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

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

doi:10.1038/s41591-018-0146-z

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

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 BitterMichael Morrissey, Piotr Pierog, Serafino Pantano, Jeffrey A. Engelman, Wendy Winckler

Research output: Contribution to journal › Article › peer-review

374 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1504-1506
Number of pages	3
Journal	Nature medicine
Volume	24
Issue number	10
DOIs	https://doi.org/10.1038/s41591-018-0146-z
State	Published - Oct 1 2018

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Orlando, E. J., Han, X., Tribouley, C., Wood, P. A., Leary, R. J., Riester, M., Levine, J. E., Qayed, M., Grupp, S. A., Boyer, M., De Moerloose, B., Nemecek, E. R., Bittencourt, H., Hiramatsu, H., Buechner, J., Davies, S. M., Verneris, M. R., Nguyen, K., Brogdon, J. L., ... Winckler, W. (2018). Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nature medicine, 24(10), 1504-1506. https://doi.org/10.1038/s41591-018-0146-z

Orlando, EJ, Han, X, Tribouley, C, Wood, PA, Leary, RJ, Riester, M, Levine, JE, Qayed, M, Grupp, SA, Boyer, M, De Moerloose, B, Nemecek, ER, Bittencourt, H, Hiramatsu, H, Buechner, J, Davies, SM, Verneris, MR, Nguyen, K, Brogdon, JL, Bitter, H, Morrissey, M, Pierog, P, Pantano, S, Engelman, JA & Winckler, W 2018, 'Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia', Nature medicine, vol. 24, no. 10, pp. 1504-1506. https://doi.org/10.1038/s41591-018-0146-z

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title = "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.",

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

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doi = "10.1038/s41591-018-0146-z",

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AU - Orlando, Elena J.

AU - Han, Xia

AU - Tribouley, Catherine

AU - Wood, Patricia A.

AU - Leary, Rebecca J.

AU - Riester, Markus

AU - Levine, John E.

AU - Qayed, Muna

AU - Grupp, Stephan A.

AU - Boyer, Michael

AU - De Moerloose, Barbara

AU - Nemecek, Eneida R.

AU - Bittencourt, Henrique

AU - Hiramatsu, Hidefumi

AU - Buechner, Jochen

AU - Davies, Stella M.

AU - Verneris, Michael R.

AU - Nguyen, Kevin

AU - Brogdon, Jennifer L.

AU - Bitter, Hans

AU - Morrissey, Michael

AU - Pierog, Piotr

AU - Pantano, Serafino

AU - Engelman, Jeffrey A.

AU - Winckler, Wendy

PY - 2018/10/1

Y1 - 2018/10/1

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

Abstract

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