Chronic lymphocytic leukemia is an incurable B-cell
malignancy that is associated with
tumor cell-mediated T-cell dysfunction. It therefore represents a challenging disease for T-cell immunotherapeutics. The CD19/CD3 bi-specific antibody construct
blinatumomab (AMG103 or MT103) has been tested clinically in
non-Hodgkin's lymphoma and
acute lymphoblastic leukemia but has not been assessed in
chronic lymphocytic leukemia. We investigated whether
blinatumomab could overcome T-cell dysfunction in
chronic lymphocytic leukemia in vitro.
Blinatumomab was tested on peripheral blood mononuclear cells from 28 patients (treatment naïve and previously treated). T-cell activation and function, as well as cytotoxicity against leukemic
tumor cells were measured.
Blinatumomab induced T-cell activation, proliferation,
cytokine secretion and
granzyme B release in a manner similar to that occurring with stimulation with anti-CD3/anti-CD28 beads. However, only
blinatumomab was able to induce
tumor cell death and this was found to require
blinatumomab-mediated conjugate formation between T cells and
tumor cells. Cytotoxicity of
tumor cells was observed at very low T-cell:
tumor cell ratios. A three-dimensional model based on confocal microscopy suggested that up to 11
tumor cells could cluster round each T cell. Importantly,
blinatumomab induced cytotoxicity against
tumor cells in samples from both treatment-naïve and treated patients, and in the presence of co-culture pro-survival signals. The potent cytotoxic action of
blinatumomab on
tumor cells appears to involve conjugation of T cells with
tumor cells at both the activation and effector stages. The efficacy of
blinatumomab in vitro suggests that the bi-specific antibody approach may be a powerful immunotherapeutic strategy in
chronic lymphocytic leukemia.