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 IL2Rgnull 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.

• Klíčová slova
• B-lymphocytes, antigens, chimeric antigen, hematologic neoplasms, receptors, translational medical research,
• MeSH
• antigeny CD19 imunologie   MeSH
• lidé MeSH
• metylace DNA imunologie   MeSH
• myši MeSH
• receptory antigenů T-buněk imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD19 MeSH
• CTL019 chimeric antigen receptor MeSH Prohlížeč
• receptory antigenů T-buněk MeSH

Chimeric antigen receptor (CAR) T-cell therapy has already achieved remarkable remissions in some difficult-to-treat patients with B-cell malignancies. Although the clinical experience in chronic lymphocytic leukemia (CLL) patients is limited, the proportion of remissions reached in this disease is clearly the lowest from the spectrum of B-cell tumors. In this review, we discuss the antigenic targets exploited in CLL CAR-T therapy, the determinants of favorable responses, as well as the mechanisms of treatment failure specific to this disease.

• Klíčová slova
• CD19, chimeric antigen receptor, chronic lymphocytic leukemia, immunotherapy,
• MeSH
• antigeny CD19 imunologie   MeSH
• B-lymfocyty imunologie   MeSH
• chimerické antigenní receptory imunologie   MeSH
• chronická lymfatická leukemie imunologie   terapie   MeSH
• imunoterapie adoptivní metody   MeSH
• indukce remise MeSH
• lidé MeSH
• T-lymfocyty imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antigeny CD19 MeSH
• CD19 molecule, human MeSH Prohlížeč
• chimerické antigenní receptory MeSH