Improving CAR T cell immunotherapy-mediated remissions for pediatric leukemia

Abstract

Chimeric antigen receptor (CAR) T cells are an effective therapy for relapsed or refractory pediatric B cell leukemia. Analysis of the starting material, the T cells collected from the patient prior to CAR manufacture, reveals possible biomarkers of cells destined to perform poorly in patients. Long-term follow-up shows that long periods of B cell aplasia, a marker of in vivo CAR activity, are associated with longer remission but also a higher chance of antigen-negative relapse. The role of transplantation as consolidative therapy is unclear in this nonrandomized data, but clearly warrants further study.

Figure 1. Model of the factors influencing CAR T cell response and persistence.

T cell intrinsic factors including the CD4/CD8 ratio, memory phenotype, expression of exhaustion markers, and metabolic profile can inform how the cells are supported in the lab during CAR manufacture. Standard assessments of CAR T cell function such as cytokine release and polyfunctional index will be important for comparison across trials. Leukemia intrinsic factors such as driver lesion (cytogenetic, fusion, or mutation), preexisting antigen-low clones, and overall antigen burden will inform relapse risk. After infusion, patient monitoring with CAR T cell proliferation area under the curve (AUC), duration of BCA, and assessment with ultrasensitive next-generation sequencing (NGS) MRD will inform the ultimate decision for post–CAR consolidation, such as use of allogeneic transplantation.