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Treatments that find a cancer by one marker on its surface can be defeated if the cancer stops showing that marker. It is one of the main reasons an antibody or CAR-T treatment that worked stops working.
There are at least four ways to lose a surface marker, and they need different answers.
Deletion and mutation. After CD19 CAR-T, relapses can carry hemizygous deletion of the CD19 locus, or frameshift and missense mutations in exon 2, the part the usual CAR binds (Sotillo 2015).
Splicing. The same study found something less obvious: relapsed cells select for an alternatively spliced CD19 messenger RNA that skips exon 2 entirely, producing a shortened protein that the CAR cannot see but which still does enough of the normal job to keep the cell alive. The splicing factor that keeps exon 2 in, SRSF3, was lower in relapsed disease. The gene is still there and a standard sequencing test would call it normal.
Transcriptional down-regulation. After rituximab, the cells that come back can simply make less CD20. In a series where 19 of 36 relapsing patients were rebiopsied, 5 had become CD20-negative by immunohistochemistry, with lower CD20 messenger RNA in the negative cells than in the positive cells from the same patient (Hiraga 2009).
Shaving. Macrophages can strip antibody-antigen complexes off the surface of a living cell, a process called trogocytosis, lowering the antigen without any change to the gene.
What follows in practice. Rebiopsy at relapse rather than assuming the antigen is still there; where it has gone, change the address rather than the format, to CD19, CD79b, CD22, CD30 or CD3-engaging bispecifics as the disease allows; and, in design terms, build constructs that need two antigens so that losing one is not enough. In B-cell acute lymphoblastic leukaemia, epitope loss follows 10 to 20% of paediatric responses to CD19 CAR-T; in large B-cell lymphoma it is documented but OnCo does not hold a share it can stand behind, because the published series are small and disagree.
In plain words · CD19 is a marker on B cells and B-cell cancers, and was the target of the first CAR-T therapies ever approved.
Showing the target this term concerns: CD19.
The glossary entry explains the word; the readout page carries the scoring rule, the thresholds approvals use, the companion diagnostics and the tests.
Shares What it costs to aim at a lineage antigen, Axicabtagene ciloleucel, Rituximab, Bispecific antibodies.
Shares CD22, CD20 expression (CD20-positive), CD19 expression (CD19-positive), Non-Hodgkin lymphoma (all types).
Shares What it costs to aim at a lineage antigen, Rituximab, Follicular lymphoma, Mantle cell lymphoma.
Shares CD19 expression (CD19-positive), CD30, What it costs to aim at a lineage antigen, Non-Hodgkin lymphoma (all types).
Shares CD20 expression (CD20-positive), CD19 expression (CD19-positive), Drug resistance (primary and acquired), CD19.
Shares CD20, CD19, Non-Hodgkin lymphoma (all types), Diffuse large B-cell lymphoma.
Shares Axicabtagene ciloleucel, CD19, Follicular lymphoma, CAR-T cell therapy.
Shares CD20, Follicular lymphoma, Monoclonal antibodies, Diffuse large B-cell lymphoma.