Correlation between increased immune checkpoint molecule expression and refractoriness to blinatumomab evaluated by longitudinal T cell analysis

Abstract

Blinatumomab enhances survival in patients with B-cell precursor acute lymphoblastic leukemia (B-ALL) by inducing T cell activation. However, approximately 50% of patients with relapsed or refractory B-ALL do not respond to blinatumomab, and the correlation between T cell phenotype and blinatumomab response remains unclear. To assess this correlation, we longitudinally compared immune checkpoint molecules in T cells before and during blinatumomab treatment between a responder and non-responder. In the responder, the expression level of granzyme B increased following infusion of blinatumomab and complete remission was achieved. On the other hand, the non-responder consistently expressed higher levels of programmed death-1 (PD-1), T cell immunoglobulin and mucin domain 3 (Tim-3), and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) in CD8\u2009+\u2009T cells than the responder during blinatumomab treatment and showed no response despite the addition of two donor lymphocyte infusions. Furthermore, the residual tumors in bone marrow after blinatumomab treatment showed increased expression of immune checkpoint ligands: PD-L1 (PD-1 ligand), Galectin-9 (Tim-3 ligand), PD-L2 (PD-1 ligand) and CD155 (TIGIT ligand). In conclusion, immune checkpoint molecule levels could correlate with response to blinatumomab.