Optimizing CAR T-cell therapy for adult patients with R/R B-ALL

Chimeric antigen receptor (CAR) T-cell therapies can significantly improve outcomes for patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL).¹ Two CAR T-cell therapies, tisagenleucel and brexucabragene autoleucel, are approved by the U.S. Food and Drug Administration (FDA) for the treatment of this patient population¹; however, while CAR T-cell therapy is associated with high response rates in B-ALL, remission durability can be limited.¹ The burden of CAR T-cell toxicity can further limit the use of these therapies.¹

Here we summarize a review published by Agrawal et al.¹ in European Journal of Hematology discussing factors associated with CAR T-cell therapy outcomes in adult patients with R/R B-ALL and strategies to optimize the use of this therapy.

Clinical data¹

Several clinical studies have demonstrated the efficacy of CD19-directed CAR T-cell therapies in patients with R/R B-ALL, including the ELIANA, ZUMA-3, and FELIX trials.

Factors influencing CAR T-cell therapy response¹

There are several patient and disease factors influencing CAR T-cell activity that can be used to inform strategies for optimization.

• The type of co-stimulatory signal domain used may impact response duration.
  • CD28 co-stimulation is associated with rapid expansion but a lack of persistence vs 4-1BB co-stimulation.
  • 4-1BB co-stimulation may be preferred in patients when no allogeneic hematopoietic stem cell transplantation (allo-HSCT) consolidation is planned.
• Clinical studies have indicated that T-cell immunophenotype may impact CAR T-cell persistence, expansion, and long-term activity; further investigation could improve CAR T-cell outcomes.
• Prior CD19-directed salvage therapy may affect outcomes after subsequent CD19-directed CAR T-cell therapy, and response to prior therapy could identify patients who are resistant to CD19-directed therapies.
  • Immediate blinatumomab salvage therapy is not recommended for patients proceeding to CAR-T cell therapy.
• Several studies have suggested that high disease burden at lymphodepletion reduces CAR T-cell response and remission durability.
• While the impact of high-risk genetics on CAR T-cell therapy response overall is unclear, KMT2A rearrangements are associated with a higher incidence of myeloid lineage switch, patients with TP53 mutations have lower complete remission rates and inferior outcomes, and genetic alterations affecting IKZF1 are associated with poor response.

Consolidation¹

• Early loss of B-cell aplasia and measurable residual disease detected by next-generation sequencing can identify patients with increased risk of relapse following CAR T-cell therapy.
• Compared with pediatric patients, the durability of response to CAR T-cell therapy for adult patients is poor, particularly when not consolidated with allo-HSCT.
  • Patients with a high risk of relapse should be considered for allo-HSCT.
• CAR-T cell therapy is typically the preferred salvage option for patients experiencing relapse after allo-HSCT.
  • Effective bridging to CAR T-cell therapy and vigilant post-CAR T-cell surveillance is necessary to achieve durable responses; second allo-HSCT can be considered for fit patients with a high risk of relapse.

Toxicity¹

CAR T-cell toxicities include off-tumor effects, such as B-cell aplasia and hypogammaglobulinemia; myelosuppression; and immune-mediated effects, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome.

• Disease burden at lymphodepletion is predictive of the risk of severe cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome.
• Studies are ongoing to determine the potential of tocilizumab used earlier in treatment,  steroids to manage immune-mediated effects, and whether fractioned dosing of CAR T-cells can reduce toxicity while maintaining response rates.
• The CD19-directed antibody’s affinity may also affect the toxicity profile.

Relapse post CAR T-cell therapy¹

• Relapse following CD19-direct CAR T-cell therapy can be categorized as either CD19-positive relapse (70–80% of cases) or CD19-negative relapse (20–30% of cases).
• CD19-positive relapse is associated with a loss of CAR T-cell persistence and decreased CD19 antigen density.
  • Several studies have investigated strategies to optimize the CAR T-cell construct to reduce the risk of CD19-positive relapse.
• CD19-negative relapse occurs due to leukemic cells evading CAR T-cell therapies and is associated with a worse prognosis vs CD19-positive relapse.
  • Other leukemic targets, such as the CD22 antigen, and the targeting of multiple antigens have been investigated to overcome relapse.

Challenges associated with access to CAR T-cell therapies¹

• Barriers to access, such as insurance authorization and transferring to CAR-specialized centers, can delay therapy.
• Manufacturing times for CAR T-cell therapies (estimated 12–20 days) can result in high dropout rates due to progression and complications.
  • Off-the-shelf allogenic CAR platforms and rapid CAR manufacturing are being explored to combat dropout rates.

Key learnings

Risk factors found to be associated with CAR T-cell therapy outcomes include disease burden, leukemia cytogenetics, costimulatory domain, early referral to CAR T-cell center, and long manufacturing times.  Several strategies are currently being investigated to improve CAR T-cell outcomes, including consolidation with allo-HSCT to prevent relapse in high-risk patients, multitargeted CARs to overcome immune escape, and the development of new CAR designs to improve persistence.