Chimeric antigen receptor T cells targeting CD79b show efficacy in lymphoma with or without co-targeting CD19

Maria Ormhøj, Irene Scarfò, Maria L Cabral, Stefanie R Bailey, Selena J Lorrey, Amanda A Bouffard, Ana P Castano, Rebecca C Larson, Lauren S Riley, Andrea Schmidts, Bryan D Choi, Rikke S Andersen, Oriane Cédile, Charlotte Guldborg Nyvold, Jacob Haaber, Morten F Gjerstorff, Henrik J Ditzel, David M Weinstock, Torben Barington, Matthew J Frigault & 1 andre Marcela V Maus

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

PURPOSE: T cells engineered to express a chimeric antigen receptor (CAR) against CD19 have recently been FDA-approved for the treatment of relapsed or refractory large B cell lymphoma. Despite the success and curative potential of CD19 CAR T cells, several reports describing disease relapse due to antigen loss are now emerging.

EXPERIMENTAL DESIGN: We developed a novel CAR construct directed against CD79b, a critical receptor for successful B cell development that remains highly expressed in several subtypes of B cell lymphoma, including mantle cell lymphoma (MCL). We tested CAR T cells directed against CD79b alone or in combination with CD19 targeting in a single construct, against cell line- and patient-derived xenograft models.

RESULTS: We demonstrate CAR79b antigen-specific recognition and cytotoxicity against a panel of cell lines and patient-derived xenograft models of MCL. Importantly, we show that downregulation of CD19 does not influence surface expression of CD79b and that anti-CD79b CAR T cells alone or arranged in a dual-targeting format with a CD19 single-chain variable fragment (scFv) are able to recognize and eliminate CD19-positive, CD19-negative, and mixed CD19+/CD19- B cell lymphoma.

CONCLUSIONS: Our findings demonstrate that CAR T cells targeting CD79b alone or in combination have promise for treating and preventing CD19 antigen escape in B cell lymphomas.

OriginalsprogEngelsk
TidsskriftClinical Cancer Research
ISSN1078-0432
DOI
StatusE-pub ahead of print - 22. aug. 2019

Fingeraftryk

Antigen Receptors
B-Cell Lymphoma
T-Cell Antigen Receptor
Lymphoma
CD19 Antigens
Mantle-Cell Lymphoma
Heterografts
Cell Line
Down-Regulation

Citer dette

Ormhøj, Maria ; Scarfò, Irene ; Cabral, Maria L ; Bailey, Stefanie R ; Lorrey, Selena J ; Bouffard, Amanda A ; Castano, Ana P ; Larson, Rebecca C ; Riley, Lauren S ; Schmidts, Andrea ; Choi, Bryan D ; Andersen, Rikke S ; Cédile, Oriane ; Nyvold, Charlotte Guldborg ; Haaber, Jacob ; Gjerstorff, Morten F ; Ditzel, Henrik J ; Weinstock, David M ; Barington, Torben ; Frigault, Matthew J ; Maus, Marcela V. / Chimeric antigen receptor T cells targeting CD79b show efficacy in lymphoma with or without co-targeting CD19. I: Clinical Cancer Research. 2019.
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title = "Chimeric antigen receptor T cells targeting CD79b show efficacy in lymphoma with or without co-targeting CD19",
abstract = "PURPOSE: T cells engineered to express a chimeric antigen receptor (CAR) against CD19 have recently been FDA-approved for the treatment of relapsed or refractory large B cell lymphoma. Despite the success and curative potential of CD19 CAR T cells, several reports describing disease relapse due to antigen loss are now emerging.EXPERIMENTAL DESIGN: We developed a novel CAR construct directed against CD79b, a critical receptor for successful B cell development that remains highly expressed in several subtypes of B cell lymphoma, including mantle cell lymphoma (MCL). We tested CAR T cells directed against CD79b alone or in combination with CD19 targeting in a single construct, against cell line- and patient-derived xenograft models.RESULTS: We demonstrate CAR79b antigen-specific recognition and cytotoxicity against a panel of cell lines and patient-derived xenograft models of MCL. Importantly, we show that downregulation of CD19 does not influence surface expression of CD79b and that anti-CD79b CAR T cells alone or arranged in a dual-targeting format with a CD19 single-chain variable fragment (scFv) are able to recognize and eliminate CD19-positive, CD19-negative, and mixed CD19+/CD19- B cell lymphoma.CONCLUSIONS: Our findings demonstrate that CAR T cells targeting CD79b alone or in combination have promise for treating and preventing CD19 antigen escape in B cell lymphomas.",
author = "Maria Ormh{\o}j and Irene Scarf{\`o} and Cabral, {Maria L} and Bailey, {Stefanie R} and Lorrey, {Selena J} and Bouffard, {Amanda A} and Castano, {Ana P} and Larson, {Rebecca C} and Riley, {Lauren S} and Andrea Schmidts and Choi, {Bryan D} and Andersen, {Rikke S} and Oriane C{\'e}dile and Nyvold, {Charlotte Guldborg} and Jacob Haaber and Gjerstorff, {Morten F} and Ditzel, {Henrik J} and Weinstock, {David M} and Torben Barington and Frigault, {Matthew J} and Maus, {Marcela V}",
note = "Copyright {\circledC}2019, American Association for Cancer Research.",
year = "2019",
month = "8",
day = "22",
doi = "10.1158/1078-0432.CCR-19-1337",
language = "English",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research (A A C R)",

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Ormhøj, M, Scarfò, I, Cabral, ML, Bailey, SR, Lorrey, SJ, Bouffard, AA, Castano, AP, Larson, RC, Riley, LS, Schmidts, A, Choi, BD, Andersen, RS, Cédile, O, Nyvold, CG, Haaber, J, Gjerstorff, MF, Ditzel, HJ, Weinstock, DM, Barington, T, Frigault, MJ & Maus, MV 2019, 'Chimeric antigen receptor T cells targeting CD79b show efficacy in lymphoma with or without co-targeting CD19', Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-19-1337

Chimeric antigen receptor T cells targeting CD79b show efficacy in lymphoma with or without co-targeting CD19. / Ormhøj, Maria; Scarfò, Irene; Cabral, Maria L; Bailey, Stefanie R; Lorrey, Selena J; Bouffard, Amanda A; Castano, Ana P; Larson, Rebecca C; Riley, Lauren S; Schmidts, Andrea; Choi, Bryan D; Andersen, Rikke S; Cédile, Oriane; Nyvold, Charlotte Guldborg; Haaber, Jacob; Gjerstorff, Morten F; Ditzel, Henrik J; Weinstock, David M; Barington, Torben; Frigault, Matthew J; Maus, Marcela V.

I: Clinical Cancer Research, 22.08.2019.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Chimeric antigen receptor T cells targeting CD79b show efficacy in lymphoma with or without co-targeting CD19

AU - Ormhøj, Maria

AU - Scarfò, Irene

AU - Cabral, Maria L

AU - Bailey, Stefanie R

AU - Lorrey, Selena J

AU - Bouffard, Amanda A

AU - Castano, Ana P

AU - Larson, Rebecca C

AU - Riley, Lauren S

AU - Schmidts, Andrea

AU - Choi, Bryan D

AU - Andersen, Rikke S

AU - Cédile, Oriane

AU - Nyvold, Charlotte Guldborg

AU - Haaber, Jacob

AU - Gjerstorff, Morten F

AU - Ditzel, Henrik J

AU - Weinstock, David M

AU - Barington, Torben

AU - Frigault, Matthew J

AU - Maus, Marcela V

N1 - Copyright ©2019, American Association for Cancer Research.

PY - 2019/8/22

Y1 - 2019/8/22

N2 - PURPOSE: T cells engineered to express a chimeric antigen receptor (CAR) against CD19 have recently been FDA-approved for the treatment of relapsed or refractory large B cell lymphoma. Despite the success and curative potential of CD19 CAR T cells, several reports describing disease relapse due to antigen loss are now emerging.EXPERIMENTAL DESIGN: We developed a novel CAR construct directed against CD79b, a critical receptor for successful B cell development that remains highly expressed in several subtypes of B cell lymphoma, including mantle cell lymphoma (MCL). We tested CAR T cells directed against CD79b alone or in combination with CD19 targeting in a single construct, against cell line- and patient-derived xenograft models.RESULTS: We demonstrate CAR79b antigen-specific recognition and cytotoxicity against a panel of cell lines and patient-derived xenograft models of MCL. Importantly, we show that downregulation of CD19 does not influence surface expression of CD79b and that anti-CD79b CAR T cells alone or arranged in a dual-targeting format with a CD19 single-chain variable fragment (scFv) are able to recognize and eliminate CD19-positive, CD19-negative, and mixed CD19+/CD19- B cell lymphoma.CONCLUSIONS: Our findings demonstrate that CAR T cells targeting CD79b alone or in combination have promise for treating and preventing CD19 antigen escape in B cell lymphomas.

AB - PURPOSE: T cells engineered to express a chimeric antigen receptor (CAR) against CD19 have recently been FDA-approved for the treatment of relapsed or refractory large B cell lymphoma. Despite the success and curative potential of CD19 CAR T cells, several reports describing disease relapse due to antigen loss are now emerging.EXPERIMENTAL DESIGN: We developed a novel CAR construct directed against CD79b, a critical receptor for successful B cell development that remains highly expressed in several subtypes of B cell lymphoma, including mantle cell lymphoma (MCL). We tested CAR T cells directed against CD79b alone or in combination with CD19 targeting in a single construct, against cell line- and patient-derived xenograft models.RESULTS: We demonstrate CAR79b antigen-specific recognition and cytotoxicity against a panel of cell lines and patient-derived xenograft models of MCL. Importantly, we show that downregulation of CD19 does not influence surface expression of CD79b and that anti-CD79b CAR T cells alone or arranged in a dual-targeting format with a CD19 single-chain variable fragment (scFv) are able to recognize and eliminate CD19-positive, CD19-negative, and mixed CD19+/CD19- B cell lymphoma.CONCLUSIONS: Our findings demonstrate that CAR T cells targeting CD79b alone or in combination have promise for treating and preventing CD19 antigen escape in B cell lymphomas.

U2 - 10.1158/1078-0432.CCR-19-1337

DO - 10.1158/1078-0432.CCR-19-1337

M3 - Journal article

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

ER -