An anti-CD19/CTLA-4 switch improves efficacy and selectivity of CAR T cells targeting CD80/86-upregulated DLBCL
Lars Fabian Prinz, Tobias Riët, Daniel Felix Neureuther, Simon Lennartz, Danuta Chrobok, Hanna Hübbe, Gregor Uhl, Nicole Riet, Petra Hofmann, Marianna Hösel, Adrian Georg Simon, Luis Tetenborg, Paul Segbers, Joji Shimono, Philipp Gödel, Hyatt Balke‐Want, Ruth Flümann, Gero Knittel, Hans Christian Reinhardt, Christoph Scheid, Reinhard Büttner, Bjoern Chapuy, Roland T. Ullrich, Michael Hallek, Markus Chmielewski
Abstract
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.