Blinatumomab, a bispecific antibody that directs CD3+ T cells to CD19+ tumor cells shows variable efficacy in B-progenitor acute lymphoblastic leukemia (B-ALL). Researchers at St. Jude have identified a potential biomarker for predicting/understanding the reason for when there is poor response to this therapy. They studied a cohort of relapsed/refractory patients treated with blinatumomab using approaches to examine genomic features of the tumor cells (whole genome sequencing, transcriptome sequencing) and the tumor microenvironment (10X single cell sequencing), and identified a high frequency of CD19 mutations in patients that are CD19 negative at the time of relapse (CD19 is the target of blinatumomab). In addition, they identified an association between elevated levels of a CD19 exon 2 intra-exonic splice variant (CD19 exon2del) and poor response – either as elevated levels prior to treatment, or rising levels following treatment in poor responders. Exon 2 encodes at least part of the epitope to which blinatumomab is directed.
The researchers demonstrated both tumor intrinsic and extrinsic factors influence blinatumomab response, and that CD19 mutations are commonly detected in CD19-negative relapse during blinatumomab treatment. They identified the CD19 ex2part splice variant represents a new biomarker predictive of failure to blinatumomab therapy, and that multiple mechanisms of acquired CD19 mutations contribute to CD19 loss and relapse to blinatumomab.
Blinatumomab, antibody, CD3+ T cells, CD19+ tumor cells, B-progenitor acute lymphoblastic leukemia (B-ALL), biomarker, poor response, mutations, CD19 ex2part splice variant.
Granted Patents or Published Applications
An international PCT patent application is pending.
Related Scientific References
Mulligan et al., “Tumor intrinsic and extrinsic determinants of response to blinatumomab in adults with B-ALL,” Blood. 2020006287. https://doi.org/10.1182/blood.2020006287
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