Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19Publication
Date: 7th October 2019 | Source: Leukemia
Every successful cancer therapy story has Exhibit B, comprised of patients who either did not respond to the initial treatment or acquired resistance after a seemingly curative intervention. The CD19-directed chimeric antigen receptor-armed T-cell therapy (commonly known as CART-19) is the case in point. Although it has revolutionized treatment for B-cell acute lymphoblastic leukemia (B-ALL) in children and adults and gained swift FDA approval, ~30% of patients relapse after complete responses, most often via the loss of the cognate CD19 epitope.
Under selective pressure of CART-19 some of MLL-rearranged B-ALL have the propensity to trans-differentiate into myeloid lineages with concomitant loss of CD19 expression. Transport of CD19 to the plasma membrane is another potentially vulnerable process requiring the dedicated CD81 chaperone; and dysregulation of this gene was reported to contribute to resistance to another CD19-targeted immunotherapeutic blinatumumab. Still, focal alterations of the CD19 gene and its transcript appear to play central role in resistance.