Commentary

Article

CAR T-Cell Therapies Move Ahead in Pediatric and Adult ALL

Author(s):

Carrie L. Kitko, MD, discusses the current standing of cellular therapies in adult and pediatric ALL and looks toward future developments.

Carrie L. Kitko, MD

Carrie L. Kitko, MD

The treatment paradigm for acute lymphoblastic leukemia (ALL) has made significant progress in recent years for both adult and pediatric patients with the addition of cellular therapies; however, significant unmet needs remain for these patients that investigators are working to address, according to Carrie L. Kitko, MD.

“There is a certain amount of effort [that is required] to be able to offer these products to our patients,” Kitko said. “[When physicians] are [wondering whether] their patient might be able to qualify for one of these emerging therapies, [whether the agent is] FDA approved or [the physician must] reach out to find out if we have the latest clinical trial available for some of these agents, [time is critical]. The earlier we put these patients on the radar, the earlier we’ll be able to help them navigate the system to be able to get that innovative treatment.”

In August 2017, the FDA approved the CAR T-cell therapy tisagenlecleucel (tisa-cel; Kymriah) for the treatment of patients up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse. The approval was based on findings from the phase 2 ELIANA trial (NCT02435849), which showed that patients with relapsed/refractory pediatric precursor B-cell ALL who received tisa-cel (n = 63) achieved an overall remission rate (ORR) of 82.5% (95% CI, 70.9%-91.0%); 63% of patients experienced complete remission (CR) and 19% experienced a complete remission with incomplete hematological recovery.1

Then, in October 2021, the FDA approved another CAR T-cell agent, brexucabtagene autoleucel (brexu-cel; Tecartus) for the treatment of adult patients with relapsed/refractory B-cell precursor ALL. The regulatory decision was supported by findings from the phase 1/2 ZUMA-3 study (NCT02614066), which showed that patients with relapsed/refractory B-cell precursor ALL who were treated with brexu-cel (n = 54) achieved a 3-month CR rate of 52% (95% CI, 38%-66%).2

In an interview with OncLive®, Kitko, the medical director of the Pediatric Stem Cell Transplantation Program, the Ingram Professorship in Pediatric Oncology in the Department of Pediatrics, and an associate professor of pediatrics in the Department of Hematology/Oncology, at Vanderbilt University Medical Center in Nashville, Tennessee, discussed a presentation she gave during the 2024 Vanderbilt Stem Cell Transplant and Cellular Therapy Symposium in May. During the presentation, Kitko outlined the current treatment landscape of pediatric and adult ALL, as well as unmet needs and future directions in the field.

OncLive: What were some of the key takeaways from the presentation you gave at the 2024 Vanderbilt Stem Cell Transplant and Cellular Therapy Symposium?

Kitko: [I discussed] the pivotal trials that led to the FDA approvals of tisa-cel for patients under the age of 26 and brexu-cel for adult patients. Those [agents] have been [approved] for a bit now, but it has been helpful that there’s more long-term follow-up for the ZUMA-3 trial looking at how durable remissions are and the differences in patient populations based on prior treatment or treatments received [following] CAR T-cell therapy.

What’s important with the pediatric population is the recognition that, unfortunately, a lot of the pharmaceutical companies have abandoned further trials of some of the other novel CAR T-cell products. We’re relying on real-world consortium data to try and tease out the different groups of patients who do better [as well as those] who are more or less likely to experience relapse post-treatment. [Also], how do we better tackle this toxicity profile?

What research is ongoing for patients with pediatric ALL?

We are hopeful that we can have more pharmaceutical interest in pediatric oncology, and there may be some hope on that horizon. A newer product, obecabtagene autoleucel [obe-cel], was developed in the UK and is now [being explored in] more global trials. It is a slightly different CAR construct; [although] the CAR still binds to CD19, which is what drives the anti-leukemia activity, it has a lower binding affinity meaning that it has fast-on, fast-off kinetics. We believe that may lead to increased T-cell persistence and less exhaustion of T cells, and it also seems to make the product potentially safer.

A product that we’re excited about potentially being able to see more of is WU-CART-007 in T-cell ALL. We’ve been talking a lot about B-cell, and that’s where a lot of work has been done, but T-cell ALL is very common in our adolescent and young adult patient populations. Luckily, work [from groups such as] the Children’s Oncology Group has found that very intensive chemotherapy can result in CR rates of approximately 90% and approximately a 70% chance of long-term cure.

However, when patients fall into that 30% where they’ve unfortunately relapsed, they are [in] a very high-risk group. Second remissions are extremely rare, and the long-term survival rate is approximately 10% to 15%. We’re desperate to find emerging therapies to help these patients and that’s where the trial [examining] WU-CART-007 potentially comes in.

This is an allogeneic CAR T-cell therapy and that is helpful because these patients tend to be quite sick, and it would be difficult to mobilize their own cells. [WU-CART-007] is an off-the-shelf product; you can use a healthy donor to manufacture these cells, and then do some CRISPR modification to decrease the chances of adverse effects. The T-cell receptor [is taken out] which will hopefully mitigate the risk of graft-vs-host disease by these allogeneic cells. CD7 [is also eliminated] which is a very common marker on T cell ALL; on the CAR T cells they get rid of CD7 so that they’re not killing off those cells that they’re trying to produce to treat the patient’s leukemia.

[Study authors] published results from a phase 1/2 [WU-CART-007 1001 (NCT04984356) trial] at the ASH Annual Meeting this past year, where several patients, including some pediatric patients as the trial went down to age 12, who had relapsed/refractory T-cell ALL or lymphoblastic lymphoma were treated. There were some encouraging results [showing] that these patients did seem to, at the highest dose that was then expanded into a phase 2 cohort, have significant responses. A few of these patients eventually [received] an allogeneic transplant for consolidation after achieving a CR. The study has since closed because [investigators] were so encouraged by those results that they’re designing a larger trial [and are] hoping to go for FDA approval [of WU-CART-007] if the follow-up study shows promising results.

What are some of the unmet needs in terms of the delivery of cellular therapies to patients with hematologic malignancies?

One of our biggest challenges is that these are expensive therapies and we’re trying to work closely with our managed care group to understand the urgency of patients and to be able to go directly up the chain as fast as possible with our insurance partners to get our patients approved to get therapy. This has been an ongoing project, [but] we’ve come to a better place where we’ve been able to streamline that process of not only getting the insurance company to say yes but agreeing to pay for the treatment as well because that’s critical.

What does the future hold for cellular therapy in ALL?

There are still some critical issues to be resolved. With the CD19-[directed CAR T-cell agents] since we have FDA-approved products, [we’re trying] to better understand who is the most likely to respond to these treatments, who is most likely to have long-term responses, and how to improve the toxicity profile. Those are essential questions to be answered to be able to deliver these treatments in the safest way possible and to provide that long-term cure that many patients and families are hoping for. There will be a combination of efforts to be able to answer those questions. A lot of that work will come from real-world consortium [studies], potentially even through groups like the Children’s Oncology Group.

References

  1. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA. August 30, 2017. Accessed May 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-b-cell-all-and-tocilizumab-cytokine-release-syndrome
  2. FDA approves brexucabtagene autoleucel for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. October 1, 2021. Accessed May 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-b-cell-precursor-acute-lymphoblastic
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