The Role for Immunotherapy in Childhood Acute Lymphoblastic Leukemia

Immunotherapy represents a breakthrough in the management of children with acute lymphoblastic leukemia (ALL). Thanks to the ability of inducing complete responses in a significant proportion of patients with an improved safety profile as compared to intensive chemotherapy regimens, immunotherapy provides an innovative and concrete option for the management of relapsed/refractory and/or frail patients. For patients with B-ALL, the bispecific T-cell engager blinatumomab, targeting simultaneously the CD3 molecule on T cell and the CD19 antigen on leukemia blasts; the antibody–drug conjugate inotuzumab, targeting CD22 and delivering the toxic compound calicheamicin in the blasts; and the more advanced approach of engineering T cells to express a chimeric antigen receptor (CAR) directed toward CD19 all led to remarkable results and are now being tested into frontline and first-relapse settings. In addition, new CAR constructs and platforms are under development to overcome the limitations of the approach, including bispecific CAR molecules, able to target two tumor antigens simultaneously, or allogeneic CAR T cells. The latter can be developed either by transducing T cells obtained directly by the transplant donor of the patient (donor-derived) or through the gene editing of T cells able to generate a universal, off-the-shelf product. For the treatment of T-ALL, the scenario has been more challenging since several specific hurdles still need to be overcome, including the lack of tumor-specific surface antigen (with the subsequent risk of T-cell aplasia), and for CAR T cells, the risk of transducing blasts and the occurrence of fratricide. The combination of the monoclonal antibody targeting CD38 daratumumab with a standard four-drug re-induction has recently shown promising results for relapsed/refractory patients. The development and clinical testing of CAR T cells, mostly targeting the CD7 antigen, has recently shown encouraging preclinical and clinical results, suggesting the possibility of a new powerful tool to induce remission of relapsed/refractory T-ALL patients.