CD127-directed immunotherapy outperforms Imatinib in preclinical ABL-class fusion+ BCP-ALL via a dual mode of action

ABL-class fusion-positive (ABL-fusion+) B-cell precursor (BCP-)ALL is treated with chemotherapy and tyrosine kinase inhibitors such as Imatinib (Ima), a combination that can cause severe toxicity. We recently showed potent preclinical efficacy of CD127-directed immunotherapy (CD127-IT) in ALL. Hence, we preclinically evaluated CD127-IT in combination with Ima in ABL-fusion+ BCP-ALL. Ima enhanced CD127 expression in ABL-class fusion+ cell lines and patient-derived xenograft (PDX) samples. Both Ima and CD127-IT induced macrophage-mediated phagocytosis as single agents, which was enhanced in combination. Ima and CD127-IT abrogated BCR-ABL1- and IL-7-mediated STAT5 induction, with strongest impact on the pathway upon combi-treatment. In a phase II-like PDX-trial, CD127-IT was effective in 7/7 PDX-samples in vivo and outperformed the effect of Ima alone. CD127-IT was more effective when combined with Ima as compared to CD127-IT alone. Mechanistically, downregulation of the “don’t eat me” signal CD47 could be demonstrated by RNA sequencing analyses. Our data shows preclinical efficacy of CD127-IT plus Ima via phagocytosis induction and CD127-signaling blockade in ABL-fusion+ ALL.

Publication History

Article published online:
09 May 2025