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

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 transmemb...

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Published inNature medicine Vol. 24; no. 10; pp. 1504 - 1506
Main Authors Orlando, Elena J, Han, Xia, Tribouley, Catherine, Wood, Patricia A, Leary, Rebecca J, Riester, Markus, Levine, John E, Qayed, Muna, Grupp, Stephan A, Boyer, Michael, De Moerloose, Barbara, Nemecek, Eneida R, Bittencourt, Henrique, Hiramatsu, Hidefumi, Buechner, Jochen, Davies, Stella M, Verneris, Michael R, Nguyen, Kevin, Brogdon, Jennifer L, Bitter, Hans, Morrissey, Michael, Pierog, Piotr, Pantano, Serafino, Engelman, Jeffrey A, Winckler, Wendy
Format Journal Article
LanguageEnglish
Published United States Nature Publishing Group 01.10.2018
Subjects
Acute lymphoblastic leukemia
Antigens
Antigens, CD19 - genetics
Antigens, CD19 - immunology
CD19 antigen
Chimeric antigen receptors
Drug Resistance, Neoplasm - genetics
Heterozygosity
Humans
Immunotherapy, Adoptive
Leukemia
Loss of heterozygosity
Loss of Heterozygosity - genetics
Lymphatic leukemia
Mutation
Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology
Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology
Proteins
Receptors, Antigen, T-Cell - genetics
Receptors, Chimeric Antigen - genetics
Receptors, Chimeric Antigen - immunology
Receptors, Chimeric Antigen - therapeutic use
T-Lymphocytes - immunology
Therapy
Tumor cells
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ISSN1078-8956
1546-170X
DOI10.1038/s41591-018-0146-z

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Summary: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.
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ISSN:1078-8956
1546-170X
DOI:10.1038/s41591-018-0146-z