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@article{1813004,
author = {Ledererová, Aneta and Dostálová, Lenka and Kozlová, Veronika and Peschelová, Helena and Ladungová, Adriana and Čulen, Martin and Loja, Tomáš and Verner, Jan and Pospíšilová, Šárka and Šmída, Michal and Mančíková, Veronika},
article_location = {Switzerland},
article_number = {8},
doi = {http://dx.doi.org/10.1136/jitc-2021-002352},
keywords = {antigens; B-lymphocytes; hematologic neoplasms; receptors; chimeric antigen; translational medical research},
language = {eng},
issn = {2051-1426},
journal = {Journal for ImmunoTherapy of Cancer},
title = {Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro},
url = {https://jitc.bmj.com/content/9/8/e002352},
volume = {9},
year = {2021}
}
TY - JOUR
ID - 1813004
AU - Ledererová, Aneta - Dostálová, Lenka - Kozlová, Veronika - Peschelová, Helena - Ladungová, Adriana - Čulen, Martin - Loja, Tomáš - Verner, Jan - Pospíšilová, Šárka - Šmída, Michal - Mančíková, Veronika
PY - 2021
TI - Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro
JF - Journal for ImmunoTherapy of Cancer
VL - 9
IS - 8
SP - 1-8
EP - 1-8
PB - Springer International Publishing AG
SN - 20511426
KW - antigens
KW - B-lymphocytes
KW - hematologic neoplasms
KW - receptors
KW - chimeric antigen
KW - translational medical research
UR - https://jitc.bmj.com/content/9/8/e002352
N2 - Background Anti-CD19 chimeric antigen receptor T cells (CART-19) frequently induce remissions in hemato-oncological patients with recurred and/or refractory B-cell tumors. However, malignant cells sometimes escape the immunotherapeutic targeting by CD19 gene mutations, alternative splicing or lineage switch, commonly causing lack of CD19 expression on the surface of neoplastic cells. We assumed that, in addition to the known mechanisms, other means could act on CD19 to drive antigen-negative relapse. Methods Herein, we studied the mechanism of antigen loss in an in vivo CD19-negative recurrence model of chronic lymphocytic leukemia (CLL) to CART-19, established using NOD-scid IL2Rg(null) mice and HG3 cell line. We validated our findings in vitro in immortalized B-cell lines and primary CLL cells. Results In our in vivo CLL recurrence model, up to 70% of CART-19-treated mice eventually recurred with CD19-negative disease weeks after initial positive response. We found that the lack of CD19 expression was caused by promoter DNA hypermethylation. Importantly, the expression loss was partially reversible by treatment with a demethylating agent. Moreover, this escape mechanism was common for 3 B-cell immortalized lines as well as primary CLL cells, as assessed by in vitro coculture experiments. Conclusions Epigenetically driven antigen escape could represent a novel, yet at least partially reversible, means of CD19 loss to CART-19 in B-cell tumors.
ER -
LEDEREROVÁ, Aneta, Lenka DOSTÁLOVÁ, Veronika KOZLOVÁ, Helena PESCHELOVÁ, Adriana LADUNGOVÁ, Martin ČULEN, Tomáš LOJA, Jan VERNER, Šárka POSPÍŠILOVÁ, Michal ŠMÍDA and Veronika MANČÍKOVÁ. Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro. \textit{Journal for ImmunoTherapy of Cancer}. Switzerland: Springer International Publishing AG, 2021, vol.~9, No~8, p.~1-8. ISSN~2051-1426. Available from: https://dx.doi.org/10.1136/jitc-2021-002352.
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