Gene-edited CAR T cells: going the distance in B-ALL Open Access

In this issue of Blood Advances, Guardo at al¹ present long-term data compiled from 2 small single-institution clinical trials (ClinicalTrials.gov identifiers: NCT02808442 and NCT04557436) and a compassionate use program, which treated 15 pediatric patients (ages 0.8-16.6 years) with B-acute lymphoblastic leukemia (B-ALL) using genome-edited allogeneic CD19-targeted chimeric antigen receptor (CAR) T cells.^2-4 Given the emerging interest in “universal” or “off-the-shelf” approaches to limit cost and improve access, this follow-up report provides a first glimpse into the longer-term safety and success with the use of gene-edited cellular therapy in children with B-ALL.

Concerns regarding the use of allogeneic or third-party donor T cells include the risk of inducing graft-versus-host disease (GVHD) and/or fostering immune rejection. By using either transcription activator-like effector nuclease (TALEN)–based strategies or clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, a 2-step process was used by Guardo et al to disrupt T-cell receptor αβ for GVHD prevention and incorporate CD52 knockout to facilitate the use of alemtuzumab (an anti-CD52 antibody) alongside fludarabine and cyclophosphamide, promoting the proliferation and persistence of CD52^– CAR T cells.

Eleven of 15 total patients achieved a post–CAR T-cell remission and proceeded to a planned allogeneic stem cell transplant (SCT). With a focus on immune reconstitution, post-SCT outcomes, and mature event-free (EFS) and overall survival for these 11 patients, outcomes were generally favorable, especially considering this highly pretreated cohort, the majority of whom had undergone prior SCT. Although all 3 patients with polymerase chain reaction–minimal residual disease (MRD) positivity and 1 patient in molecular remission relapsed, 6 remained disease-free at a median follow-up of 4 years (range, 2-10), leading to an EFS of 40%. Importantly, as Guardo et al point out, the long-term survivors had all received reduced-intensity conditioning (RIC) SCT, largely with antithymocyte globulin and low-dose total-body irradiation (TBI) in a second SCT setting. Additionally, no patient experienced severe (grade ≥3) or chronic GVHD of any degree. Although it is known that patients who maintain remission for at least 6 months after CAR T-cell therapy are much more likely to obtain cure,⁵ given the relative novelty of this allogeneic CAR T-cell approach followed by planned SCT, it is reassuring to see that late relapses did not occur in those who achieved a deep remission. Unfortunately, those with detectable MRD after CAR T cells could not be salvaged even with myeloablative conditioning, highlighting the ongoing unmet need to achieve remission before SCT.⁶ 

Viral reactivation, a notable complication of the up-front CAR T-cell treatment plan in the context of 3-agent lymphodepletion, was seen in 33% of all treated patients and included cytomegalovirus, adenovirus, and BK virus. One patient experienced transplant-related mortality due to BK virus and microangiopathy while in remission. Future strategies to optimize lymphodepletion in universal CAR T-cell platforms and/or more effective ways to prevent and treat viral reactivations/infections, such as viral cytotoxic T lymphocytes, will be imperative to advance this allogeneic approach more broadly. B-cell recovery, alongside other immune parameters, largely mirrored the anticipated time course for post-SCT recovery. Importantly, and because it relates to immune recovery, residual CAR T cells were not detected after SCT in any patient, regardless of conditioning type.

Collectively, this report highlights the translational success of gene-editing technologies (eg, TALENs and CRISPR) in achieving long-term cure in children with relapsed/refractory B-ALL.¹ Shifting away from the paradigm of highly personalized autologous cell therapeutics toward scalable, standardized biologics would advance the field, especially if the latter can induce comparable (or even superior) long-term outcomes. In this regard, the 40% EFS for a heavily pretreated patient population is notable, particularly in the context of an RIC-based second SCT. Moving this framework into an earlier time point in a patient’s treatment course, particularly for SCT-naïve patients who achieve a CAR T-cell–induced deep remission, may improve outcomes. Although the role of SCT after CAR T cells in B-ALL remains highly debated,⁷ and the desire to avoid SCT altogether cannot be dismissed, given that at least 50% of children receiving tisagenlecleucel will relapse, the role of SCT remains critical.^8,9 

Importantly, in the context of an allogeneic or “off-the-shelf” construct with limited persistence, the ability to effectively use an RIC regimen may offset the concerns for long-term SCT-associated toxicities while limiting concerns for antigen escape, potential complexities of persistence of gene-edited cells, and delayed immune reconstitution. One could hypothesize that sparing the toxicities of a TBI-containing myeloablative SCT regimen could improve long-term outcomes, including quality of life, fertility, risk of second cancers, and neurocognitive function, with this tandem gene-edited CAR T-cell infusion to RIC SCT approach. Larger studies with additional follow-up are needed, and this report is a first step in describing longer-term outcomes in B-ALL after innovative approaches in cell therapy. In examining the role of new gene-editing cell therapies for diseases outside of B-ALL, such as sickle cell disease and thalassemia, for which SCT is not necessarily indicated after cellular therapy, similar follow-up reports of the pivotal trials that led to regulatory approvals would be of great value to define the durability of efficacy and identify late-emerging side effects.

Conflict-of-interest disclosure: The authors declare no competing financial interests.