Hypermethylation of CD19 promoter enables antigen-negative
escape to CART-19 in vivo and in vitro

J 2021

Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro

LEDEREROVÁ, Aneta, Lenka DOSTÁLOVÁ, Veronika KOZLOVÁ, Helena PESCHELOVÁ, Adriana LADUNGOVÁ et. al.

Basic information

Original name

Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro

Authors

LEDEREROVÁ, Aneta (203 Czech Republic, belonging to the institution), Lenka DOSTÁLOVÁ (203 Czech Republic, belonging to the institution), Veronika KOZLOVÁ (203 Czech Republic, belonging to the institution), Helena PESCHELOVÁ (203 Czech Republic, belonging to the institution), Adriana LADUNGOVÁ (703 Slovakia, belonging to the institution), Martin ČULEN (703 Slovakia, belonging to the institution), Tomáš LOJA (703 Slovakia, belonging to the institution), Jan VERNER (203 Czech Republic, belonging to the institution), Šárka POSPÍŠILOVÁ (203 Czech Republic, belonging to the institution), Michal ŠMÍDA (203 Czech Republic, guarantor, belonging to the institution) and Veronika MANČÍKOVÁ (703 Slovakia, belonging to the institution)

Edition

Journal for ImmunoTherapy of Cancer, Switzerland, Springer International Publishing AG, 2021, 2051-1426

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 12.469

RIV identification code

RIV/00216224:14740/21:00119907

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1136/jitc-2021-002352

UT WoS

000687297900004

Keywords in English

antigens; B-lymphocytes; hematologic neoplasms; receptors; chimeric antigen; translational medical research

Abstract

V originále

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.

Links

EF18_046/0015515, research and development project

Name: Modernizace a rozšíření přístrojového vybavení Národního centra lékařské genomiky

LM2018133, research and development project

Name: Český národní uzel Evropské infrastruktury pro translační medicínu (Acronym: EATRIS-ERIC-CZ)

Investor: Ministry of Education, Youth and Sports of the CR

MUNI/A/1595/2020, interní kód MU

Name: Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VIII (Acronym: VýDiTeHeMa VIII)

Investor: Masaryk University

TN01000013, research and development project

Name: Personalizovaná medicína - diagnostika a terapie

Investor: Technology Agency of the Czech Republic, Personalized Medicine – Diagnostics and Therapy

90132, large research infrastructures

Name: NCMG II

Citovat

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. 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.

@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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