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.

• Keywords
• B-lymphocytes, antigens, chimeric antigen, hematologic neoplasms, receptors, translational medical research,
• MeSH
• Antigens, CD19 immunology   MeSH
• Humans MeSH
• DNA Methylation immunology   MeSH
• Mice MeSH
• Receptors, Antigen, T-Cell immunology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antigens, CD19 MeSH
• CTL019 chimeric antigen receptor MeSH Browser
• Receptors, Antigen, T-Cell 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.

• Keywords
• CD19, chimeric antigen receptor, chronic lymphocytic leukemia, immunotherapy,
• MeSH
• Antigens, CD19 immunology   MeSH
• B-Lymphocytes immunology   MeSH
• Receptors, Chimeric Antigen immunology   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell immunology   therapy   MeSH
• Immunotherapy, Adoptive methods   MeSH
• Remission Induction MeSH
• Humans MeSH
• T-Lymphocytes immunology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antigens, CD19 MeSH
• CD19 molecule, human MeSH Browser
• Receptors, Chimeric Antigen MeSH