Novel adapter CAR-T cell technology for precisely controllable multiplex cancer targeting
Christian Seitz, Joerg Mittelstaet, Daniel Atar, Jana Hau, Selina Reiter, Clara Illi, Verena Kieble, Fabian Engert, Britta Drees, Giulia Bender, Ann-Christin Krahl, Philipp Knopf, Sarah M. Schroeder, Nikolas Paulsen, Alexander Rokhvarguer, Sophia Scheuermann, Elena Rapp, Anna‐Sophia Mast, Armin Rabsteyn, Sabine Schleicher, Stefan Grote, Karin Schilbach, Manfred Kneilling, Bernd J. Pichler, Dominik Lock, Bettina Kotter, Sandra Dapa, Stefan Miltenyi, Andrew Kaiser, Peter Lang, Rupert Handgretinger, Patrick Schlegel
Abstract
Chimeric antigen receptor (CAR)-T therapy holds great promise to sustainably improve cancer treatment. However, currently, a broad applicability of CAR-T cell therapies is hampered by limited CAR-T cell versatility and tractability and the lack of exclusive target antigens to discriminate cancerous from healthy tissues. To achieve temporal and qualitative control on CAR-T function, we engineered the Adapter CAR (AdCAR) system. AdCAR-T are redirected to surface antigens via biotin-labeled adapter molecules in the context of a specific linker structure, referred to as Linker-Label-Epitope. AdCAR-T execute highly specific and controllable effector function against a multiplicity of target antigens. In mice, AdCAR-T durably eliminate aggressive lymphoma. Importantly, AdCAR-T might prevent antigen evasion by combinatorial simultaneous or sequential targeting of multiple antigens and are capable to identify and differentially lyse cancer cells by integration of adapter molecule-mediated signals based on multiplex antigen expression profiles. In consequence the AdCAR technology enables controllable, flexible, combinatorial, and selective targeting.