LAUSR

Three article in this issue present preclinical data aimed at improving immunotherapeutic approaches for relapsed B- and T-cell acute lymphoblastic leukemia (T-ALL). Chimeric antigen receptor T (CAR-T) cell therapy directed against relapsed T-ALL is hampered by difficulty in identifying a target antigen that is not also expressed on healthy T cells, risking “fratricide” with T-cell aplasia and loss of the CAR-T cells. Maciocia and colleagues identify CCR9 as an antigen expressed on >85% of relapsed T-ALL and on <5% of normal T cells, demonstrating in cell lines and patient-derived xenografts that CAR-T cells targeting CCR9 have potent anti-leukemic activity without any evidence of fratricide. In the second article, Müller et al explore the potential of dual antibody targeting of CD47 and CD38 in a preclinical models of T-ALL; although CD47 does not avoid the risk of aplasia, it shows efficacy in combination with daratumumab in treating relapsed T-ALL and eradicating MRD. Finally, the third article addresses relapse following CD19-directed immunotherapies for B-ALL, which may be mediated by recurrence of CD19-negative leukemia. Bueno et al identify CD34+CD19−CD22+ cells in patients at diagnosis and relapse; they further show that CD22 expression precedes CD19 expression and that this population harbors the same genetic abnormalities of the B-ALL clone. They propose that this may represent a progenitor population that can give rise to B-ALL recurrence, supporting the use of combined CAR-T therapies, perhaps directed at both CD19 and CD22.