Comparison of iTurbo domain and native cytokine receptor signaling by RNASeq analysis

While cytokine support can enhance CAR T cell function, co-administering cytokines or engineering CAR T cells to secrete cytokines can result in toxicities. To mitigate these safety risks, we engineered iTurboCARTM T cells that coexpress a novel inducible Turbo (iTurbo) cytokine signaling domain. Being modular, iTurbo domains are customizable with a variety of cytokine signaling outputs, which can be multiplexed to generate combinatorial signaling outcomes. Unlike most canonical cytokine receptors that signal as heterodimers, iTurbo domains leverage a homodimeric design that minimizes viral vector cargo. Using an iTurbo domain activatable by the clinically-validated dimerizer, AP1903, the ability of homodimeric iTurbo domains to elicit signaling mimicking that of the heterodimeric parental cytokine receptor was examined. We find that iTurbo domains phenocopy and activate transcriptional programs highly similar to native cytokine receptors RNASeq of AP1903- or vehicle control-treated iTurboCAR T cells