T cell exhaustion in pediatric B-ALL: current knowledge and future perspectives

Abstract

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy, accounting for 20-25% of all new cancer diagnoses in North American children each year. The leukemia arises, most commonly after a latency of 3-5 years, from a preleukemic B cell precursor population generated in utero. Despite the generally low immunogenicity of B-ALL cells, emerging evidence implicates T cell exhaustion - a state marked by sustained expression of inhibitory receptors and progressive functional decline - as a contributor to disease progression. Expression of inhibitory receptors is frequently detected on T cells from children with B-ALL at diagnosis and during therapy. As T cell exhaustion presents an actionable target for enhancing protective immune activity, in this review we summarize evidence from both clinical and pre-clinical settings for T cell exhaustion during pediatric B-ALL progression and discuss the opportunities and challenges to incorporating immune checkpoint blockade into pediatric B-ALL therapy regimens.

Keywords: T cell exhaustion (Tex); bispecific T cell engager (BiTE); chimeric antigen receptor (CAR T); immune checkpoint inhibition; pediatric B cell precursor acute lymphoblastic leukemia.

Figure 1

T cell exhaustion in pediatric B-cell acute lymphoblastic leukemia (B-ALL). Exhausted T cells can be detected and targeted at various timepoints during B-ALL progression: (A) Diagnosis: Exhausted T cells in bone marrow aspirates from patients at diagnosis express multiple inhibitory receptors such as PD-1,TIM-3 and CTLA-4, which impair T cell function. These receptors interact with their respective ligands expressed on leukemia blasts, contributing to immune evasion. (B) Remission: When leukemia burden is reduced to minimal residual disease (MRD) levels by induction chemoptherapy, there is an opportunity to restore anti-leukemia immunity. At this stage, immune checkpoint inhibitors - e.g. anti-PD-1 and anti-CTLA-4 antibodies (Abs) - may reinvigorate T cells, especially when combined with approved immunotherapies such as CD3/CD19 bispecific T cell engagers. (C) Relapse: CAR-T cells show an exhausted phenotype, characterized by high expression of inhibitory receptors including PD-1, TIM-3, LAG-3, and CTLA-4, at various times during production and application. ICB may enhance CAR-T functionality, but the optimal timing to achieve this remains to be determined. Abbreviations – Minimal residual disease (MRD); Bispecific T cell engager (BiTE); Chimeric antigen receptor (CAR); red blood cell (RBC); antibody (Ab).