T-cell dysfunction during blinatumomab therapy in pediatric acute lymphoblastic leukemia
Despite the high response rate to the T-cell engager blinatumomab in B-cell acute lymphoblastic leukemia (B-ALL), maintaining persistent efficacy is a challenge. Limited data from adults with relapsed B-ALL and high disease burden suggest T-cell dysfunction with continuous blinatumomab treatment contributes to loss of response; T-cell function in patients with low disease burden or pediatric B-ALL are uncharacterized. Given the recent adoption of blinatumomab in frontline post-remission pediatric B-ALL therapy and the existence of age and leukemia burden-related immune differences, a comprehensive assessment of T-cells is needed to inform optimal continuous treatment duration. Hence, we assessed T-cell function and phenotype during a 28-day continuous intravenous blinatumomab cycle in a pediatric leukemia cohort of 11 patients aged 1-21 years; 8 received blinatumomab in minimal residual disease-negative first remission. By day 14, T-cells exhibited impairments in cytotoxicity (baseline, day 14, day 28 = 72%, 56%, 54%; p = 0.008), IFN-? production (p = 0.0004), and T-cell receptor (TCR) signaling (mTOR and MEK) that persisted through day 28. The frequency of stem cell memory T-cells declined (p = 0.0004) while those of terminally differentiated (p = 0.012) and TIM3+ (p < 0.0001) cells were elevated at day 14. T-cells at day 14 were marked by exhaustion and terminal differentiation transcriptional signatures; genes encoding inhibitory receptors and negative regulators of TCR signaling were upregulated. Overall, multimodal T-cell dysfunction occurs by day 14. These findings could inform studies to optimize cycle duration and reveal candidate targets for functional studies aimed at ameliorating T-cell dysfunction. Overall design: RNA-Seq profiling of T-cells prior to and on days 14 and 28 days of continuous intravenous blinatumomab