlying disease and what they have previously received. It is appealing to think about bispecifics as a bridging therapy. I do not do that routinely right now. We need some data in this regard. I have some concern about the bispecific antibody.

 

If you give that in bridging, the bispecific antibody has a fairly long half-life, and it is going to still be in circulation when your CAR T-cell goes in. Now it is targeting a different antigen. I worry theoretically about a bispecific antibody engaging the very same T-cells that you want to engage in CAR T-cell therapy and inducing exhaustion, head of the CAR T-cells you are infusing because of the existing bispecific antibody.

 

Now, that might be unfounded. We know that folks who have gotten the bispecific and then subsequently go on to receive a CAR in the future, that seems to go fine. But those studies do not look at people who got a bispecific a week earlier, which I think is a very different scenario.

 

It needs to be studied. We are planning a study looking at bridging GemOx actually prior to CAR T-cell therapy. That is in the context of a clinical trial where we are going to actually study immunophenotyping of the cells and the immunophenotype.

 

Right now, it would not be a standard go to for me. David, how about you? Are you guys using it routinely?

 

Dr Maloney: No, we are the same. I do not know where to put them. There is some interesting data that you might be able to increase the T-cell population at some points after a bispecific therapy. Maybe it is even a way to get better T-cells prior to apheresis. We are not there yet. We need the studies.