Molecular and cellular features of blinatumomab non-response in pediatric B-cell acute lymphoblastic leukemia

B-cell acute lymphoblastic leukemia (BCP-ALL) is the most common cancer in children and is characterized by uncontrolled division of immature B-cells in the bone marrow. The cure rate exceeds 90% thanks to intensive chemotherapy regimens lasting at least two years. A promising new therapy is the immunotherapy blinatumomab, which simultaneously binds to an immune cell, called T-cell, and to a leukemic cell, enabling the T-cells to recognize and destroy the leukemic cells. The use of blinatumomab in newly diagnosed patients could reduce the need for additional chemotherapy and, consequently, the associated side effects. However, it is still unknown how well blinatumomab works in children during the first weeks of treatment.
In this dissertation, we conducted laboratory tests to determine the response of patient samples to blinatumomab. These samples were obtained from the bone marrow of children at the time of their initial diagnosis. Our study demonstrates that the majority of patient samples appear to be unresponsive to blinatumomab at the time of initial diagnosis. However, when T-cells from these patients were stimulated in the laboratory, these patient samples mostly became sensitive to blinatumomab. This suggests that at the time of diagnosis the leukemia cells can actively suppress T cells (known as immunosuppression). This also means that blinatumomab should not be administered at the time of initial diagnosis when there are large numbers of leukemia cells present that could suppress the function of the T cells. T-cell function recovered after a few weeks of chemotherapy had been administered and most of the leukemia cells had disappeared. In a small proportion of samples, leukemia cells remained resistant to blinatumomab, even after T-cell stimulation or chemotherapy. The leukemia cells of these patients appear intrinsically resistant to blinatumomab. It is clinically important to identify characteristics that can predict which patients are intrinsically resistant to blinatumomab, because in this group of patients, blinatumomab is unlikely to be effective, even after several weeks of chemotherapy. Notably, there was unexpected resistance to blinatumomab in a subtype of BCP-ALL known for excellent outcomes with chemotherapy. This demonstrates that factors predicting treatment efficacy may differ between immunotherapy and chemotherapy. Our research now provides the opportunity to identify new factors that may predict sensitivity or resistance to blinatumomab.