Although chimeric antigen receptor (CAR)-modified T cells (CAR T-cells) have been shown to be effective against hematological malignancies, evidence of their potential against immune-suppressive solid tumors is missing. Key challenges for this include the selection of tumor-specific targets and the persistence of CAR-T cells upon adoptive transfer. In this study, teams from Biontech and TRON defined and characterized Claudin 6, a tight junction molecule expressed in many solid cancers, as a novel target for CAR T-cells, in a two-component therapeutic approach. First, a liposomal systemic RNA-vaccine – also previously described by joint efforts of TRON and Biontech – was shown to specifically target Claudin 6-encoding RNA to lymphoid organs. Therein, adoptively transferred Claudin 6-specific CAR T-cells were shown to be efficiently and repetitively stimulated by tissue-resident dendritic cells presenting the RNA-encoded native Claudin 6 protein as a target. These expanded CAR T-cells then eradicated established tumors in a target-specific manner, even upon transfer of sub-therapeutic doses. These findings provide proof for the potential of such an approach against solid cancers, paving the way for clinical testing.
Science 24 Jan 2020; Vol. 367, Issue 6476, pp. 446-453; DOI