Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia.

Abstract

We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19- relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach.

• Authors: Elena J Orlando, Xia Han, Catherine Tribouley, Patricia A Wood, Rebecca J Leary, Markus Riester, John E Levine, Muna Qayed, Stephan A Grupp, Michael Boyer, Barbara De Moerloose, Eneida R Nemecek, Henrique Bittencourt, Hidefumi Hiramatsu, Jochen Buechner, Stella M Davies, Michael R Verneris, Kevin Nguyen, Jennifer L Brogdon, Hans Bitter, Michael Morrissey, Piotr Pierog, Serafino Pantano, Jeffrey A Engelman, Wendy Winckler
• Journal: Nature medicine (Nat Med) Vol. 24 Issue 10 Pg. 1504-1506 (10 2018) ISSN: 1546-170X [Electronic] United States
• PMID: 30275569 (Publication Type: Journal Article)

Chemical References

• Antigens, CD19
• Receptors, Antigen, T-Cell
• Receptors, Chimeric Antigen

Topics

• Antigens, CD19 (genetics, immunology)
• Drug Resistance, Neoplasm (genetics)
• Humans
• Immunotherapy, Adoptive
• Loss of Heterozygosity (genetics)
• Mutation
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, immunology, pathology)
• Receptors, Antigen, T-Cell (genetics)
• Receptors, Chimeric Antigen (genetics, immunology, therapeutic use)
• T-Lymphocytes (immunology)