An anti-CAR19 idiotype chimeric antigen receptor (αCAR19) has been developed to help recognize CAR19-positive leukemia cells that are resistant to CAR T-cell (CAR-T) therapy, according to a new study. In addition, αCAR19 can be used as an “antidote” to deplete CD19 CAR-T cells to reduce long-term side effects.
According to the study, unintentional transduction of B-cell acute lymphoblastic leukemia (B-ALL) cells during CART19 manufacturing can lead to CAR19-positive leukemic cells that are resistant to CART19.
“Our group recently reported the extraordinary case of a pediatric B-ALL patient treated with CTL019 whose relapse blasts aberrantly expressed CAR19, the transgene intended for the T cells, due to unintentional transduction of a single leukemic cell with the CAR19 lentivirus during CTL019 manufacturing,” the researchers wrote. “This unique circumstance led to in cis binding between the CAR19 and CD19 on the cell surface, resulting in masking of the CD19 epitope and hence inability to be recognized by CART19 cells.”
Based on this, they hypothesized that targeting CAR19 on leukemic cells with CAR would be an effective and safe strategy to treat CAR19+ leukemias. To test this, the researchers developed a product to target CAR19+ cells: αCAR19.
In a luciferase-based killing assay, αCAR19-CART efficiently killed CAR19-expressing B-ALL, but not wild-type cell lines. In a mouse model, αCART19-CART resulted in significant leukemia control compared with CART19 and control T cells.
“Moreover, we demonstrated that this product could also serve as a depletion strategy for CAR19 T cells,” the researchers wrote. “CART19 depletion could thus be used in patients who were apparently cured of their underlying malignancy with CART19 and have prolonged B-cell aplasia and hypogammaglobulinemia due to the persistence of CART19 cells.”
Ruella M, Barrett DM, Shestova O, et al. A cellular antidote to specifically deplete anti-CD19 chimeric antigen receptor positive cells [published online November 8, 2019]. Blood. doi: 10.1182/blood.2019001859