Obe-cel Represents a Tolerable CAR T-cell Therapeutic Option in B-ALL

The role of CAR T-cell therapy in B-cell acute lymphoblastic leukemia (B-ALL) treatment sequencing is still being defined, with obecabtagene autoleucel (obe-cel), an investigative CAR T-cell product, entering the scene as an additional and comparatively tolerable option, according to Elias Jabbour, MD.

The phase 1b/2 FELIX trial (NCT04404660) is evaluating the efficacy and safety of obe-cel, a CD19-targeted CAR T-cell therapy, in adult patients with relapsed or refractory B-ALL. The phase 2 portion of this trial, which is currently ongoing, has primary end points of overall response rate and minimal residual disease (MRD) negativity.¹

“All patients with acute lymphoblastic leukemia [ALL] should be referred to [CAR T-cell centers] to be enrolled in clinical trials,” Jabbour said in an interview with OncLive^®.

In the interview, Jabbour discussed the current and emerging roles of CAR T-cell therapy in B-ALL, emphasized the importance of testing patients for MRD when determining CAR T-cell treatment strategies, and highlighted how obe-cel, with its favorable safety profile, may address unmet needs related to CAR T-cell toxicities.

Jabbour is a professor in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

OncLive^®: How have CAR T-cell therapies influenced the treatment paradigm in B-ALL?

Jabbour: CAR T cells are a great innovation in science. Essentially, we take patients’ T cells, engineer them, and send them back to attack the B cells. [We have seen] great success [with this approach] in lymphoma and myeloma. Now, in leukemias, we’re also seeing success. We have 2 CAR T-cell therapies approved for ALL, and hopefully soon, another [will be approved], [obe-cel, which is manufactured by] Autolus.

Those are good [options], but we can do better. CAR T-cell therapy [should not only be used] after [a patient fails] on multiple agents. We need to use CAR T-cell therapy earlier, rather than later, in minimal disease. One day, hopefully, [this approach will] replace frontline autologous transplant in high-risk patients.

[The innovation of] CAR T-cell therapy today is [akin to] what transplant used to be in the 1980s, and we have made huge progress since then. We can build on CAR T-cell therapy to improve it [by using] novel targets, [determining whether earlier-line use helps] handle safety concerns, and maybe [introducing] allogeneic CAR T cells or other approaches. This field is in evolution, and I’m confident the future is bright.

How does MRD testing factor into the CAR T decision-making process in B-ALL?

MRD is a surrogate for outcome. We cannot improve outcomes if we don’t allocate for MRD. For [treatment in] the frontline setting, MRD allocation is a must. In the lab setting, it’s important as well.

An example [of the importance of MRD testing] is how CAR T-cell therapy [behaves in the] MRD setting. Firstly, we know from [studies with] belantamab mafodotin-blmf [Blenrep] that its efficacy is higher in the MRD setting, and that should be the case in the CAR T-cell therapy setting, as well. CAR T-cell therapy should be used in the MRD setting, especially up front.

Secondly, [we need to determine whether to] use CAR T-cell therapy [with or without] transplant. The question is: Is CAR T-cell therapy a bridging therapy for transplant, or is it an effective therapy on its own? Data show that [patients who achieve] MRD negativity post–CAR T-cell therapy have promising outcomes, and [transplant is possible]. We can tailor our therapy sequencing based on MRD assessment. That’s how we use CAR T cells.

What differentiates obe-cel from other CAR T-cell therapies that have been under investigation?

The CAR T-cell therapies available today are associated with a high risk of complications, [including] cytokine release syndrome [CRS] and neurologic events. Obe-cel essentially has a low affinity to CD19, [resulting in] a lower rate of complications, mainly no CRS and minimal neurological effects. That makes it an appealing option to consider.

Efficacy-wise, I haven’t seen a difference in outcome between obe-cel and other available CAR T-cell products, but the safety profile is promising. We’re [currently conducting the FELIX] study and hope to get an approval for this [therapy].

What specific adverse effects (AEs) have been improved with obe-cel vs other CAR T-cell therapies?

With obe-cel, we did not see grade 3 and 4 CRS, and other AEs were transient. Neurotoxicities were also transient and [occurred at a] lower rate than what we see with other CAR T-cell products, which makes this option appealing. The future for obe-cel may be to use it in the MRD setting and earlier, rather than later, in the course of treatment.

What is the goal of the FELIX trial, and how might the findings from this study potentially affect the B-ALL treatment landscape?

[Prior to FELIX], the phase 1 [ALLCAR19 trial (NCT02935257) demonstrated the efficacy of obe-cel in ALL], and these results were published in the Journal of Clinical Oncology. The phase 2 [portion of the] FELIX study is looking at the efficacy and safety of obe-cel in ALL.

Based on this study, [Autolus] is going to apply for an FDA approval [of obe-cel] in the refractory setting. An expansion [of this trial is evaluating the agent in patients with MRD], and that portion of the study is ongoing, so we will see how it goes.

What other developing therapies in B-ALL are you intrigued by?

Immunotherapy in the frontline setting has been explored extensively. We will see several presentations on that topic at the [2022 ASH Annual Meeting and Exposition]. This will set the stage for blinatumomab [Blincyto] in the frontline setting. There is a subcutaneous blinatumomab as well, [which can be given in place of] continuous intravenous administration.

New CD22 antibodies are also being explored, and there are data in Philadelphia chromosome–positive ALL, where we used an immunotherapy approach plus TKIs, leading to improved outcomes.

What is the importance of referring patients with ALL to CAR T-cell therapy clinical trials to further investigate this treatment approach?

ALL is a rare disease. Patients should be referred to centers of excellence to be enrolled in clinical trials, whether for CAR T-cell therapy or other treatment options.

Reference

1. A study of C19 targeted CAR T cell therapy in adult patients with relapsed or refractory B cell acute lymphoblastic leukemia (ALL). ClinicalTrials.gov. Updated August 31, 2022. Accessed November 23, 2022. https://www.clinicaltrials.gov/ct2/show/NCT04404660