Immunotargeting relapsed or refractory precursor B-cell acute lymphoblastic leukemia - role of blinatumomab

Abstract

Patients with refractory or relapsed (R/R) acute lymphoblastic leukemia (ALL) have a dismal prognosis of around 5% long-term survival when treated with cytotoxic chemotherapy and allogenic stem cell transplantation. T-cell immunobased strategies open up new therapeutic perspectives. Blinatumomab is the first of a new class of antibody constructs that was labeled bispecific T-cell engager (BiTE): it consists of two single chain variable fragment connected with a flexible linker, one side binding CD3, the other CD19. The tight binding and the close proximity to the CD19-positive B-cells and leukemic cells leads to non-major histocompatibility complex-restricted T-cell activation, polyclonal T-cell expansion and direct target cell killing. Applied by continuous infusion, blinatumomab achieves morphological complete response rates ranging from 39% to 69% in R/R ALL patients (compared to 25% after second-line chemotherapy) with prolonged overall survival (blinatumomab median overall survival, 7.7 months vs chemotherapy, 4.0 months). In comparison to conventional cytotoxic second-line protocols blinatumomab has a favorable safety profile. The main adverse event is related to the mode of action of blinatumomab: the induction of a cytokine-release syndrome that can be managed by interruption and/or the application of steroids or tocilizumab. Another typical complication is the occurrence of neurological side effects, such as seizures and encephalopathy. This neurotoxicity is reversible after application of steroids and/or withdrawal of blinatumomab. Blinatumomab has proven to be a powerful therapeutic option in R/R ALL patients both adult and pediatric because of its efficacy and limited toxicity.

Keywords: R/R precursor B-cell ALL; T-cell; blinatumomab; immunotherapy.

Figure 1

Blinatumomab: structure and mode of action. Notes: (A) Blinatumomab contains the variable domains (V_H and V_L) of two different IgG molecules. It is constructed out of two scFv, each formed by a pair of the V_H and V_L from two IgG molecules binding CD3 and CD19. The two scFv proteins are connected with a flexible, nonimmunogenic linker made of 25 amino acids. (B) Blinatumomab in the presence of CD3- and CD19-positive cells leads to a very close linkage with multiple connections between the two different cell types. This close contact zone forms a cytolytic synapse mediating TCR activation: granzymes and perforin are exocytosed into the CD19 positive target cell inducing its apoptosis. Abbreviations: scFv, single chain variable fragment; TCR, T-cell receptor.

Figure 2

PD-L1 expression is a possible escape mechanism for the action of blinatumomab. Notes: (A) An in vitro study observed a higher expression of the T-cell exhaustion marker PD-1 in ALL patients compared to healthy controls. PD-1/PD-L1-mediated T-cell suppression could lead to resistance to blinatumomab therapy. (B) With the simultaneous application of a specific PD-1 inhibitor, the PD-1/PD-L1-mediated T-cell suppression could be abrogated restoring the activity of blinatumomab. Abbreviation: ALL, acute lymphoblastic leukemia.