Tunable universal OR-gated CAR T cells for AML.

Acute myeloid leukemia (AML) is characterized by antigen heterogeneity and poor prognosis. Here, to tackle the heterogeneity of AML, we combined FLT3 with CD33 in a combinatorial OR-gate approach using our split, universal, programmable (SUPRA) chimeric antigen receptor (CAR) platform. The split platform affords tunability over activation levels and multiplexed targeting. We characterized the specificity and sensitivity of different SUPRA CAR adapters for each target across a panel of target cell lines. Our results demonstrate that this CAR system can effectively target two antigens with equivalent efficacy to conventional CARs while reducing the engineering burden of designing CAR T cells against multiple antigens. Furthermore, we can characterize an effective dose range where off-target cytotoxicity against hematopoietic stem and progenitor cells is minimized. Our SUPRA OR gate has the potential to provide an effective and safer solution to treating AML.