Jae Park, MD

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 Something else about this trial that was just published in 

 is the impact of response at day 28 and at 3 months. What’s interesting about this paper is that patients who responded well and had MRD [minimal residual disease] negativity on day 28 and 3 months have a long-term survival of 70% compared with the patients who didn’t respond. It seems to me that patients who are responding may not need allotransplant.

 That brings me to something very important to discuss with you today. Can we say that if somebody had a response to CAR [chimeric antigen receptor] T-cell therapy and had MRD negativity by NGS [next-generation sequencing] that we can spare the need for allotransplant?

 I think so. There’s a bit of a caveat there, where we’re beginning to know these data. Though we certainly have the most robust data with tisagenlecleucel, not every CAR is the same. We don’t have as much data analyzed for brexucabtagene. Hopefully those data will come later. But with tisagenlecleucel, given the large number of patients with longer-term follow-up, with a recent subgroup analysis in the paper, it does typically suggest deeper remission, NGS-negative, 10-6 sensitivity.

In the paper, patients who had B-cell aplasia that was maintained long term had a very long-term outcome without subsequent transplant. Very few of those patients—less than 20%—went to transplant. Based on those data, after tisagenlecleucel, for patients who have ongoing B-cell aplasia beyond 6 months and have MRD negativity by NGS at months 1 and 3, I’d feel more comfortable not recommending transplant with that particular product. Whether that can be generalized to other CD19 CARs, we have to be a little careful until we get such data.

 You mentioned something important: that in ALL [acute lymphoblastic leukemia], you can’t wait until you get the CAR T cells. Often, patients receive bridging chemotherapy or immune therapy. It can be inotuzumab or blinatumomab. I have 2 questions for you. Do you have any objection to using blinatumomab before CAR T? And we know that blinatumomab is better in MRD negativity, or minimal disease. Do you think that even with a CAR T, it will be best used in consolidation with CAR T in patients with minimal disease or no disease?

 Those are good questions. These are real-life questions that a lot of us are dealing with. I wouldn’t choose based on a potential future need of CD19 CAR T-cell therapy, meaning deciding between blinatumomab or inotuzumab. If a patient is ready for CAR T and it’s the best therapy at that moment, we’ll choose that. But if not, with previous inotuzumab or blinatumomab, there have been many subgroup analyses that show that it may not matter as much, and certainly for adult patients.

But with the bridging therapy immediately prior to CAR T-cell therapy after CAR T-cell collection, I’d avoid blinatumomab because I’m going after CD19 and I likely need some of the antigen present to enhance the T-cell expansion and antitumor efficacy. I might not use blinatumomab immediately prior to CAR T. But the month before that, I would have no problem using it.

You asked a very important and relevant question about the inotuzumab, which has a high efficacy and high MRD negativity rate as well. Can we use that as a bridge? The dose is usually a bridge to transplant. But instead of a transplant, to avoid the VOD [veno-occlusive disease] risk, can we substitute it with the CD19 CAR T cells? That’s going to probably be the next big question that we should be asking ourselves, hopefully in a clinical trial setting. We have to see. It sounds great. Hopefully it will translate to be that way. When you ablate the B cells too much with inotuzumab when there’s no disease, we don’t know how the CAR T cells will fare in this setting.

 There were also data presented at the 2021 ASH [American Society of Hematology] annual meeting from CHOP [Children’s Hospital of Philadelphia] about infusions of CAR T post the first CAR T infusion. Essentially, if somebody is progressing, losing the T cells, or emerging with MRD, is there room for more CAR T infusions as a maintenance or salvage?

 Relapse after CAR T-cell therapy is always challenging. As we discussed, even though the initial response rate to CAR T-cell therapy is 80%, anywhere from 40% to 60% of these patients can relapse, at least in the adult ALL setting. We’re trying to come up with ways to prevent such relapse. The reinfusion of CAR T has been looked at both ways. One is trying to act early for loss of B-cell aplasia or the recovery of normal hematogones. The CHOP group has looked at tisagenlecleucel reinfusion in children and young adults. These data presented at ASH look interesting as an oral abstract. When the reinfusion of the CAR Ts are used in that setting even before MRD relapse and morphologic relapse, but with B-cell recovery, it was effective compared with the historical control of prolonging the response duration for those patients.

If you receive reinfusion at the time of morphologic relapse, they don’t respond very well. We get about half the response rate, meaning typically about 40% response rates. Even when you do gain the response, the duration of remission is fairly short. While we can certainly try it for a subset of the patients, my general sense is that it isn’t a good long-term solution. After I give reinfusion, even if they respond, I’ll be concerned about potential relapse, and I’ll be monitoring those patients closely and trying to come up with what else we can do, whether blinatumomab or inotuzumab could be useful in this setting, if it was CAR relapse.

 That brings me to other abstracts from ASH, including tandem CAR T—CD19 and CD22 given concomitantly or sequentially—and the Sleeping Beauty CAR T, the NK [natural killer] cell CD19. What do you think of the novel CAR Ts?

 Along the same lines, it’s one of the other ways the field is moving. Because initial response is great, but what are the ways to prevent such relapse? One such way is targeting both antigens at the same time or sequentially. We’re somewhat doing that with blinatumomab and inotuzumab, but can we do that simultaneously with this CAR T since these T cells are genetically engineered and we have a capability to do so?

There have been several batches of bispecific CAR T-cell data presented from different groups, and there are many different ways to target them. One such way is that you can generate CD19 CAR T and CD22 CAR T and infuse them together as a T-cell product, or you can engineer the CAR itself so that it has 2 arms—one to CD19 and one to CD22—and then infuse 1 CAR product that targets 2 antigens. There are many ways of doing so. The data look promising. At the minimum, they’re generating the same response rates that we’re seeing with the single-antigen–targeted CAR T, about 80% initial response.

What’s less clear at this time is whether this dual-targeted approach will prevent relapse. We need longer-term follow-up in more patients to see whether we’re achieving a deeper response either with NGS, as we talked about before, and when they relapse, whether they’re relapsing with a CD19-positive and CD22-negative, or the negative with either of these antigens. What we have seen so far in some of the data is that even when you do a bispecific, one CAR may perform better. Either will predominate, and one CAR will persist longer, either the CD19 or CD22. The antigen specificity and their sensitivity to antigen density also differs. CD22 is very sensitive to the antigen density, so you need a more antigen-dense environment for them to work well. Even though you’re infusing them, they may not work as well, so it’s similar to infusion of single-antigen–targeted CAR T. The data generated so far are very interesting and intriguing. We need a little more time to see whether that approach will be what’s going to lead to the success of less relapse in the future.

Videos

The oncologists from MD Anderson and Memorial Sloan Kettering Cancer Centers discuss sequencing CAR T-cell therapies and other key therapies in patients with B-cell acute lymphoblastic leukemia.

Determining Order of CAR T Therapy: Elias Jabbour, MD; Jae Park, MD

poke with Jae Park, MD, hematologic oncologist, Memorial Sloan Kettering Cancer Center, about factors to consider when selecting among the available CAR T-cell therapies for the treatment of patients with mantle cell lymphoma.

Differences in these agents can be observed with respect to their individual safety profiles, according to Park. For example, lisocabtagene maraleucel (liso-cel; Breyanzi) is associated with fewer reports of cytokine release syndrome (CRS) and neurotoxicity; however, it is still important to review the manufacturing details, as this agent has now been commercialized, Park explains. Additionally, although axicabtagene ciloleucel (axi-cel; Yescarta) has a faster turnaround time with regard to manufacturing, resulting in more rapid availability, higher rates of CRS and neurotoxicity have also been reported with the product, Park notes.

The key factors to consider when making treatment decisions often include turnaround time, manufacturing success, and reliability of delivery, as well as the frequency and intensity of the monitoring required for patients, Park explains. Despite the complicated decision-making process, having a range of options available for patients is beneficial, Park concludes.

The hematologic oncologist from Memorial Sloan Kettering Cancer Center discussed factors to consider in selecting CAR T-cell therapies. 

Selecting CAR T-Cell Therapies for Mantle Cell Lymphoma: Jae Park, MD

Jae Park, MD, a hematologist oncologist at Memorial Sloan Kettering Cancer Center, discusses ​the benefits of off-the-shelf CAR T-cell therapy in acute lymphoblastic leukemia (ALL).

Patients with low lymphocyte counts after chemotherapy or allogeneic stem cell transplantation ​could benefit from off-the-shelf CAR T-cell products as collecting T cells can be challenging, says Park.

Moreover, patients may experience disease progression during the 3 to 4-week period of T-cell generation that may be mitigated by an off-the-shelf option, concludes Park.

Jae Park, MD, discusses ​the benefits of off-the-shelf CAR T-cell therapy in acute lymphoblastic leukemia.

Dr. Park on ​the Benefits of Off-the-Shelf CAR T-Cell Therapy in ALL 

Jae Park, MD, a hematologist oncologist at Memorial Sloan Kettering Cancer Center, discusses considerations for CAR T-cell therapy in relapsed/refractory acute lymphoblastic leukemia (ALL).

Several factors should be taken into account when considering CAR T-cell therapy for patients with ALL, says Park.

​Patients should be consulted early on regarding their eligibility for CAR T-cell therapy, ​Park explains. Then, optimizing bridging therapy ​is necessary to ensure patients have the best chance of deriving benefit from CAR T-cell therapy. 

Patients are encouraged to reach out regarding any questions they may have as a lot of preparation is involved ​prior to CAR T-cell administration, Park explains. 

In addition, clinical trials can be recommended to eligible patients​ as ALL remains a rare disease, Park concludes. 

Jae Park, MD, discusses considerations for CAR T-cell therapy in relapsed/refractory acute lymphoblastic leukemia.

Dr. Park on Considerations of CAR T-Cell Therapy in Relapsed/Refractory ALL 

Jae Park, MD, a hematologist oncologist at Memorial Sloan Kettering Cancer Center, discusses the use of CAR T-cell therapies in patients with acute lymphocytic leukemia (ALL).

Several different CAR T-cell products are examining ways to target CD19, says Park. For example, one product is a single-chain variable fragment that targets CD19. Preliminary data have been reported with the product in pediatric patients and it has been shown to result in a lower rate of cytokine release syndrome, says Park. If this study is further validated then that may present a safer option for adult patients with ALL.

Another CAR T-cell product is an allogeneic, off-the-shelf therapy, adds Park. Challenges exist with getting adult patients with aggressive disease autologous CAR T-cell products or generating T cells from these patients. To this end, off-the-shelf donor-derived CAR T-cell products are being investigated. Preliminary data with such products have been presented in the past, but an ongoing international study is evaluating the efficacy of this approach in a larger patient population, explains Park.

Additionally, ongoing studies are examining bispecific CAR T cells that are targeting CD19 and CD22 at the same time. The rationale for this approach is to reduce the rate of CD19-negative relapse by targeting 2 antigens simultaneously. The final data from this research are greatly anticipated, says Park. Other ongoing clinical studies are examining the efficacy of CAR T-cell therapies with the ultimate goal of providing safer and more effective products to adult patients with ALL; this continues to be a critical unmet need, concludes Park.

Jae Park, MD, a hematologist oncologist at Memorial Sloan Kettering Cancer Center, discusses the use of CAR T-cell therapies in patients with acute lymphocytic leukemia.

Dr. Park on Ongoing Research Efforts With CAR T-Cell Therapies in ALL

Jae Park, MD, hematologist oncologist, Memorial Sloan Kettering Cancer Center, discusses the potential of CD19-targeted chimeric antigen receptor (CAR) T-cell therapy in adult patients with acute lymphoblastic leukemia (ALL).

There are still no approved CD19-targeted CAR T-cell products for adult patients with ALL. However, there are many trials that have proven its efficacy in adult patients. The toxicity continues to be more of a challenge in older patients, as their physical reserve is less robust than pediatric patients. Nonetheless, the therapy has been shown to be effective. Once the therapy is modified to optimize the safety profile it is likely to be approved for adult patients with ALL, says Park.

Selecting the right patient population is critical in minimizing the toxicities and maximizing the efficacy. Park and colleagues published data from Memorial Sloan Kettering Cancer Center, in the same issue as the ELIANA trials, showing that relapsed patients with a low disease burden at the time of CD19 CAR T-cell infusion benefit the most from the therapy.

Dr. Park on CD19-Directed CAR T-Cell Therapy in Patients With ALL

Jae Park, MD, Hematologic Oncologist, Memorial Sloan Kettering Cancer Center, discusses the impact that disease burden plays on how adult patients with relapsed precursor B acute lymphoblastic leukemia (B-ALL) respond to cd19-targeted CAR modified T-cells.

Heavily pretreated B-ALL patients have demonstrated a remarkable response rate of 80% with cd19-targeted CAR modified T-cells, says Park. Disease burden does not impact how well the CAR-T cells work.

However, the side effects of CAR T- cells do differ depending on disease burden. The more disease a patient has, the more likely they are to experience toxicities, says Park.

The role of a bone marrow transplant for patients that have received CAR-T cells is also being investigated, says Park.

While the results are not definitive, researchers have found that patients with either low or high disease burden who have receive CAR-T cells and achieved a good remission do not appear to benefit form a bone marrow transplant, says Park.  

Dr. Jae Park on Impact of Disease Burden on CAR T-Cells in Relapsed B-ALL

Jae H. Park, MD, attending physician, Leukemia Service, Memorial Sloan Kettering Cancer Center, discusses a trial presented at the 2014 ASH Annual Meeting that explored CD19-targeted T cells as treatment for patients with relapsed, refractory B- cell ALL.

Park says these patients have a very poor prognosis in overall survival, with previous studies showing an overall survival of less than 10%.

In order to improve the survival of these patients, researchers have modified patients’ own T cells to express CAR to target CD19, which is expressed in all patients with B-Cell ALL, Park says.

Using these modified CAR T cells, researchers have treated up to 33 patients. Of the 27 patients that were evaluable for response, 24 patients achieved complete response for a CR rate of 80%, Park says. Those patients that achieved a complete response, the majority of them were MRD-, which proves that the treatment is providing a deep response, despite that these are very high-risk patients.

View more from the 2014 ASH Annual Meeting

Jae Park, MD

Articles

Determining Order of CAR T Therapy: Elias Jabbour, MD; Jae Park, MD

Selecting CAR T-Cell Therapies for Mantle Cell Lymphoma: Jae Park, MD

Dr. Park on the Benefits of Off-the-Shelf CAR T-Cell Therapy in ALL

Dr. Park on Considerations of CAR T-Cell Therapy in Relapsed/Refractory ALL

Dr. Park on Ongoing Research Efforts With CAR T-Cell Therapies in ALL

Dr. Park on CD19-Directed CAR T-Cell Therapy in Patients With ALL

Dr. Jae Park on Impact of Disease Burden on CAR T-Cells in Relapsed B-ALL

Dr. Park on Using CD19-Targeted CAR T Cells as Treatment for ALL

Jae Park, MD

Articles

Determining Order of CAR T Therapy: Elias Jabbour, MD; Jae Park, MD

Selecting CAR T-Cell Therapies for Mantle Cell Lymphoma: Jae Park, MD

Dr. Park on ​the Benefits of Off-the-Shelf CAR T-Cell Therapy in ALL

Dr. Park on Considerations of CAR T-Cell Therapy in Relapsed/Refractory ALL

Dr. Park on Ongoing Research Efforts With CAR T-Cell Therapies in ALL

Dr. Park on CD19-Directed CAR T-Cell Therapy in Patients With ALL

Dr. Jae Park on Impact of Disease Burden on CAR T-Cells in Relapsed B-ALL

Dr. Park on Using CD19-Targeted CAR T Cells as Treatment for ALL

Dr. Park on the Benefits of Off-the-Shelf CAR T-Cell Therapy in ALL