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

by Davies, Stella M. , Orlando, Elena J. , Riester, Markus , Morrissey, Michael , Boyer, Michael , Winckler, Wendy , Leary, Rebecca J. , Grupp, Stephan A. , Hiramatsu, Hidefumi , Buechner, Jochen , Engelman, Jeffrey A. , Qayed, Muna , Bitter, Hans , Pantano, Serafino , Nemecek, Eneida R. , Verneris, Michael R. , Han, Xia , Nguyen, Kevin , Pierog, Piotr , De Moerloose, Barbara , Bittencourt, Henrique , Tribouley, Catherine , Wood, Patricia A. , Levine, John E. , Brogdon, Jennifer L.

in 631/67/1059/2326 / 631/67/69 / 692/308/2779/109 / 692/699/67/1059/2325 / Acute lymphoblastic leukemia / Acute lymphocytic leukemia / Antigens / Antigens, CD19 - genetics / Antigens, CD19 - immunology / Antineoplastic agents / Automobiles / Biomedical and Life Sciences / Biomedicine / Brief Communication / Cancer Research / Cancer treatment / Care and treatment / CD19 antigen / Chimeric antigen receptors / Drug Resistance, Neoplasm - genetics / Gene mutation / Gene therapy / Genes / Genetic aspects / Heterozygosity / Humans / Immunotherapy, Adoptive / Infectious Diseases / Leukemia / Loss of heterozygosity / Loss of Heterozygosity - genetics / Lymphatic leukemia / Lymphocytic leukemia / Medical schools / Metabolic Diseases / Molecular Medicine / Mutation / Neurosciences / Pediatrics / 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 / Tumors

2018

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

2018

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

2018

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Journal Article

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

Davies, Stella M.,

Orlando, Elena J.,

Riester, Markus,

Morrissey, Michael,

Boyer, Michael,

Winckler, Wendy,

Leary, Rebecca J.,

Grupp, Stephan A.,

Hiramatsu, Hidefumi,

Buechner, Jochen,

Engelman, Jeffrey A.,

Qayed, Muna,

Bitter, Hans,

Pantano, Serafino,

Nemecek, Eneida R.,

Verneris, Michael R.,

Han, Xia,

Nguyen, Kevin,

Pierog, Piotr,

De Moerloose, Barbara,

Bittencourt, Henrique,

Tribouley, Catherine,

Wood, Patricia A.,

Levine, John E.,

Brogdon, Jennifer L.

2018

Overview

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. Mutations in the CD19 gene suggesting irreversible loss of its surface expression are identified in the majority of analyzed cases of CD19 – relapse in two clinical trials of pediatric ALL CD19 CAR T therapy, offering considerations for the rational choice of follow-up therapies.

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Publisher

Nature Publishing Group US,Nature Publishing Group

Subject

631/67/1059/2326

/ 631/67/69

/ 692/308/2779/109

/ 692/699/67/1059/2325

/ Acute lymphoblastic leukemia

/ Acute lymphocytic leukemia

/ Antigens