An anti-CD19/CTLA-4 switch improves efficacy and selectivity of CAR T cells targeting CD80/86-upregulated DLBCL

Chimeric antigen receptor T cell (CAR T) therapy is a potent treatment for relapsed/refractory (r/r) B cell lymphomas but provides lasting remissions in only ∼40% of patients and is associated with serious adverse events. We identify an upregulation of CD80 and/or CD86 in tumor tissue of (r/r) diffuse large B cell lymphoma (DLBCL) patients treated with tisagenlecleucel. This finding leads to the development of the CAR/CCR (chimeric checkpoint receptor) design, which consists of a CD19-specific first-generation CAR co-expressed with a recombinant CTLA-4-linked receptor with a 4-1BB co-stimulatory domain. CAR/CCR T cells demonstrate superior efficacy in xenograft mouse models compared with CAR T cells, superior long-term activity, and superior selectivity in in vitro assays with non-malignant CD19+ cells. In addition, immunocompetent mice show an intact CD80−CD19+ B cell population after CAR/CCR T cell treatment. The results reveal the CAR/CCR design as a promising strategy for further translational study. [Display omitted] •Some DLBCL patients exhibit elevated CD80/86 expression pre- and post-CAR T therapy•Switch CAR/CCR T cells show higher efficacy than conventional CAR T cells in vivo•The switch CAR/CCR design reduces on-target off-tumor activity in vitro and in vivo Prinz et al. present an “AND” switch CAR T cell construct that fully activates only when it binds to CD19 and CD80/CD86 found on lymphoma cells. Compared with CAR T cells targeting only CD19, they reveal improved anti-tumor activity while sparing healthy CD19-expressing cells, like non-malignant B cells and metaneural pericytes.