''To drive functional persistence and lower activation thresholds, we implemented a multiplex knockout (KO) strategy targeting CISH and a key SOCS family member, both negative regulators of the activation cytokine signaling. In parallel, we modulated apoptotic pathways to alleviate activation-induced cell death. This combinatorial engineering dramatically reduced cytokine dependency and enabled vigorous expansion and effector function even at physiological—or subphysiological—IL-2/IL-15 levels. Notably, these benefits were achieved without constitutive cytokine receptor or cytokine overexpression, sidestepping the risks of tonic signaling and premature exhaustion. To further amplify tumor-driven proliferation and activation, we deployed an innovative signal converter (SC) module. Upon engagement with tumor targets, a secreted ligand activates the SC, unleashing a synthetic costimulatory signal through its intracellular domain. This module selectively intensifies iCD8aßT cell expansion in the tumor microenvironment, fueling a powerful and sustained anti-tumor response.
When armed with CARs (e.g., CD19) or a KRAS G12V-specific TCR, engineered iCD8aßT cells consistently achieved antigen specific, complete and durable tumor clearance across multiple rounds of serial tumor rechallenges over the duration of >50 days—a remarkable feat of persistence and potency. Even under immunosuppressive conditions (e.g., high TGF-ß1), iCD8aßT cells retained robust and durable cytotoxicity while producing minimal cytokines associated with cytokine release syndrome (e.g., IL-6, IL-10, TNF-a), highlighting both their functional resilience and promising safety profile.''
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