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Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19


Date: 7th October 2019 | Source: Leukemia

Authors: Mukta Asnani, Katharina E. Hayer, Ammar S. Naqvi, Sisi Zheng, Scarlett Y. Yang, Derek Oldridge, Fadia Ibrahim, Manolis Maragkakis, Matthew R. Gazzara, Kathryn L. Black, Asen Bagashev, Deanne Taylor, Zissimos Mourelatos, Stephan A. Grupp, David Barrett, John M. Maris, Elena Sotillo, Yoseph Barash, Andrei Thomas-Tikhonenko.

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.

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