Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F21%3A00074842" target="_blank" >RIV/65269705:_____/21:00074842 - isvavai.cz</a>
Alternative codes found
RIV/00216224:14740/21:00119907
Result on the web
<a href="https://jitc.bmj.com/content/9/8/e002352" target="_blank" >https://jitc.bmj.com/content/9/8/e002352</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1136/jitc-2021-002352" target="_blank" >10.1136/jitc-2021-002352</a>
Alternative languages
Result language
angličtina
Original language name
Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30204 - Oncology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal for ImmunoTherapy of Cancer
ISSN
2051-1426
e-ISSN
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Volume of the periodical
9
Issue of the periodical within the volume
8
Country of publishing house
GB - UNITED KINGDOM
Number of pages
8
Pages from-to
"e002352"
UT code for WoS article
000687297900004
EID of the result in the Scopus database
2-s2.0-85113641819