B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by impaired B-cell maturation and poor prognosis in relapsed/refractory (R/R) cases. While CD20-targeted immunotherapies offer clinical benefit, their efficacy is limited by low and heterogeneous CD20 expression on BCP-ALL cells. In this study, we demonstrate that overexpression of wild-type IKZF1, a tumor suppressor frequently mutated in high-risk BCP-ALL, upregulates CD20 and promotes leukemic B cell maturation. Using a transcriptional mimicry approach, we identified mTORC1 inhibitors as compounds showing similarity to selected IKZF1-induced transcriptional signatures, including convergence on B-cell maturation and induction of CD20 expression both in vitro and in vivo. mTORC1 inhibition enhanced the antitumor efficacy of anti-CD20 monoclonal antibodies and promoted B-lineage antigen expression, while downregulating immature markers. Mechanistically, CD20 upregulation was mediated via the AKT-FOXO1 axis, with AKT phosphorylation being essential for this effect. Importantly, this phenotypic shift was observed in BCP-ALL models with IKZF1 deletions, highlighting the relevance to high-risk disease. Our findings support the use of mTORC1 inhibitors to sensitize BCP-ALL cells to CD20-directed immunotherapies and provide a strong rationale for their clinical evaluation as adjuncts to anti-CD20 immunotherapy in BCP-ALL.
CD19-CAR-T cells are a major therapy for relapsed/refractory B-cell malignancies, yet ~50% of patients relapse after infusion. Clinical data suggest that tisa-cel treatment is associated with higher rates of CD19 mutation than axi-cel, though direct comparisons have been lacking. Although both products target the FMC63 epitope, they employ different structures of hinge/transmembrane/costimulatory domains (CD8α/CD8α/4-1BB in tisa-cel, CD28/CD28/CD28 in axi-cel). Here, we show that CAR structure is a critical determinant of CD19 loss in tumor B cells. Specifically, repeated exposure to CD19-4-1BB-based CAR-T cells, but not CD19-CD28-based counterparts, drives FMC63-epitope and total CD19 protein loss. Consistent with clinical observations, resistance to CD19-4-1BB-based treatment is associated with aberrant splicing, loss of heterozygosity, and frameshift/missense mutations in CD19 in exons encoding the FMC63 epitope. Mathematical modeling indicates that the failure of CD19-4-1BB-based CAR-T cells to eliminate CD19low cells, unlike CD28-based CARs, promotes the expansion of resistant populations. These results suggest that optimizing recognition of CD19low cells could prevent the emergence of resistant clones and reduce relapse rates. We also show that commonly used diagnostic anti-CD19 monoclonal antibodies detect epitopes distinct from FMC63 and may therefore give misleading CD19-positive results, underscoring the need for FMC63-specific assessment to guide diagnostic and therapeutic decisions.
Marta Krawczyk, K. Fidyt, Narcís Fernandez-Fuentes et al.· Leukemia· 0 citations
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